Method of treatment of double WT melanoma

Abstract

Disclosed herein is a method of treating melanoma in a subject, the method comprising administering (a) naporafenib and (b) a MEK inhibitor such as trametinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF genotype.

Description

WSGRRef: 59457-793.601METHOD OF TREATMENT OF DOUBLE WT MELANOMACROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 761,528 filed February 21, 2025, which is hereby incorporated by reference in their entirety.BACKGROUND

[0002] The RAS / RAF / MEK / ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulationof this pathway underlies many instances of tumorigenesis. This pathway is activated by extracellular signals that in turn induces the small G protein RAS to exchange GDP for GTP. The activated RAS small guanidine triphosphatase (GTPase) promotes the activation of the RAF (also referred to as Raf herein) family proteins (ARAF, BRAF and CRAF, also known as RAFI). Activated RAF proteins lead to the phosphorylation and activation of MEK1 / 2 proteins, which subsequently phosphorylate and activate extracellular signal regulated kinases (ERKs). ERK1 / 2 proteins phosphorylate a variety of substrates, including multiple transcription factors, and regulate key cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis.SUMMARY

[0003] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype. In some embodiments, the MEK inhibitor is AS-701173, AS-701255, binimetinib, cobimetinib, PD0325901,PD184352, pimasertib, R04987655,RDEA436,refametinib, RG7167, RG7420, selumetinib, ortrametinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is trametinib or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the melanoma is cutaneous melanoma. In some embodiments, the melanoma has progressed following standard of care. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is notin the form of a salt. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments,WSGRRef: 59457-793.601naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amountof 0.5 mg daily. In some embodiments, trametinib is administered in an amountof 1 mg daily. In some embodiments, trametinib is administered once daily (QD). In some embodiments, the cell has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the cell has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype.

[0004] Also disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) trametinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma. In some embodiments, the melanoma has progressed following standard of care. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is not in the form of a salt. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily . In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD). In some embodiments, the cell has: 1) a wildtype NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the cell has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype.DETAILED DESCRIPTION

[0005] Although disruption of the MAPK pathway is a frequent fundamental finding in many tumors, targeting the RAS / RAF / MEK / ERK nodes of this pathway has been difficult for a variety of reasons ranging from protein structures resistant to drug targeting (e.g., RAS) to the rapid generation of resistance mechanisms. For example, inhibition of BRAF V600E / K mutant melanoma tumors with monomeric-selective BRAF inhibitors (e.g., dabrafenib, vemurafenib, encorafenib) quickly leads to the generation of RAF inhibitor-resistant RAFWSGRRef: 59457-793.601dimers resulting in adaptive resistance. One strategy to address the rapid onset of resistance is to target multiple nodes of the RAS / MAPK pathway with combination therapy. This approach has been successful in BRAF V600E / K mutant melanoma and BRAF V600E mutant NSCLC where the combination of a monomeric-selective BRAF inhibitor administered with a MEK inhibitor led to improved clinical activity compared to each class of drugs administered as monotherapy (Tafinlar®).

[0006] An additional strategy to combat the rapid onset of resistance is naporafenib, which inhibits dimeric versions of wild type BRAF, CRAF, and BRAF V600E / K mutant enzymes and is predicted to abrogate the onset of drug-resistant dimers, paired with a MEK inhibitor like trametinib, which inhibits a downstream node of the RAS / MAPK pathway, which is predicted to enhance clinical activity by delaying the onset of resistance.Naporafenib

[0007] Naporafenib is an adenosine triphosphate (ATP)-competitive inhibitor of the CRAF and BRAF protein kinases. In vitro data indicate that naporafenib inhibits wild -type BRAF (>99% inhibition), mutant BRAF V600E (>99%), and wild-type CRAF (99%) at similar, sub-nanomolar potencies. Naporafenib is also highly selective with only 5 out of 456 kinases tested showing greater than or equal to 99% of inhibition by naporafenib at 1 pM concentration compared to control.

[0008] Naporafenib has the following structure:. In some embodiments, naporafenib is not a salt.

