Combination therapy for cancer with BRAF mutations

Abstract

The present invention provides a combination therapy for treating a cancer having a BRAF mutation, the combination therapy comprising administering to a subject an effective amount of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin dependent kinase (CDK) 4 / 6 inhibitor. Compositions and kits related to the combination therapy are also provided.

Description

This application is a divisional application of the invention patent application with the application number of 201980037730.X, the application name of “Combination therapy for cancer with BRAF mutation”, the application date of April 8, 2019. Cross-reference to Related Applications

[0001] This application claims the benefit of International Application No. PCT / CN2018 / 082191, filed April 8, 2018, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates generally to combination therapies for treating or delaying progression of cancer with BRAF mutation and related compositions and kits. BACKGROUND

[0003] V-raf murine sarcoma viral oncogene homolog B1 (BRAF) is a potent activator of the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) signaling pathway, which is involved in regulating cell proliferation, differentiation, and survival in response to extracellular signaling. Cantwell-Dorris et al. (2011) Mol. Cancer Ther. 10, 385. This pathway can be activated upon extracellular ligand binding to the epidermal growth factor receptor (EGFR), initiating a cascade of ERK signaling through RAS GTPases. Once RAS is engaged, it recruits and activates RAFs (such as ARAF, BRAF, and CRAF), which phosphorylate MAPK / ERK kinase (MEK), triggering the downstream ERK pathway. Oikonomou et al. (2014) Oncotarget 5, 11752.

[0004] BRAF mutations have been detected in a variety of cancers, including approximately 59% of malignant melanomas, approximately 45% of papillary thyroid cancers, approximately 18% of colorectal cancers (CRC), approximately 4% of ovarian cancers, approximately 2% of breast cancers, and approximately 3% of lung cancers, making it a potential therapeutic target. Davies et al. (2002) Nature 417, 949; Xing et al. (2005) Endocr. Relat. Cancer 12, 245. Mutations in BRAF most often occur at nucleotide 1976, resulting in a change at the valine residue (V600). Davies et al. (2002) Nature 417, 949. Mutated BRAF can cause constitutive activation of MAPK / ERK kinase (MEK), which in turn phosphorylates ERK and leads to transcription of target genes, promoting tumor cell growth and survival without any extracellular stimuli. Hall et al. (2014) Cancer Control 21, 221; Cantwell-Dorris et al. (2011) Mol. Cancer Ther. 10, 385.

[0005] Chemotherapy, even highly aggressive regimens, has had poor responses in treating cancers with BRAF mutations. For example, in a clinical trial, metastatic CRC patients received FOLFOXIRI plus bevacizumab, a highly aggressive regimen, but patients with BRAF-mutant CRC had less than half the survival of patients with wild-type tumors (median overall survival, 19.0 months versus 41.7 months). Loupakis F et al. (2014) N Engl J Med. 371, 1609.

[0006] The U.S. Food and Drug Administration (FDA) approved BRAF inhibitors alone or in combination with MEK inhibitors for the treatment of metastatic melanoma cancer with BRAF mutations. Larkin et al. (2014) N. Engl. J. Med. 371, 1867; Robert et al. (2015) N. Engl. J. Med. 372, 30. To date, melanoma cancer with BRAF mutations V600K or V600E is the only cancer type with BRAF mutations that has an approved targeted therapy. However, due to the development of acquired and adaptive resistance, the duration of response is limited. Manzano et al. (2016) Ann. Transl. Med. 4, 237; Barras (2015) Biomarkers in Cancer 7, 9. Studies have shown that ERK can be reactivated by EGFR-mediated RAS and CRAF activation, contributing to cancer cell resistance to BRAF inhibitors. Barras (2015) Biomarkers in Cancer 7, 9. In addition, it has been reported that the use of BRAF inhibitors can lead to the occurrence of secondary skin tumors due to paradoxical activation of the MAPK pathway in cells without BRAF mutations, but the combination of BRAF inhibitors with MEK inhibitors can reduce the incidence of BRAF inhibitor-induced skin tumors. Chapman et al. (2011) N. Engl. J. Med. 364, 2507; Robert et al. (2011) Curr. Opin. Oncol. 23, 177; Larkin et al. (2014) N. Engl. J. Med. 371, 1867. Recent and current clinical trials for cancers with BRAF mutations generally involve BRAF inhibitors in combination with other therapeutic drugs or candidate drugs targeting different pathways (such as EGFR, MEK, PI3K) and cytotoxic chemotherapy. Morris et al. (2013) F1000Prime Rep. 5, 11; Hyman DM et al. (2015) N. Engl. J. Med. 373, 726.

[0007] Accordingly, there remains a need for robust therapies for the treatment of cancers with BRAF mutations.

[0008] The disclosures of all publications, patents, patent applications and published patent applications referred to in this document are hereby incorporated by reference in their entirety. SUMMARY

[0009] Provided herein are compositions comprising: (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor; wherein the composition does not comprise a BRAF inhibitor. In some embodiments, the composition consists of: (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor.

[0010] Also provided herein are methods for treating or delaying progression of a cancer in a subject comprising administering to the subject an effective amount of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein the subject has a cancer or is at risk of developing a cancer with a BRAF mutation. In some embodiments, the methods do not comprise administering to the subject a BRAF inhibitor during administration of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. In some embodiments, the methods do not comprise administering to the subject an additional therapeutic agent during administration of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor.

[0011] Also provided herein are methods for treating or delaying progression of a cancer in a subject comprising administering to the subject an effective amount of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of developing a cancer with a BRAF mutation. In some embodiments, the methods do not comprise administering to the subject a BRAF inhibitor during administration of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the methods do not comprise administering to the subject an additional therapeutic agent during administration of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered in one composition. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to the subject continuously. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to the subject intermittently.

[0012] In some embodiments, the subject is administered osimertinib or a salt thereof at a daily dose of about 20-160 mg osimertinib. In some embodiments, the subject is administered cobimetinib or a salt thereof at a daily dose of about 20-60 mg cobimetinib. In some embodiments, the subject is administered a daily dose of about 75-125 mg of palbociclib or a salt thereof. In some embodiments, the subject is a human. In some embodiments, the subject is administered osimertinib or a salt thereof at a daily dose of about 0.5-3 mg / kg osimertinib. In some embodiments, the subject is administered cobimetinib or a salt thereof at a daily dose of about 0.25-1 mg / kg cobimetinib. In some embodiments, the subject is administered palbociclib or a salt thereof at a daily dose of about 1-2.5 mg / kg palbociclib.

[0013] Also provided herein are methods for treating or delaying progression of cancer in a subject, comprising administering to the subject an effective amount of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has cancer or is at risk of developing cancer with a BRAF mutation. In some embodiments, the methods do not comprise administering to the subject a BRAF inhibitor during administration of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the methods do not comprise administering to the subject an additional therapeutic agent during administration of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered in one composition. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to the subject continuously. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to the subject intermittently.

[0014] In some embodiments, the subject is administered cetuximab in a manner of a 400 mg / m 2 infusion over 120 minutes followed by a 250 mg / m 2 infusion over 60 minutes every week. In some embodiments, the maximum infusion rate is about 10 mL / min. In some embodiments, the subject is administered cobimetinib or a salt thereof at a daily dose of about 20-60 mg cobimetinib. In some embodiments, the subject is administered palbociclib or a salt thereof at a daily dose of about 75-125 mg palbociclib. In some embodiments, the subject is administered cetuximab at a weekly dose of about 150-400 mg / m 2 per subject. In some embodiments, the subject is a human. In some embodiments, the subject is administered cobimetinib or a salt thereof at a daily dose of about 0.25-10 mg / kg cobimetinib. In some embodiments, the subject is administered palbociclib or a salt thereof at a daily dose of about 5-30 mg / kg palbociclib.

[0015] In some embodiments, the cancer has a BRAF V600 mutation or a BRAF D581D mutation. In some embodiments, the BRAF V600 mutation is a BRAF V600E, V600D, or V600K mutation. In some embodiments, the cancer is a malignant epithelial tumor or carcinoma. In some embodiments, the cancer is a carcinoma selected from one or more of the following: colon cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, oral cancer, prostate cancer, germ line cancer, rectal cancer, liver cancer, kidney cancer, papillary thyroid cancer, and ovarian cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the colorectal cancer is stage IV colorectal cancer. In some embodiments, the colorectal cancer has a BRAF V600E or D581V mutation.

[0016] In some embodiments, the subject has received a BRAF inhibitor in a prior treatment cycle. In some embodiments, the subject has not received a BRAF inhibitor in a prior treatment cycle.

[0017] In some embodiments, the methods provided herein reduce the average tumor volume. In some embodiments, the cancer cell growth reduction and / or cancer cell killing of the methods provided herein is increased by about 20-99% more than the administration of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor alone. In some embodiments, the cancer cell growth reduction and / or cancer cell killing of the methods provided herein is increased by about 20-99% more than the administration of osimertinib or a salt thereof, cobimetinib or a salt thereof, or palbociclib or a salt thereof alone. In some embodiments, the cancer cell growth reduction and / or cancer cell killing of the methods provided herein is increased by about 20-99% more than the administration of cetuximab, cobimetinib or a salt thereof, or palbociclib or a salt thereof alone. In some embodiments, the methods reduce tumor volume by about 20-95%. The methods can comprise administration of any of the compositions or kits described herein.

[0018] In another aspect, provided herein are compositions comprising: (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. In some embodiments, the compositions comprise osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the compositions do not comprise a BRAF inhibitor. In some embodiments, the compositions consist of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the compositions further comprise a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the compositions are formulated for oral administration to a subject. In some embodiments, the subject has cancer or is at risk of developing cancer with a BRAF mutation.

[0019] In another aspect, provided herein are kits comprising: (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor; wherein the kits do not comprise a BRAF inhibitor. In some embodiments, the kits consist of: (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor.

[0020] In some embodiments, the kit comprises osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit does not comprise a BRAF inhibitor. In some embodiments, the kit consists of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising osimertinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising cobimetinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, osimertinib or a salt thereof is formulated for oral administration to a subject. In some embodiments, cobimetinib or a salt thereof is formulated for oral administration to a subject. In some embodiments, palbociclib or a salt thereof is formulated for oral administration to a subject. In some embodiments, the subject has cancer or is at risk of developing cancer with a BRAF mutation. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in one composition. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to a subject continuously. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to a subject intermittently.

[0021] In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in one composition. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in separate compositions. In some embodiments, osimertinib or a salt thereof and cobimetinib or a salt thereof are formulated in one composition. In some embodiments, osimertinib or a salt thereof and palbociclib or a salt thereof are formulated in one composition. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated in one composition. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in a liquid form. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in a solid form.

[0022] In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered as one composition. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered separately. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered simultaneously. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered consecutively. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered intermittently.

[0023] In some embodiments, the kit comprises cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit does not comprise a BRAF inhibitor. In some embodiments, the kit consists of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising cetuximab and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising cobimetinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, cetuximab is formulated for administration to a subject via intravenous infusion. In some embodiments, cobimetinib or a salt thereof is formulated for oral administration to a subject. In some embodiments, palbociclib or a salt thereof is formulated for oral administration to a subject. In some embodiments, the subject has cancer or is at risk of developing cancer with a BRAF mutation. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in different compositions. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated in one composition. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered consecutively to a subject. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered intermittently to a subject. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are administered to a subject at different dosing frequencies.

[0024] In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are formulated into one composition. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are formulated into separate compositions. In some embodiments, the cetuximab and the cobimetinib or a salt thereof are formulated into one composition. In some embodiments, the cetuximab and the palbociclib or a salt thereof are formulated into one composition. In some embodiments, the cobimetinib or a salt thereof and the palbociclib or a salt thereof are formulated into one composition. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are formulated into a liquid form. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are formulated into a solid form.

[0025] In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered as one composition. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered separately. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered simultaneously. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered consecutively. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered intermittently. In some embodiments, the cetuximab, the cobimetinib or a salt thereof, and the palbociclib or a salt thereof are administered at different dosing frequencies.

[0026] In some embodiments, the kit includes a package insert containing instructions regarding indications, usage, dosage, administration, contraindications, other drugs in combination with the packaged product, and / or warnings regarding the use of such drugs. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 Representative images of stained tumor cells obtained by a high content screening (HCS) platform are shown.

[0028] Figure 2Depicted is the volume reduction of CRC (NYL132) after treatment with osimertinib, cobimetinib, and palbociclib. The graph shows the change in mean tumor volume over time during combination treatment: (closed circle) - untreated control; (closed triangle) - oxaliplatin 10 mg / kg and capecitabine 200 mg / kg every day (p.o.) for 3 weeks; (closed diamond) - osimertinib 5 mg / kg, cobimetinib 2.5 mg / kg, and palbociclib 10 mg / kg every day (p.o.) for 3 weeks; (open square) - osimertinib 7.5 mg / kg, cobimetinib 3.75 mg / kg, and palbociclib 15 mg / kg every day (p.o.) for 3 weeks; and (open circle) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg, and palbociclib 20 mg / kg every day (p.o.) for 3 weeks. The dosage unit mg / kg refers to the compound dose per kg of mouse body weight.

