Abstract 1284P
Background
In patients (pts) with EGFR-mutant non-small cell lung cancer (NSCLC) progressing on EGFR tyrosine kinase inhibitors (TKIs), the most common (∼60%) resistance mechanism is EGFR T790M mutation followed by MET dysregulation. This multicenter, phase (Ph) 1b/2 study evaluated capmatinib plus nazartinib in pts with EGFR-mutant NSCLC (NCT02335944).
Methods
In Ph 2, stage IIIB/IV NSCLC pts (≥ 18 years; ECOG PS ≤ 1; activating EGFR mut [exon19del and/or L858R]) were treated at the recommended ph 2 dose (RP2D: capmatinib 400 mg twice daily + nazartinib 100 mg once daily). Efficacy and safety are reported for pretreated pts with EGFR TKI resistance, with any T790M/MET (Group 1) and treatment (tx)-naive pts with T790M-, any MET (Group 3). Efficacy was also evaluated as per MET status (MET+: IHC 3+ and/or gene copy number ≥ 4) for a pooled group of pretreated pts from Group 1 and those Ph 1 pts treated at RP2D (Group 1 + Ph 1b RP2D group).
Results
As of Feb 5, 2019, 52 and 47 pts were enrolled in groups 1 and 3, respectively. Group 1 + Ph 1b RP2D group enrolled 68 pts (66 had known MET status: 23 MET+, 43 MET-). Key baseline characteristics are shown in the table. The ORR (primary endpoint) was 28.8% in the pretreated Group 1, 61.7% in the tx-naïve Group 3, and 43.5% and 27.9% in the MET+ and MET- pts in the pretreated combined group, respectively (Table). Key secondary efficacy endpoints are shown in the table. Most frequent (≥30%) any-grade tx-related adverse events (Group 1, 3) were peripheral edema (50%, 57.4%), nausea (42.3%, 48.9%) and diarrhea (23.1%, 46.8%). Table: 1284P
| Post-EGFR TKI | Tx-naive | |||
| Group 1 N = 52 | Group 1 + Ph 1b RP2D N = 68 | N = 47 | ||
| MET+ N = 23 | MET- N = 43 | |||
| Baseline characteristics | ||||
| Caucasian, % | 55.8 | 56.5 | 46.5 | 66 |
| Never smokers, % | 69.2 | 69.6 | 62.8 | 55.3 |
| ≥ 2 prior tx,% | 32.7 | 43.5 | 30.2 | -- |
| Baseline central nervous system metastasis, % | 36.5 | 26.1 | 37.2 | 27.7 |
| Primary Efficacy Endpoint | ||||
| ORR [95% CI], % | 28.8 [17.1, 43.1] | 43.5 [23.2, 65.5] | 27.9 [15.3, 43.7] | 61.7 [46.4, 75.5] |
| Secondary Efficacy Endpoints | ||||
| Median DOR [95% CI], months | 6.3 [3.7, 10.8] | 6.3 [3.6, 10.8] | 9.3 [3.7, 40.4] | 11.6 [6.6, 14.3] |
| Median PFS [95% CI], months | 5.6 [3.7, 7.4] | 7.7 [5.4, 12.2] | 5.4 [3.5, 6.4] | 11.0 [7.6, 13.8] |
| Median OS [95% CI], months | 18.8 [14.9, 21.7] | 18.8 [14.0, 21.3] | 17.2 [12.5, NE] | NE [15.9, NE] |
Conclusions
Efficacy observed in tx-naive pts (Group 3) does not seem to support addition of a MET inhibitor to EGFR TKI in MET unselected pts vs EGFR TKI alone. In MET+ pretreated pts, capmatinib plus nazartinib demonstrated clinically relevant efficacy and confirms the role of selective MET inhibition in this subset of post-EGFR TKI pts. Capmatinib plus nazartinib was well tolerated, with similar safety profile across the groups.
Clinical trial identification
NCT02335944.
Editorial acknowledgement
Editorial assistance was provided by Aarti Kamaraj (Novartis Healthcare Pvt. Ltd.).
