Synergistic combinations comprising lunbotinib for Anti-cancer therapy

Abstract

The present invention relates to combinations of Compound 1, or a derivative thereof, with chemotherapy. Such combinations are useful as a medicament or in methods of treatment, particularly in the treatment of cancer. It has been demonstrated herein that Compound 1 or a derivative thereof together with chemotherapy provides a synergistic therapeutic effect.

Description

[0001] SYNERGISTIC COMBINATIONS COMPRISING LUNBOTINIB FOR ANTI-CANCER THERAPY

[0002] Field of the Invention

[0003] The present invention relates to combinations of Compound 1 , or a derivative thereof, with chemotherapy. Such combinations are useful as a medicament or in methods of treatment, particularly in the treatment of cancer. It has been demonstrated herein that Compound 1 or a derivative thereof together with chemotherapy provides a synergistic therapeutic effect.

[0004] Background

[0005] Malignant tumours are a major public health issue and pose a serious threat to human life and well-being. In the USA, the lifetime risk of being diagnosed with invasive cancer is around 40%, and cancer is the second leading cause of death after heart disease (CA Cancer J Clin 2022;72:7-33). The most common cancer types are prostate, lung, and colorectal cancers in men, and breast, lung, and colorectal cancers in women (CA Cancer J Clin 2022;72:7-33). In 2018, a total of 1 ,708,921 new cancer cases and 599,265 cancer-related deaths were reported in the USA (Centers for Disease Control and Prevention. United States Cancer Statistics: Highlights from 2018 Incidence. USCS Data Brief, no. 23. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2021 .). For 2024, 2,001 ,140 new cancer cases are projected to occur in the USA (CA Cancer J Clin. 2024;74:12-49). Although the cancer-related death rate in the USA has declined over the past 40 years (CA Cancer J Clin 2022;72:7-33), an estimated 611 ,720 cancer deaths are expected in 2024, corresponding to about 1680 deaths per day (CA Cancer J Clin. 2024;74:12-49). In the USA, lung cancer has been the leading cause of cancer-related death in men and women (20% and 21% of cancer deaths in men and women, respectively), followed by breast cancer in women (15%) and prostate cancer in men (11 %) (CA Cancer J Clin. 2024;74:12-49). In Europe in 2020, 4,471 ,422 new cancer cases occurred and 1 ,986,093 people died of cancer, the leading causes of cancer-related death being prostate, lung, and colorectal cancers in men, and breast, colorectal, and lung cancers in women (Globocan, 2022). The estimated number of cancer deaths in the EU in 2024 is 1 ,270,800 (Annals of Oncology Volume 35, Issue 3, March 2024, Pages 308-316).

[0006] Cancer is commonly treated with chemotherapy, which involves the use of cytotoxic drugs that disrupt the way cells grow and divide in order to destroy cancer cells. However, because chemotherapy operates in a non-specific manner, it can be highly toxic to normal cells. Other cancer treatments also exist. For instance, molecularly targeted anti-cancer drugs have been developed based on growing understanding of the role of proto-oncogene alterations in cancer pathophysiology. Targeted therapies may precisely identify and attack cancer cells, usually by interfering with specific molecules involved in tumour growth and progression. These therapies are designed to target cancer cells while minimizing damage to normal cells. Another approach is immunotherapy, which leverages the body’s immune system to fight cancer. However, the effectiveness of these therapies, especially in the face of resistant or refractory disease, remains a challenge.

[0007] Indeed, despite the availability of many options for the treatment of cancer, there are still many patients who experience little to no response to treatment, or who relapse after successful treatment to a more advanced stage of cancer, leading to millions of deaths each year. Therefore, it is necessary to explore new treatment modalities that can improve safety and efficacy of cancer treatment, and help to overcome failures of earlier therapies. Summary of the Invention

[0008] A first aspect of the invention provides Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof for use as a medicament, wherein the Compound 1 or the derivative thereof is for use in combination with chemotherapy.

[0009] A second aspect of the invention provides chemotherapy for use as a medicament, wherein the chemotherapy is for use in combination with Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof.

[0010] A third aspect of the invention provides a combination for use as a medicament, the combination comprising:

[0011] (i) Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and

[0012] (ii) chemotherapy.

[0013] In these aspects, the Compound 1 or the derivative thereof, and the chemotherapy may be administered simultaneously, separately, or sequentially.

[0014] In these aspects, the Compound 1 or the derivative thereof, the chemotherapy, or the combination may be for use in the treatment of a disease or condition associated with RET activity, for example a RET-altered cancer, such as a RET mutation-positive or a RET fusion-positive cancer.

[0015] A fourth aspect of the invention provides a combination comprising:

[0016] (i) Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and

[0017] (ii) chemotherapy. This combination may be provided as a combined preparation for simultaneous, separate, or sequential use as a medicament.

[0018] In the aspects of the invention, the chemotherapy preferably comprises an agent which disrupts the cell cycle. Alternatively or in addition, the chemotherapy may induce apoptosis. For instance, the chemotherapy may comprise or consist of a platinum agent, an antifolate, and / or a taxane. Preferably, the Compound 1 or the derivative thereof and the chemotherapy together provide a synergistic therapeutic effect (e.g. a synergistic antiproliferative effect on cancer cells).

[0019] Description of the Drawings

[0020] FIG 1 : In vivo efficacy test results of Compound 1 and control compound pralsetinib (BLU-667) in a subcutaneous xenograft model of medullary thyroid carcinoma TT cell line.

[0021] FIG 2: In vivo efficacy test results of Compound 1 and control compounds pralsetinib (BLU-667) and selpercatinib (LOXO-292) in a subcutaneous xenograft model.

[0022] FIG 3a to 3f: Graphs showing viability of TPC1 cells treated for 5 days with carboplatin, cisplatin, pemetrexed, docetaxel, paclitaxel, or Compound 1 , respectively.

[0023] FIG 4: Plate images showing colonies of TPC1 cells treated with Compound 1 and carboplatin at the indicated concentrations for 7 days.

[0024] FIG 5a to 5d: Graphs showing cell viability (FIG 5a and FIG 5b (log scale)), Bliss score (FIG 5c), and Synergy score (FIG 5d) of TPCI cells treated with a combination of carboplatin and Compound 1 for 7 days.

[0025] FIG 6: Graph showing viability of TPCI cells treated with a combination of carboplatin and Compound 1 at the indicated concentrations for 7 days.

[0026] FIG 7: Plate images showing colonies of TPCI cells treated with Compound 1 and cisplatin at the indicated concentrations for 7 days.

[0027] FIG 8a to 8d: Graphs showing cell viability (FIG 8a and FIG 8b (log scale)), Bliss score (FIG 8c), and Synergy score (FIG 8d) of TPCI cells treated with a combination of cisplatin and Compound 1 for 7 days.

[0028] FIG 9: Graph showing cell viability of TPCI cells treated with a combination of cisplatin and Compound 1 for 7 days at the indicated concentrations.

[0029] FIG 10: Plate images showing colonies of TPCI cells treated with Compound 1 and pemetrexed at the indicated concentrations for 7 days.

[0030] FIG 11 a to 11d: Graphs showing cell viability (FIG 11a and FIB 11 b (log scale)), Bliss score (FIG 11c), and Synergy score (FIG 11d) of TPCI cells treated with a combination of pemetrexed and Compound 1 for 7 days.

[0031] FIG 12: Graph showing cell viability of TPCI cells treated with a combination of pemetrexed and Compound 1 for 7 days at the indicated concentrations.

[0032] FIG 13: Plate images showing colonies of TPC1 cells treated with Compound 1 and paclitaxel at the indicated concentrations for 7 days.

[0033] FIG 14a to 14d: Graphs showing cell viability (FIG 14a and FIG 14b (log scale)), Bliss score (FIG 14c), and Synergy score (FIG 14d) of TPCI cells treated with a combination of paclitaxel and Compound 1 for 7 days.

[0034] FIG 15: Graph showing cell viability of TPCI cells treated with a combination of paclitaxel and Compound 1 for 7 days at the indicated concentrations.

[0035] FIG 16: Plate images showing colonies of TPCI cells treated with Compound 1 and docetaxel at the indicated concentrations for 7 days. FIG 17a to 17d: Graphs showing cell viability (FIG 17a and FIG 17b (log scale)), Bliss score (FIG 17c), and Synergy score (FIG 17d) of TPC1 cells treated with a combination of docetaxel and Compound 1 for 7 days.

[0036] FIG 18: Graph showing cell viability of TPC1 cells treated with a combination of docetaxel and Compound 1 for 7 days at the indicated concentrations.

[0037] FIG 19: Plate images showing colonies of LC2 cells treated with Compound 1 and pemetrexed at the indicated concentrations for 7 days.

[0038] FIG 20a to 20c: Graphs showing cell viability (FIG 20a and FIG 20b (log scale)) and Bliss score (FIG 20c) of LC2 cells treated with a combination of pemetrexed and Compound 1 for 7 days.

[0039] FIG 21 : Graph showing cell viability of LC2 cells treated with a combination of pemetrexed and Compound 1 for 7 days at the indicated concentrations.

[0040] FIG 22: Plate images showing colonies of LC2 cells treated with Compound 1 and paclitaxel at the indicated concentrations for 7 days.

[0041] FIG 23a to 23c: Graphs showing cell viability (FIG 23a and FIG 23b (log scale)) and Bliss score (FIG 23c) of LC2 cells treated with a combination of paclitaxel and Compound 1 for 7 days.

[0042] FIG 24: Graph showing cell viability and Bliss score of LC2 cells treated with Compound 1 , a combination of cisplatin and pemetrexed, and a combination of Compound 1 , cisplatin and pemetrexed for 5 days.

[0043] FIG 25a to 25c: CT scans of lung cancer tumours in patients treated with Compound 1 and standard of care (SoC) chemotherapy, showing a reduction in tumour volume in each patient.

[0044] FIG 26: CT scans of tumours in lung (lower left lobe), lymph node (paratracheal) and liver (S4B) in patient 3 treated with Compound 1 and SoC chemotherapy, showing a reduction in tumour volume at each location.

[0045] Detailed Description

[0046] Definitions

[0047] Unless otherwise defined in the context, all technical terms and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The reference to a technology used herein is intended to refer to a technology generally understood in the art, including those technological alterations or equivalent technological replacements that are obvious to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present disclosure.

[0048] The terms "including," "comprising," "having," or "containing," and additional variations thereof herein are inclusive or open-ended, and do not exclude additional unlisted elements or method steps, although additional unlisted elements or method steps do not necessarily exist. The terms "including," "comprising," "having," "containing," or "relating to" as used in relation to the aspects and embodiments herein may be replaced by "consisting essentially of (i.e. including the stated features as well as any other elements that do not materially affect the basic properties of the aspect or embodiment) and "consisting of (i.e. including only the stated features of the aspect or embodiment).

[0049] It should also be understood that any of the therapeutic agents of the present invention (i.e. the Compound 1 and / or the chemotherapy) may exist in free form for treatment, or, where appropriate, in the form of derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof. Pharmaceutically acceptable salts of the therapeutic agents of the invention include both acid addition salts and base addition salts, for example, sodium, potassium, calcium, magnesium, ammonium, diethylamine, / V-methyl-glucamine, diethanolamine, tromethamine (TRIS), amino acids (e.g. lysine, arginine), hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p- acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates, p-toluene sulfonate, hexafluorophosphate, and meglumine salt. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0050] As used herein, “eutecticum” refers to the fact that the active molecules of a drug and additional physiologically acceptable molecules of acids, bases, salts, and non-ionic compounds may be connected by hydrogen bonds, TT-TT stacking, van der Waals forces, and / or additional non-covalent bonds in the same crystal lattice, e.g. in the form of a solid dispersion. Such arrangements may result in, e.g. a solid dispersion, that melts and / or freezes at a single temperature that is lower than the melting and / or freezing points of the separate constituents.

[0051] As used herein, the term “polymorph” encompasses all possible crystalline forms, polymorphs, or amorphous forms of the compound of the present disclosure, which may be a single polymorph or a mixture of more than one polymorph at any ratio.

[0052] As used herein, the term "ester" means an ester derived from a therapeutic agent of the invention, which includes physiologically hydrolysable esters (hydrolysable under physiological conditions to free the therapeutic agent of the invention in the form of free acid or alcohol). Any therapeutic agent of the invention itself may also be an ester.

[0053] The therapeutic agents of the invention may exist in the form of solvate (preferably hydrate), where the therapeutic agent of the invention (including salts thereof) comprises a polar solvent as a structural element of the crystal lattice of said compound, especially, for example, water, methanol, or ethanol. The amount of a polar solvent, especially water, may be present at a stoichiometric or non- stoichiometric ratio.

[0054] Those skilled in the art will understand that, since available lone pairs of electrons are required to oxidize nitrogen to form oxides, not all nitrogen-containing heterocyclic rings can form / V-oxides. Those skilled in the art will recognize nitrogen-containing heterocyclic rings that can form / V-oxides. Those skilled in the art will also recognize that tertiary amines can form / V-oxides. The synthesis methods for the preparation of / V-oxides of heterocyclic rings and tertiary amines are well known to those skilled in the art, including but not limited to the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tertbutyl hydroperoxide and sodium perborate, and dioxirane such as dimethyl dioxirane to oxidize heterocyclic rings and tertiary amines. These methods for the preparation of / V-oxides have been widely described and summarized in literature (e.g. T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.)

[0055] The present disclosure further includes, within its scope, metabolites of the therapeutic agents of the invention, i.e. substances formed in vivo when the therapeutic agent of the invention is administered. Such products may be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, and the like of the administered compound. Therefore, the present disclosure includes metabolites of the therapeutic agents of the invention, including compounds prepared by contacting the therapeutic agent of the invention with a mammal for a time sufficient to produce its metabolites.

[0056] The present disclosure further includes, within its scope, the prodrugs of the therapeutic agents of the invention, which are certain derivatives of the therapeutic agent of the invention that may themselves have less pharmacological activity or no pharmacological activity when administered into or onto a human body, and that may be converted into the therapeutic agents of the invention having the desired activity by, for example, hydrolytic cleavage. Generally, such prodrugs will be functional group derivatives of the compounds, which are easily converted into the desired therapeutically active compound in vivo. Additional information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). These prodrugs may be prepared by, for example, substituting appropriate functional groups present in the therapeutic agent of the invention with certain moieties known to those skilled in the art as "pro-moiety (for example, as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985))".

[0057] The present disclosure further includes the therapeutic agents of the invention comprising protective groups. In any process of preparing the therapeutic agent of the invention, protection of sensitive groups or reactive groups on any related molecules may be necessary and / or desirable, thereby forming a chemically protected form of the therapeutic agent of the invention. This may be achieved by conventional protective groups, for example, those protective groups as described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 . The protective groups may be removed at an appropriate subsequent stage using methods known in the art.

[0058] The term "about" means within ±10%, preferably within ±5%, more preferably within ±2%, of the stated value.

[0059] As used herein, and unless otherwise defined, the terms "treat," "treating" and "treatment" include the eradication, removal, modification, management or control, reversal, alleviation, inhibition of the progress of, or prevention of a disease or condition to which such a term applies, or one or more symptoms of such disorder or condition. In the case of a cancer or tumour, treatment includes the eradication, removal, modification, management or control of a tumour or primary, regional, or metastatic cancer cells or tissue and the minimization or delay of the spread of cancer. The term treatment includes prophylactic, curative, and palliative treatment.

[0060] The term "effective amount" as used herein refers to an amount of a therapeutic agent that, after being administered, will reverse, alleviate, inhibit the progress of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition being treated to a certain extent.

[0061] The "individual" as used herein includes mammals, preferably humans. Exemplary human individuals include human individuals suffering from diseases or conditions (such as the diseases and the conditions described herein) (referred to as patients) or normal individuals, preferably individuals suffering from diseases.

[0062] As used herein, the term “therapeutic agent” refers to a therapeutic agent is any substance or combination of substances used to diagnose, prevent, treat, or cure a disease or condition. The term encompasses at least Compound 1 and derivatives thereof, and the chemotherapy as described herein.

[0063] As used herein, the term “chemotherapy” refers to a conventional cytotoxic chemotherapeutic agent, meaning that the agent disrupts the cell cycle and interferes with the proliferation which maintains malignancy in a non-specific manner (as opposed to a targeted therapy which precisely intervenes on distinct mechanistic efforts central to malignant pathogenesis, reducing the non-specific destruction caused by conventional cytotoxic chemotherapy).