[0009] In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily . In some embodiments, naporafenib is administered twice daily (BID).MEK Inhibitor

[0010] MEK inhibitors are chemicals or drugs that inhibit the mitogen -activated protein kinase enzymes MEK1 and / or MEK2. They can be used to affect the MAPK / ERK pathway which is overactive in some cancers. In some embodiments, the MEK inhibitor is AS-WSGRRef: 59457-793.601701173, AS-701255, binimetinib, cobimetinib, PD0325901, PD184352, pimasertib, R04987655, RDEA436, refametinib, RG7167, RG7420, selumetinib, or trametinib , or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is trametinib or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the MEK inhibitor is AS-701173, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is AS-701255, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is binimetinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is cobimetinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is PD0325901, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is PD184352, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is pimasertib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is R04987655, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is RDEA436, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is refametinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is RG7167, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is RG7420, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is selumetinib, or a pharmaceutically acceptable salt or solvate thereof.Trametinib

[0011] Trametinib is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 and is approved for use as a single agent for the treatment of BRAF -inhibitor treatment-naive adult patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is also approved for use, in combination with dabrafenib, for the treatment of adult patients with unresectable or metastatic melanoma, metastatic nonsmall cell lung cancer (NSCLC), locally advanced or metastatic anaplastic thyroid cancer, and unresectable or metastatic solid tumors with BRAF V600E or V600K mutations.WSGRRef: 59457-793.601Trametinib has the following structure:. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate.

[0012] In some embodiments, trametinib is administered in an amount of between 0.5 mg and 1 mg daily. In some embodiments, trametinib is administered in an amount of 0.5 mg daily. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, trametinib is administered once daily (QD).Methods of Treatment

[0013] Disclosed herein is a method of treating a double wild-type (WT) melanoma (e.g., cutaneous melanoma) in a subject; the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor. In some embodiments, “double WT” refers to subjects with cancers (e.g., cutaneous melanoma) that include a cell having wild-type (WT) BRAF or wild-type (WT) BRAF V600 and wild-type (WT) NRAS.

[0014] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0015] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0016] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.WSGRRef: 59457-793.601

[0017] In some embodiments, the MEK inhibitor is AS-701173, AS-701255, binimetinib, cobimetinib, PD0325901, PD184352, pimasertib, R04987655, RDEA436, refametinib, RG7167, RG7420, selumetinib, or trametinib, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the MEK inhibitor is trametinib or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, trametinib is in the form of a dimethyl sulfoxide solvate. In some embodiments, naporafenib is notin the form of a salt.

[0018] In some embodiments, the melanoma has progressed following standard of care. Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) trametinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0019] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) trametinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0020] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) trametinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0021] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) AS-701173, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0022] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) AS-701173, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0023] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) AS-701173, wherein the melanoma comprises a cell that has: 1) a wild -type NRASWSGRRef: 59457-793.601genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0024] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) AS-701255, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0025] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) AS-701255, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0026] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) AS-701255, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0027] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) binimetinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0028] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) binimetinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0029] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) binimetinib, wherein the melanoma comprises a cell that has: 1) a wild -type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0030] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) cobimetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.WSGRRef: 59457-793.601

[0031] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) cobimetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0032] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) cobimetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0033] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) PD184352, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0034] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) PD184352, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0035] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) PD184352, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0036] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) pimasertib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0037] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) pimasertib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.WSGRRef: 59457-793.601

[0038] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) pimasertib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0039] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) R04987655, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0040] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) R04987655, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0041] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) R04987655, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0042] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) RDEA436, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0043] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RDEA436, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0044] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RDEA436, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.WSGRRef: 59457-793.601

[0045] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) RG7167, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0046] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RG7167, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0047] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RG7167, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0048] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) RG7420, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0049] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RG7420, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0050] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) RG7420, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0051] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) selumetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

[0052] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenibWSGRRef: 59457-793.601and (b) selumetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype. In some embodiments, the melanoma is cutaneous melanoma.

[0053] Disclosed herein is a method of treating melanoma in a subject, the method comprising administering to the subject a therapeutic treatment comprising (a) naporafenib and (b) selumetinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype. In some embodiments, the melanoma is cutaneous melanoma.Subject

[0001] In some embodiments, the subject is a human.