[0029] Figure 3 Depicted is the volume reduction of CRC (NYL132) after treatment with osimertinib, cobimetinib, and palbociclib. The graph shows the change in tumor growth inhibition (TGI) over time during combination treatment: (closed triangle) - oxaliplatin 10 mg / kg and capecitabine 200 mg / kg every day (p.o.) for 3 weeks; (closed diamond) - osimertinib 5 mg / kg, cobimetinib 2.5 mg / kg, and palbociclib 10 mg / kg every day (p.o.) for 3 weeks; (open square) - osimertinib 7.5 mg / kg, cobimetinib 3.75 mg / kg, and palbociclib 15 mg / kg every day (p.o.) for 3 weeks; and (open circle) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg, and palbociclib 20 mg / kg every day (p.o.) for 3 weeks. The dosage unit mg / kg refers to the compound dose per kg of mouse body weight. TGI = (1 - (Ti - To) / (Vi - Vo)) * 100%.

[0030] Figure 4 Depicted is the body weight of mice (NYL132) during combination therapy: (closed circle) - untreated control; (closed triangle) - oxaliplatin 10 mg / kg and capecitabine 200 mg / kg every day (p.o.) for 3 weeks; (closed diamond) - osimertinib 5 mg / kg, cobimetinib 2.5 mg / kg, and palbociclib 10 mg / kg every day (p.o.) for 3 weeks; (open square) - osimertinib 7.5 mg / kg, cobimetinib 3.75 mg / kg, and palbociclib 15 mg / kg every day (p.o.) for 3 weeks; and (open circle) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg, and palbociclib 20 mg / kg every day (p.o.) for 3 weeks.

[0031] Figure 5 Volume reduction of CRC (NYL-GZ-082) treated with combination therapy is depicted. The graph shows the mean tumor volume over time during combination therapy: (solid triangles) - control, where no treatment for 14 days, cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) starting at day 43; (solid squares) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 3 weeks, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) from day 28-56; (open circles) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) from day 28-56. Dose unit mg / kg refers to the dose of compound per kg of mouse body weight.

[0032] Figure 6 Body weight change (%) of mice (NYL-GZ-082) during combination therapy is depicted: (solid triangles) - control, where no treatment for 14 days, cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) starting at day 43; (solid squares) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 3 weeks, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) from day 28-56; (open circles) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, followed by no treatment for 1 week; second cycle (same treatment as first cycle (first 4 weeks)) from day 28-56.

[0033] Figure 7Volume reduction of CRC (NYL132) treated with combination therapy is depicted. The graph shows the mean tumor volume over time during combination treatment: (solid triangles) - untreated control; (solid squares) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, no treatment for 7 days, followed by a second cycle with the same treatment as the first cycle (first 4 weeks); (solid circles) - osimertinib 10 mg / kg, TAK-733 3 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, no treatment for 7 days, followed by a second cycle with the same treatment as the first cycle; (solid diamonds) - cetuximab 1 mg weekly (i.p.), TAK-733 3 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, no treatment for 7 days, followed by a second cycle with the same treatment as the first cycle; (open triangles) - cetuximab 1 mg weekly (i.p.) for 21 days, no treatment for 7 days, cetuximab 1 mg weekly (i.p.) for days 28-49, no treatment for another 7 days, followed by cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for another 21 days; (open circles) - cetuximab 1 mg weekly (i.p.), TAK-733 10 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, no treatment for 7 days, followed by a second cycle with the same treatment as the first cycle; (open diamonds) - osimertinib 10 mg / kg, TAK-733 10 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, no treatment for 7 days, followed by a second cycle with the same treatment as the first cycle.

[0034] Figure 8Reduction in volume of CRC (HT-29) treated with combination therapy is depicted. The graph shows the mean tumor volume over time during combination treatment: (solid triangles) - control untreated for 28 days; (solid squares) - capecitabine 200 mg / kg daily (p.o.) for 21 days; (solid circles) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg, and palbociclib 20 mg / kg daily (p.o.) for 21 days; (solid diamonds) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg, and palbociclib 13.3 mg / kg daily (p.o.) for 21 days; (open triangles) - cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg, and palbociclib 6.6 mg / kg daily (p.o.) for 21 days; (open squares) - osimertinib 10 mg / kg, cobimetinib 5 mg / kg, and palbociclib 20 mg / kg daily (p.o.) for 21 days; (open circles) - osimertinib 10 mg / kg and cobimetinib 5 mg / kg daily (p.o.) for 21 days; (open diamonds) - cobimetinib 5 mg / kg daily (p.o.) for 21 days; (dashed solid triangles) - cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days; (dashed solid circles) - 5-FU 40 mg / kg weekly for 3 weeks. At day 21, all treatments were stopped and 1 week was observed thereafter.

[0035] Figure 9Reduction in CRC (HT-29) volume following treatment with combination therapy is depicted. The graph shows the mean tumor volume over time during combination therapy: (solid triangles) - control with no treatment for 21 days; (solid squares) - TAK-733 10 mg / kg daily (p.o.) for 21 days; (solid circles) - TAK-733 30 mg / kg on day 1, then 3 mg / kg daily (p.o.) for 20 days; (solid diamonds) - palbociclib 20 mg / kg daily (p.o.) for 21 days; (open triangles) - cetuximab 1 mg weekly (i.p.) for 21 days, then 7 days off treatment, followed by 1 mg weekly (i.p.) for a further 14 days; (open squares) - capecitabine 200 mg / kg daily (p.o.) and oxaliplatin 10 mg / kg weekly (i.p.) for 21 days, then 7 days off treatment; after day 28, cetuximab 1 mg weekly (i.p.), cobimetinib 5 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 14 days; (open circles) - osimertinib 10 mg / kg, TAK-733 10 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, then 7 days off treatment, followed by the same doses for a further 14 days; (open diamonds) - cetuximab 1 mg weekly (i.p.), TAK-733 10 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days, then 7 days off treatment, followed by the same doses for a further 14 days; (dashed solid triangles) - TAK-733 10 mg / kg and palbociclib 20 mg / kg daily (p.o.) for 21 days. DETAILED DESCRIPTION

[0036] This specification is based on data from the inventors showing that a combination of an epidermal growth factor receptor inhibitor (such as osimertinib or cetuximab), a mitogen-activated protein kinase 1 / 2 inhibitor (such as cobimetinib, trametinib or TAK-733) and a cyclin-dependent kinase 4 / 6 inhibitor (such as palbociclib) provides a robust therapy for treating or delaying progression of cancers having a BRAF mutation. In particular, this combination therapy does not require a BRAF inhibitor. Despite the fact that none of the compounds in the combination are inhibitors of mutant BRAF, the combination therapy described herein has surprisingly demonstrated synergistic effects on cancers having a BRAF mutation, as well as strong efficacy in reducing tumor volume by up to about 95% in established animal models. The specification also provides compositions and kits that can be used to perform this combination therapy. I. DEFINITIONS

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference.

[0038] It should be appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of the embodiments relating to particular method steps, reagents or conditions are expressly embraced by the present disclosure and are disclosed herein, even if such combinations are not explicitly shown in the examples.

[0039] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims can be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of such exclusive terminology as "only," "solely," and the like in

[0040] As used herein, the terms "comprises," "comprising," and "including" are used in their open, non-limiting sense. It should also be understood that aspects and embodiments of the present application described herein can include "consisting" and / or "consisting essentially of aspects and embodiments.

[0041] It should be understood that every amount given herein is intended to mean an actual given value, and also to mean an approximate value close to this given value, including equivalent values and amounts that would be ascertained by one of ordinary skill in the art to be a reasonable approximation of a given value, including equivalent values and amounts that are due to experimental and / or measuring conditions.

[0042] As used herein, a subject who is "at risk" of developing a disease prior to the treatment methods described herein can or can not have detectable disease or symptoms of disease and can or can not have already shown detectable disease or symptoms of disease. A subject "at risk" has one or more risk factors that are measurable parameters associated with the development of a disease, such as cancer, as described herein and known in the art. A subject "at risk" can have one or more risk factors. A subject having one or more risk factors has a higher probability of developing a disease than a subject without one or more risk factors.

[0043] As used herein, "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include but are not limited to squamous cell cancer, lung cancer (including small-cell and non-small-cell lung cancer), adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, and various types of head and neck cancer, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy Cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. Examples of cancer can include a primary tumor of any of the above types of cancer or a metastatic tumor at a second site derived from any of the above types of cancer. This definition includes benign and malignant cancers as well as dormant tumors or micrometastases.

[0044] The terms "neoplastic cell," "tumor cell," or "cancer cell," used in either the singular or plural form, refer to a cell that has undergone malignant transformation making it pathogenic to the host organism. Primary cancer cells (i.e., cells obtained from near the site of malignant transformation) can be readily distinguished from non-cancerous cells by established techniques, particularly histological examination. As used herein, the definition of cancer cell includes not only primary cancer cells, but also any cell derived from a cancer progenitor cell. This includes metastasized cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to cancer types that typically manifest as solid tumors, a "clinically detectable" tumor is one that is detectable based on a tumor mass; for example, by procedures such as CAT scan, magnetic resonance imaging (MRI), X-ray, ultrasound, or palpation. Biochemical or immunological findings alone can not be sufficient to meet this definition.

[0045] As used herein, "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer, which is nontoxic to the cells or mammals being exposed thereto at the dosages and concentrations employed. Typically, physiologically acceptable carriers are aqueous pH buffered solutions. Non-limiting examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN TM , polyethylene glycol (PEG), and PLURONICS TM .

[0046] As used herein, "delaying progression of a disease" means to defer, hinder, slow, retard, postpone, and / or delay the development of a disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As will be appreciated by those of ordinary skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not get the disease. For example, development of late stage cancer, such as metastasis, can be delayed. A method that "delays" development of cancer is one that reduces the probability of development of disease within a given timeframe and / or reduces the extent of disease within a given timeframe when compared to not using the method. Such comparisons are typically based on clinical studies using statistically significant numbers of subjects. Cancer development can be detectable using standard methods including, but not limited to, computed axial tomography (CAT scan), magnetic resonance imaging (MRI), ultrasound, coagulation testing, arteriography, biopsy, urine cytology, and cystoscopy. Development can also refer to cancer progression, which can initially be undetectable and includes onset, recurrence, and attack.

[0047] As used herein, the term "effective amount" or "therapeutically effective amount" of a substance is at least the minimum concentration required to effect a measurable improvement or prevention of a particular disorder. An effective amount herein can vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the substance to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. With respect to cancer, an effective amount includes an amount sufficient to cause tumor shrinkage and / or reduce the rate of tumor growth, such as inhibiting tumor growth, or to prevent or delay other unwanted cell proliferation in a cancer. In some embodiments, an effective amount is an amount sufficient to delay the development of a cancer. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. In some embodiments, an effective amount is an amount sufficient to reduce the rate of recurrence in an individual. An effective amount can be given in one or more administrations. An effective amount of a drug or pharmaceutical composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of a tumor; (vii) reduce recurrence rate of a tumor, and / or (viii) relieve to some extent one or more of the symptoms associated with the cancer. An effective amount can be given in one or more administrations. For the purposes of this disclosure, an effective amount of a drug, compound, or pharmaceutical composition is an amount that is sufficient to accomplish a prophylactic or therapeutic treatment directly or indirectly. An effective amount of a drug, compound, or pharmaceutical composition can or can not be administered in combination with another drug, compound, or pharmaceutical composition to accomplish the desired therapeutic or prophylactic effect. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and an effective amount of a single agent can be considered in the context of administering that agent in combination with one or more other agents if the desired result is accomplished or is expected to be accomplished with the combination.

[0048] As used herein, the term "inhibitor" or "antagonist" refers to a biological or chemical substance that interferes with or otherwise reduces the physiological and / or biochemical action of another biological or chemical molecule. In some embodiments, an inhibitor or antagonist specifically binds to another molecule.

[0049] "Package insert" means instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, adverse reactions and / or warnings concerning the use of such products.

[0050] “Pharmaceutically acceptable salt” is a salt form that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally, Berge et al. (1977) J. Pharm. Sci. 66, 1. Particular pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, which are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or from organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like. These salts can be derived from inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. In some embodiments, pharmaceutically acceptable salts are formed when an acidic proton in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of the following: primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-ethylglucosamine, N-methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, amino acids such as lysine, arginine, histidine, and the like. Examples of pharmaceutically acceptable base addition salts include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. In some embodiments, the organic non-toxic bases are L-amino acids such as L-lysine and L-arginine, tromethamine, N-ethylglucosamine, and N-methylglucosamine. Acceptable inorganic bases include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, PA, 1985.

[0051] A "solvate" is formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0052] A "subject," "patient," or "individual" includes a mammal, such as a human or other animal, and is typically a human. In some embodiments, the subject (e.g., patient) to whom a therapeutic agent and composition is administered is a mammal, typically a primate, such as a human. In some embodiments, the primate is a monkey or an ape. The subject can be male or female, and can be at any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is a non-primate mammal, such as a rodent, dog, cat, farm animal (such as a cow or horse), and the like.

[0053] As used herein, a "tissue sample" or "cell sample" means a collection of similar cells obtained from a tissue of a subject or patient. The source of the tissue or cell sample can be solid tissue from a fresh, frozen, and / or preserved organ or tissue sample or biopsy or aspirate; blood or any blood component; a body fluid such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from a subject at any time of gestation or development. The tissue sample can also be a primary or cultured cell or cell line. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ, such as cancer or tumor tissue. A tissue sample can contain compounds not naturally admixed with the tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, and the like.

