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9056 Background: Capmatinib, a potent, selective MET inhibitor, showed substantial antitumor activity and manageable tolerability in patients with METex14-mutated advanced non-small cell lung cancer (aNSCLC) in the GEOMETRY mono-1 trial (NCT02414139). Patient-reported outcomes (PROs) from this study are reported here. Methods: GEOMETRY mono-1 enrolled patients ≥18 years with METex14-mutated or MET-amplified, ALK-negative and EGFR wild-type, treatment-naïve (1L) or pre-treated (2L+) aNSCLC, to receive capmatinib orally 400 mg bid during 21-day treatment cycles. Here we report results for patients with METex14 mutations. PROs (EORTC QLQ-C30, QLQ-LC13 and EQ-5D-5L) were collected at baseline (BL) and every 6 weeks (Wks) until end of treatment. Key PROs (in patients with BL and ≥1 post-BL value) included change from BL in QLQ-C30 global health status (GHS), QLQ-LC13 symptoms (cough, chest pain and dyspnea), and EQ-5D-5L visual analogue scale (VAS), with a ≥10-point change from BL considered clinically meaningful. Time to definitive deterioration (TTDD) in QLQ-LC13 symptoms (time from treatment initiation to first date of ≥10% symptom change from BL with no later reduction) was assessed using Kaplan-Meier. QLQ-LC13 symptoms over time were explored by BIRC-assessed clinical response to capmatinib. Results: By Jan 6, 2020 cut-off, median capmatinib exposure was 48.2 (4.0 117.4) Wks and 22.1 (0.4 136.0) Wks for 1L and 2L+ patients, respectively. A total of 27/28 1L patients and 65/69 2L+ patients completed PROs at BL, and completion rate remained high (mostly > 70%) through treatment cycles. Mean [SD] BL PRO scores were moderate-to-high in 1L and 2L+ patients (GHS: 64.7 [21.6] and 58.8 [21.0.]; cough: 35.9 [32.6] and 28.7 [28.2]; chest pain: 12.8 [23.2] and 17.2 [22.7]; dyspnea: 23.5 [23.4] and 22.2 [20.8]; VAS: 67.7 [20.8] and 61.9 [18.8], respectively). Overall change from BL in PROs was maintained over time. Cough improved early, with meaningful improvements observed through cycles, notably in 1L patients (mean change from BL [SD] at Wk 7: 1L -13.0 [39.9], 2L+ -8.2 [28.4]; Wk 25: 1L -15.6 [33.0], 2L+ -6.0 [31.5]; Wk 43: 1L -28.2 [26.7], 2L+ -10.5 [27.3]). Median TTDD in GHS was 16.6 months (95% CI: 9.7, NE [not estimated]) and 12.4 months (95% CI: 4.2, 19.4) in 1L and 2L+ patients, respectively. Median TTDD for cough and chest pain was NE in both 1L and 2L+ patients, and for dyspnea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE), respectively. QLQ-LC13 symptoms improved at all cycles in patients achieving clinical complete response or partial response, while symptom worsening was seen in those with no clinical response. Conclusions: Capmatinib was associated with clinically meaningful improvements in cough, delayed time to lung symptom deterioration, and preserved QoL, supporting its use as a treatment option in patients with METex14-mutated aNSCLC. Clinical trial information: NCT02414139.