[0064] As used herein, simultaneous administration refers to administration of the one or more therapeutic agents in the same dosage form at the same time.

[0065] As used herein, separate administration refers to administration of the one or more therapeutic agents in different dosage forms at the same time or one immediately after the other in any order.

[0066] As used herein, sequential administration refers to administration of the one or more therapeutic agents in different dosage forms at different times. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and / or are administered on different dosing schedules.

[0067] All patents, patent applications, and non-patent literature referred to herein are incorporated by reference.

[0068] Combinations

[0069] In one aspect of the invention, the invention provides a combination comprising (i) Compound 1 : or a derivative thereof; and (ii) chemotherapy.

[0070] In one aspect of the invention, the combination is provided as a combined preparation for simultaneous, separate or sequential use as a medicament. Medical Uses

[0071] In one aspect of the invention is provided Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof for use as a medicament, wherein Compound 1 or the derivative thereof is for use in combination with chemotherapy.

[0072] In one aspect of the invention is provided chemotherapy for use in therapy, wherein the chemotherapy is for use in combination with Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof. In one aspect of the invention is provided a combination for use as a medicament, the combination comprising Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof, and chemotherapy.

[0073] In these aspects, Compound 1 or the derivative thereof and the chemotherapy are administered simultaneously, separately, or sequentially.

[0074] In one aspect, the invention provides the use of Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof for the manufacture of a medicament, wherein the medicament is for administration in combination with chemotherapy. In one aspect, the invention provides the use of chemotherapy in the manufacture of a medicament, wherein the wherein the medicament is for administration in combination with Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof.

[0075] In one aspect, the invention provides the use of a combination of Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof, and chemotherapy for the manufacture of a medicament.

[0076] In these aspects, Compound 1 or the derivative thereof and the chemotherapy may be administered simultaneously, separately, or sequentially. Methods of Treatment

[0077] In one aspect, the invention provides a method of treatment, the method comprising administering to a subject Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof, in combination with chemotherapy.

[0078] In one aspect, the invention provides a method of treatment, the method comprising administering to a subject chemotherapy in combination with Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof. In one aspect, the invention provides a method of treatment, the method comprising administering to a subject a combination of Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof, and chemotherapy.

[0079] In these methods, Compound 1 or the derivative thereof and chemotherapy can be administered, simultaneously, separately, or sequentially.

[0080] Compound 1

[0081] Compound 1 is a next-generation selective RET inhibitor (SRI). The RET (rearranged during transfection) proto-oncogene encodes a transmembrane receptor tyrosine kinase involved in cell growth, differentiation, and survival. Abnormal activation of RET can lead to uncontrolled cell growth and cancer. RET inhibitors work by blocking the activity of the RET protein, thereby inhibiting cancer cell proliferation and survival. RET can be activated through two main mechanisms: first, chromosomal rearrangement can result in hybrid proteins that fuse the RET kinase domain with a partner protein containing the dimerization domain; second, RET mutations may directly or indirectly lead to activation of the kinase domain and subsequent downstream signalling through pathways including the RAF / MEK / ERK and PI3K / AKT pathways, resulting in increased cell survival, invasion, and angiogenesis (Nat Rev Clin Oncol. 2018 March; 15(3): 151-167).

[0082] Abnormally activated RET proteins are involved in the proliferation and invasion of different tumour cells through a variety of signal pathways, thereby affecting the occurrence and development of tumours. The alteration of the RET gene has a significant effect on downstream cascade reactions, whereas the mutation of the RET gene is mainly associated with medullary thyroid cancer and papillary thyroid cancer, and the fusion of the RET gene is mainly associated with non-small cell lung cancer and chronic myeloid leukemia. Therefore, inhibiting the RET activity has great medical value, in a variety of diseases.

[0083] At present, two compounds (selpercatinib (also known as LOXO-292) and pralsetinib (also known as BLU-667)) have been approved for marketing, and multiple compounds are in clinical trials. However, clinical studies have shown that long-term administration of RET inhibitors can lead to RET drugresistant mutations (such as G810R, G810S, G810C, Y806C, Y806N, and V738A), which can easily lead to decreased efficacy, relapse, and poor prognosis (Journal of Thoracic Oncology, 2020, 15(4), 541-549, etc.). Compound 1 is a next generation selective RET inhibitor (SRI) with advantageous properties, such as broad activity against common RET fusions and mutations, and good brain penetration (see W02020 / 168939 and WO2022 / 022398). Therefore, Compound 1 may overcome resistance mechanisms to first-generation SRIs.

[0084] In the aspects of the invention, Compound 1 is provided in free form or as a derivative thereof selected from the group consisting of a tautomer, or mixture of tautomers thereof, a N-oxide thereof, a pharmaceutically acceptable salt, eutecticum, polymorph, or solvate thereof, or a stable isotope derivative, metabolite, or prodrug thereof. In one embodiment, Compound 1 is provided in free form, i.e. as Compound 1 itself. In a preferred embodiment, Compound 1 is provided as a derivative which is a salt form, more preferably the fumarate salt:

[0085] Chemotherapy

[0086] Chemotherapy as used herein refers to a conventional cytotoxic chemotherapeutic agent, meaning that the agent disrupts the cell cycle and interferes with the proliferation which maintains malignancy in a non-specific manner (as opposed to a targeted therapy which precisely intervenes on distinct mechanistic efforts central to malignant pathogenesis).

[0087] Examples of such chemotherapies useful in the present invention include, but are not limited to: antimicrotubule agents such as diterpenoids, vinca alkaloids, maitansine or maytansine and maytansinoids, auristatins such as monomethyl auristatin E (MMAE), eribulin and taxanes; platinum agents (also called platinum coordination complexes); alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, duocarmycins, pyrrolobenzodiazepines, and triazenes; antitumour antibiotic agents such as anthracyclins (e.g. doxorubicin), actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifolates; topoisomerase I inhibitors such as camptothecins and camptothecin analogues; and hormones and hormonal analogues. Any of these agents may be provided in free form or as a derivative thereof, for instance as a salt thereof.

[0088] The chemotherapy may contain an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental authority, for example, the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the UK Medicines and Healthcare products Regulatory Agency (MHRA), Health Canada, the Australian Therapeutic Goods Administration (TGA), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Indian Central Drugs Standard Control Organization (CDSCO), the Chinese National Medical Products Administration (NMPA), the Brazilian Agencia Nacional de Vig ilancia Sanitaria (ANVISA), the South Korean Ministry of Food and Drug Safety (MFDS), the Russian Ministry of Health of the Russian Federation, and / or the Swiss Agency for Therapeutic Products (Swissmedic). The chemotherapy used in the invention may act by disrupting the cell cycle, and / or by inducing apoptosis, i.e. “programmed cell death”, an intracellular cell death mechanism. Induction of cell death is a key mechanism of tumour response to traditional cytotoxic chemotherapy. Preferably, the chemotherapy acts by disrupting the cell cycle.

[0089] In a more preferred embodiment of the invention, the chemotherapy is a platinum agent, and / or an antimetabolite such as an antifolate, and / or an anti-microtubule or anti-mitotic agent such as a taxane.

[0090] Platinum Agents

[0091] Platinum agents bind to DNA, forming intra- and inter-stranded crosslinks, significantly distorting the DNA double helix, and causing DNA damage / DNA lesions. DNA lesions are recognized by cellular machinery which either repairs the lesion, bypasses it, or prevents the cell cycle and induces apoptosis in rapidly proliferating tumour cells. Platinum agents can induce apoptotic cell death by inhibition of transcription.

[0092] In the aspects of the invention, the chemotherapy may comprise a platinum agent. For example, platinum agent can be selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin. For example, the platinum agent may be cisplatin or carboplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the platinum agent is carboplatin.

[0093] In some embodiments, the chemotherapy comprises a platinum agent and an antifolate. For instance, the chemotherapy may be cisplatin or carboplatin in combination with an antifolate such as pemetrexed or a salt thereof. In some embodiments, the platinum agent is cisplatin and the antifolate is pemetrexed or a salt thereof. In some embodiments, the platinum agent is carboplatin and the antifolate is pemetrexed or a salt thereof. Alternatively, the chemotherapy comprises a platinum agent but not an antifolate.

[0094] In some embodiments, the chemotherapy comprises a platinum agent and a taxane. For instance, the chemotherapy may be cisplatin or carboplatin in combination with a taxane such as docetaxel or paclitaxel. In some embodiments, the platinum agent is cisplatin and the taxane is docetaxel. In some embodiments, the platinum agent is carboplatin and the taxane is docetaxel. In some embodiments, the platinum agent is cisplatin and the taxane is paclitaxel. In some embodiments, the platinum agent is carboplatin and the taxane is paclitaxel.

[0095] Where the chemotherapy comprises a platinum agent (optionally with an antifolate or a taxane), the invention may have utility in the treatment of a RET-altered cancer, such as RET-altered non-small cell lung cancer (in particular RET-fusion positive NSCLC), RET-altered thyroid cancer (such as RET mutation positive medullary thyroid cancer or RET fusion positive papillary thyroid cancer), RET-altered ovarian cancer, RET-altered breast cancer, RET-altered pancreatic cancer, or RET- altered solid tumours.

[0096] Antimetabolites

[0097] Antimetabolite chemotherapies are phase-specific chemotherapies that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite chemotherapies include, but are not limited to, pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, fluorouracil, cytarabine, mecaptopurine, thioguanine, gemcitabine, or a salt thereof.

[0098] Antifolates, also called, inter alia, folate antimetabolites, belong to the antimetabolite class of chemotherapy. Antifolates block the action of folic acid, leading to inhibition of cell division, DNA and RNA synthesis and repair, and protein synthesis. Antifolates may inhibit one or more different enzymes, for example, dihydrofolate reductase (DHFR), thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT). In the aspects of the invention, the chemotherapy may comprise an antifolate. For instance, the antifolate may be selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof. Preferably, the antifolate is pemetrexed or a salt thereof. In the aspects of the invention, pemetrexed may be provided as pemetrexed disodium, pemetrexed ditromethamine, pemetrexed diacid, pemetrexed dipotassium, pemetrexed diarginine, pemetrexed diethanolamine, and / or pemetrexed lysine. Pemetrexed or a salt thereof may also be provided as an anhydrous form, or as a hydrate, for example as a monohydrate, dihydrate, hemipentahydrate, or heptahydrate. For example, pemetrexed may be provided as pemetrexed monohydrate, pemetrexed disodium hemipentahydrate, pemetrexed disodium heptahydrate, or pemetrexed ditromethamine dihydrate.

[0099] In some embodiments, the chemotherapy comprises an antifolate and a platinum agent. For instance, the chemotherapy may contain pemetrexed or a salt thereof in combination with a platinum agent such as cisplatin or carboplatin. In some embodiments, the antifolate is pemetrexed or a salt thereof and the platinum agent is cisplatin. In some embodiments, the antifolate is pemetrexed or a salt thereof and the platinum agent is carboplatin.

[0100] In some embodiments, the chemotherapy comprises an antifolate and a taxane. For instance, the chemotherapy may contain pemetrexed or a salt thereof in combination with a taxane such as docetaxel or paclitaxel. In some embodiments, the antifolate is pemetrexed or a salt thereof and the taxane is docetaxel. In some embodiments, the antifolate is pemetrexed or a salt thereof and the taxane is paclitaxel.

[0101] In embodiments of the invention where the chemotherapy comprises an antifolate agent (optionally with a platinum agent and / or taxane), a folic acid and / or a vitamin B12 supplement may also optionally be administered.

[0102] Where the chemotherapy comprises an antifolate agent (optionally with a platinum agent or taxane), the invention may have utility in the treatment of a RET-altered cancer, such as RET-altered nonsmall cell lung cancer (in particular RET-fusion positive NSCLC), RET-altered thyroid cancer (such as RET mutation positive medullary thyroid cancer or RET fusion positive papillary thyroid cancer), RET-altered ovarian cancer, RET-altered breast cancer, RET-altered pancreatic cancer, or RET- altered solid tumours.

[0103] Anti-microtubule or Anti-mitotic agents

[0104] Anti-microtubule or anti-mitotic agents are phase specific agents against the microtubules of tumour cells during the M (mitosis) phase of the cell cycle. Examples of anti-microtubule or anti-mitotic agents that can be used as chemotherapy in the present invention include, but are not limited to, diterpenoids and taxanes, and vinca alkaloids.

[0105] Diterpenoids and taxanes are chemotherapies that operate at the G2 / M phases of the cell cycle. Taxanes disrupt microtubule formation during cell division by preventing depolymerization of microtubules and thus prevent progression of cells through the M-phase of the cell cycle, leading to cell death.

[0106] Vinca alkaloids are phase specific chemotherapies. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

[0107] Other chemotherapies which act on the microtubule include maitansine (also called maytansine) and maytansinoids, auristatins, and eribulin. Maitansine and maytansinoids inhibit the assembly of microtubules by binding to tubulin at the rhizoxin binding site. Examples of maytansinoids include ansamitocin, mertansine (also called emtansine in some forms), and ravtansine (also called soravtansine in some forms). Auristatins inhibit microtubule formation through the interaction with tubulin at the “peptide sub-site” of tubulin’s “Vinca domain” to disrupt tubulin-dependent GTP hydrolysis. Auristatins lead to the arrest of cancer cells in the mitosis stage of the cell cycle and eventually, apoptosis. Examples of auristatins include dolastatin 10 and monomethyl auristatin E (MMAE) (also known as vedotin when linked to an antibody). Eribulin is an inhibitor of microtubule dynamics and binds predominantly to high affinity sites at the plus ends of microtubules, leading to inhibition of mitosis.

[0108] In the aspects of the invention, the chemotherapy may comprise an anti-microtubule or anti-mitotic agent. For example, the chemotherapy agent may comprise a taxane. The taxane may be selected from docetaxel, paclitaxel, abraxane (nab-paclitaxel), cabazitaxel, larotaxel, and tesetaxel. Preferably, the taxane is docetaxel or paclitaxel. In some embodiments, the taxane is doxetaxel. In some embodiments, the taxane is paclitaxel.

[0109] In some embodiments, the chemotherapy comprises a taxane and a platinum agent. For instance, the chemotherapy may be docetaxel or paclitaxel in combination with a platinum agent such as cisplatin or carboplatin. In some embodiments, the taxane is docetaxel and the platinum agent is cisplatin. In some embodiments, the taxane is docetaxel and the platinum agent is carboplatin. In some embodiments, the taxane is paclitaxel and the platinum agent is cisplatin. In some embodiments, the taxane is paclitaxel and the platinum agent is carboplatin.

[0110] In some embodiments, the chemotherapy comprises a taxane and an antifolate. For instance, the chemotherapy may contain docetaxel or paclitaxel in combination with an antifolate such as pemetrexed or a salt thereof. In some embodiments, the taxane is docetaxel and the antifolate is pemetrexed or a salt thereof. In some embodiments, the taxane is paclitaxel and the antifolate is pemetrexed or a salt thereof.

[0111] Where the chemotherapy comprises a taxane (optionally with an platinum agent or antifolate), the invention may have utility in the treatment of a RET-altered cancer, such as RET-altered non-small cell lung cancer (in particular RET-fusion positive NSCLC), RET-altered thyroid cancer (such as RET mutation positive medullary thyroid cancer or RET fusion positive papillary thyroid cancer), RET-altered ovarian cancer, RET-altered breast cancer, RET-altered pancreatic cancer, or RET- altered solid tumours. Antibody-Drug Conjugates (ADCs)

[0112] In some embodiments, the chemotherapy described herein is provided as an antibody-drug conjugate (ADC). The term “antibody-drug conjugate” refers to an antibody or antibody fragment linked, e.g. covalently, to any of the chemotherapeutic agents described herein. The ADC includes chemotherapy which is conjugated to an antibody via a linker structure moiety.

[0113] Examples of such chemotherapies which may be provided as antibody-drug conjugates in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids, vinca alkaloids, maitansine or maytansine and maytansinoids, auristatins such as monomethyl auristatin E (MMAE), eribulin and taxanes; platinum agents (also called platinum coordination complexes); alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, duocarmycins, pyrrolobenzodiazepines, and triazenes; antitumour antibiotic agents such as anthracyclins (e.g. doxorubicin), actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifolates; topoisomerase I inhibitors such as camptothecins and camptothecin analogues; and hormones and hormonal analogues.