[0054] As used herein, the term "treatment" refers to clinical intervention designed to alter the natural course of the individual or cell being treated, for the better. For the purposes of this disclosure, the desired effects of treatment include, but are not limited to, decreasing the rate of disease progression, ameliorating or palliating disease state, and relieving or ameliorating symptoms. For example, an individual is successfully "treated" for cancer if one or more symptoms associated with the cancer are reduced or eliminated, including but not limited to reducing the proliferation of (or destroying) cancer cells, increasing cancer cell killing, reducing symptoms caused by the disease, preventing spread of the disease, preventing recurrence of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or prolonging survival of the individual. II. Methods of treating and delaying progression of cancers having a BRAF mutation

[0055] Provided herein are methods for treating or delaying progression of a cancer in a subject, the method comprising administering to the subject an effective amount of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, wherein the subject has a cancer or is at risk of developing a cancer having a BRAF mutation.

[0056] In some embodiments, (a) is a small molecule or an antibody (or antigen binding fragment thereof) that specifically binds to EGFR or a ligand thereof, and is optionally selected from one or more of cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, erlotinib, gefitinib, afatinib, lapatinib, osimertinib, brigatinib, and icotinib. In some embodiments, (b) is a small molecule or an antibody (or antigen binding fragment thereof) that specifically binds to MEK 1 / 2 or a ligand thereof, and is optionally selected from one or more of trametinib, selumetinib, TAK-733, CI-1040, PD0325901, MEK162, AZD8330, GDC-0623, selumetinib, pimasertib, RO4987655, RO5126766, WX-554, HL-085, and cobimetinib. See Chen et al. (2017) Molecules 22, 1551. In some embodiments, (c) is a small molecule or an antibody (or antigen binding fragment thereof) that specifically binds to CDK 4 / 6 or a ligand thereof, and is optionally selected from one or more of palbociclib, ribociclib, and abemaciclib. In some embodiments, the method does not comprise administering to the subject a BRAF inhibitor during administration of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. In some embodiments, the method does not comprise administering an additional therapeutic agent during administration of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor; and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. In some embodiments, the subject has received a BRAF inhibitor in a prior treatment cycle. In some embodiments, the subject has not received a BRAF inhibitor in a prior treatment cycle. In some embodiments, the subject is a human.

[0057] In one aspect, the methods disclosed herein can be used to treat or delay progression of a cancer having a BRAF mutation. BRAF is a serine-threonine kinase and BRAF mutations have been found in 28 primary cancers, including 6 primary melanomas, 12 melanoma short-term cultures, colorectal cancer, ovarian cancer, glioma, lung cancer, breast cancer, sarcoma, etc. Without wishing to be bound by theory, it is proposed that BRAF mutations lead to constitutive BRAF kinase activity, phosphorylation of MEK and ERK kinases, and sustained MAPK pathway signaling, leading to tumor cell proliferation and survival. BRAF has been reported to be mutated at several sites, but the vast majority of mutated BRAF is V600E, corresponding to a T to A transversion mutation at nucleotide 1796. BRAF mutations V600K, V600D, and D581V have also been observed. Detection of these mutations can be performed using routine methods, such as the non-limiting example reported in Lasota et al. (2015) Am. J. Surg. Pathol. 38, 1235. In some embodiments, a BRAF mutation is detected in a tissue or cell sample containing cancer cells from a subject. In some embodiments, the BRAF mutation is a somatic mutation. In some embodiments, the method is used to treat or delay progression of a cancer having a BRAF V600E mutation. In some embodiments, the method is used to treat or delay progression of a cancer having a BRAF V600D. In some embodiments, the method is used to treat or delay progression of a cancer having a BRAF V600K. In some embodiments, the method is used to treat or delay progression of a cancer having a BRAF D581V. In some embodiments, the method does not include administering a BRAF inhibitor to the subject during administration of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the method does not include administering an additional therapeutic agent during administration of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the subject has received a BRAF inhibitor in a prior treatment cycle. In some embodiments, the subject has not received a BRAF inhibitor in a prior treatment cycle.

[0058] In some embodiments, the cancer is adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, and small cell carcinoma. In some embodiments, the cancer is melanoma and carcinoma, such as an epithelial tumor, squamous cell tumor, basal cell tumor, transitional cell carcinoma, adenocarcinoma, tumor of an appendix or cutaneous appendages, mucoepidermoid tumor, cystic, mucinous or serous tumor, ductal, lobular or medullary tumor, acinar cell tumor, and complex epithelial tumor. In some embodiments, the cancer is colon cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, oral cancer, prostate cancer, germ line cancer, rectal cancer, liver cancer, kidney cancer, and ovarian cancer. In some embodiments, the cancer is an advanced cancer, such as stage IV colorectal cancer. In some embodiments, the cancer is advanced colorectal cancer.

[0059] Also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation. In another aspect, also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation. In another aspect, also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation. In another aspect, also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation. In another aspect, also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation. In another aspect, also provided herein are methods for treating or delaying progression of a cancer in a subject, comprising administering to the subject an effective amount of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof, wherein the subject has a cancer or is at risk of having a cancer with a BRAF mutation.

[0060] Osimertinib is an oral, third-generation EGFR inhibitor approved by the US FDA and the European Commission (EC) for the treatment of non-small cell lung cancer with EGFR mutations. Osimertinib targets EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutations and, in particular, T790M, which often contributes to acquired resistance to EGFR TKI therapy. Cobimetinib is a MEK inhibitor approved by the US FDA in combination with the BRAF inhibitor vemurafenib for the treatment of metastatic melanoma with BRAF V600E or V600K mutations. Cobimetinib and vemurafenib target different components of the MAPK / ERK pathway: MEK and BRAF, respectively. Palbociclib is a CDK4 / 6 inhibitor approved by the US FDA in combination with an aromatase inhibitor for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer as endocrine-based therapy in postmenopausal women. Cetuximab is a chimeric monoclonal antibody given by intravenous infusion and is an EGFR inhibitor approved by the US FDA in 2009 for the treatment of colon cancer with wild-type KRAS. TAK-733 is an orally bioavailable, non-ATP-competitive small molecule MEK1 / 2 inhibitor that has completed Phase I clinical studies. Trametinib is a MEK inhibitor approved by the US FDA as a single agent or in combination with the BRAF inhibitor dabrafenib for the treatment of melanoma with BRAF V600E or V600K mutations. The structures of osimertinib, TAK-733, cobimetinib, trametinib, and palbociclib are shown below.

[0061] In some embodiments, the method comprises administering salts of osimertinib, cobimetinib, and palbociclib. In some embodiments, the salt is a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, mesylate, propylsulfonate, benzenesulfonate, xylene sulfonate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. In some embodiments, the pharmaceutically acceptable salt is a fumarate salt. In some embodiments, the pharmaceutically acceptable salt is a mesylate salt. In some embodiments, the method comprises administering fumarate salts of osimertinib, cobimetinib, and palbociclib. In some embodiments, the method comprises administering fumarate salts of osimertinib, cobimetinib, and palbociclib. In some embodiments, the method comprises administering fumarate salts of osimertinib, cobimetinib, and palbociclib. In some embodiments, the method comprises administering mesylate salts of osimertinib, fumarate salts of cobimetinib, and palbociclib. In some embodiments, the method comprises administering osimertinib, cobimetinib, and palbociclib or solvates or salts of any of the foregoing.

[0062] The method can comprise administering any of the compositions or kits described herein.

[0063] In another aspect, the method comprises administering an effective amount of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the daily dose of osimertinib or a salt thereof is in an amount of about 0.25-0.5 mg / kg, 0.5-1 mg / kg, about 1-1.5 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 3.5-4 mg / kg, or about 0.5-3 mg / kg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is in an amount of about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is in an amount of less than about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the dose of osimertinib or a salt thereof is in an amount of about 20-240 mg, about 20-40 mg, about 40-80 mg, about 80-160 mg, about 160-240 mg, or about 40-160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is in an amount of about 0.6-2.7 mg / kg of osimertinib. In some embodiments, osimertinib is in the mesylate salt form. The amounts of inhibitors described herein and throughout the specification refer to the amount of the inhibitor without considering the weight of the counterion if the inhibitor is present in a salt form. For example, the term“80 mg of osimertinib” can include, but is not limited to, 80 mg of osimertinib in a salt-free form or 95.4 mg of osimertinib mesylate.

[0064] In some embodiments, the daily dose of cobimetinib or a salt thereof is in an amount of about 0.1-0.25 mg / kg, about 0.25-0.5 mg / kg, about 0.5-0.75 mg / kg, about 0.75-1 mg / kg, about 1-1.25 mg / kg, about 1.25-1.5 mg / kg, about 1.5-1.75 mg / kg, about 1.75-2 mg / kg, or about 0.25-1 mg / kg of cobimetinib. In some embodiments, the daily dose of cobimetinib or a salt thereof is in an amount of about 10 mg, about 20 mg, about 40 mg, or about 60 mg of cobimetinib. In some embodiments, the daily dose of cobimetinib or a salt thereof is in an amount of less than about 10 mg, about 20 mg, about 40 mg, or about 60 mg of cobimetinib. In some embodiments, the daily dose of cobimetinib or a salt thereof is in an amount of about 3.5-100 mg, about 3.5-10 mg, about 10-20 mg, about 20-40 mg, about 40-60 mg, about 20-60 mg, or about 60-100 mg of cobimetinib. In some embodiments, the daily dose of cobimetinib or a salt thereof is in an amount of about 0.3-1 mg / kg of cobimetinib. In some embodiments, cobimetinib is in the hemifumarate salt form.

[0065] In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering osimertinib or a solvate or salt thereof, cobimetinib or a solvate or salt thereof, and palbociclib or a solvate or salt thereof.

[0066] In some embodiments, the daily dose of osimertinib or a salt thereof is an amount of about greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90%, or greater than 95% by weight of the combined daily dose of osimertinib, cobimetinib, and palbociclib or a salt of the foregoing. In some embodiments, the daily dose of osimertinib or a salt thereof is an amount of about less than 20%, or less than about 25%, or less than about 30%, or less than about 35%, or less than about 40%, or less than about 45%, or less than about 50%, or less than about 55%, or less than about 60%, or less than about 65%, or less than about 70%, or less than about 75%, or less than about 80%, or less than about 85%, or less than about 90%, or less than 95% by weight of the combined daily dose of osimertinib, cobimetinib, and palbociclib or a salt of the foregoing.

[0067] In some embodiments, the daily dose of cobimetinib or a salt thereof is an amount greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35% or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90% or greater than 95% by weight of the combined daily dose of osimertinib, cobimetinib and palbociclib or a salt of the foregoing. In some embodiments, the daily dose of cobimetinib or a salt thereof is an amount less than 20%, or less than about 25%, or less than about 30%, or less than about 35% or less than about 40%, or less than about 45%, or less than about 50%, or less than about 55%, or less than about 60%, or less than about 65%, or less than about 70%, or less than about 75%, or less than about 80%, or less than about 85%, or less than about 90% or less than 95% by weight of the combined daily dose of osimertinib, cobimetinib and palbociclib or a salt of the foregoing.

[0068] In some embodiments, the daily dose of palbociclib or a salt thereof is an amount greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35% or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90% or greater than 95% by weight of the combined daily dose of osimertinib, cobimetinib and palbociclib or a salt of the foregoing. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount less than 20%, or less than about 25%, or less than about 30%, or less than about 35% or less than about 40%, or less than about 45%, or less than about 50%, or less than about 55%, or less than about 60%, or less than about 65%, or less than about 70%, or less than about 75%, or less than about 80%, or less than about 85%, or less than about 90% or less than 95% by weight of the combined daily dose of osimertinib, cobimetinib and palbociclib or a salt of the foregoing.

[0069] In another aspect, the method comprises administering an effective amount of cetuximab, cobimetinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, the dose of cetuximab is an amount of about 0.1-20 mg / kg, about 0.1-0.5 mg / kg, about 0.5-1 mg / kg, about 1-2 mg / kg, about 2-3 mg / kg, about 3-5 mg / kg, about 5-7.5 mg / kg, about 7.5-10 mg / kg, about 10-15 mg / kg, about 15-20 mg / kg or about 0.1-10 mg / kg. In some embodiments, the dose of cetuximab is about 150-200 mg / m 2about 200-250 mg / m 2 about 250-300 mg / m 2 about 300-400 mg / m 2 about 400-500 mg / m 2 about 500-750 mg / m 2 about 150-250 mg / m 2 about 250-400 mg / m 2 or about 400-750 mg / m 2 In some embodiments, the cetuximab is infused over 30-180 minutes, about 30-60 minutes, about 60-120 minutes, or about 120-180 minutes. In some embodiments, the maximum infusion rate is about 5 mL / min or about 10 mL / min. In some embodiments, the cetuximab is administered about every day, about every week, about every two weeks, about every three weeks, or about every four weeks. In some embodiments, the dose of cetuximab is about 500 mg / m 2 In some embodiments, the cetuximab is administered according to a schedule comprising an initial dose followed by several subsequent doses. In some embodiments, the initial dose is about 250-500 mg / m 2 about 250-300 mg / m 2 about 300-400 mg / m or about 400-500 mg / m 2 In some embodiments, the initial dose is about 250 mg / m 2 about 400 mg / m 2 or about 500 mg / m 2 In some embodiments, the subsequent doses are about 50-300 mg / m 2 about 50-150 mg / m 2 about 150-200 mg / m 2 or about 200-300 mg / m 2 In some embodiments, the subsequent doses are about 50 mg / m 2 about 150 mg / m 2 or about 250 mg / m 2 In some embodiments, the cetuximab is administered in a manner of 400 mg / m 2 infused over 120 minutes followed by 250 mg / m 2 infused over 60 minutes weekly. In some embodiments, the cetuximab is administered in a manner of 400 mg / m 2 infused over 120 minutes followed by 150 mg / m 2 infused over 60 minutes weekly.

