RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/421,523, filed on November 1, 2022, U.S. Provisional Application No. 63/440,804, filed on January 24, 2023, and U.S. Provisional Application No. 63/468,875, filed on May 25, 2023. The entire contents of each of the above-referenced applications are incorporated herein by reference.

BACKGROUND

Lung cancer is the second most common cancer worldwide and the leading cause of cancer deaths. In 2020, lung cancer accounted for over 2 million new global cancer diagnoses and over 1 million deaths. Non-small cell lung cancers (NSCLCs) make up approximately 80% of all lung cancers, with adenocarcinoma being the most common histology. While the most common causes of lung cancer are smoking and exposure to other environmental toxins, oncogenic driver mutations are frequently present and provide an opportunity for targeted therapy.

Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase which is activated by epidermal growth factor ligand. In a subset of NSCLC and certain other tumors, specific mutations in the EGFR gene result in ligand-independent receptor activation and drive uncontrolled tumor cell survival and proliferation. The incidence of EGFR mutations in NSCLC varies by location and ethnicity. According to a study in 2021, EGFR mutations are most common in adenocarcinomas, which comprise approximately 40% of all lung cancers, and are enriched in women, Asian populations, and non-smokers. Epidermal growth factor receptor-associated lung cancers have a predilection for CNS metastases, with approximately 25% of patients having brain metastases at initial presentation and up to 50% at some time during the course of their disease.

Comprehensive genomic profiling of tumor samples from 14,483 NSCLC cases in the course of clinical care identified 2,251 cases with EGFR mutations. EGFR Exon 19 deletions (47%) and EGFR L858R (32%) were the most common EGFR mutations. Uncommon EGFR mutations were identified, such as G719X (4%), L861Q (2%), and S768I (1%), as well as cases with compound EGFR-activating mutations (2%). Two hundred and sixty-three of the 2,251 mutant EGFR cases harbored Exon 20 insertion, representing 12% of all EGFR-mutant NSCLC and 1.8% of all NSCLC, making it the third most common type of oncogenic EGFR mutation (Riess JW, et al. J Thorac Oncol. 2018;13: 1560-8).

Epidermal growth factor receptor Exon 20 insertion mutations (Ex20ins) are characterized by inframe mutations leading to insertions of 1 to 7 amino acids across a span of approximately 15 amino acids. In addition to NSCLC, EGFR Ex20ins are found in a small percentage of urothelial and endometrial cancers, glioblastomas, sinonasal cancers, and pediatric bithalamic gliomas. Like other EGFR-mutated NSCLCs, approximately one quarter of patients with EGFR Ex20ins have brain metastases at the time of initial presentation.

Because of their unique structural characteristics, EGFR Ex20ins are generally insensitive to the first three generations of EGFR tyrosine kinase inhibitors (TKIs). Standard of care for first-line metastatic disease therefore remains platinum-based chemotherapy. The role of immune checkpoint inhibitors remains poorly defined. For patients with EGFR Ex20ins and progression after platinum-based chemotherapy, standard of care has recently changed with the approval of two agents, amivantamab and mobocertinib. Both agents received accelerated approval from the US FDA as treatment for NSCLC with EGFR Ex20ins that has progressed on or after platinum-based chemotherapy. Although the development of targeted TKIs such as amivantamab and mobocertinib for NSCLC with EGFR mutations has led to significant improvement in patient outcomes, there still remains a significant unmet need, particularly for patients with EGFR Ex20ins with and without brain metastases. Over half of patients treated with either amivantamab or mobocertinib in clinical trials did not achieve an objective response, and both agents have yet to demonstrate a survival benefit. Further, neither drug has demonstrated meaningful CNS activity, and tolerability remains a concern. Thus, there is a need for new methods of treating EGFR Ex20ins non-small cell lung cancer with a highly CNS penetrant agent administered in a safe and effective oral dose.

International Application Publication WO 2022/094354, the entire teachings of which are incorporated herein by reference, discloses Compound I, shown below (also referred herein as “BLU-451”.

Compound (I) is a CNS-penetrant, irreversible small molecule inhibitor of EGFR designed to have greater selectivity for oncogenic EGFR Ex20ins and certain other EGFR point mutations relative to WT EGFR.

SUMMARY

Disclosed herein are improved methods for treating a subject with NSCLC, including EGFR Ex20ins and other EGFR mutations with Compound (I) or a pharmaceutically acceptable salt thereof. The disclosure provides dosing regimens of Compound (I) or a pharmaceutically acceptable salt there for the treatment of non-small cell lung cancer. More specifically, the disclosure provides methods for treating a subject with a non-small cell lung cancer characterized by EGFR Ex20ins or certain other EGFR mutations by administering Compound (I) orally in an amount of 100 mg to 800 mg daily. Alternatively, Compound (I) is administered orally in an amount of 100 mg to 800 mg once daily. Alternatively, Compound (I) is administered orally in an amount of 100 to 800 mg twice daily (The total daily amount administered 100 mg to 800 mg). An object of this disclosure is to provide new methods of treating a subject with a non-small cell lung cancer characterized by EGFR mutations described herein with a safe and effective once or twice daily dose. For example, 100-800 mg QD or 100-400 mg BID.