[0114] In some embodiments, the ADC comprises a platinum agent, an antifolate, and / or an antimitotic agent linked to an antibody or antibody fragment. For example, the platinum agent may be cisplatin or carboplatin, the antifolate may be pemetrexed or a salt thereof, and / or the antimitotic agent may be a taxane selected from docetaxel and paclitaxel.

[0115] In some embodiments, the conjugate has a structure according to Formula (A) below:

[0116] Bm- ( - M - l)a

[0117] Formula (A) in which I is chemotherapy, M is a linker moiety, and Bmis a binding moiety that is capable of specifically binding to an antigen. The binding moiety may be an antibody, antibody fragment, or an antibody-binding fragment. Suitable conjugation methods are known in the art (e.g. Bioconjugate Chem. 2023, 34, 1951-2000).

[0118] The term “binding moiety” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding moiety may be an antibody, antibody fragment, or an antigenbinding fragment. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by complementarity-determining regions (CDRs) on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. The term “antibody” herein is used in the broadest sense and specifically covers monoclonal antibodies, single domain antibodies, polyclonal antibodies, multi-specific antibodies (e.g. bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B cell hybridoma technique, and the EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs of use in this disclosure may be cultivated in vitro or in vivo. The skilled person would understand how to provide an appropriate binding moiety for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery, 22, 641-661 (2023). In particular, an antibody, antibody fragment or an antibody-binding fragment used as a binding moiety must be capable of targeting a particular cell surface marker or receptor associated with the disorder to be treated.

[0119] Moreover, suitable binding moieties for use in the ADCs are known in the art (e.g. MABS 2023, VOL. 15, NO. 01 , 2229101 and Conilh et al. Journal of Hematology & Oncology (2023) 16:3). For example, the binding moiety may be capable of binding to a4p7, CD3, CD4, 0X4, CD28, PD-1 , ICOS, BCMA / TAC1 , CD52, CCR8, CD7, CD38, HER2, HER3, TROP2, B7-H3, GPR20, CEACAM5, HLA-DR, CD22, CD20, CD74, IL-7R, EpCam, Collagen-4, FRa, CD70, CD30, LeY, EGFR, Nectn-4, CD79b, CD142, CD33, and / or CD19, or combinations thereof. Additionally or alternatively, the antibody may be selected from the group consisting of adalimumab, infliximab, vedolizumab, etrolizumab, teplizumab, zanolimumab, ublituximab, ofatumumab, ocrelizumab, inebilizumab, rocatinlimab, nivolumab, pembrolizumab, alemtuzumab, brentuximab, tafasitamab, loncastuximab, mogamulizumab, polatuzumab, inotuzumab, epratuzumab, isatuximab, daratumumab, traztuzumab, patritumab, daptopotamab,, sacituzumab (hRS7), labetuzumab (hMN-14), IMMU-112 (hL243), epratuzumab (hLL2), veltuzumab, milatuzumab, A7R, rituximab, B8-4, 35-4, B7-H4 antibody, Fra antibody, cAC10, h1 F6, cBR96, h1 F6, cBR96, and cetuximab.

[0120] Synergy

[0121] Compound 1 is a selective inhibitor of the transmembrane receptor tyrosine kinase RET. Compound 1 works by inhibiting cell signalling pathways involved in the abnormal growth of cancer cells (e.g. growth factor signal transduction pathways). Growth factor signalling plays a vital role in driving cell proliferation by activating and the downstream signalling cascades. The aberrant activity of these signalling cascades frequently leads to cancer. Cell proliferation can only be realized through cell division, and stimulation through the growth factor pathway can be the driving force of cell cycle initiation and progression. The transmembrane receptor tyrosine kinase RET plays a key role in this pathway - RET activation stimulates several downstream pathways, including RAS / MAPK, PI3K / AKT, JAK / STAT, PKA, and PKC pathways, ultimately leading to initiation of the cell cycle and cell proliferation.

[0122] By pairing selective RET inhibitor Compound 1 with chemotherapeutic agents, e.g. agents which disrupt the cell cycle, the inventors have discovered combinations which target different levels of the cancer cell proliferation pathway, leading to the synergistic anti-cancer effect demonstrated herein (i.e. an effect greater than expected from the sum of the effects of the components of the combination alone).

[0123] The synergistic effect of Compound 1 and the chemotherapy provides a more effective treatment of disease, such as treatment of the diseases listed herein. Furthermore, the synergistic effect may allow control of resistance to known treatments and / or mutations. Tumours are a heterogeneous population of cells which evolve in response to therapies. As a result, development of resistance to known treatments is a common issue within several cancers. Therefore, combination therapies may offer a solution to this problem, to ensure that cancer cells which may be developing resistance are still effectively killed. The synergistic effect may also allow for a lower dose of Compound 1 and / or the chemotherapy to be administered to the patient than the dose of Compound 1 and / or the chemotherapy when administered alone, whilst achieving an equivalent or greater effect. These lower doses may limit toxicity and reduce side effects. The combination of Compound 1 or the derivative thereof and the chemotherapy may provide a synergistic therapeutic effect, which is a greater therapeutic effect than the effect of other combinations. For example, the combination of Compound 1 or the derivative thereof and the chemotherapy may provide a greater effect than a first-generation selective RET inhibitor (SRIs), such as selpercatinib (LOXO-292) or pralsetinib (BLU-667) with chemotherapy. The improved therapeutic effect relative to these combinations may be due to resistance to first generation SRIs, and / or may be because the combination of the invention is more efficacious (e.g. due to a greater degree of synergy) than other combinations.

[0124] Thus, in a preferred embodiment of the invention, the combination of Compound 1 or the derivative thereof and the chemotherapy provides a greater therapeutic effect than Compound 1 or the derivative thereof or the chemotherapy administered alone, preferably a synergistic effect.

[0125] The synergy of the combination of the invention can be calculated based on the Bliss definition (Biochemical Pharmacology 80 (2010) 801-810), wherein:

[0126] Xis the fraction of inhibition caused by the first agent;

[0127] Y is the fraction of inhibition caused by the second agent;

[0128] Z is the fraction of inhibition caused by the combination of both agents.

[0129] In the presence of the first agent, the remaining possible fraction of inhibition is 1 -X. If the two agents are Bliss independent, then the fraction of inhibition to the second agent in the present of the first agent is Y(1 - X). Thus, Z = X+ Y(1 -X) = X+ Y-XY.

[0130] If Z = X+ Y-XY, then the effect of the two agents is additive.

[0131] If Z > X+ Y-XY, then the effect of the two agents is synergistic. If Z < X + Y- XY, then the effect of the two agents is antagonistic.

[0132] Therefore, a Bliss score can be calculated using the following equation:

[0133] Bliss score = Z - (X + Y- XY) wherein, if Z > X+ Y-XY, the Bliss score will be greater than 0 and the effect of the two agents is synergistic, if Z = X+ Y-XY, the Bliss score will equal 0 and the effect of the two agents is additive, and if Z < X + Y- XY, the Bliss score will be less than 0 and the effect of the two agents is antagonistic.

[0134] Additionally, or alternatively, a Synergy score can be calculated using the following equation:

[0135] Synergy score, S = (X + Y- XY) - Z wherein, if Z > X+ Y-XY, the Synergy score will be less than 0 and the effect of the two agents is synergistic, if Z = X+ Y-XY, the Synergy score will equal 0 and the effect of the two agents is additive, and if Z < X+ Y-XY, the Synergy score will be less than 0 and the effect of the two agents is antagonistic.

[0136] Diseases

[0137] In the aspects of the invention, Compound 1 , chemotherapy, or their combination may be used as a medicament. Preferably, Compound 1 , the chemotherapy, or the combination of Compound 1 and chemotherapy is used in the treatment of a disease associated with RET activity. For instance, the disease may be a RET-altered disease, for instance a RET mutation-positive or a RET fusion-positive disease or a disease where RET is abnormally expressed, e.g. overexpressed.

[0138] In preferred embodiments of the invention, the disease is a cancer or tumour. For instance, the disease may be lung cancer (such as non-small cell lung cancer), breast cancer (such as oestrogen receptor positive (ER+), progesterone receptor positive (PR+), oestrogen and progestrerone receptor positive (ER+ / PR+), human epidermal growth factor 2 positive (HER2+), human epidermal growth factor 2 negative (HER2-), and triple negative breast cancer (TNBC), or combinations thereof), head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), pheochromocytoma, colon cancer, multiple myeloma, melanoma, glioma, brain tumour, sarcoma, salivary gland, prostate, ovarian, pancreatic, or neuroendocrine colorectal cancer, leukemia (such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML)), ganglioglioma (such as anaplastic ganglioglioma), Erdheim-Chester disease, Spitz tumours and Spitzoid melanomas, primary myelofibrosis (PMF) with secondary acute myeloid leukemia, and spindle mesenchymal tumours (such as infantile fibrosarcoma), or a metastasis thereof.

[0139] In one embodiment, the cancer is a solid tumour. Preferably, the cancer is lung cancer (such as non- small cell lung cancer), thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), breast cancer, pancreatic cancer, or ovarian cancer, or a metastasis thereof. More preferably, the cancer is non-small cell lung cancer, or thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer) or a metastasis thereof. In one preferred embodiment, the cancer is lung cancer, preferably non-small cell lung cancer. In another preferred embodiment, the cancer is thyroid cancer, preferably medullary thyroid cancer. In another preferred embodiment, the cancer is breast cancer (such as oestrogen receptor positive (ER+), progesterone receptor positive (PR+), oestrogen and progestrerone receptor positive (ER / PR+), human epidermal growth factor 2 positive (HER2+), human epidermal growth factor 2 negative (HER2-), and triple negative breast cancer (TNBC), or combinations thereof). In another preferred embodiment, the cancer is pancreatic cancer. In another preferred embodiment, the cancer is ovarian cancer. Most preferably, the cancer is non-small cell lung cancer.

[0140] Preferably, the disease is a RET-altered cancer. A RET-altered cancer may be a RET mutationpositive or a RET fusion-positive cancer, or a cancer where the expression of RET is abnormal, e.g. where RET is overexpressed. For instance, the disease treated according to the invention is preferably RET-altered non-small cell lung cancer, RET-altered thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), RET-altered breast cancer, RET-altered pancreatic cancer, RET-altered ovarian cancer, or a RET-altered solid tumour. More preferably, the disorder may be RET-fusion positive NSCLC, RET mutation positive medullary thyroid cancer, or RET fusion positive papillary thyroid cancer.

[0141] In some embodiments of the invention, the disease includes a metastasis of one of the cancers or tumours listed herein. For instance, the metastasis is a metastasis of non-small cell lung cancer, thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), breast cancer, pancreatic cancer, or ovarian cancer. In one embodiment of the invention, the metastasis is a bone, brain, liver, and / or lung metastasis. In a preferred embodiment, the metastasis is a brain metastasis. Prior Therapy, Resistance and Mutations

[0142] Long-term administration of certain drugs can lead to drug-resistant mutations, which in turn lead to decreased efficacy, relapse, and poor prognosis. Thus, therapies which can function in a drug-resistant setting are valuable.

[0143] In the aspects of the invention, the disease or condition may be refractory or resistant to a RET inhibitor or a multikinase (MKI) inhibitor. In one embodiment, the disease or condition is refractory or resistant to a multikinase (MKI) inhibitor, for example anlotinib, cabozatinib, apatinib, CX1003, sorafenib, Lenvatinib, vandetanib, and / or sunitinib.

[0144] In the aspects of the invention, the disease or condition may be resistant to a selective RET inhibitor (SRI). Alternatively, the disease or condition may be refractory to a selective RET inhibitor (SRI). In particular, the disease or condition may be resistant to selective RET inhibitors other than Compound 1 , for instance selpercatinib (LOXO-292), pralsetinib (BLU-667), SY5007, YP01001 , and / or HA121- 28. Indeed, clinical studies have shown that long-term administration of RET inhibitors can lead to RET drug-resistant mutations (such as G810R, G810S, G810C, Y806C, Y806N, and V738A), which can easily lead to decreased efficacy, relapse, and poor prognosis (Journal of Thoracic Oncology, 2020, 15(4), 541-549). In the invention, the disease or condition may be a disease resistant to selpercatinib (LOXO-292) and / or pralsetinib (BLU-667). In the invention, the disease or condition may be a disease resistant to selpercatinib (LOXO-292). In the invention, the disease or condition may be a disease resistant to pralsetinib (BLU-667).

[0145] As such, the invention may be used in subjects who have already been subjected to prior treatments for the disease or condition for which they are being treated with the invention (i.e. as second-, third-, or fourth-line therapy). In particular, the invention may be used in subjects who have already been treated with chemotherapy, a multikinase (MKI) inhibitor, a selective RET inhibitor (SRI), or an immunotherapy.

[0146] For example, the invention may be used in subjects treated with chemotherapy, for instance a chemotherapy as defined herein, but administered without Compound 1 . The invention may also be used in subjects who have already been treated with an MKI, such as anlotinib, cabozatinib, apatinib, CX1003, sorafenib, Lenvatinib, vandetanib, and / or sunitinib. The invention may also be used in subjects who have already been treated with a selective RET inhibitor (SRI), for instance selpercatinib (LOXO-292), pralsetinib (BLU-667), SY5007, YP01001 , and / or HA121-2, or Compound 1. The invention may also be used in subjects who have already been treated with an immunotherapeutic agent, for instance a checkpoint inhibitor such as an anti-PD-1 , anti-PD-L1 , or anti CTLA-4 antibody. For instance, the prior treatment may be dostarlimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab.

[0147] Alternatively, the invention may be used in a first-line setting, i.e. in patients who have not yet received treatment for their condition.

[0148] In the aspects of the invention, the disease or condition may be associated with wild-type RET or the disease or condition may be associated with a RET alteration. For example, the disease or condition may be associated with a RET alteration, such as a RET fusion, a RET mutation, RET overexpression, or a combination thereof. In aspects of the invention, the RET alteration may additionally, or alternatively, be a RET drug-resistant mutation. For instance, the disease or condition may be associated with a RET solvent-front mutation, and / or a RET gatekeeper mutation. RET mutations include, but are not limited to, point mutations (substitutions or insertions) or deletions at the 810, 806, 738, 918, and / or 804 positions. In the invention, the RET mutation may be selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, V738A, M918T, V804M, V804L, V804E, and combinations thereof. Preferably, the RET mutation is selected from G810R, G810S, G801 C, and / or M918T.

[0149] In the invention, the disease or condition may be associated with a RET fusion-type mutation. The RET fusion may either result in the juxtaposition of a N-terminal portion of a fusion partner to the C- terminal portion of the RET protein, including its catalytic domain, or vice versa, the juxtaposition of the N-terminal portion of the RET protein, with its catalytic domain, to the C-terminal portion of a fusion partner. The retention of an intact kinase domain in the fusion product is essential to distinguish cancer-driving RET protein fusions from random chimeric products secondary to genetic instability. In aspects of the invention, the fusion may be a 3’ kinase fusion, or the fusion may be a 5’ kinase fusion.

[0150] RET fusion-type mutations include, but are not limited to, ACBD5-RET, AFAP1 L2-RET, AKAP13- RET, ANKRD26-RET, BCR-RET, CDC123-RET, CCDC6-RET (RET / PTC1), CLIP2-RET, CUX1 -RET, DLG5-RET, EPHA5-RET, ERC1 -RET, ETL4-RET, ETV6-RET, FGFR1 OP-RET, FKBP15-RET, FRMD4A-RET, GEMIN5-RET, COLGA5-RET (RET / PTC5), HOOK3-RET, KHDRBS1-RET, KIAA1468-RET, KIF13A-RET, KIF5B-RET, KTN1-RET (RET / PTC8), MYH10-RET, MYH13-RET, MYO5A-RET, MYO5C-RET, MCOA4-RET (RET / PCT3), PCM1-R, PCDC10-RET, PICALM-RET, PPFIBP2-RET, PRKAR1A-RET (RET / PTC2), RASGEF1A-RET (ARET) RASSF4-RET, RET-RET, RRBP1-RET, RUFY2-RET, SNRNP70-RET, SPECC1 L-RET, SQSTM1-RET, RBC1 D23-RET, TBL1XR1-RET, TFG-RET, TNIP1-RET, TRIM24-RET (RET / PRC6), TRIM27-RET, TRIM33-RET (RET / PTC7), UEVLD-RET, VCL-RET, WAC-RET, and ZNF485-RET. In the invention, the RET fusiontype mutation may be selected from the group consisting of RET-CCDC6, KIF5B-RET, NCOA4-RET, RELCH-RET, ERC1-RET, TRIM33, ABHD17C-RET, and combinations thereof. Preferably, the RET fusion-type mutation is selected from CCDC6-RET and / or KIF5B-RET.