[0070] In some embodiments, the daily dose of copanlisib, or a salt thereof, is an amount of about 0.1-0.25 mg / kg, about 0.25-0.5 mg / kg, about 0.5-0.75 mg / kg, about 0.75-1 mg / kg, about 1-1.25 mg / kg, about 1.25-1.5 mg / kg, about 1.5-1.75 mg / kg, about 1.75-2 mg / kg, or about 0.25-1 mg / kg of copanlisib. In some embodiments, the daily dose of copanlisib, or a salt thereof, is an amount of about 10 mg, about 20 mg, about 40 mg, or about 60 mg of copanlisib. In some embodiments, the daily dose of copanlisib, or a salt thereof, is an amount of less than about 10 mg, about 20 mg, about 40 mg, or about 60 mg of copanlisib. In some embodiments, the daily dose of copanlisib, or a salt thereof, is an amount of about 3.5-100 mg, about 3.5-10 mg, about 10-20 mg, about 20-40 mg, about 40-60 mg, about 20-60 mg, or about 60-100 mg of copanlisib. In some embodiments, the daily dose of copanlisib, or a salt thereof, is an amount of about 0.3-1 mg / kg of copanlisib. In some embodiments, copanlisib is in the form of its hemifumarate salt.

[0071] In some embodiments, the daily dose of palbociclib, or a salt thereof, is an amount of about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib, or a salt thereof, is an amount of about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib, or a salt thereof, is an amount of less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib, or a salt thereof, is an amount of about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib, or a salt thereof, is an amount of about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering cetuximab, copanlisib, or a solvate or salt thereof, and palbociclib, or a solvate or salt thereof.

[0072] In another aspect, the method comprises administering an effective amount of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 0.001-1 mg / kg, about 0.001-0.002 mg / kg, about 0.002-0.005 mg / kg, about 0.005-0.01 mg / kg, about 0.01-0.05 mg / kg, about 0.05-0.1 mg / kg, about 0.1-0.2 mg / kg, about 0.2-0.3 mg / kg, about 0.3-0.4 mg / kg, about 0.4-0.5 mg / kg, about 0.5-0.6 mg / kg, about 0.6-0.7 mg / kg, about 0.7-0.8 mg / kg, about 0.8-0.9 mg / kg, or about 0.9-1 mg / kg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 10 mg, about 15 mg, about 20 mg, or about 25 mg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of less than about 10 mg, about 15 mg, about 20 mg, or about 25 mg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 0.1-25 mg, about 0.1-1 mg, about 1-5 mg, about 5-10 mg, about 8-16 mg, about 10-15 mg, about 15-20 mg, or about 20-25 mg of TAK-733.

[0073] In some embodiments, the dose of cetuximab is an amount of about 0.1-20 mg / kg, about 0.1-0.5 mg / kg, about 0.5-1 mg / kg, about 1-2 mg / kg, about 2-3 mg / kg, about 3-5 mg / kg, about 5-7.5 mg / kg, about 7.5-10 mg / kg, about 10-15 mg / kg, about 15-20 mg / kg, or about 0.1-10 mg / kg. In some embodiments, the dose of cetuximab is an amount of about 150-200 mg / m 2 , about 200-250 mg / m 2 , about 250-300 mg / m 2 , about 300-400 mg / m 2 , about 400-500 mg / m 2 , about 500-750 mg / m 2 , about 150-250 mg / m 2 , about 250-400 mg / m 2 , or about 400-750 mg / m 2In some embodiments, cetuximab is infused over 30-180 minutes, about 30-60 minutes, about 60-120 minutes, or about 120-180 minutes. In some embodiments, the maximum infusion rate is about 5 mL / min or about 10 mL / min. In some embodiments, cetuximab is administered about every day, about every week, about every two weeks, about every three weeks, or about every four weeks. In some embodiments, the dose of cetuximab is about 500 mg / m2over 60-120 minutes every two weeks. 2 In some embodiments, cetuximab is administered according to a schedule comprising an initial dose followed by several subsequent doses. In some embodiments, the initial dose is about 250-500 mg / m2. 2 , about 250-300 mg / m2. 2 , about 300-400 mg / m2, or about 400-500 mg / m2. 2 In some embodiments, the initial dose is about 250 mg / m2. 2 , about 400 mg / m2. 2 , or about 500 mg / m2. 2 In some embodiments, the subsequent doses are about 50-300 mg / m2. 2 , about 50-150 mg / m2. 2 , about 150-200 mg / m2. 2 , or about 200-300 mg / m2. 2 In some embodiments, the subsequent doses are about 50 mg / m2. 2 , about 150 mg / m2. 2 , or about 250 mg / m2. 2 In some embodiments, cetuximab is administered as 400 mg / m2over 120 minutes followed by 250 mg / m2over 60 minutes every week. In some embodiments, cetuximab is administered as 400 mg / m2over 120 minutes followed by 150 mg / m2over 60 minutes every week. 2 2 2 2

[0074] ​​​​In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering cetuximab, TAK-733 or a solvate or salt thereof, and palbociclib or a solvate or salt thereof.

[0075] In another aspect, the method comprises administering an effective amount of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the daily dose of osimertinib or a salt thereof is an amount of about 0.25-0.5 mg / kg, 0.5-1 mg / kg, about 1-1.5 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 3.5-4 mg / kg, or about 0.5-3 mg / kg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is an amount of about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is an amount less than about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the dose of osimertinib or a salt thereof is an amount of about 20-240 mg, about 20-40 mg, about 40-80 mg, about 80-160 mg, about 160-240 mg, or about 40-160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is an amount of about 0.6-2.7 mg / kg of osimertinib. In some embodiments, the osimertinib is in the form of a mesylate salt.

[0076] In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 0.001-1 mg / kg, about 0.001-0.002 mg / kg, about 0.002-0.005 mg / kg, about 0.005-0.01 mg / kg, about 0.01-0.05 mg / kg, about 0.05-0.1 mg / kg, about 0.1-0.2 mg / kg, about 0.2-0.3 mg / kg, about 0.3-0.4 mg / kg, about 0.4-0.5 mg / kg, about 0.5-0.6 mg / kg, about 0.6-0.7 mg / kg, about 0.7-0.8 mg / kg, about 0.8-0.9 mg / kg, or about 0.9-1 mg / kg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 10 mg, about 15 mg, about 20 mg, or about 25 mg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of less than about 10 mg, about 15 mg, about 20 mg, or about 25 mg of TAK-733. In some embodiments, the daily dose of TAK-733 or a salt thereof is an amount of about 0.1-25 mg, about 0.1-1 mg, about 1-5 mg, about 5-10 mg, about 8-16 mg, about 10-15 mg, about 15-20 mg, or about 20-25 mg of TAK-733.

[0077] In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is an amount of about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering osimertinib or a solvate or salt thereof, TAK-733 or a solvate or salt thereof, and palbociclib or a solvate or salt thereof.

[0078] In another aspect, the method comprises administering an effective amount of cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the daily dose of trametinib or a salt thereof is an amount of about 0.01-1 mg / kg, about 0.01-0.02 mg / kg, about 0.02-0.03 mg / kg, about 0.03-0.05 mg / kg, about 0.05-0.08 mg / kg, about 0.08-0.1 mg / kg, about 0.1-0.2 mg / kg, about 0.2-0.3 mg / kg, about 0.3-0.4 mg / kg, about 0.4-0.5 mg / kg, about 0.5-0.6 mg / kg, about 0.6-0.7 mg / kg, about 0.7-0.8 mg / kg, about 0.8-0.9 mg / kg, or about 0.9-1 mg / kg of trametinib. In some embodiments, the daily dose of trametinib or a salt thereof is an amount of about 0.5 mg, about 1 mg, about 2 mg, or about 4 mg of trametinib. In some embodiments, the daily dose of trametinib or a salt thereof is an amount less than about 0.5 mg, about 1 mg, about 2 mg, or about 4 mg of trametinib. In some embodiments, the daily dose of trametinib or a salt thereof is an amount of about 0.1-25 mg, about 0.1-0.5 mg, about 0.5-1 mg, about 1-2 mg, about 2-4 mg, about 4-10 mg, or about 0.5-2 mg of trametinib.

[0079] In some embodiments, the dose of cetuximab is an amount of about 0.1-20 mg / kg, about 0.1-0.5 mg / kg, about 0.5-1 mg / kg, about 1-2 mg / kg, about 2-3 mg / kg, about 3-5 mg / kg, about 5-7.5 mg / kg, about 7.5-10 mg / kg, about 10-15 mg / kg, about 15-20 mg / kg, or about 0.1-10 mg / kg. In some embodiments, the dose of cetuximab is about 150-200 mg / m 2 , about 200-250 mg / m 2 , about 250-300 mg / m 2 , about 300-400 mg / m 2 , about 400-500 mg / m 2 , about 500-750 mg / m 2 , about 150-250 mg / m 2 , about 250-400 mg / m 2 , or about 400-750 mg / m 2In some embodiments, cetuximab is infused over 30–180 minutes, about 30–60 minutes, about 60–120 minutes, or about 120–180 minutes. In some embodiments, the maximum infusion rate is about 5 mL / min or about 10 mL / min. In some embodiments, cetuximab is administered about daily, about weekly, about every two weeks, about every three weeks, or about every four weeks. In some embodiments, the dose of cetuximab is about 500 mg / m² infused over 60–120 minutes every two weeks. 2 In some embodiments, cetuximab is administered according to a schedule that includes an initial dose followed by several subsequent doses. In some embodiments, the initial dose is approximately 250-500 mg / m². 2 Approximately 250-300 mg / m² 2 Approximately 300-400 mg / m² or approximately 400-500 mg / m² 2 In some implementations, the initial dose is approximately 250 mg / m². 2 Approximately 400 mg / m 2 or approximately 500 mg / m 2 In some implementations, the subsequent dose is approximately 50-300 mg / m². 2 Approximately 50-150 mg / m² 2 Approximately 150-200 mg / m² 2 Or approximately 200-300 mg / m 2 In some implementations, the subsequent dose is approximately 50 mg / m². 2 Approximately 150 mg / m 2 or approximately 250 mg / m 2 In some implementations, 400 mg / m² is infused over 120 minutes. 2 Subsequently, 250 mg / m² was infused weekly over 60 minutes. 2 Cetuximab is administered via a specific method. In some implementations, it is administered as an infusion of 400 mg / m² over 120 minutes. 2 Subsequently, 150 mg / m² was infused weekly over 60 minutes. 2 Cetuximab was administered in a manner that facilitated its delivery.

[0080] In some embodiments, the daily dose of palbociclib or its salts is about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib or its salts is about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or its salts is less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering cetuximab, TAK-733, or a solvation or salt thereof, and palbociclib or a solvation or salt thereof.

[0081] In another embodiment, the method comprises administering an effective amount of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the daily dose of osimertinib or a salt thereof is about 0.25-0.5 mg / kg, 0.5-1 mg / kg, about 1-1.5 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 3.5-4 mg / kg, or about 0.5-3 mg / kg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or a salt thereof is less than about 20 mg, about 40 mg, about 80 mg, or about 160 mg of osimertinib. In some embodiments, the dosage of osimertinib or its salts is about 20-240 mg, about 20-40 mg, about 40-80 mg, about 80-160 mg, about 160-240 mg, or about 40-160 mg of osimertinib. In some embodiments, the daily dose of osimertinib or its salts is about 0.6-2.7 mg / kg of osimertinib. In some embodiments, osimertinib is in the form of mesylate.

[0082] In some embodiments, the daily dose of trametinib or its salts is about 0.01-1 mg / kg, about 0.01-0.02 mg / kg, about 0.02-0.03 mg / kg, about 0.03-0.05 mg / kg, about 0.05-0.08 mg / kg, about 0.08-0.1 mg / kg, about 0.1-0.2 mg / kg, about 0.2-0.3 mg / kg, about 0.3-0.4 mg / kg, about 0.4-0.5 mg / kg, about 0.5-0.6 mg / kg, about 0.6-0.7 mg / kg, about 0.7-0.8 mg / kg, about 0.8-0.9 mg / kg, or about 0.9-1 mg / kg of trametinib. In some embodiments, the daily dose of trametinib or its salts is about 0.5 mg, about 1 mg, about 2 mg, or about 4 mg of trametinib. In some embodiments, the daily dose of trametinib or its salts is less than about 0.5 mg, about 1 mg, about 2 mg, or about 4 mg of trametinib. In some embodiments, the daily dose of trametinib or its salts is about 0.1-25 mg, about 0.1-0.5 mg, about 0.5-1 mg, about 1-2 mg, about 2-4 mg, about 4-10 mg, or about 0.5-2 mg of trametinib.