Embodiment 1. A method of treating a subject with a non-small cell lung cancer (NSCLC) characterized by an epidermal growth factor receptor (EGFR) mutation, comprising administering to a subject in need thereof an amount of 100 mg to 800 mg of Compound (I): pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 800 mg of Compound (I).

Embodiment 2. The method of embodiment 1, wherein the subject in need thereof is administered an amount of Compound (I) or a pharmaceutically acceptable salt thereof once a day orally. For example, Compound (I) is administered lOOmg, 200mg,

300mg, 400mg, 500 mg, 600 mg, 700mg, or 800 mg QD.

Embodiment 3. The method of embodiment 1, wherein the subject in need thereof is administered an amount of Compound (I) or a pharmaceutically acceptable salt thereof twice a day orally. For example, Compound (I) is administered lOOmg, 200mg,

300mg, or 400mg BID.

Embodiment 4. The method of any one of embodiments 1-3, wherein the epidermal growth factor receptor (EGFR) mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.

Embodiment 5. The method of embodiment 4, wherein the non-small cell lung cancer is characterized by epidermal growth factor receptor (EGFR) exon 20 insertion.

Embodiment 6. The method of embodiment 5, wherein the EGFR exon 20 insertion is selected from A763_Y764insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, H773_V774insX, and V774_C775insX.

Embodiment 7. The method of embodiment 4, wherein the EGFR mutation is selected from dell9/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insAS V EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. Embodiment 8. The method of embodiment 4, wherein the ECrEK mutation is exon 18

G719X or exon 21 L861Q.

Embodiment 9. The method of any one of embodiments 1-8, wherein the non-small cell cancer has progressed after one or more prior systemic therapies.

Embodiment 10. The method of any one of embodiments 1-9, wherein the subject is with brain metastases.

Embodiment 11. The method of any one of embodiments 1-9, wherein the subject is without brain metastases.

Embodiment 12. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 100 mg to 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 400 mg of Compound (I).

Embodiment 13. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 100 mg to 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 500 mg of Compound (I).

Embodiment 14. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 100 mg to 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 600 mg of Compound (I).

Embodiment 15. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 100 mg to 400 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, or 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 400 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, or 600 mg to 800 mg, or 700 mg to 800 mg of Compound (I).

Embodiment 16. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound (I).

Embodiment 17. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 200 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg of Compound (I). For example, the dosage is 200 mg QD. In another example, the dosage is 100 mg BID.

Embodiment 18. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 300 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 300 mg of Compound (I). For example, the dosage is 300 mg QD. In another example, the dosage is 150 mg BID.

Embodiment 19. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 400 mg of Compound (I). For example, the dosage is 400 mg QD. In another example, the dosage is 200 mg BID.

Embodiment 20. The method of any one embodiments 1-11, wherein the subject in need thereof is administered an amount of 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 500 mg of Compound (I). For example, the dosage is 500 mg QD. In another example, the dosage is 250 mg BID.

Embodiment 21. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 600 mg of Compound (I). For example, the dosage is 600 mg QD. In another example, the dosage is 300 mg BID.

Embodiment 22. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 700 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 700 mg of Compound (I). For exxample, the dosage is 700 mg QD. In another example, the dosage is 350 mg BID.

Embodiment 23. The method of any one of embodiments 1-11, wherein the subject in need thereof is administered an amount of 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 800 mg of Compound (I). For example, the dosage is 800 mg QD. In another example, the dosage is 400 mg BID.

Embodiment 24. The method of any one of embodiments 1-23, wherein Compound (I) is administered as the free base.

Embodiment 25. The method of any one of embodiments 1-23, wherein a pharmaceutically acceptable salt of Compound (I) is administered.

Embodiment 26. The method of embodiment 25, wherein the pharmaceutically acceptable salt is a mesylate salt of Compound (I), wherein the molar ratio between Compound (I) and methanesulfonic acid is 1 : 1

Embodiment 27. The method of any one of embodiments 1-26, wherein the non-small cell lung cancer is characterized by epidermal growth factor receptor (EGFR) atypical mutations including, but not limited to, G719X, L861Q, and S768I.

Embodiment 28. The method of any one of embodiments 1-27, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with a platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed.

Embodiment 29. The method of any one of embodiments 1-28, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject who have previously received platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed.

Embodiment 30. The method of any one of embodiments 1-28, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject who have previously received platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed, and one or both of amivantamab and mobocertinib.

Embodiment 31. The method of any one of embodiments 1-30, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject with food.

Embodiment 32. The method of any one of embodiments 1-30, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject without food.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 A shows a baseline PET scan of the lungs of a patient with EGFR Ex20in

NSCLC. Figure IB shows a PET scan of the same patient in Figure 1 A atter treatment for 6 weeks with Compound (I) at 200 mg once daily

Figure 2 shows the schematic of phase 1/2 study of BLU-451 in advanced cancers with EGFR Exon20 insertions mutations.