[0054] In some embodiments, the subject has a disease or condition associated with the RAS / MAPK pathway. In some embodiments, the subject is a cancer patient. In some embodiments, the subject is a melanoma patient. In some embodiments, the melanoma is advanced melanoma or metastatic melanoma. In some embodiments, the melanoma is advanced melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the melanoma has progressed after treatment with standard therapy. In some embodiments, the patient is intolerant to standard therapy. In some embodiments, the patient decline standard therapy. In some embodiments, the subject is a cutaneous melanoma patient. In some embodiments, the cutaneous melanoma is unresectable cutaneous melanoma. In some embodiments, the subject is a double WT melanoma patient. In some embodiments, the subject is a melanoma patient, wherein the melanoma is characterized by having a BRAF V600 WT genotype and a NRAS WT genotype. In some embodiments, the patient has a documentation of a BRAF V600 WT and NRAS WT melanoma in tumor tissue prior to the first dose of the treatment. In some embodiments, the patient has a documentation of an anomaly in BRAF which his not a BRAF V600 point mutation. In some embodiments, the patient has at least 1 measurable lesion according to RECIST vl.l. In some embodiments, the patient has a ECOG performance status 0, 1 or 2. In some embodiments, the patient has a ECOG performance status 0. In some embodiments, the patient has a ECOG performance status 1. In some embodiments, the patient has a ECOG performance status 2.

[0055] In some embodiments, the subject is a previously untreated subject. In some embodiments, the subject is a previously treated subject. In some embodiments, the subject is a previously treated subject, wherein the prior therapy is not an ERK inhibitor, a MEK inhibitor, a RAF inhibitor, a RAS inhibitor, or any combination thereof. In someWSGRRef: 59457-793.601embodiments, the subject has not been previously treated with an ERK inhibitor, a MEK inhibitor, a RAF inhibitor, a RAS inhibitor, or any combination thereof.

[0056] In some embodiments, the subject does not have an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the treatment. In some embodiments, the impairment of gastrointestinal (GI) function or GI disease comprises ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or any combination thereof.

[0057] In some embodiments, the subject does not have a history or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. In some embodiments, the risk factors for RVO comprises uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, hypercoagulability syndrome, or any combination thereof.

[0058] In some embodiments, the subject does not have a corrected QT interval >450 ms using Fridericia’s formula (QTcF) at Screening based on triplicate average, wherein the subject does not have a right or left bundle branch block.

[0059] In some embodiments, the subject has a Left Ventricular Ejection Fraction (LVEF) lower than 50%.

[0060] In some embodiments, the subject does not have a primary CNS tumor. In some embodiments, the subject has a controlled CNS metastases. In some embodiments, the subject does not have a symptomatic CNS metastases that are neurologically unstable.

[0061] In some embodiments, the patient is not receiving treatment with medications that are known to be strong inhibitors and / or inducers of cytochrome P450. In some embodiments, the patient is not receiving treatment with medications that are known to be strong inhibitors and / or inducers of cytochrome CYP3 A. In some embodiments, the patient is not receiving treatment with medications that are known to be substrates of CYP2C8, CYP2C9, and CYP3 A with a narrow therapeutic index and sensitive substrates of CYP3 A. In some embodiments, the patient is not receiving treatment with medications that are known to be substrates of CYP2C8, CYP2C9, or CYP3A. In some embodiments, the patient is not receiving treatment with medications that are known to be sensitive substrates of CYP3 A.Dosing

[0062] In some embodiments, naporafenib is administered orally to the patient. In some embodiments, naporafenib is administered to the patient on a continuous dosing schedule. In some embodiments, naporafenib is administered to the human on a continuous daily dosing schedule. In some embodiments, naporafenib is administered in an amount of between 100 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount ofWSGRRef: 59457-793.601between 100 mg and 300 mg daily. In some embodiments, naporafenib is administered in an amount of between 100 mg and 200 mg daily. In some embodiments, naporafenib is administered in an amount of between 200 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of between 300 mg and 400 mg daily. In some embodiments, naporafenib is administered in an amount of 100 mg daily. In some embodiments, naporafenib is administered in an amount of 200 mg daily. In some embodiments, naporafenib is administered in an amount of 300 mg daily. In some embodiments, naporafenib is administered in an amount of 400 mg daily. In some embodiments, naporafenib is administered twice daily (BID). In some embodiments, naporafenib is administered in an amount of 200 mg twice daily (BID).