[0083] In some embodiments, the daily dose of palbociclib or its salts is about 0.5-1 mg / kg, about 1.5-2 mg / kg, about 2-2.5 mg / kg, about 2.5-3 mg / kg, about 3-3.5 mg / kg, about 1-2.5 mg / kg, about 1-3 mg / kg, or about 3-5 mg / kg of palbociclib. In some embodiments, the daily dose of palbociclib or its salts is about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or its salts is less than about 50 mg, about 75 mg, about 100 mg, or about 125 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is about 25-225 mg, about 25-50 mg, about 50-75 mg, about 75-125 mg, about 125-150 mg, about 150-200 mg, or about 200-225 mg of palbociclib. In some embodiments, the daily dose of palbociclib or a salt thereof is about 1.25-2.1 mg / kg of palbociclib. In some embodiments, the method comprises administering osimertinib or a solvation or salt thereof, trametinib or a solvation or salt thereof, and palbociclib or a solvation or salt thereof.

[0084] In another embodiment, the method provides administration of an effective amount of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) until disease progression or unacceptable toxicity occurs. In some embodiments, the method provides administration of an effective amount of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) for at least about 1-2 weeks, about 2-3 weeks, about 3-4 weeks, about 4-5 weeks, about 5-6 weeks, about 6-7 weeks, about 7-8 weeks, about 8-9 weeks, about 9-10 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-12 months, or about 12-24 months. In some implementations, an effective amount of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) is administered for 21 consecutive days, followed by a 7-day break, to constitute a complete 28-day cycle. In some implementations, the subject is given an effective amount of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) for one, two, three, four, five, six, seven, eight, nine, ten, or more 28-day cycles. In some implementations, EGFR inhibitors (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitors (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitors (e.g., palbociclib) are administered for different durations.

[0085] In another embodiment, effective amounts of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) are formulated into a composition. In another embodiment, effective amounts of an EGFR inhibitor (e.g., osimertinib or cetuximab), a MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and a CDK 4 / 6 inhibitor (e.g., palbociclib) are formulated separately. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. In some embodiments, TAK-733 or a salt thereof and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. In some embodiments, trametinib or a salt thereof and palbociclib or a salt thereof are formulated into a single composition or separate compositions for oral administration. For oral administration, the method may include formulating the compound into a solid form, such as tablets or capsules, or into a solution, emulsion, or suspension. To prepare the oral composition, the compound may be formulated to obtain the daily dose described herein. In some embodiments, cetuximab is formulated for intravenous infusion.

[0086] In some embodiments, EGFR inhibitors (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitors (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitors (e.g., palbociclib) are formulated in the same form. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and / or palbociclib or a salt thereof are formulated in a solid form, such as tablets or capsules. In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and / or palbociclib or a salt thereof are formulated in a solid form, such as tablets or capsules. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and / or palbociclib or a salt thereof are formulated in a solid form, such as tablets or capsules. In some embodiments, cetuximab, cobimetinib or a salt thereof, and / or palbociclib or a salt thereof are formulated in a liquid form, such as a suspension, solution, emulsion, or syrup, or may be lyophilized. In some embodiments, cetuximab, TAK-733 or a salt thereof, and / or palbociclib or a salt thereof are formulated into liquid forms, such as suspensions, solutions, emulsions, or syrups, or may be lyophilized.

[0087] On the other hand, EGFR inhibitors (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitors (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitors (e.g., palbociclib) are administered simultaneously or intermittently. In some embodiments, the EGFR inhibitor (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitor (e.g., palbociclib) are formulated into a composition and administered as a composition. In some embodiments, the EGFR inhibitor (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitor (e.g., palbociclib) are formulated separately and administered simultaneously. In some embodiments, EGFR inhibitors (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitors (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitors (e.g., palbociclib) are formulated separately and administered intermittently. In other embodiments, EGFR inhibitors (e.g., osimertinib or cetuximab), MEK 1 / 2 inhibitors (e.g., cobimetinib, trametinib, or TAK-733), and CDK 4 / 6 inhibitors (e.g., palbociclib) are formulated separately and administered at different dosing frequencies.

[0088] In another aspect, the method includes administering effective amounts of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, osimertinib or a salt thereof is administered before cobimetinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, cobimetinib or a salt thereof is administered before osimertinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before osimertinib or a salt thereof and cobimetinib or a salt thereof. In some embodiments, osimertinib or a salt thereof and cobimetinib or a salt thereof are administered together in the same or separate compositions. In some embodiments, osimertinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions.

[0089] In another embodiment, the method includes administering an effective amount of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, cetuximab is administered before cobimetinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, cobimetinib or a salt thereof is administered before cetuximab and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before cetuximab and cobimetinib or a salt thereof. In some embodiments, cetuximab and cobimetinib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab is administered as a separate composition from cobimetinib or a salt thereof and palbociclib or a salt thereof. In some implementations, cetuximab is given weekly or every two weeks, while cobimetinib or its salt and palbociclib or its salt are given daily.

[0090] In another embodiment, the method includes administering an effective amount of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, cetuximab is administered before TAK-733 or a salt thereof and palbociclib or a salt thereof. In some embodiments, TAK-733 or a salt thereof is administered before cetuximab and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before cetuximab and TAK-733 or a salt thereof. In some embodiments, cetuximab and TAK-733 or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, TAK-733 or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab is administered in a composition separate from TAK-733 or a salt thereof and palbociclib or a salt thereof. In some implementations, cetuximab is given weekly or every two weeks, while TAK-733 or its salt and palbociclib or its salt are given daily.

[0091] In another aspect, the method includes administering effective amounts of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, osimertinib or a salt thereof is administered before TAK-733 or a salt thereof and palbociclib or a salt thereof. In some embodiments, TAK-733 or a salt thereof is administered before osimertinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before osimertinib or a salt thereof and TAK-733 or a salt thereof. In some embodiments, osimertinib or a salt thereof and TAK-733 or a salt thereof are administered together in the same or separate compositions. In some embodiments, osimertinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, TAK-733 or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions.

[0092] In another embodiment, the method includes administering an effective amount of cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, cetuximab is administered before trametinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, trametinib or a salt thereof is administered before cetuximab and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before cetuximab and trametinib or a salt thereof. In some embodiments, cetuximab and trametinib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, trametinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, cetuximab is administered in a composition separate from trametinib or a salt thereof and palbociclib or a salt thereof. In some implementations, cetuximab is given weekly or every two weeks, while trametinib or its salt and palbociclib or its salt are given daily.

[0093] In another aspect, the method includes administering an effective amount of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, osimertinib or a salt thereof is administered before trametinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, trametinib or a salt thereof is administered before osimertinib or a salt thereof and palbociclib or a salt thereof. In some embodiments, palbociclib or a salt thereof is administered before osimertinib or a salt thereof and trametinib or a salt thereof. In some embodiments, osimertinib or a salt thereof and trametinib or a salt thereof are administered together in the same or separate compositions. In some embodiments, osimertinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions. In some embodiments, trametinib or a salt thereof and palbociclib or a salt thereof are administered together in the same or separate compositions.

[0094] In some implementations, the administration is intermittently administered at intervals of approximately 1-30 minutes, 30-60 minutes, 60-120 minutes, 120-240 minutes, 240-480 minutes, 480-720 minutes, 720-960 minutes, or 960-1440 minutes. In some implementations, the administration is intermittently administered at intervals of approximately 1-2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, or 6-7 days.

[0095] In another scenario, the subject has previously been treated with a BRAF inhibitor. In another scenario, the subject has not previously been treated with a BRAF inhibitor. In another scenario, the subject has previously been treated with a combination of a BRAF inhibitor and a MEK inhibitor. In another scenario, the subject has not previously been treated with a combination of a BRAF inhibitor and a MEK inhibitor. In some embodiments, the subject has developed acquired or adaptive resistance to a BRAF inhibitor or a MEK inhibitor. In some embodiments, the subject has not developed acquired or adaptive resistance to a BRAF inhibitor or a MEK inhibitor. MEK inhibitors include, but are not limited to, small molecules or antibodies that specifically bind to MEK 1 / 2 or its ligands, such as trametinib, selmetinib, TAK-733, CI-1040, PD0325901, MEK162, AZD8330, GDC-0623, remetinib, pimasetinib, RO4987655, RO5126766, WX-554, HL-085, and cobimetinib. BRAF inhibitors include, but are not limited to, small molecules or antibodies that specifically bind to wild- or mutated BRAF or its ligands, such as verafenib and dabrafenib.

[0096] On the other hand, compared with administration of only one or two of osimertinib or its salts, cobimetinib or its salts, and palbociclib or its salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more. On the other hand, compared with administration of only one or both of cetuximab, cobimetinib or its salts and palbociclib or its salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000% or more. On the other hand, compared with administration of only one or two of cetuximab, TAK-733, and palbociclib or their salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more. On the other hand, compared with administration of only one or both of osimertinib or its salts, TAK-733 and palbociclib or its salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000% or more. On the other hand, compared with administration of only one or two of cetuximab, trametinib, and palbociclib or their salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more.On the other hand, compared with administration of only one or two of osimertinib or its salts, trametinib and palbociclib or their salts, the methods described herein reduce cancer cell growth and / or increase cancer cell killing by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000% or more.

[0097] Furthermore, the methods described herein have been shown to have a synergistic effect in the treatment of cancers with BRAF mutations. In some embodiments, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more compared to the additive efficacy of administering osimertinib or its salts alone, cobimetinib or its salts, and palbociclib or its salts. In some implementations, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more compared to the cumulative efficacy of administering cetuximab, cobimetinib, or salts thereof, and palbociclib or salts thereof alone. In some implementations, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more compared to the cumulative efficacy of administering cetuximab, TAK-733 or its salts, and palbociclib or its salts alone. In some embodiments, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000% or more compared to the cumulative efficacy of administering osimertinib or its salts alone, TAK-733 or its salts, and palbociclib or its salts. In some implementations, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more compared to the cumulative efficacy of administering cetuximab, trametinib, or salts thereof, and palbociclib, or salts thereof, alone.In some embodiments, the efficacy of the methods described herein is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more compared to the cumulative efficacy of administering osimertinib or its salts alone, trametinib or its salts, and palbociclib or its salts.

[0098] On the other hand, the methods described herein reduce the average tumor volume. In some embodiments, the methods described herein reduce the average tumor volume by approximately 20-95%. In some embodiments, the average tumor volume is reduced by at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0099] On the other hand, the methods described herein cause a change in the subject's weight of less than about 25%, less than about 20%, less than about 15%, or less than about 5%. In some embodiments, the methods do not cause a change in weight.

[0100] In another aspect, the methods described herein comprise administering a loading dose of a combination of the following: (a) an epidermal growth factor receptor (EGFR) inhibitor (e.g., osimertinib or cetuximab); (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733); and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor (e.g., palbociclib), followed by multiple separate maintenance doses of the combination. In some embodiments, each loading dose of the three inhibitors is higher than each maintenance dose. In some embodiments, the methods described herein provide lower dose, safety, and / or tolerability for long-term administration and / or treatment. III. Composition

[0101] This document also provides compositions comprising: (a) an epidermal growth factor receptor (EGFR) inhibitor (e.g., osimertinib or cetuximab); (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733); and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor (e.g., palbociclib); wherein said compositions do not contain a BRAF inhibitor. In some embodiments, said compositions consist of: (a) an epidermal growth factor receptor (EGFR) inhibitor (e.g., osimertinib or cetuximab); (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor (e.g., cobimetinib, trametinib, or TAK-733); and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor (e.g., palbociclib).

[0102] This document also provides compositions comprising osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. This document also provides compositions comprising osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. This document also provides compositions comprising osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. These compositions can be used in the methods described herein to treat cancers with BRAF mutations and to delay their progression. In some embodiments, the compositions do not contain a BRAF inhibitor.

[0103] In one aspect, the composition may also comprise a pharmaceutically acceptable carrier, excipient, binder, or diluent. Pharmaceutically acceptable excipients are substances that are non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the compound described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, fillers, emulsifiers, or taste modifiers. In some embodiments, the pharmaceutical composition according to the embodiment is a sterile composition. The pharmaceutical composition can be prepared using known or readily available formulation techniques to those skilled in the art. The embodiments also contemplate sterile compositions, including compositions that comply with national and local regulations governing such compositions.

[0104] The pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated with solid carriers into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules. The pharmaceutical compositions provided herein can be administered via suitable routes of delivery, such as oral, parenteral, rectal, nasal, or topical routes, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.

[0105] In another aspect, the composition is formulated for oral administration. For oral administration, the composition may be formulated in a solid form, such as tablets or capsules, or in a solution, emulsion, or suspension. Oral tablets may contain one or more active ingredients mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerin, water, etc. Starch, polyvinylpyrrolidone (PVP), sodium glycolate starch, microcrystalline cellulose, and alginate are exemplary disintegrants. Binders may include starch and gelatin. If present, lubricants may be magnesium stearate, stearic acid, or talc. If desired, tablets can be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or they can be coated with an enteric coating.

[0106] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, one or more active ingredients may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with: water, oil (such as peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0107] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as dry products for reconstitution with water or other suitable media prior to use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and, if desired, flavoring or coloring agents.

[0108] In another embodiment, the composition comprises osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the composition comprises, by weight, greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70% of osimertinib or a salt thereof.

[0109] In some embodiments, the composition comprises, by weight, greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50% of cobixitinib or a salt thereof.

[0110] In some embodiments, the composition comprises, by weight, greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90% of palbociclib or a salt thereof.