Figure 3 shows mean BLU-451 plasma concentrations versus time after once daily (QD) dosing of 100-400 mg or BID dosing of 200 mg or 300 mg.

Figure 4A shows reduction and clearance of cDNA at Day 15 in patients with ex20ins mutations. Figure 4B shows tumor reduction in patients with ex20ins mutations.

Figure 5 A shows reduction and clearance of cDNA at Day 15 in patients with atypical EGFR mutations. Figure 5B shows tumor reduction in patients with typical EGFR mutations.

Figure 6 shows PET scans of liver segments and brain lesions at baseline v. at week 7 in patent #1.

DETAILED DESCRIPTION

Methods of Treatment

The present disclosure provides a method of treating a subject with a non-small cell lung cancer (NSCLC) characterized by an EGFR mutation, including EGFR Ex20 and certain other EGFR mutation comprising administering to the subject in need thereof orally an amount of 100 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 800 mg of Compound (I), or a pharmaceutical composition disclosed comprising the same daily.

The term “pharmaceutically-acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

Compound (I) disclosed herein can be useful in the form of a free base or as a salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, mesylate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

In some embodiments, in the methods of treatment disclosed herein, Compound (I) is administered as the free base. In some embodiments, in the methods of treatment disclosed herein, a pharmaceutically acceptable salt of Compound (I) is administered.

When the stereochemical configuration at a chiral center in Compound (I) is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

In some embodiments, the NSCLC in the subject in need thereof has metastasized (e.g. to the brain).

In some embodiments, NSCLC in the subject is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology and NSCLC with non- squamous histology. In some embodiments, the NSCLC in the subject is incurable recurrent or metastatic cancer with EGFR Ex20ins. In some embodiments, EGFR Ex20ins mutations include, but are not limited to, A763_Y764insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, H773_V774insX, and V774_C775insX. In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and asymptomatic active CNS metastases. In some embodiments, the NSCLC in the subject is with other selected EGFR mutations, including EGFR Exon 18 G719X (G719A, G719S, G719C, G719R, G719D, or G719V) or Exon 21 L861Q. In some embodiments, the NSCLC in the subject is characterized by EGFR atypical mutations including, but are not to, G719X (G719A, G719S, G719C, G719R, G719D, or G719V), L861Q, and S768I.

In some embodiments, Compound (I) is administered in combination with a platinumbased chemotherapy, including, but not limited to, carboplatin and pemetrexed. In some embodiments, Compound (I) is administered in combination with an effective amount of carboplatin and an effective amount of pemetrexed. In some embodiments, carboplatin is administered intravenously with a standard dose used for the treatment of NSCLC. In some embodiments, carboplatin is administered with a dose that achieves a plasma AUC (area under the curve) 5-6 mg/mL-min. In some embodiments, pemetrexed is administered intravenously with a standard dose used for the treatment of NSCLC. In some embodiments, pemetrexed is administered with a daily dose of 500 mg/m ² .

In some embodiments, the subject being treated by the methods described herein has previously received a platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed. In some embodiments, the subject being treated by the methods described herein has previously received a platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed, and one or both amivantamab and mobocertinib. In some embodiments, the subject being treated by the methods described herein has previously received a platinum-based chemotherapy, including, but not limited to, carboplatin and pemetrexed, and one or more ex20ins EGFR inhibitors, including, but no limited to, amivantamab, mobocertinib, zipalertinib (CLN-081), sunvozertinib (DZD-9008) and poziotinib. In some embodiments, the subject being treated by the methods described herein has previously received one or more other chemotherapy agents, including, but not limited to pembrolizumab.

In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and at least one atypical mutations, including, but not limited to EGFR G719X and L861Q. In some embodiments, the subject has previously received standard of care systemic therapies.

Standard of care for metastatic NSCLC has been dramatically changed by the identification of molecular targets leading to the development of effective targeted therapies, as well as by the introduction of immune checkpoint inhibitors (ICIs). For NSCLC without EGFR or other selected oncogenic driver mutations, treatment of metastatic disease with an ICI-based regimen is the preferred initial therapeutic approach. However, for patients with activating EGFR mutations, current treatment guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend treatment with a targeted TKI and chemotherapy before considering an ICI (Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, Version 7. J Natl Compr Cane Netw. 2021; Hanna NH, Robinson AG, Temin S, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2021;39(9): 1040-91; Hanna NH, Schneider BJ, Temin S, et al. Therapy for Stage IV Non- Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2020;38(14): 1608-32). This recommendation is based on retrospective analyses that suggest lower response rates and lower survival rates with ICIs in patients with EGFR-driver mutations as well as limited availability of randomized clinical trial data. Standard treatment for metastatic NSCLC with common EGFR mutations (L858R or Exon 19 deletions) utilizes an EGFR-targeted TKI. Recommended first-line treatment is the third- generation TKI osimertinib (Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, Version 7. J Natl Compr Cane Netw. 2021; Hanna NH, Robinson AG, Temin S, et al. Therapy for Stage IV Non- Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol. 2021;39(9): 1040-91). For patients with EGFR Ex20ins and progression after platinum-based chemotherapy, standard of care has recently changed with the approval of two agents, amivantamab and mobocertinib. Amivantamab is a bispecific EGFR-MET targeted antibody that received accelerated approval from the US FDA as treatment for NSCLC with EGFR Ex20ins that has progressed on or after platinum-based chemotherapy. Mobocertinib is a TKI that also received accelerated approval from the US FDA as treatment for NSCLC with EGFR Ex20ins that has progressed on or after platinumbased chemotherapy.

