2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations

Background

The RELAY (NCT02411448) phase III study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for ERL plus RAM (RAM+ERL) versus ERL plus PL (PL+ERL) in patients with previously untreated EGFR mutation (mut)-positive (EGFR exon 19 deletion or exon 21 mut (L858R)) mNSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p < 0.0001). EGFR sensitizing and T790M mut status was monitored in circulating tumor DNA (ctDNA) from patients who participated in the Japan liquid biopsy exploratory substudy.

Methods

Plasma samples were collected before and during treatment (Baseline, Cycle 4, 13 and every 6 cycles up to Cycle 53) as well as post-discontinuation (the 30-day follow-up). Isolated ctDNA of plasma were subjected to droplet digital PCR (ddPCR) to determine EGFR mut status. Statistical analyses for T790M were performed for the population of patients with disease progression who had valid results from baseline and 30 day follow-up.

Results

The ddPCR population included 42 patients and had a similar PFS HR (0.61, 95% CI 0.33-1.15) to the full ITT population. The rates of EGFR T790M mut positivity at the 30-day follow-up were not different between treatment groups: 26% (5 of 19) (95% CI 12-49%) in RAM+ERL and 30% (7 of 23) (95% CI, 16-51%) in PL+ERL (p = 1.0). When evaluating the cumulative post-progression T790M rates according to the number of cycles received prior to disease progression, the rates for patients who had progressed by Cycle 4, Cycle 12, or Cycle 53 were 0%, 17% and 26% for RAM+ERL, and 0%, 33%, and 30% for PL+ERL, suggesting that RAM+ERL potentially may delay the occurrence of resistance by the T790M mutation.

Conclusions

Treatment with RAM+ERL resulted in superior PFS, with similar T790M rates at progression as compared to PL+ERL, suggesting the potential for effective EGFR-directed therapy after progression on RAM+ERL.

Clinical trial identification

NCT02411448.

Editorial acknowledgement

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

K. Nishio: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly Japan K.K.; Research grant / Funding (institution): Ignyta,Inc.; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co.,Ltd.; Speaker Bureau / Expert testimony: Eisai Co., Ltd.; Speaker Bureau / Expert testimony: Pfizer Inc.; Speaker Bureau / Expert testimony: Novartis Pharma K.K.; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Company; Speaker Bureau / Expert testimony: SymBio Pharmaceuticals Limited. ; Speaker Bureau / Expert testimony: Life Technologies Japan Ltd.; Speaker Bureau / Expert testimony: Solasia Pharma K.K. ; Speaker Bureau / Expert testimony: Yakult Honsha Co., Ltd.; Speaker Bureau / Expert testimony: Roche Diagnostics K.K. K. Sakai: Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co.; Speaker Bureau / Expert testimony: Roche Diagnostics K.K.; Speaker Bureau / Expert testimony: SRL. T. Seto: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Research grant / Funding (institution): Pfizer Japan; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self): Thermo Fisher Scientific; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): LOXO Oncology; Research grant / Funding (institution): Kissei Pharmaceutical. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer-ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono. M. Reck: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche. E.B. Garon: Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Neon; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Mirati; Advisory / Consultancy: Dracen; Honoraria (self), Personal Fee for Steering Committee: EMD Serono. C.M. Visseren-Grul: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. R.R. Hozak: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. S.R. Wijayawardana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. S. Enatsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. K. Nakagawa: Research grant / Funding (institution): MSD K.K., Icon Japan K.K., Takeda Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb Company, Taiho Pharmaceutical Co.,Ltd., Parexel International Corp., Ono Pharmaceutical Co.,Ltd., IQVIA., A2 Healthcare Corp., AbbVie Inc., ; Research grant / Funding (institution): Chugai Pharmaceutical Co.,Ltd., SymBio Pharmaceuticals Limited., Merck Serono Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., Novartis Pharma K.K., Quintiles Inc., CMIC Shift Zero K.K., Eisai Co., Ltd., Nippon Boehringer Ingelheim Co.,Ltd., ; Research grant / Funding (institution): Kissei Pharmaceutical Co.,Ltd., Pfizer Japan Inc., Kyowa Hakko Kirin Co.,Ltd., EPS Corporation., Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd. ; Honoraria (institution): Astellas Pharma Inc., AstraZeneca K.K. MSD K.K., Ono Pharmaceutical Co.,Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bristol-Myers Squibb Company, Kyorin Pharmaceutical Co.,Ltd., CareNet,Inc, Nichi-Iko Pharmaceutical Co., Ltd., ; Honoraria (institution): Hisamitsu Pharmaceutical Co.,Inc., Yodosha Co., LTD., Takeda Pharmaceutical Co.,Ltd., Chugai Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co.,Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Nikkei Business Publications, Inc., ; Honoraria (institution): Medicus Shuppan, Publishers Co., Ltd., Thermo Fisher Scientific K.K., Nanzando Co.,Ltd, Medical Review Co., Ltd., Yomiuri Telecasting Corporation; Advisory / Consultancy: Astellas Pharma Inc., Takeda Pharmaceutical Co.,Ltd. Linguistic correction