[0111] In some embodiments, the ratio of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof in the composition by weight is about 1:1:1, 2:1:1, 3:1:1, 4:1:1, 1:2:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 3:1:1, 3:1:2, 3:1:3, 3:1:4, 3:1:5, 3:1:6, 3:1:7, 3:1:8, 3:1:9, or 3:1:10. In some embodiments, the ratio of osimertinib or a salt thereof, cobiceptinib or a salt thereof, and palbociclib or a salt thereof in the composition is about 2:1:4 by weight. In some embodiments, the ratio of osimertinib or a salt thereof to cobiceptinib or a salt thereof by weight is in the range of about 2:3 to 4:1. In some embodiments, the ratio of osimertinib or a salt thereof to palbociclib or a salt thereof by weight is in the range of about 40:125 to 80:75. In some embodiments, the ratio of cobiceptinib or a salt thereof to palbociclib or a salt thereof by weight is in the range of about 20:125 to 60:75.

[0112] In another embodiment, the composition comprises a salt of osimertinib, cobimetinib, TAK-733, trametinib, or palbociclib. In some embodiments, the salt is a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, hexanoates, heptarates, propargylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, etc. The composition comprises 1,4-diacetate of acetylenic acid, 1,6-diacetate of hexylenic acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate methanesulfonate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. In some embodiments, the composition comprises mesylates of osimertinib, cobimetinib, and palbociclib. In some embodiments, the composition comprises fumarates of osimertinib, cobimetinib, and palbociclib. In another embodiment, the composition comprises a solvate of osimertinib, cobimetinib, TAK-722, or palbociclib.

[0113] In another embodiment, the composition comprises osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the composition comprises, by weight, greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70% of osimertinib or a salt thereof.

[0114] In some embodiments, the composition contains, by weight, more than about 20%, or more than about 25%, or more than about 30%, or more than about 35%, or more than about 40%, or more than about 45%, or more than about 50% of TAK-733 or a salt thereof.

[0115] In some embodiments, the composition comprises, by weight, greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90% of palbociclib or a salt thereof.

[0116] In some embodiments, the ratio of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof in the composition by weight is about 1:1:1, 2:1:1, 3:1:1, 4:1:1, 1:2:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 3:1:1, 3:1:2, 3:1:3, 3:1:4, 3:1:5, 3:1:6, 3:1:7, 3:1:8, 3:1:9, or 3:1:10. In some embodiments, the ratio of osimertinib or a salt thereof to TAK-733 or a salt thereof in the composition, by weight, is in the range of about 5:2 to 10:1. In some embodiments, the ratio of osimertinib or a salt thereof to palbociclib or a salt thereof in the composition, by weight, is in the range of about 40:125 to 80:75. In some embodiments, the ratio of TAK-733 or a salt thereof to palbociclib or a salt thereof in the composition, by weight, is in the range of about 8:125 to 16:75.

[0117] In another embodiment, the composition comprises osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the composition comprises, by weight, greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70% of osimertinib or a salt thereof.

[0118] In some embodiments, the composition comprises, by weight, greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50% of trametinib or a salt thereof.

[0119] In some embodiments, the composition comprises, by weight, greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90% of palbociclib or a salt thereof.

[0120] In some embodiments, the ratio of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof in the composition by weight is about 15:1:10, 20:1:10, 25:1:10, 30:1:10, 35:1:10, 40:1:10, 50:1:10, 15:1:20, 20:1:20, 25:1:20, 30:1:20, 35:1:20, 40:1:20, 50:1:20, 15:1:30, 20:1:30, 25:1:30, 30:1:30, 35:1:30, 40:1:30, 50:1:30, or 40:1:50. In some embodiments, the ratio of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof in the composition is about 15:1:12 by weight. In some embodiments, the ratio of osimertinib or a salt thereof and trametinib or a salt thereof in the composition ranges from about 20:1 to 160:1 by weight. In some embodiments, the ratio of osimertinib or a salt thereof and palbociclib or a salt thereof in the composition ranges from about 40:125 to 80:75 by weight. In some embodiments, the ratio of trametinib or a salt thereof and palbociclib or a salt thereof in the composition ranges from about 1:250 to 2:75 by weight. IV. Reagent Kit

[0121] This document also provides kits comprising: (a) an epidermal growth factor receptor (EGFR) inhibitor (e.g., osimertinib or cetuximab); (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor (e.g., TAK-733, trametinib, or cobimetinib); and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor (e.g., palbociclib); wherein the kit does not contain a BRAF inhibitor. In some embodiments, the kit comprises: (a) an epidermal growth factor receptor (EGFR) inhibitor (e.g., osimertinib or cetuximab); (b) a mitogen-activated protein kinase (MEK) 1 / 2 inhibitor (e.g., TAK-733, trametinib, or cobimetinib); and (c) a cyclin-dependent kinase (CDK) 4 / 6 inhibitor (e.g., palbociclib). The kits may be used in accordance with the methods described herein to treat cancers with BRAF mutations and to delay their progression. In some embodiments, the kits do not contain a BRAF inhibitor. The kit may contain any of the compositions described herein.

[0122] This document also provides kits comprising osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising osimertinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising cobimetinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0123] In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated as a composition in a kit. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, osimertinib or a salt thereof, cobimetinib or a salt thereof, and / or palbociclib or a salt thereof are formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated together with a solid carrier into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms.

[0124] In some embodiments, the kit provides osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof in a ratio of approximately 1:1:1, 2:1:1, 3:1:1, 4:1:1, 1:2:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 3:1:1, 3:1:2, 3:1:3, 3:1:4, 3:1:5, 3:1:6, 3:1:7, 3:1:8, 3:1:9, or 3:1:10 by weight. In some embodiments, the ratio of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof in the kit, by weight, is about 2:1:4. In some embodiments, the ratio of osimertinib or a salt thereof to cobimetinib or a salt thereof in the kit, by weight, is in the range of about 2:3 to 4:1. In some embodiments, the ratio of osimertinib or a salt thereof to palbociclib or a salt thereof in the kit, by weight, is in the range of about 40:125 to 80:75. In some embodiments, the ratio of cobimetinib or a salt thereof to palbociclib or a salt thereof in the kit, by weight, is in the range of about 20:125 to 60:75.

[0125] This document also provides kits comprising cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising cetuximab and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising cobimetinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0126] In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated as two or more compositions in a kit. In some embodiments, cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, cobimetinib or a salt thereof and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, cetuximab, cobimetinib or a salt thereof, and / or palbociclib or a salt thereof are formulated as solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated with a solid carrier as pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms. In some embodiments, cetuximab is formulated for administration via intravenous infusion. In some embodiments, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated into a composition for oral administration.

[0127] In some embodiments, the kit provides cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof in a ratio of approximately 1:1:1, 2:1:1, 3:1:1, 4:1:1, 1:2:1, 3:1:2, 3:1:3, 3:1:4, 3:1:5, 3:1:6, 3:1:7, 3:1:8, 3:1:9, 3:1:10, 4:1:2, 4:1:3, 4:1:4, 4:1: 5, 4:1:6, 4:1:7, 4:1:8, 4:1:9, 4:1:10, 5:1:1, 5:1:2, 5:1:3, 5:1:4, 5:1:5, 5:1:6, 5:1:7, 5:1:8, 5:1:9, 5:1:10, 6:1:1, 6:1:2, 6:1:3, 6:1:4, 6:1:5, 6:1:6, 6:1:7, 6:1:8, 6:1:9, or 6:1:10. In some embodiments, the ratio of cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof in the kit by weight is about 20:3:6. In some embodiments, the ratio of cetuximab and cobimetinib or a salt thereof in the kit by weight is in the range of about 85:60 to 85:2. In some embodiments, the ratio of cetuximab to palbociclib or a salt thereof in the kit, by weight, ranges from about 17:25 to 34:3. In some embodiments, the ratio of cobimetinib or a salt thereof to palbociclib or a salt thereof in the kit, by weight, ranges from about 20:125 to 60:75.

[0128] This document also provides kits comprising cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising cetuximab and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising TAK-733 or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0129] In some embodiments, cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated as one composition in the kit. In some embodiments, cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated as two or more compositions in the kit. In some embodiments, cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, TAK-733 or a salt thereof and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, TAK-733 or a salt thereof and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, cetuximab, TAK-733 or its salts, and / or palbociclib or its salts, are formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated together with a solid carrier into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms. In some embodiments, cetuximab is formulated for administration via intravenous infusion. In some embodiments, TAK-733 or its salts and palbociclib or its salts are formulated into a composition for oral administration.

[0130] In some embodiments, the ratio of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof provided by the kit, by weight, is approximately 5:1:5, 10:1:5, 15:1:5, 20:1:5, 10:2:1, 10:1:2, 10:1:3, 10:1:4, 10:1:5, 10:1:6, 10:1:7, 10:1:8, 5:1:9, 1 The ratios are 0:1:10, 15:1:2, 15:1:3, 15:1:4, 15:1:5, 15:1:6, 15:1:7, 15:1:8, 15:1:9, 15:1:10, 20:1:1, 20:1:2, 20:1:3, 20:1:4, 20:1:5, 20:1:6, 20:1:7, 20:1:8, 20:1:9, or 20:1:10. In some embodiments, the ratio of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof in the kit is approximately 20:1:6 by weight. In some embodiments, the ratio of cetuximab and TAK-733 or a salt thereof in the kit is in the range of approximately 85:16 to 850:8 by weight. In some embodiments, the ratio of cetuximab to palbociclib or a salt thereof in the kit, by weight, is in the range of about 17:25 to 34:3. In some embodiments, the ratio of TAK-733 or a salt thereof to palbociclib or a salt thereof in the kit, by weight, is in the range of about 8:125 to 16:75.

[0131] This document also provides kits containing osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition containing osimertinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition containing TAK-733 or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition containing palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0132] In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated as a composition in a kit. In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, osimertinib or its salts, TAK-733 or its salts, and / or palbociclib or its salts are formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated together with a solid carrier into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms.

[0133] In some embodiments, the kit provides osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof in a ratio of approximately 1:1:1, 2:1:1, 3:1:1, 4:1:1, 1:2:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 3:1:1, 3:1:2, 3:1:3, 3:1:4, 3:1:5, 3:1:6, 3:1:7, 3:1:8, 3:1:9, or 3:1:10 by weight. In some embodiments, the ratio of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof in the composition is about 3:1:6 by weight. In some embodiments, the ratio of osimertinib or a salt thereof and TAK-733 or a salt thereof in the kit is in the range of about 5:2 to 10:1 by weight. In some embodiments, the ratio of osimertinib or a salt thereof and palbociclib or a salt thereof in the kit is in the range of about 40:125 to 80:75 by weight. In some embodiments, the ratio of TAK-733 or a salt thereof and palbociclib or a salt thereof in the kit is in the range of about 8:125 to 16:75 by weight.

[0134] This document also provides kits comprising cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising cetuximab and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising trametinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0135] In some embodiments, cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated as one composition in the kit. In some embodiments, cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated as two or more compositions in the kit. In some embodiments, cetuximab, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, trametinib or a salt thereof and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, trametinib or a salt thereof and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, cetuximab, trametinib or salts thereof, and / or palbociclib or salts thereof are formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated together with a solid carrier into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms. In some embodiments, cetuximab is formulated for administration via intravenous infusion. In some embodiments, trametinib or salts thereof and palbociclib or salts thereof are formulated into a composition for oral administration.

[0136] This document also provides kits comprising osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. In some embodiments, the kit comprises a pharmaceutical composition comprising osimertinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising trametinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent. In some embodiments, the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder, or diluent.

[0137] In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated as a composition in a kit. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated separately. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and / or palbociclib or a salt thereof are formulated for oral administration. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof are formulated in the same form, such as a solid or liquid form. In some embodiments, osimertinib or a salt thereof, trametinib or a salt thereof, and / or palbociclib or a salt thereof are formulated into solutions, emulsions, suspensions, dispersants, or inclusion complexes (such as cyclodextrins) in suitable pharmaceutical solvents or carriers, or formulated together with a solid carrier into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstituted powders, or capsules, according to conventional methods known in the art for preparing various dosage forms.

[0138] In some embodiments, the kit provides osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof in a ratio of approximately 15:1:10, 20:1:10, 25:1:10, 30:1:10, 35:1:10, 40:1:10, 50:1:10, 15:1:20, 20:1:20, 25:1:20, 30:1:20, 35:1:20, 40:1:20, 50:1:20, 15:1:30, 20:1:30, 25:1:30, 30:1:30, 35:1:30, 40:1:30, 50:1:30, or 40:1:50 by weight. In some embodiments, the ratio of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof in the composition is about 15:1:12 by weight. In some embodiments, the ratio of osimertinib or a salt thereof to trametinib or a salt thereof in the kit is in the range of about 20:1 to 160:1 by weight. In some embodiments, the ratio of osimertinib or a salt thereof to palbociclib or a salt thereof in the kit is in the range of about 40:125 to 80:75 by weight. In some embodiments, the ratio of trametinib or a salt thereof to palbociclib or a salt thereof in the kit is in the range of about 1:250 to 2:75 by weight.

[0139] On the other hand, the kit also includes a packaging insert, which includes, but is not limited to, appropriate instructions for the preparation and administration of the formulation, side effects of the formulation, and any other relevant information. The instructions may be in any suitable format, including but not limited to printed materials, videotapes, computer-readable disks, optical discs, or internet-based instructional guidance.

[0140] On the other hand, a kit is provided for treating individuals who have or are susceptible to the conditions described herein, comprising a first container and a packaging insert for use, the first container containing a dose of the composition or formulation disclosed herein. The container may be any container known in the art and suitable for storing and delivering intravenous formulations. In some embodiments, the kit further includes a second container containing pharmaceutically acceptable carriers, diluents, adjuvants, etc., for preparing the formulation to be administered to the individual.