In some embodiments, the NSCLC in the subject is with EGFR Exon 19 deletion or L858R mutation and the subject is treated with an effective amount (e.g., any of the amounts described herein) of Compound (I) or a pharmaceutically acceptable salt thereof (e.g., mesylate salt) in combination with an effective amount of carboplatin and an effective amount of pemetrexed. In some embodiments, the subject has previously received a third- generation EGFR TKI, such as osimertinib, nazartinib, or avitinib. In some embodiments, carboplatin is administered intravenously with a standard dose used for the treatment of NSCLC. In some embodiments, carboplatin is administered with a dose that achieves a plasma AUC (area under the curve) of 5-6 mg/mL-min. In some embodiments, carboplatin is administered every 3 weeks. In some embodiments, pemetrexed is administered intravenously with a standard dose used for the treatment of NSCLC In some embodiments, pemetrexed is administered with a daily dose of 500 mg/m ² . In some embodiments, pemetrexed is administered every 3 weeks.

In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has previously received platinum -based chemotherapy, including, but not limited to carboplatin and pemetrexed. In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has previously received platinum -based chemotherapy, including, but not limited to, carboplatin and pemetrexed, and one or both of amivantamab and mobocertinib. In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has previously received platinum -based chemotherapy, including, but not limited to carboplatin and pemetrexed, and the subject has not previously received any EGFR Ex20ins-targeted therapy. As used herein, EGFR Ex20ins-targeted therapy is an effective treatment for patients with EGFR Ex20ins. In some embodiment, EGFR Ex20ins-targeted therapy is an effective treatment for patients with EGFR Ex20ins and progression after platinum-based chemotherapy. Exemplary EGFR Ex20ins-targeted therapy includes, but is not limited to, amivantamab and mobocertinib.

In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has measurable brain lesion(s) by RECIST vl.l (see E.A. Eisenhauer et al. , New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), European Journal of Cancer, 45 (2009), 228-247) and has previously received platinum-based chemotherapy including, but not limited to, carboplatin and pemetrexed. In some embodiments, the subject has not previously received any Ex20ins-targeted therapy. In some embodiments, the subject has previously an Ex20ins-targeted therapy

In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has previously received platinum -based chemotherapy including, but not limited to, carboplatin and pemetrexed, and both amivantamab and mobocertinib. In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has previously received platinum-based chemotherapy including, but not limited to, carboplatin and pemetrexed, and an investigational Ex20ins targeted agent.

In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the treatment with Compound (I) or a pharmaceutically acceptable salt thereof is the first-line treatment. In some embodiments, the NSCLC in the subject is with EGFR Ex20ins and the subject has not previously received any treatment for metastatic NSCLC.

In some embodiments, the NSCLC in the subject is with one or more EGFR atypical mutations, In some embodiments, the NSCLC in the subject is with one or more EGFR atypical mutations, including, but not limited to, G719X (G719A, G719S, G719C, G719R, G719D, or G719V), L861Q and S768I, and the subject has previously received one or more EGFR TKI.

In some embodiments, the NSCLC in the subject is with one or more EGFR atypical mutations, including, but not limited to, G719X (G719A, G719S, G719C, G719R, G719D, or G719V), L861Q and S768I, and the treatment with Compound (I) or a pharmaceutically acceptable salt thereof is the first-line treatment. In some embodiments, the NSCLC in the subject is with one or more EGFR atypical mutations, including, but not limited to, G719X, L861Q and S768I, and the subject has not previously received any treatment tor metastatic NSCLC.In a particular embodiment, the deletions, mutations, and insertions disclosed herein are detected by an FDA-approved test.

A person of ordinary skill in the art can readily determine the certain EGFR alterations a subject possesses in a cell, cancer, gene, or gene product, e.g., whether a subject has one or more of the mutations or deletions described herein using a detection method selected from those known in the art such as hybridization-based methods, amplificationbased methods, microarray analysis, flow cytometry analysis, DNA sequencing, nextgeneration sequencing (NGS), primer extension, PCR, in situ hybridization, fluorescent in situ hybridization, dot blot, and Southern blot.