[0063] In some embodiments, trametinib is administered orally to the patient. In some embodiments, trametinib is administered to the patient on a continuous dosing schedule. In some embodiments, trametinib is administered to the human on a continuous daily dosing schedule. In some embodiments, trametinib is administered in an amount of 1 mg daily. In some embodiments, naporafenib is administered once daily (QD). In some embodiments, trametinib is administered in an amount of 1 mg once daily (QD).Definitions

[0064] As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and / or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms, suitably of one or more discernible symptoms, of the disorder resulting from the administration of one or more therapies. In specific embodiments, the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat,” “treatment” and “treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat,” “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.

[0065] Within the meaning of the present disclosure, the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease. The term “protect” is used herein to mean prevent, delay, or treat, or all, as appropriate, development, continuance, or aggravation of a disease in a subject, e.g., a mammal or human.WSGRRef: 59457-793.601

[0066] The term “subject” or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non -human animals. In some embodiments, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a proliferative disease, such as cancer.

[0067] As used herein, the term “cancer” refers to a disease characterized by the undesired and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. The term “cancer” is used herein to mean a broad spectrum of tumors, including all solid and hematological malignancies. In some embodiments, the cancer is melanoma.EXAMPLE

[0068] This study is an open-label study to assess the safety and efficacy of naporafenib administered with trametinib in previously treated patients with “double WT” cutaneous melanoma. Documentation of a BRAF V600 WT / and NRAS WT melanoma in tumor tissue prior to the first dose of study treatment is required.Arms and Interventions> ><Outcome MeasuresPrimary Outcome Measure:

[0069] To evaluate the efficacy of naporafenib administered with trametinib in patients with v-raf murine sarcoma viral oncogene Homolog Bl (BRAF) V600 wild type (WT) / neuroblastoma rat sarcoma (NRAS) WT cutaneous melanoma.

[0070] Based on assessment of Objective response rate (ORR) per RECIST version 1.1 [Time Frame: Assessed up to 24 months from time of first dose].Secondary Outcome Measure:Adverse EventsWSGRRef: 59457-793.601

[0071] Incidence and severity of treatment-emergent AEs and serious AEs [Time Frame: Assessed up to 24 months from time of first dose].Duration of Response (DOR)

[0072] Based on assessment of radiographic imaging per RECIST version 1.1 [Time Frame: Assessed up to 24 months from time of first dose]Time to Response (TTR).

[0073] Based on assessment of radiographic imaging per RECIST version 1.1 [Time Frame: Assessed up to 24 months from time of first dose]Progression Free Survival (PFS).

[0074] Based on assessment of radiographic imaging per RECIST version 1.1 [Time Frame: Assessed up to 24 months from time of first dose]Disease Control Rate (DCR).

[0075] Based on assessment of radiographic imaging per RECIST version 1.1 [Time Frame: Assessed up to 24 months from time of first dose].Plasma concentration (Cmax)

[0076] Maximum plasma concentration of naporafenib and trametinib [Time Frame: Study Day 1 up to Day 29],Time to achieve Cmax (Tmax)

[0077] Time to achieve maximum plasma concentration of naporafenib and trametinib [Time Frame: Study Day 1 up to Day 29],Area under the curve (AUC)

[0078] Area under the plasma concentration-time curve [Time Frame: Study Day 1 up to Day 29],Overall survival

[0079] Survival Status [Time Frame: Assessed up to 24 months from time of first dose].Other Pre-specified Outcome Measures:Duration of Response (DOR) for CNS disease in participants

[0080] Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) [Time Frame: Assessed up to 24 months from time of first dose]Overall Response Rate (ORR) for CNS disease in participants.

[0081] Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) [Time Frame: Assessed up to 24 months from time of first dose]Disease Control Rate (DCR) for CNS disease in participants.

[0082] Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM)WSGRRef: 59457-793.601[Time Frame: Assessed up to 24 months from time of first dose]Pharmacodynamic assessment.