e21150 Background: Capmatinib is a selective inhibitor of MET receptor that got accelerated FDA approval in May 2020 to treat NSCLC with MET ex 14 mutation (METex14). Here, we proclaim the first review of capmatinib efficacy and safety profile in METex14 positive NSCLC patients. Methods: A systematic literature search was conducted using PubMed, Cochrane Library, Clinicaltrials.gov, and Google Scholar. We compiled and analyzed the original studies evaluating the clinical response of capmatinib in MET ex14 mutated advanced NSCLC. Results: The most recent results (as of January 6, 2020) of the GEOMETRY Mono-1 phase 2 study showed an overall response rate (ORR) of 41% (69/97; 95% CI, 29-53) with 41% partial response (PR), and 36% stable disease (SD) in patients who previously received 1-2 prior therapy lines (cohort 4). While the ORR, PR, and SD were 68% ( n = 29/97; 95% CI, 48-84), 64%, and 25%, respectively in treatment naïve patients (cohort 5b). Median progression-free survival (mPFS) and duration of response (DOR) were 5.4 months (mon) and 9.7 mon (95%CI, 5.6-13.0) in cohort 4 vs. 12.4 mon and 12.6 mon (CI, 5.6- not estimated), respectively in cohort 5b. Moreover, disease control was shown in n = 54/69 patients in cohort 4 (95% CI 78 (97-87) and n = 27/28 patients (95% CI 96 (82-100). A post-hoc analysis of 19 patients out of 69 who were pre-treated with immunotherapy demonstrated an ORR of 57.9% (n = 11/19; 95%CI 33.5-79.7) with capmatinib. In contrast, treatment-naive had an ORR of 34% (n = 17/50; 95%CI 21.2-48.8) as per the investigator. Median PFS was 3.29 mon noted on prior therapy. In the phase 1 retrospective analysis reported by Choi et al., ORR was 50% with a median duration of 16.1 (5.3-36.4) mon. Among 45 Japanese pts with MET ex 14 mutated or MET amplified status, the ORR was 36.4% (95% CI 10.9%-69.2%) with a PFS of 4.70 mon in the MET ex 14 mutated groups who had received a second or third line of therapy. Most commonly reported adverse events were peripheral edema, nausea, vomiting, and elevated creatinine across all studies and were mostly grade 1-2. Conclusions: Our results showed that capmatinib has promising anti-tumor activity in patients with NSCLC harboring MET exon 14 skipping mutation. The efficacy and tolerability profile of capmatinib is remarkable, particularly in treatment-naïve patients. Although the GEOMETRY Mono-1 trial is still ongoing, further clinical studies with long-term follow-up are needed.

9048 Background: Primary findings from the phase 1b/2 study (NCT01610336) demonstrated clinical activity of combination therapy with capmatinib, a potent and selective MET inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in heavily pre-treated patients with EGFR-mutated and MET dysregulated non-small cell lung cancer (NSCLC). The objective response rate (ORR) was 27% in patients across phase 1b/2 of the study. At the recommended phase 2 dose (R2PD) of capmatinib 400 mg twice-daily (bid) and gefitinib 250 mg once-daily (qd), the ORR was 47% in patients with high MET-amplified tumors ( MET gene copy number ≥6). Here, we report the updated data on the efficacy and safety from the NCT01610336 study. Methods: Patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutation with a recorded clinical benefit on prior single-agent EGFR-TKI before progression and confirmed dysregulated MET pathway after progression on EGFR TKIs were included. Patients in phase 1b received capmatinib 100 to 800-mg capsules qd or 200 to 600-mg capsules or tablets bid, plus gefitinib 250 mg qd. Patients in phase 2 received the R2PD dose. Data on the overall survival (OS) and cumulative safety endpoints are reported in this final analysis. Results: Overall, 161 patients received the combination treatment in this study; phase 1b (n = 61) and phase 2 (n = 100). The median age of patients was 60.0 years, mostly Asian (67.1%) with an Eastern Cooperative Oncology Group performance status of 0/1: 18.0%/78.3%. At data cut-off on May 27, 2020, all patients had discontinued the study; 82 out of the 100 patients in phase 2 had died and 18 were censored (mostly lost to follow-up [n = 15]). One patient was still on treatment with a partial response and rolled over to another study. The median (range) follow-up time for OS was 12.2 (0.9-70.2) months. The median OS was 13.9 months (95% confidence interval, 11.6-15.7 months). The median (range) duration of exposure for capmatinib plus gefitinib was 16 weeks (0.4-209.7 weeks) during phase 1b and 18.5 weeks (0.4-268.0 weeks) during phase 2. Majority of the patients (98.8%) experienced ≥1 adverse event (AE); 87% of the patients had treatment-related AEs. Most common treatment-related AEs (reported in ≥20%) were nausea (28.0%), peripheral edema (23%), rash (21.7%), and decreased appetite (21.1%). Grade 3 or 4 treatment-related AEs occurred in 51 patients (31.7%) across both phases, of which, the most frequent (reported in ≥5%) were increased amylase and increased lipase (6.2% each) and peripheral edema (5%). Conclusions: Capmatinib 400 mg bid in combination with gefitinib 250 mg qd was well-tolerated and showed encouraging clinical activity in patients with EGFR-mutant and MET-dysregulated NSCLC. Clinical trial information: NCT01610336.