To detect one or more EGFR deletions and/or mutations, a primary tumor sample, circulating tumor DNA (ctDNA), circulating tumor cells (CTC), and/or circulating exosomes may be collected from a subject. The samples are processed, the nucleic acids are isolated using techniques known in the art, then the nucleic acids are sequenced using methods known in the art. Sequences are then mapped to individual exons, and measures of transcriptional expression (such as RPKM, or reads per kilobase per million reads mapped), are quantified. Raw sequences and exon array data are available from sources such as TCGA, ICGC, and the NCBI Gene Expression Omnibus (GEO). For a given sample, individual exon coordinates are annotated with gene identifier information, and exons belonging to kinase domains are flagged. The exon levels are then z-score normalized across all tumors samples. ctDNA is being increasingly adopted as a method to monitor response to treatment and emergence of resistance in clinical practice. Clearance of ctDNA after 6-8 weeks of treatment is predictive of TKI benefit while increases in ctDNA or appearance of new mutations has been associated with progression (Ku BM et al. Oncology. 2022; Epub ahead of print. PMID: 35196661; Ma L. et al. Front Oncol. 2021; 11 :643199; Fernandes et al. Cells. 2021;10:1912.).

Compound (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions disclosed herein may be used for treating to a subject who has become resistance to treatment with one or more other EGFR inhibitors. “Resistance” means that the subject’s cancer previously responded to drugs but later responds poorly or not at all. In some embodiments, the subject has become refractory to one or more first generation EGFR inhibitors such as erlotinib, gefitinib, icotinib or lapatinib. In some embodiments, the subject has been become refractory to treatment with one or more second generation EGFR inhibitors such as afatinib, dacomitinib, poziotinib, or neratinib. In some embodiments the subject has become refractory to treatment with one or more first generation inhibitors and one or more second generation inhibitors. In some embodiments, the subject has become refractory to treatment with one or more third generation inhibitors such as osimertinib, nazartinib, or avitinib. In one embodiment, the subject has become refractory to treatment with one or more first generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more second generation EGFR inhibitors and one or more third generation EGFR inhibitors. In some embodiments, the subject has become refractory to treatment with one or more first generation inhibitors, and one or more third generation EGFR inhibitors.

In some embodiments, Compound (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions disclosed herein may be used for treating to a subject who has received other NSCLC treatment prior to the treatment with BLU-451 described herein. In some embodiments, the subject has been treated with platinum -based including, but not limited to, carboplatin and pemetrexed. In some embodiment, the subject has been treated with at least one of amivantamab and mobocertinib. In some embodiment, the subject has been treated with an ex20in-targeted therapy.

Pharmaceutical Compositions

In certain embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered as a pure chemical. In other embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least Compound (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers. One embodiment provides a pharmaceutical composition comprising a Compound (I) and a pharmaceutically acceptable excipient.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

“Treating” or “treatment” refers to obtaining a desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or substantially reducing the extent of the disease, condition or tumor/cancer; ameliorating or improving a clinical symptom or indicator associated with the disease, condition or cancer; delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or cancer; or decreasing the likelihood of recurrence of the disease, condition or cancer.

The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the tumor of the cancer being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day).

As used herein, the term “subject” or “patient” refers to an organism to be treated by the methods of the disclosure. Non-limiting example organisms include mammals, e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like. In some embodiments, the organism is a human.

As used herein, a “once daily dose” (or QD dose) refers to the total daily amount of Compound (I) or a pharmaceutically acceptable salt thereof being administered, wherein the compound or a pharmaceutically acceptable salt thereof is administered once during the day.

As used herein, unless specified otherwise, the term “twice daily dose” refers to the total daily amount of Compound (I) or a pharmaceutically acceptable salt thereof being administered, wherein the compound or a pharmaceutically acceptable salt thereof is administered at two different times during the day. For example, a twice daily dose of 600 mg of Compound (I) means that the compound is administered at two different times during the day and the total amount of the compound administered is 600 mg. In an exemplary embodiment, a twice daily dose of Compound (I) can be administered two times during the day with equal amount of the compound each time (i.e., a BID dose). For example, a twice daily dose of 600 mg can be administered as 300 mg dose two times during the day (i.e., 300 mg BID). As used herein, a BID dose means the amount being given to the patient twice during the day with the total daily dosage amount being two times of the BID dose. For example, a BID dose of 300 mg means that 300 mg of Compound (1) is given to a patient twice during the day with the total daily dosage being 600 mg.

In some embodiments, the subject in need thereof is administered a once daily dose of 100 mg to 200 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 100 mg to 200 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 200 mg to 300 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 200 mg to 300 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 300 mg to 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 300 mg to 400 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 400 mg to 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 400 mg to 500 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 500 mg to 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 500 mg to 600 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 600 mg to 700 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 600 mg to 700 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 700 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 700 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 100 mg to 200 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 100 mg to 200 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 200 mg to 300 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 200 mg to 300 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 300 mg to 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 300 mg to 400 mg of Compound (I). In some embodiments, the subject in need thereof is administered a twice daily dose of 400 mg to 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once twice dose of 400 mg to 500 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 500 mg to 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 500 mg to 600 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 600 mg to 700 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 600 mg to 700 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 700 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 700 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a once daily dose of 100 mg to 250 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 100 mg to 250 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a once daily dose of 200 mg to 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 200 mg to 400 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a once daily dose of 400 mg to 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 400 mg to 600 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a once daily dose of 400 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 400 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a once daily dose of 600 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 600 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered a twice daily dose of 100 mg to 250 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 100 mg to 250 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a twice daily dose of 200 mg to 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 200 mg to 400 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a twice e daily dose of 400 mg to 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 400 mg to 600 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a twice daily dose of 400 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 400 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of a twice daily dose of 600 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose of 600 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 100 mg to 200 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, or 600 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 200 mg, 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, or 600 mg to 800 mg of Compound (I). In some embodiments, the amount is administered once daily. In some embodiments, the amount is administered twice daily, where in the total daily dosage is 100 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 100 mg, 125 mg, 150 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg, 125 mg, 150 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound (I). In some embodiments, the amount is administered once daily. In some embodiments, the amount is administered twice daily, where in the total daily dosage is 100 mg to 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg to 800 mg of Compound (I) . In some embodiments, the subject in need thereof is administered an amount ot 100 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 200 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 300 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 300 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 400 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 500 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 600 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 700 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 700 mg of Compound (I).

