Abstract 1218P
Background
The phase I/II study (NCT02716116) of mobocertinib 160 mg QD in platinum-pretreated pts (PPP) with EGFRex20ins+ NSCLC, demonstrated a confirmed objective response rate (ORR) of 28% per independent review committee (IRC); GI toxicities were the most common adverse events (AEs).
Methods
We report ORR, duration of response (DoR), and progression-free survival (PFS) per IRC in pts with and without AEs leading to dose reductions, most of which were due to GI toxicity. We report all-grade (gr) and gr 3/4 diarrhea, vomiting, and nausea; further characterize diarrhea in an exposure-safety analysis; and explore the relationship between diarrhea and various covariates, including age.
Results
In PPP (N=114), ORR was 21% (95% CI: 8.0, 39.7) in pts with AEs leading to dose reductions and 31% (21.1, 41.5) in those without; DoR was 5.7 mo (3.7, not reached [NR]) and 17.5 mo (7.4, NR); PFS was 5.9 mo (3.7, 11.0) and 7.3 mo (5.5, 10.8), respectively. Among pts with AEs leading to dose reductions, 21/29 pts had dose reduction due to GI toxicity. 96% of pts in PPP had at least 1 GI toxicity: all-gr and gr 3/4 diarrhea, 93% and 22%; nausea, 40% and 4%; vomiting, 41% and 3%. For all-gr diarrhea, onset was within first 7 days in 62% of pts, mostly low grade at onset, with median time to resolution of 0.29 weeks, and was managed with antidiarrheal medication in 74% of pts (Table). Statistically significant predictors of gr ≥2 diarrhea were mobocertinib plasma exposure (40-mg dose increase; hazard ratio [HR] 1.11 [95% CI: 1.04, 1.19]) and age (≥75 vs <75 y; HR 2.13 [95% CI, 1.38, 3.30]). Table: 1218P
| GI AEs, n (%) | All Gr | Gr 3/4 | Serious | Led to dose reduction | Led to discontinuation |
| Diarrhea | 106 (93) | 25 (22) | 9 (8) | 12 (11) | 5 (4) |
| Nausea | 46 (40) | 5 (4) | 3 (3) | 6 (5) | 4 (4) |
| Vomiting | 47 (41) | 3 (3) | 6 (5) | 3 (3) | 2 (2) |
| All-Gr Diarrhea | Gr 3/4 Diarrhea | ||||
| Incidence by time, n (%) | 465 events | 35 events | |||
| >1 to 2 d | 6 (1) | 0 | |||
| >2 to 7 d | 67 (14) | 12 (34) | |||
| >7 to 14 d | 21 (5) | 7 (20) | |||
| >14 to 21 d | 21 (5) | 1 (3) | |||
| >21 to 30 d | 20 (4) | 3 (9) | |||
| >1 to 2 mo | 69 (15) | 5 (14) | |||
| >2 to 3 mo | 48 (10) | 2 (6) | |||
| >3 to 6 mo | 95 (20) | 5 (14) | |||
| >6 to 9 mo | 43 (9) | 0 | |||
| >9 to 12 mo | 39 (8) | 0 | |||
| >12 to 15 mo | 32 (7) | 0 | |||
| >15 to 18 mo | 2 (<1) | 0 | |||
| Median time to onset, d (range) [n=106] | 5.0 (1, 253) | - | |||
| Median time to resolution, wk (range) [n=106] | 0.29 (0.1, 93.7) | 0.93 (0.1, 38.9) |
Conclusions
Efficacy outcomes were impacted by dose reductions, which were primarily due to GI toxicity. Most GI toxicity was low grade. Diarrhea, the most frequent GI toxicity, occurred most often in the first week, and was influenced by mobocertinib exposure and age ≥75 y.
Clinical trial identification
NCT02716116; Release date: March 23, 2006.
Editorial acknowledgement
Professional medical writing assistance was provided by Amy Zannikos, PharmD, of Peloton Advantage, LLC, an OPEN Health Company, Parsippany, NJ, USA, and funded by Millennium Pharmaceuticals, Inc.