9111 Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 skipping mutation (METex14) NSCLC in the US and Japan, with the FoundationOne CDx (tissue NGS assay), based on results of the ongoing GEOMETRY mono-1 study (NCT02414139). Here, we report efficacy findings in pts from GEOMETRY mono-1, who were identified as METex14 using a next-generation sequencing (NGS)-based liquid biopsy test (LDx), which detects METex14 in circulating tumor (ct)DNA. Methods: During the GEOMETRY mono-1 study, pts were screened for METex14 status using a METex14 RT-PCR clinical trial assay (CTA) on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from pts enrolled in the GEOMETRY mono-1 study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and 21 tissue-matched NSCLC plasma samples from commercial sources to supplement the total number of METex14 deletion negative patients. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). This retrospective analysis reports overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all by BIRC, and overall survival (OS) in pts identified as METex14 by the LDx (data cutoff: Sep 18, 2020). Results: Of the 97 pts with METex14 NSCLC in C4 (n = 69) and C5b (n = 28), 88 pts had plasma volume ≥2.5 mL and cell free DNA ≥20 ng (minimum input); of these 57 were LDx positive (C4, n = 41; C5b, n = 16), 26 were negative; 5 had invalid sequencing results. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; none of the CTA METex14-negative pts (N = 97) were reported as positive by the LDx. The PPA and NPA for these were 68.7% (95% CI: 57.6%, 78.4%) and 100% (95% CI: 95.9%, 100%), respectively, when excluding LDx invalid results. In pts identified as METex14 positive by LDx, the ORR (95% CI) was 81.3% (54.4‒96.0; n = 16) in C5b and 48.8% (32.9‒64.9; n = 41) in C4; median DOR (95% CI) was 20.3 (4.2, NE; n = 13) months in C5b and 9.8 (4.2‒19.5; n = 20) months in C4; median PFS (95% CI) was 12.4 (4.5‒NE; n = 16) months in C5b and 5.4 (4.0‒6.6; n = 41) months in C4; median OS was 17.9 (9.8‒NE; n = 16) months in C5b and 13.6 (6.6‒23.3; n = 41) months in C4. Clinical findings in those identified as METex14 positive by LDx were comparable with those identified by the CTA. Conclusions: Current findings from the GEOMETRY mono-1 study support the activity of capmatinib in advanced NSCLC pts with METex14 identified using LDx. For pts identified as METex14-negative by the LDx, further testing should be performed on tissue samples, as a negative LDx result does not preclude a positive result by tissue biopsy. Clinical trial information: NCT02414139.

Molecular profiling of non-small cell lung cancer (NSCLC) in the past decade has revealed numerous oncogenic driver events in NSCLC leading to several highly effective therapies. While a promising target, small-molecule inhibition of MET signaling has proven difficult. Capmatinib is a specific inhibitor of MET with Food and Drug Administration (FDA) accelerated approval in 2020 for the treatment of NSCLC harboring MET exon 14 skipping mutations. As a first-line therapy, 68% of patients in phase II clinical trials responded to capmatinib with a median duration of 12.6 months and a manageable safety profile. Although FDA approval is currently limited to MET exon 14 skipping mutations, capmatinib has shown potential in other subsets of MET-dysregulated NSCLC for which ongoing studies are underway. This review covers the preclinical and early clinical data leading to capmatinib's approval, discusses the management of treatment-related toxicities, and offers potential avenues of further research.