[0151] Compound 1 or the derivative thereof is an inhibitor of wild-type and mutants of RET (see WG2020 / 186939, WO2022 / 022398, WO2022 / 199503 and PCT / CN2024 / 093044).

[0152] Identification of the RET alteration (e.g. the RET solvent-front and / or RET fusion-type mutation) may be carried out by one or more of a tumour biopsy, circulating tumour DNA (ctDNA) analysis, sequencing methods (e.g. next-generation sequencing (NGS), rtPCT, qPCR), immunohistochemistry analysis for key RET kinase targets and / or other pathway related biomarkers. The RET alteration (e.g. the RET solvent-front mutation and / or the RET fusion-type mutation) may be identified prior to administration of Compound 1 or the derivative thereof and / or the chemotherapy. Further analysis may be conducted during or following treatment with the invention.

[0153] Pharmaceutical Compositions and Route of Administration

[0154] The Compound 1 , the chemotherapy, or the combination of the invention may be administered to a subject in one or more pharmaceutical compositions, optionally wherein the pharmaceutical composition comprises one or more excipients.

[0155] Thus, in one aspect, Compound 1 or a derivative thereof and the chemotherapy are provided in the same composition. In another aspect, Compound 1 or a derivative thereof and the chemotherapy are provided in separate compositions, for example, Compound 1 is provided in a first composition and the chemotherapy is provided in a second composition. Excipients which may be found in the pharmaceutical compositions of the present invention include diluents, adjuvants, or vehicles which are administered together with a therapeutic agent, and are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. Examples of suitable pharmaceutically acceptable excipients are as described in, for example, Handbook of Pharmaceutical Excipients (2020) and Remington's Pharmaceutical Sciences (2020).

[0156] Pharmaceutical compositions of the present disclosure may act systemically and / or locally. For this purpose, they may be administered through a suitable route. For these administration routes, the pharmaceutical composition of the present disclosure may be administered in a suitable dosage form. In one aspect, the pharmaceutical composition or pharmaceutical formulation is preferably administered through an oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, rectal, or transdermal route. Preferably, Compound 1 is administered orally, and the chemotherapy is administered intravenously, orally, intramuscularly, subcutaneously, intrathecally, or intraperitoneally.

[0157] In one aspect of the invention, Compound 1 is administered orally as a tablet or capsule, for example, as a 10 mg or a 50 mg (based on the weight of Compound 1) capsule. For instance, Compound 1 may be administered as a capsule containing Compound 1 and one or more excipients selected from the group consisting of microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and combinations thereof. For instance, the capsule may have one of the following representative formulations:

[0158] Dosaqes / Dosaqe Regimes

[0159] The dosage of the therapeutic agent of the invention to be administered will depend on the individual being treated, the severity of the disease or condition, the rate of administration, the disposal of the compound, and the judgement of the prescribing physician. The dosage regimen may be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered overtime, or the dose may be proportionally reduced or increased as indicated by the exigencies of the treatment. It should be noted that the dose may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the needs of the individual and the professional judgement of the person administering the composition or supervising the administration of the composition.

[0160] In general, the effective dosage ranges from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

[0161] The content or amount of the therapeutic agent of the invention in the pharmaceutical composition may be from about 0.01 mg to about 1 ,000 mg.

[0162] In the aspects of the invention, the dose of Compound 1 or the derivative thereof may be 200 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 200 mg. In one embodiment, the dose of Compound 1 or the derivative thereof may be 150 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 150mg. In one embodiment, the dose of Compound 1 or the derivative thereof may be 120 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 120mg. In one embodiment, the dose of Compound 1 or the derivative thereof may be 90 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 90 mg. In one embodiment, the dose of Compound 1 or the derivative thereof may be 60 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 60 mg. In one embodiment, the dose of Compound 1 or the derivative thereof may be 20 mg or less per day (based on the weight of Compound 1). For instance, the dose may be 20 mg.

[0163] Preferably, the dose of Compound 1 or the derivative thereof is from 20 mg to 200 mg (based on the weight of Compound 1). For instance, the dose may be selected from 200 mg, 150 mg, 90 mg, 60 mg or 20 mg per day. More preferably, the dose is 90 mg, 60 mg or 20 mg per dose. More preferably, the dose is 90 mg.

[0164] In the aspects of the invention, Compound 1 or the derivative thereof may be administered in a single dosage form. Alternatively, Compound 1 or the derivative thereof is administered in more than one dosage form, e.g. multiple tablets, multiple capsules, or multiple infusions.

[0165] In the aspects of the invention, Compound 1 or the derivative thereof and the chemotherapy are administered simultaneously, separately, or sequentially.

[0166] In the aspects of the invention, Compound 1 or the derivative thereof is administered once daily, less than once daily, or more than once daily. For instance, Compound 1 or the derivative thereof is administered twice daily, three times daily, four times daily, five times daily etc. Preferably, Compound 1 or the derivative thereof is administered once daily.

[0167] In the aspects of the invention, Compound 1 or the derivative thereof may be administered in cycles. For example, Compound 1 or the derivative thereof may be administered once, followed by a period where no compound is administered. The period of administration may be one day, more than one day, one week, more than one week, etc. The period where no compound is administered may be one day, more than one day, one week, more than one week, etc. The period where no compound is administered may be absent from the treatment cycle. In one embodiment, a treatment cycle is one week (7 days). In one embodiment, aspect of the invention, a treatment cycle is two weeks (14 days). In one embodiment, a treatment cycle is three weeks (21 days). In one embodiment, a treatment cycle is four weeks (28 days). In one embodiment, Compound 1 or the derivative thereof is administered each day of a 28-day treatment cycle, for example, once per day each day for 28 days. In one aspect of the invention, Compound 1 or the derivative thereof is administered each day of a 21 -day treatment cycle, for example, once per day each day for 21 days.

[0168] In the aspects of the invention, the chemotherapy may be administered in cycles. In one embodiment, the chemotherapy is administered on day 1 of a 21 -day treatment cycle, optionally wherein the cycle is conducted as needed until disease progression, one, two, three, four, or more than four times. In these embodiments, the chemotherapy may be a platinum therapy such as carboplatin or cisplatin and / or an antifolate such as pemetrexed or a salt thereof. Preferably, Compound 1 is administered daily and carboplatin or cisplatin and pemetrexed, or a salt thereof, are administered once every three weeks for four cycles, followed by administration of Compound 1 daily with pemetrexed, or a salt thereof, administered once every three weeks.

[0169] In one aspect of the invention, the patient receives Compound 1 or the derivative thereof at the same time as the chemotherapy. In one aspect of the invention, the patient receives Compound 1 or the derivative thereof before the chemotherapy. In one aspect of the invention, the patient receives Compound 1 or the derivative thereof after the chemotherapy.

[0170] In one aspect of the invention, the patient receives Compound 1 , a platinum agent (for example, carboplatin or cisplatin) and pemetrexed or a salt thereof, after which the treatment regimen is adjusted so the patient receives Compound 1 and pemetrexed or a salt thereof. In such an aspect, the treatment cycle is preferably 21 days. Preferably, the patient receives Compound 1 , a platinum agent (for example, carboplatin or cisplatin) and pemetrexed or a salt thereof for four treatment cycles.

[0171] In one aspect of the invention, the patient has already received or is already receiving treatment with chemotherapy, for example, is already receiving treatment with pemetrexed or a salt thereof, carboplatin, cisplatin, pemetrexed or a salt thereof and carboplatin, and / or pemetrexed or a salt thereof and cisplatin and then additionally receives treatment with Compound 1 or a derivative thereof.

[0172] Response to the Combination of Compound 1 or the Derivative Thereof and the Chemotherapy

[0173] In one aspect of the invention, the use of the combination of Compound 1 or the derivative thereof and the chemotherapy results in a response to treatment in a target lesion or target lesions. Definitions of the criteria used to determine objective tumour response for target lesions according to RECIST 1 .1 criteria are as follows:

[0174] • Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.

[0175] • Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0176] • Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

[0177] • Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. In one aspect of the invention, the combination of Compound 1 or the derivative thereof and the chemotherapy results in a complete response, a partial response, or stable disease according to RECIST 1.1 criteria. In one embodiment, the combination of Compound 1 or the derivative thereof and the chemotherapy results in a partial response according to RECIST 1.1 criteria. In one embodiment, the combination of Compound 1 or the derivative thereof and the chemotherapy results in a complete response according to RECIST 1.1 criteria.

[0178] Numbered Embodiments

[0179] 1. Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof for use as a medicament, wherein Compound 1 or the derivative thereof is for use in combination with chemotherapy.

[0180] 2. Chemotherapy for use as a medicament, wherein the chemotherapy is for use in combination with Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof. 3. A combination for use as a medicament, the combination comprising:

[0181] (i) Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and

[0182] (ii) chemotherapy.

[0183] 4. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-3, wherein Compound 1 or the derivative thereof and the chemotherapy are administered simultaneously, separately, or sequentially.

[0184] 5. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-4 in the treatment of a disease or condition associated with RET activity.

[0185] 6. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 1-5 in the treatment of a cancer or tumour.

[0186] 7. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 6, wherein the cancer or tumour is lung cancer (such as non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), pheochromocytoma, colon cancer, multiple myeloma, melanoma, glioma, brain tumour, sarcoma, salivary gland, prostate, ovarian, pancreatic, or neuroendocrine colorectal cancer, leukemia (such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML)), ganglioglioma (such as anaplastic ganglioglioma), Erdheim-Chester disease, Spitz tumours and Spitzoid melanomas, primary myelofibrosis (PMF) with secondary acute myeloid leukemia, and spindle mesenchymal tumours (such as infantile fibrosarcoma), or a metastasis thereof.

[0187] 8. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 7, wherein the cancer or tumour is a solid tumour, for example, lung cancer (such as non-small cell lung cancer), thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), breast cancer, pancreatic cancer, or ovarian cancer, or a metastasis thereof. 9. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 7 or 8, wherein the cancer or tumour is non-small cell lung cancer, or a metastasis thereof.

[0188] 10. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 7 or 8, wherein the cancer or tumour is medullary thyroid cancer, or a metastasis thereof.

[0189] 11 . The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 7 or 8, wherein the cancer or tumour is papillary thyroid cancer, or a metastasis thereof.

[0190] 12. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 7 or 8, wherein the cancer or tumour is breast cancer, or a metastasis thereof.

[0191] 13. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 7 or 8, wherein the cancer or tumour is pancreatic cancer, or a metastasis thereof.

[0192] 14. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-13 in the treatment of a disease or condition which is resistant or refractory to one or more drugs.

[0193] 15. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 14, wherein the disease or condition is resistant or refractory to a selective RET inhibitor (SRI).

[0194] 16. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiments 14 or 15, wherein the drug-resistant disease or condition is resistant or refractory to selpercatinib (LOXO-292) and / or pralsetinib (BLU-667).

[0195] 17. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-16, wherein the disease or condition is associated with wild-type RET or the disease or condition is associated with a RET alteration.

[0196] 18. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-17 in the treatment of a disease or condition which is associated with a RET alteration, such as a RET fusion, a RET mutation, RET overexpression, or a combination thereof.

[0197] 19. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 18, wherein the RET alteration is a point mutation (substitution or insertion) or a deletion at the 810, 806, 738, 918 and / or 804 positions, and combinations thereof.

[0198] 20. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 19, wherein the mutation is a RET mutation selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, V738A, M918T, V804M, V804L, V804E, and combinations thereof. 21 . The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 17-20, wherein the alteration is a RET fusion-type mutation selected from the group consisting of ACBD5-RET, AFAP1 L2-RET, AKAP13-RET, ANKRD26-RET, BCR-RET, CDC123-RET, CCDC6-RET (RET / PTC1), CLIP2-RET, CUX1-RET, DLG5-RET, EPHA5-RET, ERC1- RET, ETL4-RET, ETV6-RET, FGFR1 OP-RET, FKBP15-RET, FRMD4A-RET, GEMIN5-RET, COLGA5-RET (RET / PTC5), HOOK3-RET, KHDRBS1-RET, KIAA1468-RET, KIF13A-RET, KIF5B- RET, KTN1-RET (RET / PTC8), MYH10-RET, MYH13-RET, MYO5A-RET, MYO5C-RET, MCOA4-RET (RET / PCT3), PCM1-R, PCDC10-RET, PICALM-RET, PPFIBP2-RET, PRKAR1A-RET (RET / PTC2), RASGEF1A-RET (ARET) RASSF4-RET, RET-RET, RRBP1-RET, RUFY2-RET, SNRNP70-RET, SPECC1 L-RET, SQSTM1-RET, RBC1 D23-RET, TBL1XR1-RET, TFG-RET, TNIP1-RET, TRIM24- RET (RET / PRC6), TRIM27-RET, TRIM33-RET (RET / PTC7), UEVLD-RET, VCL-RET, WAC-RET, and ZNF485-RET.

[0199] 22. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 17-21 , wherein the mutation is a RET fusion-type mutation selected from the group consisting of RET-CCDC6, KIF5B-RET, NCOA4-RET, RELCH-RET, ERC1-RET, TRIM33, ABHD17C-RET, and combinations thereof.

[0200] 23. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 17-22, wherein the mutation is a RET fusion-type mutation selected from CCDC6-RET and / or KIF5B-RET.

[0201] 24. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-23, wherein the subject to be treated has already been subjected to prior treatments fortheir disease or condition.

[0202] 25. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 21 , wherein the subject has already been treated with chemotherapy, a multikinase (MKI) inhibitor, a selective RET inhibitor (SRI), or an immunotherapy.

[0203] 26. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 25, wherein the subject has already been treated with a selective RET inhibitor (SRI), for example selpercatinib and / or pralsetinib.

[0204] 27. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of embodiments 1-26, wherein the dose of Compound 1 or the derivative thereof is 200 mg or less, based on the weight of Compound 1 , per day, such as 200 mg, 150 mg, 120 mg, 90 mg, 60 mg, or 20 mg, based on the weight of Compound 1 , per day.

[0205] 28. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to embodiment 27, wherein the dose of Compound 1 or the derivative thereof is 90 mg or 60 mg, based on the weight of Compound 1 , per day, preferably wherein the dose of Compound 1 is 90 mg, based on the weight of Compound 1 , per day. 29. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-28, wherein the pharmaceutically acceptable salt of Compound 1 is the fumarate salt:

[0206] 30. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-29, wherein the chemotherapy comprises an agent which disrupts the cell cycle.

[0207] 31 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-30, wherein the chemotherapy comprises an agent which induces apoptosis in cells.

[0208] 32. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1 -31 , wherein the chemotherapy comprises anti-microtubule agents such as diterpenoids, vinca alkaloids, maitansine and maytansinoids, auristatins, eribulin and taxanes, platinum agents, alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, duocarmycins, pyrrolobenzodiazepines, and triazenes, antitumour antibiotic agents such as anthracyclins (e.g. doxorubicin), actinomycins and bleomycins, topoisomerase II inhibitors such as epipodophyllotoxins, antimetabolites such as purine and pyrimidine analogues and antifolates, topoisomerase I inhibitors such as camptothecins, and / or hormones and hormonal analogues.

[0209] 33. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-32, wherein the chemotherapy comprises a platinum agent, an antimetabolite, for example an antifolate, and / or an anti-microtubule or anti-mitotic agent, for example a taxane.

[0210] 34. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-33, wherein the chemotherapy comprises a platinum agent.

[0211] 35. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiment 34, wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin.

[0212] 36. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 35, wherein the platinum agent is cisplatin. 37. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 35, wherein the platinum agent is carboplatin.

[0213] 38. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-37, wherein the chemotherapy comprises an antimetabolite, for example an antifolate.

[0214] 39. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-38, wherein the antimetabolite is an antifolate selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof.