Legal entity responsible for the study
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Funding
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Disclosure
S.S. Ramalingam: Financial Interests, Personal, Other, Honoraria or advisory role: Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Lilly, Genentech/Roche, GlaxoSmithKline, Takeda; Financial Interests, Institutional, Other, research support: Amgen, Advaxis, BMS, Genmab, AstraZeneca, Takeda. A. Spira: Financial Interests, Personal, Other, Consulting/advisory role: ARIAD, AstraZeneca, Clovis Oncology, Roche, Amgen, Mirati, BMS, Merck. G.J. Riely: Financial Interests, Personal, Other, Travel: Merck, Sharp & Dohme; Financial Interests, Institutional, Other, research funding: Novartis, Roche/Genentech, Millennium, GSK, Pfizer, Infinity Pharmaceuticals, ARIAD, Mirati Therapeutics, Merck. T.M. Kim: Financial Interests, Personal, Other, Honoraria or advisory role: AstraZeneca, Boryung, F. Hoffmann-La Roche Ltd./Genentech, Inc., Novartis, Sanofi, Takeda; Financial Interests, Personal, Other, research funding: AstraZeneca-Korea Health Industry Development Institute. J.C. Yang: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Merck Serono, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Puma Pharmaceuticals, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Novartis; Financial Interests, Personal, Other, coordinating PI: AstraZeneca, Daiichi Sankyo, Dizal Pharmaceutical, MSD; Financial Interests, Personal, Other, Steering Committee: Bayer, Eli Lilly, Ipsen, Janssen, Merck, Novartis, Numab, Takeda Oncology. Z. Piotrowska: Financial Interests, Personal, Other, Consulting/advisory role: AstraZeneca, Guardant Health, Eli Lilly, Medtronic, Incyte, Genentech, C4 Therapeutics, Blueprint Medicines, Jazz Pharmaceuticals, Janssen, Takeda; Financial Interests, Institutional, Other, Research funding: Novartis, ARIAD/Takeda, Spectrum Pharmaceuticals, AstraZeneca, Tesaro, Johnson & Johnson, Cullinan Oncology, Daiichi Sankyo Europe GmbH, AbbVie; Financial Interests, Personal, Other, travel, accommodations, expenses: Genentech, AstraZeneca. M.R. Garcia Campelo: Financial Interests, Personal, Other, Consulting/advisory role: Takeda, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim, Pfizer, Janssen, Eli Lilly, MSD, Sanofi. E. Felip: Financial Interests, Personal, Other, Consulting/advisory role: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda, Merck. L. Bazhenova: Financial Interests, Personal, Other, stock and other ownership interests: Epic Sciences; Financial Interests, Personal, Other, consulting or advisory role: Neuvogen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, Merck, Regeneron, Bristol Myers Squibb, Novartis; Financial Interests, Personal, Other, research funding: BeyondSpring. S. Jin: Financial Interests, Personal, Full or part-time Employment: Takeda. C. Griffin: Financial Interests, Personal, Full or part-time Employment: Takeda. P.M. Diderichsen: Financial Interests, Personal, Full or part-time Employment: Certara; Financial Interests, Personal, Other, consulting: Takeda. N. Gupta: Financial Interests, Personal, Full or part-time Employment: Takeda. V. Bunn: Financial Interests, Personal, Full or part-time Employment: Takeda. J. Lin: Financial Interests, Personal, Full or part-time Employment: Takeda. E.N. Churchill: Financial Interests, Personal, Full or part-time Employment: Takeda. M. Mehta: Financial Interests, Personal, Full or part-time Employment: Takeda. C. Zhou: Financial Interests, Personal, Other, Honoraria or advisory role: Lilly China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc., Amoy Diagnostics. P.A. Janne: Financial Interests, Personal, Other, Consulting: Araxes Pharmaceuticals, ARIAD/Takeda, AstraZeneca, Boehringer Ingelheim, Chugai, Ignyta, Lilly, Loxo Oncology, Merrimack, Mirati Therapeutics, Pfizer, Roche, Novartis, Voronoi, Daiichi Sankyo, SFJ Pharmaceuticals, Biocartis; Financial Interests, Personal, Other, research support: Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, Puma Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper and Loxo Oncology; Financial Interests, Personal, Royalties: Dana-Farber Cancer Institute-owned patent on EGFR mutations licensed to LabCorp. All other authors have declared no conflicts of interest.