In some embodiments, the subject in need thereof is administered an amount of 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 800 mg of Compound (I).

In some embodiments, the subject in need thereof is administered Compound (I) or a pharmaceutically acceptable salt thereof once daily orally with the amount identified above.

As used herein, unless specified otherwise, administering an amount of “xx mg” of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to “xx mg” of Compound (I) “twice daily” or “twice a day” refers to administrating Compound (I) in a twice daily dose of “xx mg” or a pharmaceutically acceptable salt thereof in an amount equivalent to a twice daily dose “xx mg” of Compound (I), i.e., administering the compound or a pharmaceutically acceptable salt thereof two times daily and the total amount of the two administrations is equal to “xx mg” for Compound (I) or an amount equivalent to “xx mg” of Compound (I) for the pharmaceutically acceptable salt. Moreover, the administering an amount of “xx mg” of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to “xx mg” of Compound (I) “twice daily” or “twice a day” can also be represented as a BID dose, in which the total daily dosage of “xx mg” of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to “xx mg” of Compound (I) would be administered in two equal doses of (0.5)xx mg for Compound (I) or a dose equivalent to (0.5)xx mg for a pharmaceutically acceptable salt thereof during the day to arrive at the total daily dose of xx mg of Compound (I) or a total daily dose equivalent to xx mg of Compound (I) for the pharmaceutically acceptable salt thereof.

In some embodiments, the subject in need thereof is administered an amount of 100 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of Compound (I) twice daily. The total daily amount is 100 mg. For example, 50 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 200 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg of Compound (I) twice daily. The total daily amount is 200 mg. For example, 100 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 300 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 300 mg of Compound (I) twice daily. The total daily amount is 300 mg. For example, 150 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 400 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 400 mg of Compound (I) twice daily. The total daily amount is 400 mg. For example, 200 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 500 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 500 mg of Compound (I) twice daily. The total daily amount is 500 mg. For example, 250 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 600 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 600 mg of Compound (I) twice daily. The total daily amount is 600 mg. For example, 300 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 700 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 700 mg of Compound (I) twice daily. The total daily amount is 700 mg. f or example, 350 mg BID dose.

In some embodiments, the subject in need thereof is administered an amount of 800 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 800 mg of Compound (I) twice daily. The total daily amount is 800 mg. For example, 400 mg BID dose.

The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration to human beings.

Typically, for oral therapeutic administration, a compound of the disclosure or a pharmaceutically acceptable salt thereof may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.

EXEMPLIFICATION

Example 1

This is a Phase 1/2, open-label study of the safety, PK, pharmacodynamics, and antitumor activity of single-agent Compound (I) as a pharmaceutically acceptable salt. All references to “Compound (I)” in this example refer to the pharmaceutically acceptable mesylate salt of Compound (I). All patients will receive Compound (I) as a single agent administered QD or BID on a 21 -day treatment cycle. Phase 1 is an open-label, 3+3 dose-escalation and cohort expansion study in patients with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that has progressed after prior systemic therapies. Phase 1 will be conducted in two parts.

Part 1 Dose-Escalation

In Part 1, 2 to 6 evaluable patients per dose cohort are enrolled to determine the MTD or RP2D of single agent Compound (I). In addition to prespecified dose levels, additional cohorts may be added to evaluate intermediate dose levels or a BID dosing schedule. A 3+3 design is used to define the MTD for Compound (I) treatment in 21 -day cycles. The MTD is defined as the highest tested dose level at which at least 6 evaluable patients have been treated and which is associated with a DLT within the first 28 days of treatment in < 33% of patients.

Dose escalation will begin using a QD dosing schedule. An evaluation of a BID dosing using a 3+3 design for dose escalation may also be considered. The initial dose to be evaluated using BID dosing will not exceed a total daily dose that has been found to be safe using the QD schedule (i.e., 0/3 or 0-1/6 patients have experienced a DLT at that dose).

Patient Vignette from Part 1

The patient is a 63-year-old female with EGFR Ex20ins NSCLC. She was previously treated with 3 lines of therapy carboplatin/pemetrexed/pembro (discontinued for progression), CLN-081 (discontinued for toxicity) and BDTX-189 (discontinued for progressive disease). She enrolled at 200 mg QD and the only related adverse event is grade 1 rash. The patient has a confirmed partial response (PR). Figures 1 and 2 show a tumor decrease of -58% decrease at cycle 2. .