[0215] 40. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 39, wherein the antimetabolite is pemetrexed or a salt thereof.

[0216] 41 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-40, wherein the chemotherapy comprises a platinum agent and an antimetabolite, for example an antifolate.

[0217] 42. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 41 , wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin.

[0218] 43. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 42, wherein the platinum agent is cisplatin.

[0219] 44. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 42, wherein the platinum agent is carboplatin.

[0220] 45. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 41-44, wherein the antimetabolite is an antifolate selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof.

[0221] 46. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 45, wherein the antimetabolite is pemetrexed or a salt thereof.

[0222] 47. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-46, wherein the chemotherapy comprises an anti-microtubule or anti-mitotic agent, for example a taxane.

[0223] 48. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1 -47, wherein the anti-microtubule or antimitotic agent is a taxane selected from docetaxel, paclitaxel, abraxane (nab-paclitaxel), cabazitaxel, larotaxel, and tesetaxel. 49. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 48, wherein the anti-microtubule or anti-mitotic agent is docetaxel.

[0224] 50. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 48, wherein the anti-microtubule or anti-mitotic agent is paclitaxel.

[0225] 51 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1-50, wherein the chemotherapy is conjugated to an antibody, such that the chemotherapy is provided as an antibody-drug conjugate (ADC).

[0226] 52. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any of embodiments 1 -51 , wherein the combination of Compound 1 or the derivative thereof and the chemotherapy provides a greater therapeutic effect than Compound 1 or the derivative thereof administered alone.

[0227] 53. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to embodiment 52, wherein the combination of Compound 1 or the derivative thereof and the chemotherapy provides a synergistic effect.

[0228] 54. The Compound 1 or the derivative thereof for use, the chemotherapy for use, or the combination for use according to any preceding embodiment, wherein the combination of the Compound 1 or the derivative thereof and the chemotherapy results in a complete response, partial response, or stable disease according to RECIST 1 .1 criteria.

[0229] 55. A combination comprising:

[0230] (i) Compound 1 : or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and

[0231] (ii) chemotherapy.

[0232] 56. The combination of embodiment 55 as a combined preparation for simultaneous, separate or sequential use as a medicament. 57. The combination according to embodiment 55 or 56, wherein the pharmaceutically acceptable salt of Compound 1 is the fumarate salt:

[0233] 58. The combination according to any of embodiments 55-57, wherein the chemotherapy comprises an agent which disrupts the cell cycle.

[0234] 59. The combination according to any of embodiments 55-58, wherein the chemotherapy comprises an agent which induces apoptosis in cells.

[0235] 60. The combination according to any of embodiments 55-59, wherein the chemotherapy comprises anti-microtubule agents such as diterpenoids, vinca alkaloids, maitansine and maytansinoids, auristatins, eribulin and taxanes, platinum agents, alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, duocarmycins, pyrrolobenzodiazepines, and triazenes, antitumour antibiotic agents such as anthracyclins (e.g. doxorubicin), actinomycins and bleomycins, topoisomerase II inhibitors such as epipodophyllotoxins, antimetabolites such as purine and pyrimidine analogues and antifolates, topoisomerase I inhibitors such as camptothecins, and / or hormones and hormonal analogues.

[0236] 61 . The combination according to any of embodiments 55-60, wherein the chemotherapy comprises a platinum agent, an antimetabolite, for example an antifolate, and / or an anti-microtubule or anti-mitotic agent, for example a taxane.

[0237] 62. The combination according to any of embodiments 55-61 , wherein the chemotherapy comprises a platinum agent.

[0238] 63. The combination according to any of embodiments 55-62, wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin.

[0239] 64. The combination according to embodiment 63, wherein the platinum agent is cisplatin.

[0240] 65. The combination according to embodiment 63, wherein the platinum agent is carboplatin.

[0241] 66. The combination according to any of embodiments 55-65, wherein the chemotherapy comprises an antimetabolite, for example an antifolate. 67. The combination according to any of embodiments 55-66, wherein the antimetabolite is an antifolate selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof.

[0242] 68. The combination according to embodiment 67, wherein the antimetabolite is pemetrexed or a salt thereof.

[0243] 69. The combination according to any of embodiments 55-68, wherein the chemotherapy comprises a platinum agent and an antimetabolite, for example an antifolate.

[0244] 70. The combination according to any of embodiments 55-69, wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin.

[0245] 71 . The combination according to embodiment 70, wherein the platinum agent is cisplatin.

[0246] 72. The combination according to embodiment 70, wherein the platinum agent is carboplatin.

[0247] 73. The combination according to any of embodiments 69-72, wherein the antimetabolite is an antifolate selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof.

[0248] 74. The combination according to any of embodiments 69-73, wherein the antimetabolite is pemetrexed or a salt thereof.

[0249] 75. The combination according to any of embodiments 55-74, wherein the chemotherapy comprises an anti-microtubule, or anti-mitotic agent, such as a taxane.

[0250] 76. The combination according to any of embodiments 55-75, wherein the anti-microtubule, or anti-mitotic agent is a taxane selected from docetaxel, paclitaxel, abraxane (nab-paclitaxel), cabazitaxel, larotaxel, and tesetaxel.

[0251] 77. The combination according to embodiment 76, wherein the anti-microtubule, or anti-mitotic agent is docetaxel.

[0252] 78. The combination according to embodiment 76, wherein the anti-microtubule, or anti-mitotic agent is paclitaxel.

[0253] 79. The combination according to any of embodiments 55-78, wherein the chemotherapy is conjugated to an antibody, such that the chemotherapy is provided as an antibody-drug conjugate (ADC).

[0254] 80. The combination according to any of embodiments 55-78, wherein the combination of Compound 1 or the derivative thereof and the chemotherapy provides a greater therapeutic effect than Compound 1 or the derivative thereof administered alone.

[0255] 81 . The combination according to embodiment 80, wherein the combination of Compound 1 or the derivative thereof and the chemotherapy provides a synergistic effect. 82. The combination according to any of embodiments 55-81 , wherein the combination of the Compound 1 or the derivative thereof and the chemotherapy results in a complete response, partial response, or stable disease according to RECIST 1 .1 criteria.

[0256] 83. The combination of any of embodiments 55-82 for use in the treatment of a disease or condition associated with RET activity.

[0257] 84. The combination of any of embodiments 55-82 for use according to embodiment 83, wherein the disease or condition associated with RET activity is cancer or tumour.

[0258] 85. The combination of any of embodiments 55-82 for use according to embodiment 84, wherein the cancer or tumour is lung cancer (such as non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), pheochromocytoma, colon cancer, multiple myeloma, melanoma, glioma, brain tumour, sarcoma, salivary gland, prostate ovarian, pancreatic, or neuroendocrine colorectal cancer, leukemia (such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML)), ganglioglioma (such as anaplastic ganglioglioma), Erdheim-Chester disease, Spitz tumours and Spitzoid melanomas, primary myelofibrosis (PMF) with secondary acute myeloid leukemia, and spindle mesenchymal tumours (such as infantile fibrosarcoma), or a metastasis thereof.

[0259] 86. The combination of any of embodiments 55-82 for use according to embodiment 85, wherein the cancer or tumour is a solid tumour, for example lung cancer (such as non-small cell lung cancer), thyroid cancer (such as medullary thyroid cancer or papillary thyroid cancer), breast cancer, pancreatic cancer, or ovarian cancer, or a metastasis thereof.

[0260] 87. The combination of any of embodiments 55-82 for use according to embodiments 85 or 86, wherein the cancer or tumour is non-small cell lung cancer, or a metastasis thereof.

[0261] 88. The combination of any of embodiments 55-82 for use according to embodiments 85 or 86, wherein the cancer or tumour is medullary thyroid cancer, or a metastasis thereof.

[0262] 89. The combination of any of embodiments 55-82 for use according to embodiments 85 or 86, wherein the cancer or tumour is papillary thyroid cancer, or a metastasis thereof.

[0263] 90. The combination of any of embodiments 55-82 for use according to embodiments 85 or 86, wherein the cancer or tumour is breast cancer, or a metastasis thereof.

[0264] 91 . The combination of any of embodiments 55-82 for use according to embodiments 85 or 86, wherein the cancer or tumour is pancreatic cancer, or a metastasis thereof.

[0265] 92. The combination of any of embodiments 55-82 for use according to any of embodiments 83- 91 in the treatment of a disease or condition which is resistant or refractory to one or more drugs.

[0266] 93. The combination of any of embodiments 55-82 for use according to embodiment 92, wherein the disease or condition is resistant or refractory to a selective RET inhibitor (SRI).

[0267] 94. The combination of any of embodiments 55-82 for use according to embodiments 92 or 93, wherein the drug-resistant disease or condition is resistant or refractory to selpercatinib (LOXO-292) and / or pralsetinib (BLU-667). 95. The combination of any of embodiments 55-82 for use according to any of embodiments 83-

[0268] 94, wherein the disease or condition is associated with wild-type RET or the disease or condition is associated with a RET alteration.

[0269] 96. The combination of any of embodiments 55-82 for use according to any of embodiments 83-

[0270] 95, in the treatment of a disease or condition which is associated with a RET alteration, such as a RET fusion, a RET mutation, RET overexpression, or a combination thereof.

[0271] 97. The combination of any of embodiments 55-82 for use according to embodiment 96, wherein the RET alteration is a point mutation (substitution or insertion) or a deletion at the 810, 806, 738, 918 and / or 804 positions.

[0272] 98. The combination of any of embodiments 55-82 for use according to embodiment 97, wherein the mutation is a RET solvent-front mutation selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, V738A, M918T, V804M, V804L, V804E, and combinations thereof.

[0273] 99. The combination of any of embodiments 55-82 for use according to any of embodiments 95-

[0274] 98, wherein the alteration is a RET fusion-type mutation selected from the group consisting of ACBD5-RET, AFAP1 L2-RET, AKAP13-RET, ANKRD26-RET, BCR-RET, CDC123-RET, CCDC6-RET (RET / PTC1), CLIP2-RET, CUX1-RET, DLG5-RET, EPHA5-RET, ERC1-RET, ETL4-RET, ETV6-RET, FGFR1OP-RET, FKBP15-RET, FRMD4A-RET, GEMIN5-RET, COLGA5-RET (RET / PTC5), HOOK3- RET, KHDRBS1-RET, KIAA1468-RET, KIF13A-RET, KIF5B-RET, KTN1-RET (RET / PTC8), MYH10- RET, MYH13-RET, MYO5A-RET, MYO5C-RET, MCOA4-RET (RET / PCT3), PCM1-R, PCDC10-RET, PICALM-RET, PPFIBP2-RET, PRKAR1A-RET (RET / PTC2), RASGEF1A-RET (ARET) RASSF4-RET, RET-RET, RRBP1-RET, RUFY2-RET, SNRNP70-RET, SPECC1 L-RET, SQSTM1-RET, RBC1 D23- RET, TBL1XR1-RET, TFG-RET, TNIP1-RET, TRIM24-RET (RET / PRC6), TRIM27-RET, TRIM33-RET (RET / PTC7), UEVLD-RET, VCL-RET, WAC-RET, and ZNF485-RET.

[0275] 100. The combination of any of embodiments 55-82 for use according to any of embodiments 95-

[0276] 99, wherein the mutation is a RET fusion-type mutation selected from the group consisting of RET- CCDC6, KIF5B-RET, NCOA4-RET, RELCH-RET, ERC1-RET, TRIM33, ABHD17C-RET, and combinations thereof.

[0277] 101 . The combination of any of embodiments 55-82 for use according to any of embodiments 95-

[0278] 100, wherein the mutation is a RET fusion-type mutation selected from CCDC6-RET and / or KIF5B- RET.

[0279] 102. The combination of any of embodiments 55-82 for use according to any of embodiments 83-

[0280] 101 , wherein the subject to be treated has already been subjected to prior treatments fortheir disease or condition.

[0281] 103. The combination of any of embodiments 55-82 for use according to embodiment 102, wherein the subject has already been treated with chemotherapy, a multikinase (MKI) inhibitor, a selective RET inhibitor (SRI), or an immunotherapy.

[0282] 104. The combination of any of embodiments 55-82 for use according to embodiment 103, wherein the subject has already been treated with a selective RET inhibitor (SRI), for example selpercatinib and / or pralsetinib. 105. The combination of any of embodiments 55-82 for use according to any of embodiments 83- 104, wherein the dose of Compound 1 or the derivative thereof is 200 mg or less, based on the weight of Compound 1 , per day, such as 200 mg, 150 mg, 120 mg, 90 mg, 60 mg, or 20 mg, based on the weight of Compound 1 , per day.

[0283] 106. The combination of any of embodiments 55-82 for use according to embodiment 105, wherein the dose of Compound 1 or the derivative thereof is 90 mg or 60 mg, based on the weight of Compound 1 , per day, preferably wherein the dose of Compound 1 is 90 mg, based on the weight of Compound 1 , per day.

[0284] Examples

[0285] The invention is described by the following non-limiting examples.

[0286] Example 1 : Synthesis and activity testing of Compound 1

[0287] Example 1A: Synthesis of Compound 1 (2-(6-(6-((6-(4-fluoro-1 H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6- diazabicyclo[3.1 .11heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1 H-pyrazol-3-yl)pyrimidin-4-amine)

[0288] Step 1 : Preparation of tert-butyl 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1 ,1]heptane-6-carboxylate (Compound 1c)

[0289] Compound 1 a (1 .50 g) and Compound 1 b (1 .77 g) were successively added into a 100 mL singlenecked flask, and then DMSO (20.0 mL) and K2CO3 (5.83 g) were successively added. The mixture was heated to 90 °C, and stirred under the protection of nitrogen at this temperature for 20 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by flash silica gel column chromatography (PE:EA=5:1), to provide Compound 1c (2.03 g). MS m / z (ESI): 354.1 [M+H]+. Step 2: Preparation of tert-butyl 3-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1 ,1]heptane-6-carboxylate (Compound 1d)

[0290] Compound 1 c (2.03 g), B2(pin)2 (4.01 g), KOAc (1 .55 g), 1 ,4-dioxane (15.0 mL), and Pd(dppf)Cl2'DCM (644.67 mg) were successively added into a 100 mL single-necked flask, and were heated to 90 °C for reaction under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mLx3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by flash silica gel column chromatography (DCM:MeOH=15:1), to provide Compound 1d (2.11 g). MS m / z (ESI): 402.3 [M+H]+.

[0291] Step 3: Preparation of tert-butyl 3-(5-(4-methyl-6-((5-methyl-1 H-pyrazol-3-yl)-amino)pyrimidin-2- yl)pyridin-2-yl)-3,6-diazabicyclo[3.1 ,1]heptane-6-carboxylate (Compound 1 f)

[0292] Compound 1 e (950 mg) was dissolved in 1 ,4-dioxane (50.0 mL), Compound 1d (2.11 g), CS2CO3 (3.15 g), and water (5.0 mL) were successively added, and then Pd(dppf)Cl2'DCM (477.83 mg) was added. The mixture was heated to 90°C, and kept for reaction under the protection of nitrogen at this temperature for 14 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mLx3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated to dryness under reduced pressure, to provide Compound 1f (587.0 mg). MS m / z (ESI): 463.3 [M+H]+.

[0293] Step 4: Preparation of 2-(6-(3,6-diazabicyclo[3.1 .1 ]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1 H- pyrazol-3-yl)pyrimidin-4-amine (Compound 1g)

[0294] Compound 1 f (1 .36 g) was dissolved in DCM (20.0 mL), TFA (20.0 mL) was then added, and the mixture was kept for reaction under the protection of nitrogen at room temperature. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to provide trifluoroacetate of Compound 1g (587.0 mg). MS m / z (ESI): 363.3 [M+H]+.

[0295] Compound 1

[0296] Step 5: Preparation of 6-(4-fluoro-1 H-pyrazol-1-yl)nicotinaldehyde (Compound 1 k)

[0297] Compound 1 h (2.0 g), hydrochloride of Compound 1j (1 .58 g), and potassium carbonate (4.45 g) were successively added into DMF (15 mL), heated to 80 °C, and stirred at this temperature for 14 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (50 mLx2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by flash silica gel column chromatography (PE:EA=10:1), to provide Compound 1 k (0.81 g).

[0298] MS m / z (ESI): 192.1 [M+H]+.