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479)., MET dysregulation is an important newly established molecular driver of tumorigenesis in various cancers and is recognized as a negative prognostic factor. The findings of this study provide the recommended phase 2 dose (RP2D) of capmatinib and also safety and efficacy data in selected expansion cohorts treated at the RP2D.

BACKGROUND c-MET and PI3K pathways are dysregulated in GBM and can drive cancer growth in pre-clinical models. INC280 is a small molecule inhibitor of c-MET; BKM120 is a pan-class I PI3K inhibitor. A phase Ib/II study was designed to evaluate INC280+BKM120 in patients with recurrent GBM ({"type":"clinical-trial","attrs":{"text":"NCT01870726","term_id":"NCT01870726"}}NCT01870726).

9004 Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METΔex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-naïve pts (Cohort 5b). Here we report the results in METΔex14–mutated NSCLC for duration of response (DOR) and progression-free survival (PFS) as well as the updated results for ORR. Methods: GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in pts with METΔex14-mutated or MET-amplified advanced NSCLC across 6 cohorts. Pts (≥18 yrs) with ECOG PS 0–1, ALK and EGFR wt, and stage IIIB/IV NSCLC were eligible. Pts with METΔex14 mutation (centrally confirmed) were assigned (regardless of MET amplification status/gene copy number) to Cohorts 4 and 5b and received capmatinib tablets 400 mg BID. Primary endpoint was ORR by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Key secondary endpoint was DOR by BIRC. Results: As of Nov 08, 2018, 97 pts with METΔex14-mutated NSCLC (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. ORR (95% CI) by BIRC was 39.1% (27.6-51.6) in Cohort 4 and 71.4% (51.3-86.8) in Cohort 5b. While still immature at the time of this analysis, data on durability are promising: median DOR (95% CI) by BIRC was 9.72 (4.27-11.14) and 8.41 (5.55-NE) mo for Cohorts 4 and 5b, respectively; median PFS (95% CI) by BIRC was 5.42 (4.17-6.97) and 9.13 (5.52-13.86) mo for Cohorts 4 and 5b, respectively. Safety profile remains favourable and unchanged. Most common AEs (≥25% all grades) across all cohorts (n = 315), were peripheral edema (49.2%), nausea (43.2%), and vomiting (28.3%); majority of the AEs were grade 1/2. Final efficacy analysis (12-mo f-u on DOR) including biomarker data will be presented during meeting. Conclusions: These data confirm capmatinib to be a promising new treatment option for pts with METΔex14-mutated advanced NSCLC regardless of the line of therapy with deep and durable responses and manageable toxicity profile. Clinical trial information: NCT02414139.

9067Background: cMET dysregulation occurs in 3–10% of NSCLC and is a negative prognostic factor. INC280 is a highly selective cMET inhibitor with preclinical and clinical antitumor activity. The dose-escalation part of this ongoing Ph I study (NCT01324479) included a cMET-dysregulated NSCLC expansion group. Preliminary efficacy was seen in NSCLC pts with high cMET expression, prompting the addition of a second expansion group of pts with EGFRwt, high cMET-expressing NSCLC. We report here on both NSCLC groups. Methods: The primary objective of this Ph I study was met; INC280 RP2D was established at 400 mg BID in a tablet formulation. Secondary objectives included exploring the antitumor activity of INC280 at the RP2D in the original and additional NSCLC groups. Eligible pts (aged ≥ 18 years; ECOG PS ≤ 2) in the original group had documented cMET+ (H-score ≥ 150 or cMET/centromere ratio ≥ 2.0 or gene copy number [GCN] ≥ 5 or IHC 2+ or 3+) NSCLC. In the additional NSCLC group, pts had documented EGFRwt and c...

9020Background: Most pts withEGFR-mut NSCLC progress on EGFR tyrosine kinase inhibitor (TKI) therapy despite high initial response rates. cMET is dysregulated in 15−25% of NSCLC pts with acquired E...

4074Background: Overexpression/activation of cMET occurs in 20‒48% of HCC, and predicts worse survival. Capmatinib (INC280) is a potent, selective cMET inhibitor that causes regression of cMET dysr...