Example 2

This is a Phase 1/2, open-label first-in-human study of the safety, pharmacokinetics (PK), pharmacodynamics, and anti -tumor activity of BLU-451 monotherapy and BLU-451 in combination with platinum-based chemotherapy (carboplatin and pemetrexed). Figure 2 shows the study schematic. All patients will receive BLU-451 on a 21 -day treatment cycle. The study will include two portions. An initial Phase 1 portion will enroll patients with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that have progressed after prior systemic therapies and will determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-451 as monotherapy (Part 1A dose-escalation; Part 2 enrichment), as well as an additional Part IB dose-escalation (in the USA only) to determine the MTD and/or RP2D of BLU-451 in combination with carboplatin and pemetrexed. A Phase 2 portion will further evaluate the efficacy and safety of BLU-451 as monotherapy in patients with NSCLC.

Phase 1 Part 1 A utilizes 3+3 dose-escalation design, 2 to 6 evaluable patients per dose cohort will be enrolled to determine the MTD and/or RP2D of single-agent BLU-451. Phase 1 Part 2 may enroll additional patients in Dose Enrichment Cohorts to further evaluate safety and PK at a given dose level or in specific sub-populations of patients, once a dose has been found to be safe in Part 1 A (< 1/6 patients with DLT), based upon the recommendation of the Sponsor and SRC.

Phase 1 Part IB will utilize BOIN design and enroll patients with EGFR mutant NSCLC (Ex 19 del or L858R) and treated with at least one prior 3rd line generation EGFR TKI, such as osimertinib. Dose escalation or de-escalation will be conducted based on observation of DLT during the first 21 -day treatment cycle. The first cohort will receive BLU 451 at approximately 50% of the BLU-451 monotherapy RP2D, in combination with standard doses of carboplatin and pemetrexed. Dose escalation will not proceed beyond the BLU-451 monotherapy RP2D. The total number of patients evaluable for DLT for any given dose level should not exceed 12, and dose escalation will be considered complete when 12 patients are evaluable for DLT at one dose level. The MTD will be determined based on isotonic regression, while the RP2D, which will not exceed the MTD, may be selected with consideration to all clinical data, including safety, PK, PD, and antitumor activity. Enrichment Cohorts to further evaluate safety and PK at a given dose level or in specific subpopulations of patients can also be open, once a dose has been found to be safe, based upon the recommendation of the Sponsor and SRC.

Phase 2 will evaluate the anti -tumor activity of BLU-451 monotherapy administered at the RP2D in patients with metastatic non-small cell lung cancer (NSCLC) with EGFR Ex20ins or atypical mutations.

Eligibility for both Phase 1 and 2 will be based on the presence of EGFR Ex20ins (or other mutation per the eligibility criteria) as determined by local assessment of new or archival tumor biopsies or circulating tumor DNA (ctDNA).

All patients will be required to provide an archived or new tumor biopsy and blood sample for retrospective central review and exploratory analyses of potential biomarkers of activity and response.

Safety will be monitored through the collection of adverse events (AEs), physical examinations, vital signs, and assessment of clinical laboratory values. Electrocardiograms (ECGs) will also be collected for central review. Safety data will be reviewed throughout the study by the study Medical Monitor and by the study Safety Review Committee (SRC), comprised of the Sponsor Medical Monitor and the Principal Investigators from sites participating in Phase 1 dose escalation.

Pharmacokinetics will be assessed by evaluating plasma levels of BLU-451 in Cycle 1 and periodically in subsequent cycles. Plasma samples may also be evaluated for the presence of metabolites of BLU-451. Efficacy will be assessed using standard Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247) with assessments performed every 6 or 12 weeks. All patients will be required to undergo a baseline brain magnetic resonance imaging (MRI) scan. Central nervous system efficacy in patients with baseline brain metastases will be evaluated using both the RECIST vl .1 and the Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) Criteria (Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the Response assessment in Neuro-Oncology (RANO) Working Group. Lancet Oncology 2015;16:e270-78). Tumor biomarkers may be collected, but documentation of progression will require radiologic evidence of progression or unequivocal demonstration of clinical progression.

Example 3

Patients were enrolled and treated with BLU-451 in the Phasel/2 study described in Example 2. Key eligibility of the patients include i) adults with metastatic NSCLC ex20ins or other select EGFR mutations (as determined by local next-generation sequencing (NGS) testing for ctDNA profiling); ii) ECOG PS 0-1; iii) asymptomatic CNS metastases allowed; iv) no other known oncogenic drivers; and v) progression on or after intolerance to the most recent systemic therapy. Prior platinum-based chemotherapy was required for patients with ex20ins and >1 EGFR tyrosine kinase inhibitor was required for patients with atypical mutations. Prior ex20ins-targeted therapy was allowed but not required for patients with ex20ins mutations.