[0299] Step 6: Preparation of 2-(6-(6-((6-(4-fluoro-1 H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6- diazabicyclo[3.1 .1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1 H-pyrazol-3-yl)pyrimidin-4-amine (Compound 1)

[0300] Trifluoroacetate of Compound 1g (22.82 mg) and Compound 1 k (27.47 mg) were added into methanol (1 .0 mL), and then triethylamine (4.45 mg) and sodium cyanoborohydride (13.86 mg) were successively added. The mixture was kept for reaction at room temperature for 14 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to provide Compound 1 (7.0 mg).

[0301] MS m / z (ESI): 538.3 [M+H]+.

[0302] 1H NMR (400 MHz, DMSO-c / 6) 6 11 .98 (s, 1 H), 9.66 (s, 1 H), 9.12 (d, J = 2.16 Hz, 1 H), 8.67 (dd, J = 4.54, 0.64 Hz, 1 H), 8.43 (dd, J = 8.94, 2.28 Hz, 1 H), 8.41 (d, J = 1 .68, 1 H), 7.98 (dd, J = 8.48 Hz, 2.12 1 H), 7.92 (d, J = 4.28, 1 H), 7.87 (d, J = 8.4, 1 H), 6.78 (d, J = 9.0 Hz, 2H), 6.31 (br, 1 H), 3.78-3.71 (m, 4H), 3.68-3.52 (m, 4H), 2.59-2.52 (m, 1 H), 2.33 (s, 3H), 2.25 (s, 3H), 1 .60 (d, J= 8.36 Hz, 1 H).

[0303] Example 1 B: Synthesis of Compound 1 fumarate salt (Compound 1-A)

[0304] Compound 1 (5 g) was added to 200 mL of THF and stirred until it was completely dissolved. Then 1 .56 g of fumaric acid was added slowly, and the reaction mixture was kept for reaction at 20-45°C for 46 h. After completion of the reaction, the mixture was filtered and washed with THF to obtain 7.06 g of a wet solid, which was then dried under vacuum at 40-45°C to give 4.78 g of solid powder.

[0305] 1H NMR (400 MHz, DMSO-c / 6) 6 12.43 (br, 3H), 9.66 (s, 1 H), 9.13 (d, J = 2.4 Hz, 1 H), 8.60 (d, J = 4.4 Hz, 1 H), 8.44 (dd, J = 8.8, 2.4 Hz, 1 H), 8.41 (d, J = 1.2 Hz, 1 H), 7.97 (dd, J = 8.4, 2.0 Hz, 1 H), 7.91 (d, J = 4.4 Hz, 1 H), 7.86(d, J = 8.4 Hz, 1 H), 6.81 (br, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 6.62 (s, 2H), 6.31 (br, 1 H), 3.79-3.76 (m, 4H), 3.68-3.58 (m, 4H), 2.62-2.56 (m, 1 H), 2.33 (s, 3H), 2.25 (s, 3H), 1.61 (d, J = 8.4 Hz, 1 H).

[0306] Example 1 C: Compound 1 activity against RET-WT, RET-V804M, RET-V804L, RET-M918T, and RET-CCDC6

[0307] Compound 1 was tested for its inhibitory effect on the activity of wild-type RET enzyme (RET-WT), mutant RET enzyme (RET-V804M, RET-V804L, and RET-M918T) and fusion-type RET enzyme (RET-CCDC6).

[0308] After pre-incubation of different RET enzymes and the test compound at room temperature for 30 min, a substrate and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at room temperature for 40 min, TK antibody-cryptate and streptavidin-XL665 were added, and the test was performed after incubation at room temperature for 45 min. The solvent group (DMSO) was used as the negative control and the buffer group (without RET enzyme) as the blank control. The relative inhibitory activity percentages of different concentrations of the compounds were plotted with respect to the compound concentrations, and the curve was fitted according to a four-parameter model to compute the IC50 value as per the following formula: where y is the relative inhibitory activity percentage, max is the maximum value of the fitted curve, min is the minimum value of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0309] The IC50 (nM) of Compound 1 for inhibiting different RET enzymes is presented in Table 1 below.

[0310] Table 1

[0311] As can be seen from Table 1 , Compound 1 has a significant inhibitory effect on the enzymes RET-WT, RET-CCDC6, RET-V804L, RET-V804M, and RET-M918T.

[0312] Example 1 D: Compound 1 activity against RET-WT, RET-V804M, RET-V804L, RET-M918, RET- CCDC6 and RET-KIF5B

[0313] The inhibitory effects of Compound 1 (tested as the fumarate salt) on the activity of wild-type RET (RET-WT), mutant-type RET (RET-V804M, RET-V804L, and RET-M918T), and fusion-type RET (RET-CCDC6 and RET-KIF5B) were determined using HTRF KinEASE-TK (Cisbio) kit. After preincubation of the above different types of RET enzymes and different concentrations of the test compounds (9 concentration points) at room temperature for 30 min, a substrate and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at room temperature for 40 min, TK antibody-cryptate and streptavidin-XL665 were added, and after incubation at room temperature for 60 min, the detection was performed. The reaction conditions for the different types of RET enzymes are shown in the table below: The solvent group (DMSO) was used as the negative control and the buffer group (without RET enzyme) as the blank control. The relative inhibitory activity percentages of the compound at different concentrations were plotted with respect to the compound concentrations, and the curve was fitted in accordance with a four-parameter model to compute the IC50 value as per the following equation: where y is the relative inhibitory activity percentage, max and min are a maximum value of the fitted curve, and a minimum value of the fitted curve respectively, x is a logarithmic concentration of the compound, and Hillslope is a slope of the curve.

[0314] The inhibitory effects of Compound 1 in the present invention on the wild-type RET (RET-WT), mutant-type RET (RET-V804M, RET-V804L, and RET-M918T), and fusion-type RET (RET-CCDC6 and RET-KIF5B) enzyme are as shown in Table 2.

[0315] Table 2

[0316] The data in Table 2 shows that Compound 1 has clear inhibitory effects on enzymatic activities of the 6 tested types of RET kinases (wild-type RET (RET-WT), mutant-type RET (RET-V804M, RET- V804L, and RET-M918T), and fusion-type RET (RET-CCDC6 and RET-KIF5B)).

[0317] Example 1 E: Compound 1 activity against RET-G8010R, RET-G810S and RET-G810C

[0318] According to the instructions of HTRF KinEASE-TK kit (Cisbio), the inhibitory effect of Compound 1 on the activity of drug-resistant mutant RET enzymes (RET-G810R, RET-G810S and RET-G810C) was determined.

[0319] The three drug-resistant mutant RET enzymes were each pre-incubated with different concentrations of test compounds (for the IC50 test of Compound 1 for RET-G810R and RET-G810C, the compound concentration was 1-10,000 nM; for RET-G810S, the compound concentration was 0.1-10,000 nM, 9 concentrations in each experiment). After pre-incubation for 30 min at room temperature, the substrate and adenosine triphosphate (ATP) were added to start the reaction. For RET-G810R and RET-G81 OS, incubation was carried out at room temperature for 90 min; for RET-G810C, incubation was carried out at room temperature for 120 min. TK antibody-cryptate and streptavidin-XL665 were added, and the test was performed after incubation at room temperature for 60 min. The solvent group (DMSO) was used as the negative control and the buffer group (without RET enzyme) as the blank control. The relative inhibitory activity percentages of the compounds with different concentrations were plotted with respect to the compound concentrations, and the curve was fitted according to a four- parameter model to calculate the IC50 value as per the following formula: where y is the relative inhibitory activity percentage, max and min are a maximum value of the fitted curve, and a minimum value of the fitted curve respectively, x is a logarithmic concentration of the compound, and Hillslope is a slope of the curve.

[0320] The experimental results are shown in Table 3.

[0321] Table 3

[0322] As can be seen from Table 3, Compound 1 remarkably inhibited RET-G810R enzyme, RET-G810S enzyme, and RET-G81 OC enzyme with a lower IC50 (i.e. greater potency) than selpercatinib (LOXO- 292) and pralsetinib (BLU-667).

[0323] Example 1 F: Compound 1 activity in six BaF3 cell lines

[0324] Ba / F3 cells (Ba / F3 KIF5B-RETG810R, Ba / F3 KIF5B-RETG810S, Ba / F3 KIF5B-RETG810C) were seeded into 96-well plates, 2000 cells / 95 pl / well. 5 pl of BLU-667, LOXO-292, and Compound 1 fumarate salt was added to the 96-well plate (final concentration: 1 ,52~10000 nM). In addition, negative control wells (without test compound) and blank control wells (without cells) were set. The cells were cultured at 37 °C, 5% CO2 for 3 days, then Cell Titer Gio reagent was added at 50 pl / well to lyse the cells, the Luminescence signal value was detected by a microplate reader, and the inhibition rate % was calculated.

[0325] Separately, Ba / F3 cells (Ba / F3 KIF5B-RETV804E, Ba / F3 KIF5B-RETV804L, Ba / F3 KIF5B-RETV804M) collected separately during logarithmic growth phase and seeded to 96-well plates, 1000 cells / 95 pl well. 5 pl of BLU-667, LOXO-292, and Compound 1 fumarate salt was added to the 96-well plate (final concentration: 4~25000 nM). In addition, negative control wells (without test compound) and blank control wells (without cells) were set. The cells were cultured at 37 °C, 5% CO2 for 3 days, then Cell Titer Gio reagent was added at 50 pl / well to lyse the cells, the Luminescence signal value was detected by a microplate reader, and the inhibition rate % was calculated. The inhibition rate % was fitted using the four-parameter equation "log(agonist) vs response-variable slope (four parameters)" in GraphPad Prism 6.0, and the IC50 was obtained by calculation.

[0326] The results are presented in Table 4.

[0327] Table 4: Inhibition IC50 (nM) of Compound 1 fumarate salt on the proliferation of six cell lines

[0328] The results show that Compound 1 is very effective against Ba / F3 KIF5B-RETG810R, Ba / F3 KIF5B-RETG810SBa / F3 K|F5B.RETG810CBa / F3KIF5B-RETV804E,Ba / F3 K|F5B.RET804Lgnd Ba / F3KIF5B-RE-|- 804Mce||S-j- g proliferation of inhibition was better than that of pralsetinib (BLU-667) and selpercatinib (LOXO-292).

[0329] Example 2: In vivo Activity of Compound 1

[0330] Example 2A: Pharmacokinetics and tissue distribution of Compound 1 in rats

[0331] By intragastric administration (PO) of pralsetinib (BLU-667) (prepared according to Example 5 of WO2017 / 079140A1) and Compound 1 to male SD rats respectively, the plasma concentrations and the tissue concentrations of BLU-667 and Compound 1 in brains, lungs and thyroid of rats were determined to investigate the pharmacokinetic characteristics. The dosage of administration by PO was 5 mg / kg, and the solvent was 0.5% MC (methylcellulose). With administration by PO, blood samples were collected at different time points (0 h before administration, and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration). The blood samples were anticoagulated with dipotassium edetate, and centrifuged to provide plasma samples, which were stored at -80 °C. Rats were sacrificed by exsanguination from abdominal aorta at 0.5 h, 2 h, 8 h, and 24 h after PO administration. Brain, lung and thyroid were collected, washed, and homogenized with normal saline at a certain ratio, to provide tissue samples which were stored at -80 °C. The plasma samples and tissue samples were processed with precipitated protein and then analyzed by LC-MS / MS. The pharmacokinetic parameters were computed using WinNonlin 6.3 software and using a non-compartmental model. The results are shown in Table 5.

[0332] Table 5 Pharmacokinetic Parameters of Compound 1 and BLU-667 Administered by PO in Plasma and Tissues of Rats

[0333] The data in Table 5 shows that after intragastric administration of 5 mg / kg of pralsetinib (BLU-667) and Compound 1 to SD rats, the exposed quantity of Compound 1 in each target organ tissue, such as brain, lung, and thyroid, was better than the exposed quantity of BLU-667.

[0334] Example 2B: Efficacy test of Compound 1 in mice

[0335] In vivo efficacy of Compound 1 and pralsetinib (BLU-667) in a Balb / c-nu mouse model with a subcutaneous xenograft tumour of human medullary thyroid carcinoma TT cells was evaluated.

[0336] Compound 1 was dissolved in 0.1 M aqueous solution of H3PO4, and pralsetinib (BLU-667) was dissolved in 0.1 M aqueous solution of HOAc, to prepare clear solutions (pH: about 4.0). An aqueous solution of H3PO4 at a pH of about 4.0 was used for the solvent control group. The mode of administration was PO, BID.

[0337] The tumour diameter was measured with a vernier caliper twice a week. The computing formula of the tumour volume is: V=0.5xaxb2, where a represents a long diameter of the tumour, and b represents a short diameter of the tumour. Evaluation of tumour growth inhibition rate (TGI (%)) for tumour inhibition efficacy of the compounds: Prism Graphpad5.0 software was used for statistical analysis based on the relative tumour volume at the end of the experiment. The comparison between multiple groups was analyzed by two-way ANOVA, and p<0.05 was considered as a significant difference.

[0338] The results are shown in FIG 1 . In the TT nude mouse xenograft model of human medullary thyroid carcinoma, Compound 1 has a significant dose-dependent anti-tumour effect at a dose of 5 mg / kg. The anti-tumour effect of Compound 1 at a dose of 5 mg / kg (T / C=17.44%, TGI=131 .36%, p<0.05) is better than that of the pralsetinib (BLU-667) group at a dose of 5 mg / kg (T / C=33.62 %, TGI=88.82%, p<0.05). Relative tumour growth rate T / C (%)= TRT / CRT *100% , where TRT is the mean relative tumour volume of the test compound group, CRT is the relative tumour volume of the solvent control group; and the relative tumour volume RTV = WVo, where Vo is the mean tumour volume at the commencement of the administration, and Vt is the mean tumour volume measured on day t after the administration.

[0339] Example 2C: Pharmacokinetic study of Compound 1 in Mice

[0340] Female Balb / c mice (6 mice) were orally administered with 1 mg / kg of the fumarate salt of Compound 1 by gavage. The compound was first dissolved with 0.5% methylcellulose solution and ultrasonicated to ensure complete dissolution or uniform suspension of the compound. 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 16 h, and 24 h after administration, 0.2 mL of blood (EDTA-K2 anticoagulated) was venously collected. The collected whole blood was temporarily stored in an ice box and centrifuged for 10 min within 2 h to separate the plasma (4 °C). The collected plasma was stored in a refrigerator at -80 °C prior to testing.

[0341] The blood concentration of the compound 1 was detected by LC-MS / MS, and the linear range was from 10 to 10000 ng / mL. The computed pharmacokinetic parameters are as shown in Table 6 below.

[0342] Table 6: Pharmacokinetic Study of Compound 1 in Mice

[0343] The data in Table 6 shows that Compound 1 (tested as the fumarate salt) has excellent pharmacokinetic properties in mice.

[0344] Example 2D: Efficacy test of Compound 1 in mice

[0345] In vivo efficacy of Compound 1 was studied in BALB / c Nude mouse model with Ba / F3 KIF5B- RETG810Rsubcutaneous tumour. Compound 1 fumarate salt, pralsetinib (BLU-667) and selpercatinib (LOXO-292) were respectively mixed with 0.5% methyl cellulose (MC) as the solvent to prepare homogenous suspensions for administration (PO (IG), BID).

[0346] The tumour diameter was measured with a vernier caliper twice a week. The formula for calculation of tumour volume is: V = 0.5xaxb2, where a and b represent the long and short diameters of the tumour respectively. The antitumour effect of the compound was evaluated by TGI (%). TGI (%) represents the tumour growth inhibition rate.

[0347] Evaluation of tumour growth inhibition rate (TGI (%)) for tumour inhibition efficacy of the compounds:

[0348] Statistical analysis: Prism Graphpad 8.0 software was used for statistical analysis based on the relative tumour volume at the end of the experiment. The comparison between two groups and multiple groups was analysed by two-way ANOVA, and p<0.05 represented significant difference.

[0349] The results are shown in Table 7 and FIG 2. No mouse died in the experiment. In the Ba / F3 KIF5B- RETG8ioRmodel, the tumour growth inhibition rate (TGI (%)) of Compound 1 fumarate salt and the control compounds pralsetinib (BLU-667) and selpercatinib (LOXO-292), at the same dose of 30 mg / kg, was 72.37%, 29.78% and 2.69%, respectively, indicating that the tumour inhibition effect of Compound 1 is better than that of the control compounds pralsetinib (BLU-667) and selpercatinib (LOXO-292), with p<0.05 in both cases.