[0083] DUSP6: changes from baseline in the expression of DUSP-6 mRNA in blood, a marker of MAPK pathway Inhibition. [Time Frame: Assessed up to 24 months from time of first dose].EligibilityKey Inclusion Criteria:

[0084] A locally advanced or metastatic tumor who has progressed on or for which no standard therapy exists. Patients who are intolerant to standard therapy or who are not a candidate for standard therapy (in the opinion of the Investigator) or who decline standard therapy are also eligible.

[0085] Documentation of BRAF V600 WT and NRAS WT prior to first dose of study treatment as determined locally with an analytically validated assay in a certified testing laboratory. Patients with other abnormalities of BRAF (i.e., genetic alterations that are not point mutations ofV600) are eligible.

[0086] Archival tumor tissue collected within 5 years prior to enrollment must be confirmed to be available at the time of Screening, which may be submitted before or after enrollment for exploratory biomarker analysis.

[0087] ECOG performance status 0, 1 or 2.

[0088] Presence of at least 1 measurable lesion according to RECIST vl .1.

[0089] Able to swallow oral medication.Exclusion Criteria:

[0090] Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor.

[0091] Impairment of GI function or gastrointestinal (GI) disease that may significantly alter the absorption of study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).

[0092] History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome).Corrected QT interval using Fridericia’s formula (QTcF) at Screening >450 ms based on triplicate average NOTE: criterion does not apply to patients with a right or left bundle branch block.

[0093] Left Ventricular Ejection Fraction lower than 50% (LVEF <50%).WSGRRef: 59457-793.601

[0094] All primary CNS tumors.

[0095] Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.

[0096] Patients receiving treatment with medications that are known to be strong inhibitors and / or inducers of cytochrome P450 (CYP)3 A; substrates of CYP2C8, CYP2C9, and CYP3A with a narrow therapeutic index and sensitive substrates of CYP3A.

[0097] Patients that are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial.

Claims

WSGRRef: 59457-793.601CLAIMSWhat is claimed is:

1. A method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) a MEK inhibitor, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF or a wild-type BRAF V600 genotype.

2. The method of claim 1, wherein the MEK inhibitor is AS-701173, AS-701255, binimetinib, cobimetinib, PD0325901, PD184352, pimasertib, R04987655, RDEA436, refametinib, RG7167, RG7420, selumetinib, or trametinib, or a pharmaceutically acceptable salt or solvate thereof.

3. The method of claim 1, wherein the MEK inhibitor is trametinib or a pharmaceutically acceptable salt or solvate thereof.

4. A method of treating melanoma in a subject, the method comprising administering to the subject, a therapeutic treatment comprising (a) naporafenib and (b) trametinib, wherein the melanoma comprises a cell that has: 1) a wild-type NRAS genotype and 2) a wildtype BRAF or a wild-type BRAF V600 genotype.

5. The method of any one of claims 1-4, wherein the melanoma is cutaneous melanoma.

6. The method of any one of claims 1-5, wherein trametinib is in the form of a dimethyl sulfoxide solvate.

7. The method of any one of claims 1-6, wherein naporafenib is not in the form of a salt.

8. The method of any one of claims 1-7, wherein the melanoma has progressed following standard of care.

9. The method of any one of claims 1-8, wherein naporafenib is administered in an amount of between 100 mg and 400 mg daily.

10. The method of any one of claims 1-8, wherein naporafenib is administered in an amount of 100 mg daily.

11. The method of any one of claims 1-8, wherein naporafenib is administered in an amount of 400 mg daily.

12. The method of any one of claims 9-11, wherein naporafenib is administered twice daily (BID).

13. The method of any one of claims 1-12, wherein trametinib is administered in an amount of between 0.5 mg and 1 mg daily.WSGRRef: 59457-793.60114. The method of any one of claims 1-12, wherein trametinib is administered in an amount of 0.5 mg daily.

15. The method of any one of claims 1-12, wherein trametinib is administered in an amount of 1 mg daily.

16. The method of any one of claims 13-15, wherein trametinib is administered once daily (QD).

17. The method of any one of claims 1-16, wherein the cell has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF genotype.

18. The method of any one of claims 1-16, wherein the cell has: 1) a wild-type NRAS genotype and 2) a wild-type BRAF V600 genotype.

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