Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

Abstract

MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non–small‐cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono‐1, NCT02414139) in patients with advanced METΔex14‐mutated/MET‐amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14‐mutated or MET‐amplified) and line of therapy (first‐ [1L] or second‐/third‐line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14‐mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%‐69.2%), median DOR was not evaluable, and progression‐free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET‐amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment‐related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET‐amplified NSCLC, consistent with the overall population.

Tepotinib in patients with NSCLC harbouring MET exon 14 skipping: Japanese subset analysis from the Phase II VISION study

“…Although in a different patient population, with EGFR -mutated NSCLC, preliminary data suggest savolitinib in combination with osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is well tolerated in Japanese patients ( 27 ). In Japanese patients who received the selective MET inhibitor capmatinib for MET exon 14 skipping advanced NSCLC in the GEOMETRY mono-1 study, ORRs of 50.0% and 36.4% were observed for treatment-naïve ( n = 2) and previously treated ( n = 11) Japanese patients, respectively ( 28 ). The efficacy of tepotinib in Japanese patients presented here is consistent with previously reported outcomes for the overall VISION study population ( 15 ), in which tepotinib demonstrated consistent efficacy irrespective of the number of prior lines of therapy received.…”

“…Of note, blood creatinine increase was the most common treatment-related AE experienced in Japanese patients (63.2%, all Grade 1–2). Blood creatinine increase was also the most common treatment-related AE in Japanese patients in the GEOMETRY mono-1 study of capmatinib ( 28 ). Based on non-clinical studies, increases in creatinine may reflect direct inhibitory effects on renal tubular transporters ( 29 , 30 ).…”

Safety of MET Tyrosine Kinase Inhibitors in Patients With MET Exon 14 Skipping Non-small Cell Lung Cancer: A Clinical Review

“…Capmatinib, another oral, ATP-competitive selective type Ib MET inhibitor, was first approved in 2020 in the US for treatment of METex14 skipping NSCLC, 9,12,13 based upon data from the Phase II GEOMETRY mono-1 study (Table 1; NCT02414139). [26][27][28] In the GEOMETRY mono-1 study, 364 patients with either METex14 skipping NSCLC or MET amplification were enrolled and treated with 400 mg capmatinib tablets twice daily for a 21day cycle (the recommended Phase II dose [RP2D], either with or without fasting restrictions; a maximum of two dose reductions were permitted (to 300 mg twice daily, then 200 mg twice daily). 26,27 Across the study, 151 patients with METex14 skipping NSCLC were treated and 128 analyzed for efficacy.…”

“…Raised creatinine is typically associated with renal impairment; however, MET TKIs are known to inhibit creatinine transporters, causing creatinine levels to rise by approximately 20% to 25%. 28,59 In patients with ALK-rearranged NSCLC treated with crizotinib, increased creatinine levels have been reported as being approximately 25%, 40,41 and retrospective data suggest that crizotinib can decrease creatinine-driven eGFR by 24% over the first 12 weeks of treatment (p< 0.0001). 41 Once treatment was stopped, eGFR recovered to baseline levels or above in 56% of patients; the remainder recovered to within 84% to 97% of their baseline eGFR.…”

“…In GEOMETRY mono-1, TRAEs in the Japanese cohort (n = 45) were comparable to those in the overall cohort shown in Table 2, although it is worth noting that this cohort also contains patients with MET amplification. 27,28 In the Japanese cohort, TRAEs were reported in 98% of patients (grade ≥ 3 in 56%), with 27% having serious TRAEs (grade ≥ 3 in 20%). 28 In the VISION study, Japanese patients (n=15) with METex14 skipping treated with tepotinib reported mostly mild to moderate AEs that were in line with the overall VISION population, as well a low rate of TRAEs leading to discontinuation.…”