[0350] Table 7. Analysis of efficacy of compound 1 on Ba / F3 KIF5B-RETG810Rtumour-bearing mouse model (based on tumour volume)

[0351] Vp-i: tumour volume one day before administration; Vpi2: tumour volume on Day 12 of administration.

[0352] Example 3: 96-well cell viability assay for TPCI and LC-2 / ad cells treated with monotherapy

[0353] Cells were plated in 50 pl of cell culture medium in triplicate in 96-well plate, at a density of 250 cells / well in RPMI-1640 / 5% fetal bovine serum (FBS) plus 10 units of penicillin and streptomycin for TPC1 cells, and at a density of 1000 cells / well in RPMI1640 / F12 medium / 10% FBS plus 10 units of penicillin and streptomycin for LC-2 / ad cells. Cells were cultured overnight at 37 °C, 5% CO2. The appropriate drug was prepared at 2x required concentrations in cell culture medium.

[0354] 50 pl of drugs in 2x required concentrations was added to the cell culture wells and cells were cultured at 37 °C for 5 days.

[0355] 25 pL CellTiter-Glo luminescent cell viability assay reagent (Promega Cat. No. G7573) was added to each well of cells and incubated at 37 °C / 5% CO2 for 10 min. Luminescence signal was measured using a luminometer.

[0356] The results are shown in Table 8 and FIG 3.

[0357] Table 8: IC50 of compound 1 and chemotherapy in TPC1 cells

[0358] Example 4: Synergistic anti-proliferative effect of the combination of Compound 1 and chemotherapy

[0359] TPC1 cells were cultured in RPMI-1640 plus 5% (v / v) fetal bovine serum (FBS) plus 10 units of penicillin and streptomycin. LC-2 / ad cells were cultured in RPMI-1640 / F-12 medium (1 :1 mixture) plus 10% (v / v) FBS plus 10 units of penicillin and streptomycin. Cells were seeded at 5000 / well into 24- well plate (0.5 ml / well). Experiments were performed with 3 or 4 replicates. Cells were cultured at 37 °C / 5% CG2for 24 hours.

[0360] Medium was removed, and fresh medium containing the test compound(s) (see table below, Compound 1 tested as the fumarate salt) at the designated concentration was added. Test compounds were prepared in DMSO, then at a final concentration of <0.1% (v / v) DMSO in the medium. Cells were incubated at 37 °C / 5% CO2 for 7 days. Medium was removed and replaced with fresh, compound-containing medium. Cells were incubated at 37 °C / 5% CO2 for a further 7 days for a total of 14-day treatment.

[0361] Medium was removed and cells were washed once with PBS at room temperature. 0.8 ml fixation solution per well was added to the 24-well plates. The plates were stored at room temperature for 10 minutes. Fixation solution was discarded and 0.8 ml staining solution per well was added to the 24- well plates. Plates were stained for 3 minutes at room temperature. Staining solution was removed and plates were immediately rinsed with water. Plates were allowed to air dry upside down overnight at room temperature.

[0362] Plates were scanned using a colony counter (GelCount by Oxford Optronix) and scanned data quantified using Imaged: i) Open the figure in Imaged. ii) Go to “lmage->Adjust->Threshold”, set value approximately between 200-235, apply the setting. iii) Go to “lmage->Adjust->AutoThreshold”, select “Isodata”, select “Ignore white”, and deselect “white object on black background”. iv) Go to “Analyze->measure”, then transfer the data to Excel.

[0363] Data analysis was performed, including calculation of synergy using the Bliss score and Synergy score definitions. The results are summarised in Table 9 below.

[0364] All combinations of Compound 1 and chemotherapy in the table below showed a synergistic effect as defined by a Bliss score of > 0 and a Synergy score of < 0 in the RET-altered TPC1 and LC2 cell lines.

[0365] Table 9: Analysis of effect of Compound 1 in combination with chemotherapy in TPC1 and LC2 cells

[0366] The plate images are presented in FIG 4, 7, 10, 13, 16, 19, and 22. The synergy data are presented in FIG 5a to 5d, 6, 8a to 8d, 9, 11a to 11d, 12, 14a to 14d, 15, 17a to 17d, 18, 20a to 20c, 21 , and 23a to 23c.

[0367] Example 5: 96-well plate cell viability assay for LC-2 / ad cells treated with triple combination

[0368] Cells were plated in 50 pl of cell culture medium in triplicate in 96-well plate, at a density of 1000 cells / well in RPMI1640 / F12 medium / 10% FBS plus 10 units of penicillin and streptomycin for LC-2 / ad cells. Cells were cultured overnight at 37 °C, 5% CO2. The combination of Compound 1 , cisplatin and pemetrexed was prepared at 2x required concentrations in cell culture medium.

[0369] 50 pl of drug combination in 2x required concentrations was added to the cell culture wells and cells were cultured at 37 °C for 5 days.

[0370] 25 pL CellTiter-Glo luminescent cell viability assay reagent (Promega Cat. No. G7573) was added to each well of cells and incubated at 37 °C / 5% CO2 for 10 min. Luminescence signal was measured using a luminometer.

[0371] The results are shown in FIG 24. The combination of Compound 1 , cisplatin and pemetrexed showed a synergistic effect compared to Compound 1 or the combination of cisplatin and pemetrexed as defined by a Bliss score of > 0 in the RET-altered LC2 cell line.

[0372] Example 6: Dose Escalation and Expansion Study

[0373] Patients are recruited to a modular, interventional Phase l / ll dose escalation and expansion study to investigate the safety, tolerability, optimal dose, and efficacy of Compound 1. Study Purpose and Rationale

[0374] There are currently no approved RET-targeted treatment options for patients who progress on first- generation SRIs (Journal of Thoracic Oncology Vol. 15 No. 4: 541-549). It is proposed that Compound 1 can overcome resistance mechanisms to first-generation selective RET inhibitors (SRIs). The available preclinical evidence indicates that Compound 1 has an activity profile that is differentiated from first-generation SRIs (selpercatinib and pralsetinib):

[0375] • Compound 1 is a potent and selective RET inhibitor with broad activity against common RET fusions and mutations (KIF5B-RET, CCDC6-RET, RET9187)

[0376] ■ Compound 1 inhibits tumour growth in a dose-dependent manner in a number of relevant in vivo xenograft models, comparing favourably with first-generation SRIs;

[0377] ■ Compound 1 is active against RET'804 E / M / Lgatekeeper mutations and RET3810 C / S / Rsolvent front mutations;

[0378] ■ Non-clinically, Compound 1 was shown to penetrate the brain and was found to extend the survival time with a numerical, but not statistical, benefit compared with both pralsetinib and selpercatinib in a mouse brain orthotopic PDX model of CR2518 (CCDC6-RET) colon cancer. Therefore, Compound 1 has the potential to have activity in brain metastases;

[0379] ■ In addition, Compound 1 has good selectivity for RET over VEGFR.

[0380] Rationale for Combination of Compound 1 with Chemotherapy

[0381] Non-clinical data (see Example 4 above) show synergy between Compound 1 and platinum-based chemotherapy, between Compound 1 and antifolate chemotherapy, and between Compound 1 and taxane chemotherapy. The study will evaluate the safety and efficacy of Compound 1 as a monotherapy in patients naive to or following prior therapy with first-generation selective RET inhibitors (SRIs) in combination with platinum-based doublet chemotherapy in patients with advanced RET fusion-positive NSCLC.

[0382] Objectives

[0383] Module A: monotherapy, dose escalation

[0384] • Primary: to investigate the safety and tolerability of Compound 1 given as monotherapy

[0385] • Secondary: to characterise the PK of Compound 1 given as monotherapy, after a single dose and at steady state after multiple dosing

[0386] • Exploratory: to assess the efficacy of Compound 1 given as monotherapy in patients with RET-altered tumours who have progressed following first-generation SRI therapy and in patients with RET-altered tumours with no prior SRI therapy (by RECIST v1 .1)

[0387] Modules B and C: monotherapy, dose expansion

[0388] • Primary: to assess the efficacy of Compound 1 given as monotherapy in patients with RET- altered tumours who have received one first-generation SRI therapy and in patients with RET- altered tumours with no prior SRI therapy (by RECIST v1 .1)

[0389] • Secondary: to investigate the safety and tolerability of Compound 1 given as monotherapy; to characterise the PK of Compound 1 given as monotherapy

[0390] • Exploratory: To assess Health related Quality of Life (HRQoL) for patients receiving Compound 1 as monotherapy Module B: chemotherapy combinations

[0391] • Primary: to assess the safety and tolerability of Compound 1 given in combination with standard of care (SoC) chemotherapy in RET fusion-positive NSCLC patients who have received a first-generation SRI therapy or who have received no prior SRI therapy

[0392] • Secondary: to investigate the efficacy of Compound 1 given in combination with SoC chemotherapy (by RECIST v1 .1); to characterise the PK of Compound 1 given in combination with SoC chemotherapy

[0393] • Exploratory: to assess HRQoL for patients receiving Compound 1 in combination with SoC chemotherapy

[0394] Modules A, B, and C

[0395] • Exploratory biomarker objectives: to assess the PD responses and mode of action of Compound 1 ; to explore the relationship between Compound 1 PK exposure and PD biomarkers; to investigate biomarkers that might predict response or resistance to Compound 1

[0396] Chemotherapy Combination

[0397] Compound 1 QD (provided as the fumarate salt) in combination with pemetrexed plus cisplatin or carboplatin as every 3 weeks for 4 cycles, followed by continuation of Compound 1 QD with pemetrexed maintenance every 3 weeks.

[0398] Compound 1 fumarate may be dosed orally at the RP2D of 60 mg or 90 mg QD (based on the weight of Compound 1). All doses should be taken on an empty stomach (at least 2 hours after and 1 hour prior to meals) and at approximately the same time each day (morning). Capsules should be swallowed whole, with water if necessary, and not chewed. Subsequent doses will be taken by the patient, at home. On visit days, any doses due to be taken should be taken while at the clinic to ensure that pre-dose blood samples can be taken. The patient will be provided with sufficient capsules to last until the next visit, detailed instructions on how the medication should be taken, and a Dosing Diary to record details of each dose taken at home. Patients will be instructed to bring all unused medication and empty study medication bottles and their Dosing Diary to each visit.

[0399] Pemetrexed will be administered after Compound 1 has been ingested. The recommended dose of pemetrexed for maintenance treatment of NSCLC in patients with a CrCI (calculated by Cockcroft- Gault equation) of 45 mL / min or greater is 500 mg / m2 as an IV infusion over 10 min on Day 1 of each 21 -day cycle until disease progression or unacceptable toxicity. In this study, pemetrexed maintenance will continue until a discontinuation criterion is met. To reduce the severity of haematological and gastrointestinal toxicity of pemetrexed, patients treated with pemetrexed must also receive vitamin B12 and folic acid supplementation as per prescribing information. To reduce the incidence and severity of skin reactions, a corticosteroid must be administered as per prescribing information.

[0400] Platinum agents may be administered as an IV infusion according to local practice and labels approximately 30 minutes after the pemetrexed infusion and should be immediately preceded and followed by hydration. Patients who are receiving platinum agents are at increased risk of developing nephrotoxicity, ototoxicity, neuropathy, myelosuppression, allergic reactions, and nausea and vomiting, and should be carefully monitored according to local standards of care. Core Study Design

[0401] The design consists of a core study protocol and individual modules. This study will consist of 3 modules:

[0402] • Module A: Monotherapy dose escalation in RET-altered solid tumours (including a paired biopsy cohort). The Compound 1 starting dose and schedule of Compound 1 in Module A was selected using non-clinical data, available clinical data from the first-in-human trial, and the FDA and ICH S9 Guideline on Non-Clinical Evaluation for Anti-Cancer Pharmaceuticals for selection of a starting dose in cancer patients.

[0403] • Module B: Dose expansion in patients who have received one first-generation SRI therapy (pralsetinib or selpercatinib) (Cohorts 1 , 3, and 5) and in patients who have had no prior SRI therapy (Cohorts 2, 4, and 6), with the following RET-altered tumours: o Cohort 1 : RET fusion-positive NSCLC (prior SRI), with 3 sub-cohorts:

[0404] ■ 1 a: prior SRI and chemotherapy (Compound 1 monotherapy)

[0405] ■ 1 b: prior SRI only (Compound 1 monotherapy)

[0406] ■ 1 c: prior SRI only (Compound 1 chemotherapy combination) o Cohort 2: RET fusion-positive NSCLC (no prior SRI), with 2 sub-cohorts

[0407] ■ 2a: SRI naive (Compound 1 monotherapy)

[0408] ■ 2b: SRI naive (Compound 1 chemotherapy combination) o Cohort 3: RET mutation-positive MTC (prior SRI) o Cohort 4: RET mutation-positive MTC (no prior SRI) o Cohort 5: other RET-altered solid tumours (prior SRI) o Cohort 6: other RET-altered solid tumours (no prior SRI)

[0409] • Module C: Further dose expansion in patients who have received one first-generation SRI therapy, in patients with RET-altered tumours: o Cohorts 1 a: RET fusion-positive NSCLC o Cohort 3: RET mutation-positive MTC o Cohort 5: other RET-altered solid tumours

[0410] Module C, Cohorts 1 a, 3, and 5 are continuations of Module B, Cohorts 1 a, 3, and 5.

[0411] Endpoints

[0412] Module A: monotherapy, dose escalation

[0413] • Primary: incidence of DLTs, AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG

[0414] • Secondary: plasma PK parameters (AUCo-48, AUCiast, AUCinf, Cmax and / or Cmin, tmax, t%, CL / F, V / F, and / or Vz / F) after single and multiple doses)

[0415] • Exploratory: Tumour response as per RECIST v1 .1 : objective response rate (ORR), best overall response (BOR), duration of response (DOR), time to response (TTR), change in tumour size, progression-free survival (PFS), overall survival (OS)

[0416] Modules B and C: monotherapy, dose expansion

[0417] • Primary: Tumour response as per RECIST v1 .1 (ORR, BOR, DOR, TTR, change in tumour size and PFS)

[0418] • Secondary: Incidence of AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG; plasma PK parameters (e.g. AUCo-48, AUCiast, AUCinf, Cmax and / or Cmin, tmax, t%, CL / F, V / F, and / or Vz / F)

[0419] • Exploratory: HRQoL scores as assessed by EORTC QLQ-C30 (all patients), EORTC QLQ- LC29 (NSCLC patients) and EORTC QLQ-THY34 (MTC patients) Module B: chemotherapy combination cohorts

[0420] • Primary: Incidence of DLTs, AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG

[0421] • Secondary: Tumour response as per RECIST v1 .1 (ORR, BOR, DOR, TTR, change in tumour size and PFS); OS; plasma PK parameters (e.g. AUCo-48, AUCiast, AUCinf, Cmax and / or Cmin, tmax, t%, CL / F, V / F, and / or Vz / F) after single and multiple doses

[0422] • Exploratory: HRQoL scores as assessed by EORTC QLQ-C30 and EORTC QLQ-LC29

[0423] Modules A, B and C

[0424] • Exploratory biomarker endpoints: biomarkers in blood (e.g. growth factors, gene expression, and ctDNA) may be examined for correlations with dose and efficacy endpoints; tumour biopsy and ctDNA may be used to determine RET gene fusions and mutations; tumour biopsy tissue may be examined for evidence of downregulation of RET pathway activation and potential mechanisms of resistance to Compound 1 ; response to Compound 1 may be assessed through determination of tumour-related biomarkers, such as calcitonin, CA 19.9, CEA, CYFRA 21-1 , thyroglobulin, and TG Abs, depending on tumour type; ctDNA may be used to monitor response through determination of levels of ctDNA during and postprogression on Compound 1 , and by monitoring the emergence of new RET alterations and other tumour-specific mutations through NGS

[0425] Inclusion Criteria

[0426] Inclusion criteria applicable to all patients:

[0427] 1 . Male or female patients > 18 years of age at the time of informed consent, with a diagnosis of advanced solid tumour

[0428] 2. Documented RET-altered cancers, as determined by DNA- or RNA-based assay of tumour tissue and / or liquid biopsy