Legal entity responsible for the study
Novartis Pharmaceuticals.
Funding
Novartis Pharmaceuticals.
Disclosure
E. Felip: Advisory/Consultancy: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Guardant Health, Novartis, Takeda, AbbVie, Blueprint Medicines, Lilly, Merck Kgaa, Merck Sharp & Dohme, Janssen, Samsung ; Speaker Bureau/Expert testimony: Pfizer, Roche, AstraZeneca, Bristol-Myers Squibb, Novartis, Takeda, Lilly, Merck Sharp & Dohme, Medscape, Prime Oncology, Touchtime ; Research grant/Funding (self): Fundación Merck Salud, Grant for Oncology Innovation (GOI) ; Officer/Board of Directors, Independent member: Grífols . R. Soo: Honoraria (self): AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan), Honararia (Institution) (AbbVie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Ignyta, Merck, Merck Serono, Novartis, Pfizer, Roche, Ta; Research grant/Funding (self): AstraZeneca, Boehringer Ingelheim ; Research grant/Funding (institution): AbbVie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Ignyta, Merck, Merck Serono, Novartis, Pfizer, Roche, Takeda, Yuhan. J. Wolf: Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AbbVie, Amgen, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Takeda; Research grant/Funding (institution): BMS, Janssen, Novartis, Pfizer, Roche . B. Solomon: Honoraria (self): Novartis, AstraZeneca, Roche-Genentech, Bristol-MyersSquibb, Merck, Loxo Oncology, Gritstone Oncology ; Honoraria (institution): Pfizer, Bristol-Myers Squibb; Advisory/Consultancy: Novartis, AstraZeneca, Roche-Genentech, Bristol-Myers Squibb, Merck, Loxo Oncology, Gritstone Oncology, Pfizer. D.S.W. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Advisory/Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant/Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer; Travel/Accommodation/Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda. A. Ardizzoni: Honoraria (self): BMS, MSD, Roche, AstraZeneca, Eli Lilly; Research grant/Funding (institution): Celgene, BMS, Ipsen, Roche. D.H. Lee: Non-remunerated activity/ies: Blueprint Medicine, Takeda; Advisory/Consultancy, Personal fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie, Takeda, Genexine, Menarini, BC Pharma. L.V. Sequist: Research grant/Funding (self): AZ, Merrimack Pharmaceuticals, Genentech, BI, Loxo, Blueprint medicines, Novartis; Advisory/Consultancy: Janssen, AZ, Merrimack Pharmaceuticals, Genentech. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Honoraria (institution): AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis. L. Paz-Ares: Advisory/Consultancy, Speaker Bureau/Expert testimony, Personal fees (Scientific advice/Speaker): Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb; Research grant/Funding (self): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Advisory/Consultancy, Advisory board: Genomica; Officer/Board of Directors, Co-founder and Board member: Altum Sequencing. D. Rodriguez-Abreu: Honoraria (self), Advisory/Consultancy: Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, and Novartis; Travel/Accommodation/Expenses: Roche, Bristol-Myers Squibb, MSD and Novartis; Research grant/Funding (self): BMS. M.R. Garcia Campelo: Honoraria (self): MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Advisory/Consultancy: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda; Speaker Bureau/Expert testimony: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda. M. Sprauten: Honoraria (self): AstraZeneca, Pierre Fabre, Pfizer; Honoraria (institution): Roche, Astra, Pierre Fabre, Pfizer; Advisory/Consultancy: AstraZeneca.L. O’Sullivan Djentuh: Full/Part-time employment: Novartis Pharma AG. R. Belli: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. S. Glaser: Full/Part-time employment: Novartis; Shareholder/Stockholder/Stock options: Novartis, Alcon. M. Zou: Full/Part-time employment: Novartis. M. Giovannini: Full/Part-time employment: Novartis. J.C-H. Yang: Honoraria (self): Boehringer Ingelheim, Eli Lilly, Roche/Genentech/Chugai, MSD, Novartis, BMS, Ono pharmaceutical, AstraZeneca, Takeda Oncology; Advisory/Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceutical, G1 The. All other authors have declared no conflicts of interest.