As of data cut-off (April 21, 2023), 59 patients were treated with BLU-451 monotherapy in phase 1 (Part 1 A + Part 2) at total daily doses of 100 mg to 600 mg fasted (N=54) and 100 mg to 200 mg with food (N=5) (Table 1). Of patients with ex20ins (n=48), 54% had 3 or more prior systemic therapies, and 75% received prior ex20ins-targeted agents. Of patients with atypical mutations (n=9), 67% had 3 or more prior systemic therapies.

Table 1: Demographics and baseline characteristics (April 21, 2023 cut-off date) aTwo patients were not included in this table: 1 with ex20ins and 1 with L861 Q EGFR mutations. bMutations included A763_Y764insX, V769_D770insX, D770_N771 InsX, N771_P772insX, P772_H773insX, H773_V774insX, V774_C775insX, and others. cMutations included G719X, L861 Q, and others.

CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ex20ins, exon 20 insertion; RECIST v1 .1 , Response Evaluation Criteria in Solid Tumors version 1 .1 . dECOG Performance Status (ECOG PS) (https://training.seer.cancer.gov/followup/procedures/datase t/ecog.html): grade 0 - Fully active, able to carry on all pre-disease performance without restriction; grade 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

Pharmcokinetics (April 21, 2023 cut-off date)

In early escalation, dose-dependent increases in plasma exposure to BLU-451 were observed from 100 to 400 mg QD and from 200 mg to 300 mg BID (Figure 3). BLU-451 200 mg BID achieved similar exposure to 400 mg QD at steady state (Day 15), based on estimated plasma AUC _{0 24} values Mean plasma elimination half-life ranged from 12 to 25 hours. Protocol was amended to initiate dose escalation with food to explore the effect of food on PK as a part of RP2D optimization.

BLU-451 activity in EGRFm e20ins NSCLC (April 21, 2023 cut-off date) During dose escalation, evidence of on-target activity via circulating tumor DN A (ctDNA) was observed, with reduction and clearance of ctDNA at Day 15 in patients with ex20ins mutations (Figure 4A). Early evidence of tumor reduction was observed in efficacy- evaluable patients (Figure 4B). Confirmed partial responses (PR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST vl. l) were seen. Early evidence of meaningful CNS antitumor activity was also seen (Figure 4B, patient cases 1 and 2).

BLU-451 activity in atypical EGFRm NSCLC (April 21, 2023 cut-off date)

In the atypical EGFRm NSCLC patient subset, comparable evidence of on-target activity via ctDNA reductions was observed, with dose-dependent reduction and clearance of ctDNA at Day 15 in patients with atypical mutations (Figure 5A), Early evidence of dosedependent tumor reduction was also observed in efficacy-evaluable patients (Figure 5B).

Safety

At the April 21, 2023 data cut-off, 41 (69.5%) patients experienced treatment related adverse events (TRAE); most were Grade 1-2 (Table 2). The most common TRAEs (>15%) included rash (22%) and dermatitis acneiform (15%). No Grade >3 EGFR WT-associated toxicity such as rash, diarrhea, or paronychia were observed. No DLTs were observed; no patients discontinued due to a TRAE.

Table 2. Treatment-related adverse events reported in >10% of patients in the overall safety population (N=59) (April 21, 2023 cut-off date)

Furthermore, as of September 29, 2023, patients were also treated at 600 mg QD, 800 mg QD, or 400 mg BID and a confirmed partial response was seen in at least one patient in each of the 600 mg QD, 800 mg QD, and 400 mg BID cohorts.

Patient Vignettes from Part 1

Patient case #1

A 59-year-old, White, never-smoker female with NSCLC metastatic to the liver and brain. She presented with EGFR ex20ins (D770>GY) and non-EGFR alterations (BRIP N1006FS*l, DNMT3AR326H, TP53 M246V) by local NGS-testing. The patient previously received systemic therapy in the metastatic setting that included carboplatin and pemetrexed, followed by dacomitinib.

The patient was enrolled in the phase 1 portion of the study and initiated BLU-451 monotherapy at 300 mg QD. Through intrapatient dose escalation, her dose was adjusted to 200 mg BID after 40 days of treatment.

PR per RECIST vl .1 was seen on the first scan at Week 7, which was confirmed at Week 13, with 71% reduction in the target lesions from baseline. CNS activity was seen, with 2 brain target lesions being stable at Week 7 but showing PR at Week 13. See Figure 6.

Patient case #2

A 59-year-old, White, never-smoker female had NSCLC metastatic to the brain. She presented with EGFR ex20ins (D770_N771insSVD) and non-EGFR alterations (CDKN2B loss, CDKN2A loss, MTAP loss) by local NGS-testing. The patient previously received systemic therapy in the metastatic setting that included carboplatin, pemetrexed, and pembrolizumab, followed by amivantamab.

The patient was enrolled in and initiated BLU-451 monotherapy at 400 mg QD. Stable disease per RECIST vl.1 was seen on the first, second, and third scans (Weeks 7, 13, and 19). The patient had multiple non-target lesions in the brain, which were stable on the Week 7 scan, but showed complete response on Week 13 and was confirmed on Week 19 imaging.