[0141] On the other hand, kits containing sufficient doses of the compositions described herein (including pharmaceutical compositions thereof) may also be provided to provide individuals with effective treatment for extended periods of time (such as 1-3 days, 1-5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles or longer).

[0142] In some embodiments, the kit may also comprise multiple doses and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy). In some embodiments, the kit may comprise a dose of at least one composition as disclosed herein. Example

[0143] The following embodiments are provided to illustrate, but not to limit, the invention. Those skilled in the art will recognize that the following procedures can be modified using methods known to those of ordinary skill in the art. Example 1: In vitro drug testing using conditionally reprogrammed cell pools

[0144] Surgical specimens from colorectal cancer patients were obtained from hospitals in Beijing after obtaining informed consent from the patients. Patient-derived xenograft tumor samples were obtained from Nod / SCID mice inoculated with surgical tumor samples from the patients.

[0145] For in vitro drug susceptibility assays, colorectal tumor cells (CRC) are isolated from patient tissue samples or PDX xenograft tumor tissue. Briefly, the tumor tissue is cut into small pieces less than 1 mm in diameter using scissors. The tumor fragments are transferred to a sterile 100 ml Erlenmeyer flask equipped with a magnetic stir bar. 10–15 ml of digestion medium containing 0.25 U / ml Liberase DH is added to the chopped tumor tissue to initiate enzymatic digestion. The enzyme mixture is incubated at 37°C for 1–2 hours with moderate stirring. The digested tumor tissue is filtered through a 100 μm cell retainer. The filtrate is refiltered through a 40 μm cell retainer. The CRC clusters retained on the 40 μm cell retainer are collected, washed twice with HBSS, and then resuspended in defined growth medium supplemented with several stem cell growth factors.

[0146] CRC clusters retained on 40 μm cell retainers were collected, washed twice with HBSS, and then resuspended in defined growth medium supplemented with cell growth factors and small molecule inhibitors. The CRC clusters were recovered overnight in the defined growth medium. The defined growth medium is... hESC SFM (specific serum-free and feeder-free medium (SFM)) supplemented with: nicotinamide, Wnt3A, Noggin (bone morphogenetic protein (BMP) inhibitor), Rspondin-1 (Wnt / β-catenin signaling agonist) and Y27632 (Rho-associated coiled-coil protein kinase (ROCK-1) inhibitor).

[0147] For conditional reprogramming, the recovered cancer tissue-derived spheroids (CTOS) were dissociated into single cells and seeded at approximately 3000 cells per well in a cell culture plate in a feeder cell / Rock inhibitor (Y27632) co-culture system and grown at 37°C for 3 days.

[0148] For in vitro drug testing, inoculated CRCs were exposed to a combination of osimertinib (mesylate), cobimetinib (fumarate), and palbociclib (fumarate) for 72 hours. This combination was prepared in DMSO with a final DMSO concentration of 0.1%. Typical compound concentrations for in vitro drug testing were: osimertinib 0.1–0.5 μM, cobimetinib 0.025–0.2 μM, and palbociclib 0.125–1 μM.

[0149] Following drug exposure, CRC cells were labeled with 5-ethynyl-2'-deoxyuridine (Edu) to assess tumor cell proliferation. Labeling was maintained for 24 hours in the presence of drug exposure. In the control group, epithelial tumor cells were not exposed to the drug but were similarly labeled with Edu after a culture medium change. Labeled CRC cells were fixed in blocking buffer containing 0.5% Triton X-100 and 3% BSA at 4°C and stained overnight with Hoechst 33342. Tumor cells were incubated with EpCAM antibody (1:4000) at room temperature for 2 hours and washed with PBST. Subsequently, CRC cells were compared with Alexa... The 647-conjugated goat anti-mouse secondary antibody was incubated together at room temperature for 30 minutes and then washed with PBST.

[0150] Incorporated Edu was detected by a Click-iT reaction in which fixed cells were incubated in the dark with a reaction mixture containing 1X Click-iT Edu reaction buffer, CuSO4, and an azide-conjugated Alexa Fluor dye. The stained cells were washed twice with PBS before image acquisition and analysis.

[0151] For image acquisition and analysis, stained tumor cells were imaged using a High Content Screening (HCS) platform (Thermo Scientific Cellomics ArrayScan XTi HCS reader). Images were acquired using a 10x objective lens. Twenty-five fields of view were imaged for each well during analysis. Three fluorescence signals were obtained from the images using the HCS reader. A blue fluorescence signal recorded nuclear signals stained with Hoechst 33342, a green fluorescence signal detected Edu incorporated into newly synthesized DNA, and a red fluorescence signal detected EpCAM-positive epithelial cell populations. Representative images are shown in... Figure 1 middle.

[0152] MI (Maximum Inhibition Index) was calculated using EpCAM and Edu-positive readings (Table 1). MI = Edu-positive cells in control / Edu-positive cells in treatment. As shown in Table 1, the combination therapy had the highest specificity for CRC with BRAF V600E or D581V mutations. Table 1. Maximum Inhibition Index (MI) of CRC treated with combination therapy

[0153] Table 2 shows the selectivity of combination therapy for CRC with and without BRAF mutations. Selectivity (%) = Number of CRCs with MI ≥ 1000 / Total number of CRCs * 100% Table 2 Selectivity of combination therapy for BRAF mutations in CRC

[0154] The data presented in Table 2 show that colorectal cancer cells with BRAF mutations are extremely sensitive to the drug combination, with 3 out of 4 cases showing a reduction in cell proliferation greater than 10,000-fold compared to the no-drug control. In contrast, 2 out of 11 colorectal cancer cells without BRAF or KRAS / NRAS mutations showed a reduction in cell proliferation greater than 1,000-fold, and none showed a reduction greater than 10,000-fold. Example 2: Test of tumor volume reduction in mice during combination therapy using a PDX model of patient NYL132

[0155] The study was conducted in a xenograft tumor PDX model, which used tumors derived from BRAF. V600E - Surgical tumor tissue establishment for CRC patient NYL132. Mean tumor volume during combination therapy is shown in Table 3 and... Figure 2 In short, the study used 6-8 week old female NOD / SCID mice. Tumor samples obtained from patients were immediately transferred to tissue preservation solution and cut into small pieces. These pieces were subcutaneously inoculated on one side of the mouse to produce a xenograft termed generation 1 (P1). Successive generations of xenografts were generated using the same procedure. The study continued until the average tumor size in the mice reached approximately 250-300 mm. 3 Animals were randomly assigned to different groups, with 5 mice in each group. The date of randomization was defined as day 0 of the study. Tumor volume was expressed in mm using the following formula. 3 It means: V (volume) = (a × b) 2 ) / 2, where a and b are the long and short diameters of the tumor, respectively. Tumor inhibition is expressed as tumor growth inhibition (TGI) calculated according to the following formula: TGI = (1 - (Ti - T0) / (Vi - V0)) * 100%, where Ti is the mean tumor volume of the treatment group on the measurement day; T0 is the mean tumor volume of the treatment group at D0; Vi is the mean tumor volume of the control group on the measurement day; and V0 is the tumor volume of the control group at D0. The TGI values ​​of the combination therapy are shown in Table 4 and Figure 3 middle. Table 3. Average tumor volume during combination therapy. Table 4 Tumor growth inhibition during combination therapy

[0156] The data presented in Tables 3 and 4 show that the combination therapy reduced tumor volume in a dose-dependent manner. These data demonstrate the critical value of the combination therapy, proving its ability to regress established tumors (not just slow tumor growth), whereas standard chemotherapy regimens for colorectal cancer were completely ineffective in BRAF-mutant colorectal tumor models. Example 3: Body weight of mice during combination therapy in a PDX model using patient NYL132

[0157] Using BRAF V600E - CRC patient NYL132, following the same procedure as in Example 2. The average body weight of the mice is shown in Table 5 and... Figure 4 middle. Table 5. Mouse body weight during combination therapy.

[0158] The data presented in Table 4 show that the combination therapy was tolerable in animals, especially at dose levels that demonstrated significant in vivo efficacy. Example 4. Testing of tumor volume reduction and body weight change in mice during combination therapy in a PDX model using patient NYL-GZ-082

[0159] Using BRAF V600E -CRC patient NYL-GZ-082, using various combinations, followed the same procedures as in Examples 2 and 3. Tumor volume values ​​and weight changes are shown in... Figure 5 and Figure 6 In the control group, both combination therapies—osimertinib + cobimetinib + palbociclib and cetuximab + cobimetinib + palbociclib—reduced tumor volume. Furthermore, in the control group (… Figure 5 In the triangle (likely referring to a specific region or area), the tumor volume increased to >900 mm² after 14 days without treatment. 3 Starting on day 15, combination therapy (cetuximab + cobimetinib + palbociclib) was administered, and the tumor volume rapidly decreased, even after the tumor had grown to a large size. Furthermore, wet weight maintained tumor regression throughout two treatment cycles. Example 5. BRAF treated with monotherapy and combination therapy in a PDX model using patient NYL132 V600E Comparison of maximal inhibition index (MI) and tumor growth inhibition index (TGI) in CRC

[0160] Using BRAF V600E- CRC patient NYL132 followed the same procedure as in Example 2. MI (Maximum Inhibition Index) was calculated using EpCAM and Edu-positive readings (Table 6). MI = Edu-positive cells in the control group / Edu-positive cells in the treatment group. Tumor growth inhibition (TGI) was calculated according to the following formula: TGI = (1 - (Ti - T0) / (Vi - V0)) * 100%, where Ti is the mean tumor volume in the treatment group on the measurement day; T0 is the mean tumor volume in the treatment group at D0; Vi is the mean tumor volume in the control group on the measurement day; and V0 is the tumor volume in the control group at D0. Table 6. BRAF treated with monotherapy and combination therapy in a PDX model using patient NYL132 V600E -CRC MI and TGI values

[0161] Figure 7 Tumor volume changes during treatment with various monotherapy and combination therapies are shown in a PDX model using patient NYL132. All three combinations tested (1) cetuximab + cobimetinib + palbociclib, (2) osimertinib + TAK-733 + palbociclib, and (3) cetuximab + TAK-733 + palbociclib reduced tumor volume by >85% during the first treatment cycle (21 days) (see also Table 7). Single cetuximab treatment only slightly inhibited tumor growth (hollow triangle, 2 cycles of treatment from start to day 56), and tumors treated with single cetuximab were sensitive to a combination of cetuximab 1 mg weekly (ip), cobimetinib 5 mg / kg, and palbociclib 20 mg / kg daily (po) for 21 days. Table 7. Originating from BRAF V600E Tumor growth inhibition in a PDX model of NYL132 patients with CRC Example 6. BRAF treated with monotherapy and combination therapy in a CDX model using the HT-29 cell line. V600E Comparison of maximal inhibition index (MI) and tumor growth inhibition index (TGI) in CRC

[0162] To conduct an in vivo efficacy study of xenografts (CDX) derived from the HT-29 cell line. The experimental procedure is briefly described below. Culture sufficient donor cells (HT-29) and prepare them for seeding. Suspend at least 3 x 10⁻⁶ cells in a matrix gel. 6 Cells were injected into the dorsal side of female nude mice. When the tumor volume in the mice grew to 100-300 mm...3 Mice with irregular tumor shapes and poor health were excluded based on their body weight and tumor growth. The remaining mice were randomly assigned to multiple groups, typically 3-5 mice per group. The randomization date was defined as day 0 of the study. Tumor volume was expressed in mm using the following formula. 3 It means: V (volume) = (a × b) 2 ) / 2, where a and b are the long and short diameters of the tumor, respectively. Tumor inhibition is expressed as tumor growth inhibition (TGI) calculated according to the following formula: TGI = (1 - (Ti - T0) / (Vi - V0)) * 100%, where Ti is the mean tumor volume of the treatment group on the measurement day; T0 is the mean tumor volume of the treatment group at D0; Vi is the mean tumor volume of the control group on the measurement day; and V0 is the tumor volume of the control group at D0.