[0429] 3. Patients with RET-altered cancers that may be eligible for the study who have not received a prior SRI should be well informed and consented about alternative treatment options, including approved RET-targeted therapies

[0430] 4. Patients with RET-altered cancers that may be eligible for the study having progressed on a prior SRI should be well informed and consented about alternative approved therapies, as applicable

[0431] 5. ECOG performance status of 0 or 1 at screening and life expectancy > 3 months

[0432] 6. Ability to swallow and retain oral medication

[0433] 7. Ability to understand and provide written informed consent before any study-specific procedures

[0434] 8. Willing to participate in all required evaluations and procedures

[0435] Inclusion criteria for Module A:

[0436] 9. Measurable or non-measurable disease as per RECIST v1 .1

[0437] 10. Patients in the paired biopsy cohort must have progressed on prior SRI and have a tumour that is accessible (provided that the Investigator judges the biopsy is technically feasible with minimal risk to the patient and with patient consent)

[0438] Inclusion criteria for Modules B and C, Cohorts 1 and 2 (NSCLC)

[0439] 11 . Measurable disease as defined by RECIST v1 .1 12. Cohort 1a (monotherapy): Patients with locally advanced or metastatic NSCLC with RET fusion who have only received one prior first-generation SRI and one line of platinum-based doublet chemotherapy ± immunotherapy (in any order)

[0440] 13. Cohort 1b (monotherapy): Patients with locally advanced or metastatic NSCLC with RET fusion who have only received one prior first-generation SRI in the front-line setting and have not received any other systemic treatment

[0441] 14. Cohort 1c (chemotherapy combination): Patients with locally advanced or metastatic NSCLC with RET fusion who are eligible to receive platinum-based doublet chemotherapy, have only received one prior first-generation SRI and have not received any other chemotherapy ± immunotherapy treatment

[0442] 15. Cohort 2a (monotherapy, first line): Patients with locally advanced or metastatic NSCLC with RET fusion and with no prior anticancer therapy

[0443] 16. Cohort 2b (chemotherapy combination, first line): Patients with locally advanced or metastatic NSCLC with RET fusion who are eligible to receive platinum-based doublet chemotherapy and with no prior anticancer therapy

[0444] Inclusion criteria for Modules B and C, cohorts 3 and 4 (MTC)

[0445] 17. Measurable disease as defined by RECIST v1 .1

[0446] 18. Cohort 3: Patients with locally advanced or metastatic MTC with RET mutation who have received one prior first-generation SRI (one multi-kinase inhibitor is permitted)

[0447] 19. Cohort 4: Patients with locally advanced or metastatic MTC with RET mutation with no prior SRI (one prior multi-kinase inhibitor is permitted)

[0448] Inclusion criteria for Module B, cohorts 5 and 6 (other solid tumours)

[0449] 20. Solid tumour measurable by RECIST v1 .1

[0450] 21 . Cohort 5: Patients with other locally advanced or metastatic solid tumours with RET fusions (tumour agnostic) who have received one prior first-generation SRI. Up to three prior lines of standard therapies are allowed

[0451] 22. Cohort 6: Patients with other locally advanced or metastatic solid tumours with RET fusions (tumour agnostic) with no prior SRI and no satisfactory alternative treatment option. Up to three prior lines of standard therapies are allowed

[0452] Inclusion criteria for paired biopsy cohort (relevant to Module B, cohorts 1 , 3 and 5, only if insufficient paired biopsies were collected in Module A):

[0453] 23. Patients who have a tumour that is accessible and this will not interfere with RECIST assessments (i.e. the patient has more than one measurable target lesion)

[0454] Exclusion Criteria

[0455] 1 . Any known major driver gene alterations other than RET. If a patient has any other significant molecular alterations besides RET, the Investigator should discuss with the Medical Monitor whether he or she can be enrolled

[0456] 2. Any other invasive malignancy that has been active or treated within the past 2 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer

[0457] 3. Any unresolved toxicities from prior systemic therapy greater than CTCAE Grade 1 at the time of starting study drug, with the exception of alopecia and Grade 2 chemotherapy-induced neuropathy

[0458] 4. Spinal cord compression or unstable brain metastases. Patients with stable brain metastases, steroid treatment and neurological status (for at least 2 weeks) after completion of definitive radiotherapy can be enrolled. Patients with asymptomatic brain metastases may be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated

[0459] 5. Active infection requiring intravenous antibiotic, antifungal, or antiviral medication within 7 days prior to first dose of Compound 1

[0460] 6. Severe or uncontrolled medical condition (e.g. severe Parkinson’s disease, active inflammatory bowel disease, severe chronic obstructive pulmonary disease, or ILD / pneumonitis - patients with a history of ILD / pneumonitis that has recovered to < Grade 1 can be enrolled after discussion with the Medical Monitor)

[0461] 7. Active bleeding diatheses; patients on anticoagulation medication should be on a stable dose

[0462] 8. Chronic glomerulonephritis or renal transplant

[0463] 9. Known active hepatitis B or C infection

[0464] 10. Patients with active HIV infection. Patients living with HIV will be eligible if they have CD4+ T- cell count > 350 cells / pL, no history of AIDS-defining opportunistic infections in the past 12 months, and can be managed on a regimen consistent with the permitted concomitant medications defined in this protocol

[0465] 11. Breastfeeding or pregnancy

[0466] 12. Receipt of any immunotherapy or antibody therapy within 21 days before the first dose of Compound 1

[0467] 13. Receipt of any systemic anticancer therapy (with the exception of immunotherapy or antibody therapy) and all forms of radiotherapy within 14 days or < 5 half-lives, whichever is shorter, before the first dose of compound 1

[0468] 14. Receipt of any strong inhibitor or inducer of CYP3A4 within 14 days or < 5 half-lives, whichever is shorter, before the first dose of compound 1

[0469] 15. Known hypersensitivity to other SRIs or to the excipients of compound 1

[0470] 16. Impaired hepatic or renal function as demonstrated by any of the following laboratory values: a) AST or ALT > 3 x ULN b) Patients with liver metastases: AST or ALT > 5 x ULN c) Total bilirubin > 1 .5 x ULN d) CrCI < 50 mL / min (based on Cockcroft Gault)

[0471] 17. Serum calcium, magnesium, or potassium below institutional LLN (can be corrected prior to enrolment)

[0472] 18. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a) ANC < 1.5 x 1O9 / L b) Platelet count < 100 x 109 / L c) Haemoglobin < 90 g / L

[0473] 19. Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (e.g. complete left bundle branch block, third-degree heart block, confirmed QTcF > 470 msec on screening ECG). Controlled AF is permitted

[0474] 20. Any factor that increases the risk of QTc prolongation or of arrhythmic events (e.g. heart failure, congenital long QT syndrome, immediate family history of long QT syndrome, or unexplained sudden death under 40 years of age or requirement for concomitant medications that are known to prolong the QTc interval and cause Torsade de Pointes within < 5 half-lives before the first dose of compound 1

[0475] 21 . Congestive heart failure Grade 111— IV according to the New York Heart Association, myocardial infarction, or unstable angina within the previous 6 months

[0476] 22. Uncontrolled hypertension (i.e. sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg)

[0477] 23. Corneal ulceration or untreated keratitis at the screening ophthalmic assessment 24. For MTC patients: involvement of the trachea or oesophagus, or complete encasement of great vessels (e.g. aorta or pulmonary artery) that could result in life-threatening complications due to rapid tumour regression

[0478] 25. Any major surgical procedure within 4 weeks of the first dose of study treatment or planned or anticipated during study treatment.

[0479] As described in European Journal of Cancer 45 (2009) 228-247, to assess objective response or future progression according to RECIST 1.1 guidelines, it is necessary to estimate the overall tumour burden at baseline and use this as a comparator for subsequent measurements. Measurable disease is defined by the presence of at least one measurable lesion. Tumour lesions are accurately measured in at least one direction (longest diameter in the plane of measurement is to be recorded) with a minimum size of:

[0480] • 10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

[0481] • 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable);

[0482] • 20 mm by chest X-ray.

[0483] For malignant lymph nodes to be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when measured by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.

[0484] All other lesions are considered non-measurable, including small lesions (longest diameter < 10 mm or pathological lymph nodes with > 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses / abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.

[0485] When more than one measurable lesion is present at baseline, all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline (this means in instances where patients have only one or two organ sites involved a maximum of two and four lesions respectively will be recorded). Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements.

[0486] A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterise any objective tumour regression in the measurable dimension of the disease.

[0487] All other lesions (or sites of disease) including pathological lymph nodes should be identified as nontarget lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form. Definitions of the criteria used to determine objective tumour response for target lesions are as follows:

[0488] • Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.

[0489] • Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0490] • Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

[0491] • Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[0492] Definitions of the criteria used to determine the tumour response for the group of non-target lesions are as follows. While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol.

[0493] • Complete response (CR): disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).

[0494] • Non-CR / non-PD: persistence of one or more non-target lesion(s) and / or maintenance of tumour marker level above the normal limits.

[0495] • Progressive disease (PD): unequivocal progression of existing non-target lesions. Unequivocal progression is an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumour burden has increase sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The appearance of one or more new lesions is also considered progression.

[0496] Results

[0497] The clinical trial is ongoing. Patients recruited into Cohort 2b (naive to other treatments, including RET inhibitors) were treated with Compound 1 fumarate salt and SoC chemotherapy. Results are presented in Table 10 below and in Figures 25a-c (patients 1-3) and 26 (patient 3) (measured tumours circled). Tumour reduction was observed in all patients receiving the combination of Compound 1 and SoC chemotherapy. A partial response was observed in all patients.

[0498] The combination of Compound 1 with SoC demonstrates acceptable tolerability. Increased liver function tests and haematological abnormalities are the most common significant adverse effects, which are managed with dose reductions, treatment interruptions or discontinuation of chemotherapy.

[0499] Pharmacokinetic data is within the expected range for all patients, compared to monotherapy patients. Table 10: Effect of Compound 1 in combination with SoC chemotherapy in lung cancer patients Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMSCompound 1 :or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof for use as a medicament, wherein the Compound 1 or the derivative thereof is for use in combination with chemotherapy.

2. Chemotherapy for use as a medicament, wherein the chemotherapy is for use in combination with Compound 1 :or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof.

3. A combination for use as a medicament, the combination comprising:(i) Compound 1 :or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and(ii) chemotherapy.

4. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-3, wherein the Compound 1 and the chemotherapy are administered simultaneously, separately, or sequentially.

5. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-4 in the treatment of a disease or condition associated with RET activity.

6. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 1-5 in the treatment of a cancer or tumour.

7. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 6, wherein the cancer or tumour is lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer, pheochromocytoma, colon cancer, multiple myeloma, melanoma, glioma, brain tumour, sarcoma, salivary gland, ovarian, pancreatic, or neuroendocrine colorectal cancer, or a metastasis thereof.

8. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 7, wherein the cancer or tumour is a solid tumour, for example, lung cancer, thyroid cancer, breast cancer, pancreatic cancer, or ovarian cancer, or a metastasis thereof.

9. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 7 or 8, wherein the cancer or tumour is non-small cell lung cancer, or a metastasis thereof.

10. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 7 or 8, wherein the cancer or tumour is medullary thyroid cancer, or a metastasis thereof.11 . The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 7 or 8, wherein the cancer or tumour is papillary thyroid cancer, or a metastasis thereof.

12. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 7 or 8, wherein the cancer or tumour is breast cancer, or a metastasis thereof.

13. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claims 7 or 8, wherein the cancer or tumour is pancreatic cancer, or a metastasis thereof.

14. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-13 in the treatment of a disease or condition which is resistant or refractory to one or more drugs.

15. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 14, wherein the disease or condition is resistant or refractory to a selective RET inhibitor (SRI).

16. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 15, wherein the drug-resistant disease or condition is resistant or refractory to selpercatinib and / or pralsetinib.

17. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-16, wherein the disease or condition is associated with wild-type RET or the disease or condition is associated with a RET alteration.

18. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-17, in the treatment of a disease or condition which is associated with a RET alteration, such as a RET fusion, a RET mutation, RET overexpression, or a combination thereof.

19. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 18, wherein the RET alteration is a RET mutation selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, V738A, M918T, V804M, V804L, V804E, and combinations thereof.

20. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 18 or 19, wherein the RET alteration is a RET fusion-type mutation selected from the group consisting of RET-CCDC6, KIF5B-RET, NCOA4-RET, RELCH-RET, ERC1-RET, TRIM33, ABHD17C-RET and combinations thereof.21 . The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to any of claims 1-20, wherein the subject to be treated has already been subjected to prior treatments for their disease or condition.

22. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 21 , wherein the subject has already been treated with chemotherapy, a multikinase (MKI) inhibitor, a selective RET inhibitor (SRI), or an immunotherapy.

23. The Compound 1 or the derivative thereof, the chemotherapy, or the combination for use according to claim 22, wherein the subject has already been treated with a selective RET inhibitor (SRI), for example selpercatinib and / or pralsetinib.

24. The Compound 1 , the chemotherapy, or the combination for use according to any of claims 1 - 23, wherein the dose of the Compound 1 or the derivative thereof is 200 mg or less, based on the weight of Compound 1 , per day.

25. The Compound 1 , the chemotherapy, or the combination for use according to claim 24, wherein the dose of the Compound 1 or the derivative thereof is 90 mg or 60 mg, based on the weight of Compound 1 , per day, preferably wherein the dose of the Compound 1 is 90 mg, based on the weight of Compound 1 , per day.

26. A combination comprising:(i) Compound 1 :or a derivative thereof selected from the group consisting of: a tautomer, or mixture of tautomers thereof; a N-oxide thereof; a pharmaceutically acceptable salt, eutecticum, polymorph, and / or solvate thereof; and / or a stable isotope derivative, metabolite, or prodrug thereof; and(ii) chemotherapy.

27. The combination of claim 26 as a combined preparation for simultaneous, separate or sequential use as a medicament.

28. The Compound 1 for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim wherein the Compound 1 is provided as a fumarate salt:

29. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises an agent which disrupts the cell cycle.

30. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises an anti-microtubule agent, a platinum agent, an alkylating agent, an antitumour antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, and / or a hormone or hormone analogue.31 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises an anti-microtubule agent, a platinum agent, and / or an antimetabolite.

32. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 31 , wherein the chemotherapy comprises a platinum agent, an antifolate, and / or a taxane.

33. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises a platinum agent.

34. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 33, wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and mirtaplatin.

35. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 34, wherein the platinum agent is cisplatin.

36. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 34, wherein the platinum agent is carboplatin.

37. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises an antifolate.

38. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 37, wherein the antifolate is selected from pemetrexed, aminopterin, methotrexate, raltitrexed, lometrexol, TNP-351 , pralatrexate, or a salt thereof.

39. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 38, wherein the antifolate is pemetrexed or a salt thereof.

40. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises a platinum agent and an antifolate.41 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 40, wherein the platinum agent is selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin, satraplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, transplatin, loboplatin, heptaplatin, and miraplatin.

42. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 41 , wherein the platinum agent is cisplatin.

43. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 41 , wherein the platinum agent is carboplatin.

44. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any of claims 40-43, wherein the antifolate is selected from pemetrexed, aminopterin, methotrexate, pralatrexate, or a salt thereof.

45. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 44, wherein the antifolate is pemetrexed or a salt thereof.

46. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy comprises a taxane.

47. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 46, wherein the taxane is selected from docetaxel, paclitaxel, abraxane (nab-paclitaxel), cabazitaxel, larotaxel, and tesetaxel.

48. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 47, wherein the taxane is docetaxel.

49. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to claim 47, wherein the taxane is paclitaxel.

50. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the chemotherapy is conjugated to an antibody, such that the chemotherapy is provided as an antibody-drug conjugate (ADC).51 . The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the Compound 1 or the derivative thereof and the chemotherapy together provides a greater therapeutic effect than the Compound 1 or a derivative thereof or the chemotherapy alone.

52. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the combination of the Compound 1 or the derivative thereof and the chemotherapy provides a synergistic therapeutic effect.

53. The Compound 1 or the derivative thereof for use, the chemotherapy for use, the combination for use, or the combination according to any preceding claim, wherein the combination of the Compound 1 or the derivative thereof and the chemotherapy results in a complete response, partial response, or stable disease according to RECIST 1.1 criteria.

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