[0163] MI (Maximum Inhibition Index) was calculated using EpCAM and Edu-positive readings (Table 8). MI = Edu-positive cells in the control group / Edu-positive cells in the treatment group. Tumor growth inhibition (TGI) was calculated using the following formula: TGI = (1 - (Ti - T0) / (Vi - V0)) * 100%, where Ti is the mean tumor volume in the treatment group on the measurement day; T0 is the mean tumor volume in the treatment group at D0; Vi is the mean tumor volume in the control group on the measurement day; and V0 is the tumor volume in the control group at D0. Table 8. BRAF treated with monotherapy and combination therapy in a CDX model using the HT-29 cell line. V600E -CRC MI and TGI values Sample Concentration (uM) MI %TGI Osimertinib 0.5 1.20 16.9639％ Afatinib 0.2 1.24 19.2409％ Cobimetinib 0.4 331.41 99.6983％ Trametinib 0.02 17.16 94.1714％ Palbociclib 0.15 4.64 78.4714％ Rebimibib 5 11.24 91.1053％ Osimertinib + Cobimetinib + Palbociclib 0.5+0.4+0.15 23332.49 99.9957％ Osimertinib + Cobimetinib + Rebimibib 0.5+0.4+5 12790.35 99.9922％ Osimertinib + Trametinib + Palbociclib 0.5+0.02+0.15 24849.10 99.9960％ Osimertinib + Trametinib + Rebimibib 0.5+0.02+5 24849.10 99.9960％ Afatinib + Cobimetinib + Palbociclib 0.2+0.4+0.15 24849.10 99.9960％ Afatinib + Cobimetinib + Rebimibib 0.2+0.4+5 24849.10 99.9960％ Afatinib + Trametinib + Palbociclib 0.2+0.02+0.15 6598.97 99.9848％ Afatinib + Trametinib + Rebimibib 0.2+0.02+5 24849.10 99.9960％

[0164] Figure 8 and Figure 9 Tumor volume changes during treatment with various single agents and dual and triple combinations are shown in a CDX model using the HT-29 cell line. All four combinations tested (1) osimertinib + cobimetinib + palbociclib, (2) cetuximab + cobimetinib + palbociclib, (3) osimertinib + TAK-733 + palbociclib, and (4) cetuximab + TAK-733 + palbociclib reduced tumor volume by >50% during the first treatment cycle (21 days). Chemotherapy agents capecitabine (square) and 5-FU (dashed circle) showed no efficacy, and tumor growth trends were similar to those of the mediator control (triangle). The triple combination of cetuximab, cobitinib, and palbociclib, as well as the triple combination of osimertinib, cobitinib, and palbociclib, showed superior tumor growth inhibition compared to single therapy (cobitinib), the dual combination of cobitinib and osimertinib, and the dual combination of cobitinib and palbociclib (see also Table 9). Table 9. Tumor growth inhibition using the CDX model with HT-29 cell line Example 7. Clinical study of combination therapy

[0165] In patients with any BRAF V600E A phase 2 open-label clinical trial was conducted in patients with advanced colorectal cancer harboring BRAF. The study was designed to evaluate the safety and efficacy of the combination therapy (cetuximab + cobimetinib + palbociclib) in patients with advanced colorectal cancer. The study population included adult men and women aged 18–75 years diagnosed with any BRAF. V600E Advanced colorectal cancer with mutations and an expected survival of more than 12 months.

[0166] The subject was given: (1) cetuximab at a maximum infusion rate of 10 mg / min at a dose of 400 mg / m³. 2 Infusion over 120 minutes for one week, followed by weekly administration of 250 mg / m². 2 (2) Cobimetinib, 20-60 mg orally daily; and (3) Palbociclib, 75-125 mg orally daily. Vital signs, clinical laboratory measurements, resting ECG measurements, adverse events, and serious adverse events were monitored and assessed. Overall response rate, disease control rate, overall survival, duration of response, and quality of life were also monitored and assessed. Study parameters are summarized in Table 10. Table 10 This disclosure relates to the following implementation plan. 1. A composition comprising: (a) Epidermal growth factor receptor (EGFR) inhibitors; (b) Inhibitors of mitogen-activated protein kinase (MEK) 1 / 2; and (c) Cyclin-dependent kinase (CDK) 4 / 6 inhibitors; The composition described herein does not contain BRAF inhibitors. 2. The composition according to claim 1, wherein the EGFR inhibitor is osimertinib or a salt thereof, wherein the MEK1 / 2 inhibitor is cobimetinib, trametinib, TAK-733 or a salt thereof, and wherein the CDK4 / 6 inhibitor is palbociclib or a salt thereof. 3. A composition comprising (a) osimertinib or a salt thereof, (b) cobimetinib, trametinib, TAK-733 or a salt thereof, and (c) palbociclib or a salt thereof. 4. The composition according to any one of items 1-3, further comprising a pharmaceutically acceptable carrier, excipient, binder or diluent. 5. The composition according to any one of items 1-4, wherein the composition is formulated for oral administration to a subject. 6. A method of treating cancer or delaying its progression in a subject, the method comprising administering to the subject an effective amount of (a) an epidermal growth factor receptor (EGFR) inhibitor; (b) Inhibitors of mitogen-activated protein kinase (MEK) 1 / 2; and (c) Cyclin-dependent kinase (CDK) 4 / 6 inhibitors; The subjects mentioned above have cancer or are at risk of developing cancer with BRAF mutations. 7. The method according to item 6, wherein the subject is not given a BRAF inhibitor. 8. The method according to claim 6 or 7, wherein the EGFR inhibitor is osimertinib or a salt thereof or cetuximab, wherein the MEK 1 / 2 inhibitor is cobimetinib, trametinib, TAK-733 or a salt thereof, and wherein the CDK4 / 6 inhibitor is palbociclib or a salt thereof. 9. The method according to any one of claims 6-8, wherein the method comprises administering effective amounts of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. 10. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof. 11. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of osimertinib or a salt thereof, trametinib or a salt thereof, and palbociclib or a salt thereof. 12. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of cetuximab, cobimetinib or a salt thereof and palbociclib or a salt thereof. 13. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of cetuximab, TAK-733 or a salt thereof, and palbociclib or a salt thereof. 14. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of cetuximab, trametinib or a salt thereof and palbociclib or a salt thereof. 15. The method according to claim 9, wherein osimertinib or a salt thereof, cobimetinib or a salt thereof and palbociclib or a salt thereof are administered in a composition. 16. The method according to claim 9, wherein the subject is simultaneously given osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. 17. The method of claim 9, wherein the subject is intermittently administered osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof. 18. The method of claim 12, wherein cetuximab, cobimetinib or a salt thereof and palbociclib or a salt thereof are administered in two or more compositions. 19. The method of claim 12, wherein the subject is intermittently administered cetuximab, cobimetinib or a salt thereof, and palbociclib or a salt thereof. 20. The method according to claim 12, wherein cobimetinib or a salt thereof and palbociclib or a salt thereof are administered in a composition. 21. The method according to item 12, wherein cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated for oral administration. 22. The method according to claim 12, wherein the subject is simultaneously given cobimetinib or a salt thereof and palbociclib or a salt thereof. 23. The method according to any one of items 6-22, wherein the cancer has a BRAF V600 mutation or a BRAFD581V mutation. 24. The method according to item 23, wherein the BRAF V600 mutation is V600E, V600D, or V600K. 25. The method according to any one of items 6-24, wherein the cancer is a malignant epithelial tumor or carcinoma. 26. The method according to claim 25, wherein the cancer is selected from one or more of the following: adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, and small cell carcinoma. 27. The method according to claim 25 or 26, wherein the cancer is selected from one or more of the following: epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell carcinomas, adenocarcinomas, adnexal or skin adnexal tumors, mucoepidermoid tumors, cystic, mucinous or serous tumors, ductal, lobular or medullary tumors, acinar cell tumors, and complicated epithelial tumors. 28. The method according to any one of items 6-27, wherein the cancer is selected from one or more of the following: colon cancer, stomach cancer, lung cancer, breast cancer, pancreatic cancer, oral cancer, prostate cancer, reproductive system cancer, rectal cancer, liver cancer, kidney cancer, papillary thyroid cancer, and ovarian cancer. 29. The method according to any one of items 6-28, wherein the cancer is colorectal cancer. 30. The method according to item 29, wherein the cancer is stage IV colorectal cancer. 31. The method according to claim 30, wherein the colorectal cancer has a BRAF V600E or D581V mutation. 32. The method according to any one of items 7-31, wherein the reduction in cancer cell growth and / or the increase in cancer cell killing by the method is about 20-99% greater than that achieved by administering (a) the EGFR inhibitor, (b) the MEK 1 / 2 inhibitor, or (c) the CDK 4 / 6 inhibitor alone. 33. The method according to any one of items 6-32, wherein the method reduces the average tumor volume by about 20-95%. 34. The method according to item 9, wherein osimertinib or a salt thereof is administered to the subject at a daily dose of about 40-80 mg. 35. The method according to item 9, wherein the subject is given cobimetinib or a salt thereof at a daily dose of about 20-60 mg. 36. The method according to item 9, wherein the subject is given palbociclib or a salt thereof at a daily dose of about 75-125 mg. 37. The method according to claim 12, wherein cetuximab is administered to the subject in the manner described above: approximately 400 mg / m² is infused over 120 minutes at a maximum infusion rate of 10 mg / min. 2 The weekly dose was followed by an infusion of 250 mg / m² over 60 minutes at a maximum infusion rate of 10 mg / min. 2 The weekly dose. 38. The method according to any one of items 6-37, wherein the subject is a human being. 39. The method according to any one of items 6-38, wherein the method reduces the tumor volume by at least about 85%. 40. A kit comprising: (a) Epidermal growth factor receptor (EGFR) inhibitors; (b) Inhibitors of mitogen-activated protein kinase (MEK) 1 / 2; and (c) Cyclin-dependent kinase (CDK) 4 / 6 inhibitors; The kit does not contain BRAF inhibitors. 41. The kit according to claim 40, wherein the EGFR inhibitor is osimertinib or a salt thereof or cetuximab, wherein the MEK 1 / 2 inhibitor is cobimetinib, trametinib, TAK-733 or a salt thereof, and wherein the CDK4 / 6 inhibitor is palbociclib or a salt thereof. 42. A kit comprising (a) osimertinib or a salt thereof or cetuximab, (2) cobimetinib, trametinib, TAK-733 or a salt thereof, and (3) palbociclib or a salt thereof. 43. The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising osimertinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent. 44. The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising cobimetinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent. 45. The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising palbociclib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent. 46. ​​The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising trametinib or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent. 47. The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising TAK-733 or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent. 48. The kit according to claim 41 or 42, wherein the kit comprises a pharmaceutical composition comprising cetuximab and a pharmaceutically acceptable carrier, excipient, binder or diluent. 49. The kit according to item 41 or 42, wherein osimertinib or a salt thereof is formulated for oral administration to a subject. 50. The kit according to item 41 or 42, wherein cobimetinib or a salt thereof is formulated for oral administration to a subject. 51. The kit according to item 41 or item 42, wherein palbociclib or a salt thereof is formulated for oral administration to a subject. 52. The kit according to item 41 or 42, wherein trametinib or a salt thereof is formulated for oral administration to a subject. 53. The kit according to item 41 or item 42, wherein TAK-733 or a salt thereof is formulated for oral administration to a subject. 54. The kit according to claim 41 or 42, wherein the kit comprises osimertinib or a salt thereof, cobimetinib or a salt thereof and palbociclib or a salt thereof. 55. The kit according to claim 54, wherein osimertinib or a salt thereof, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated in a composition. 56. The kit according to claim 54, wherein osimertinib or a salt thereof, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated for simultaneous administration to a subject. 57. The kit according to claim 54, wherein osimertinib or a salt thereof, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated for intermittent administration to a subject. 58. The kit according to claim 41 or 42, wherein the kit comprises cetuximab, cobimetinib or a salt thereof and palbociclib or a salt thereof. 59. The kit according to item 58, wherein cetuximab is formulated for intravenous administration to a subject. 60. The kit according to claim 58, wherein cetuximab, cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated in two or more compositions. 61. The kit according to item 58, wherein cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated for oral administration. 62. The kit according to claim 58, wherein cobimetinib or a salt thereof and palbociclib or a salt thereof are administered in a composition. 63. The kit according to item 58, wherein cobimetinib or a salt thereof and palbociclib or a salt thereof are formulated for oral administration. 64. The kit according to claim 58, wherein the subject is simultaneously administered cobimetinib or a salt thereof and palbociclib or a salt thereof.

Claims

1. A composition comprising: (a) Epidermal growth factor receptor (EGFR) inhibitors; (b) Inhibitors of mitogen-activated protein kinase (MEK) 1 / 2; and (c) Cyclin-dependent kinase (CDK) 4 / 6 inhibitors; The composition described herein does not contain BRAF inhibitors.

2. The composition of claim 1, wherein the EGFR inhibitor is osimertinib or a salt thereof, wherein the MEK 1 / 2 inhibitor is cobimetinib, trametinib, TAK-733 or a salt thereof, and wherein the CDK 4 / 6 inhibitor is palbociclib or a salt thereof.

3. A composition comprising (a) osimertinib or a salt thereof, (b) cobimetinib, trametinib, TAK-733 or a salt thereof, and (c) palbociclib or a salt thereof.

4. The composition according to any one of claims 1-3, further comprising a pharmaceutically acceptable carrier, excipient, binder, or diluent.

5. The composition according to any one of claims 1-4, wherein the composition is formulated for oral administration to a subject.

6. A method for treating cancer or delaying its progression in a subject, the method comprising administering to the subject an effective amount of (a) Epidermal growth factor receptor (EGFR) inhibitors; (b) Inhibitors of mitogen-activated protein kinase (MEK) 1 / 2; and (c) Cyclin-dependent kinase (CDK) 4 / 6 inhibitors; The subjects mentioned above have cancer or are at risk of developing cancer with BRAF mutations.

7. The method of claim 6, wherein the subject is not given a BRAF inhibitor.

8. The method according to claim 6 or claim 7, wherein the EGFR inhibitor is osimertinib or a salt thereof or cetuximab, wherein the MEK 1 / 2 inhibitor is cobimetinib, trametinib, TAK-733 or a salt thereof, and wherein the CDK 4 / 6 inhibitor is palbociclib or a salt thereof.

9. The method according to any one of claims 6-8, wherein the method comprises administering an effective amount of osimertinib or a salt thereof, cobimetinib or a salt thereof, and palbociclib or a salt thereof.

10. The method according to any one of claims 6-8, wherein the method comprises administering to the subject an effective amount of osimertinib or a salt thereof, TAK-733 or a salt thereof, and palbociclib or a salt thereof.

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