Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non-small Cell Lung Cancer

Abstract

Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer (NSCLC).

Patients and methods: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.

Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.

Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.See related commentary by Garon, p. 905.

Conflict of interest statement

Conflict of Interest Disclosure statements (for each author):

Helena A. Yu: Personal fees from AstraZeneca, Daiichi, and Eli Lilly and Company; research support to institution from AstraZeneca, Daiichi, Eli Lilly and Company, Novartis, and Pfizer, outside the submitted work.

Luis G. Paz-Ares: Personal fees from Adacap, Amgen, Bayer, Blueprint, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Incyte, Ipsen, Merck, Novartis, Pharmamar, Roche, Sanofi, Servier, and Sysmex; grants and personal fees from AstraZeneca, Bristol Myers Squibb, MSD, and Pfizer; co-founder and board membership of Altum Sequencing, advisory board membership of Genómica, outside the submitted work.

James Chih-Hsin Yang: Personal fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly and Company, Hansoh Pharmaceuticals, Merck Serono, MSD, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals, outside the submitted work.

Ki Hyeong Lee: Personal fees from AstraZeneca, BMS, and MSD, outside the submitted work.

Pilar Garrido Lopez: Personal fees from AbbVie, Blueprint, Boehringer Ingelheim, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer, Rovi, and Takeda; personal fees and non-financial support from AstraZeneca, BMS, and Roche; outside the submitted work.

Keunchil Park: Personal fees from AstraZeneca and Eli Lilly and Company; research funding from Astra Zeneca, outside the submitted work.

Joo-Hang Kim: The author declares no potential conflict of interest.

Dae Ho Lee: Personal fees from AbbVie, AstraZeneca, BC Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, ChongKeunDang, CJ Healthcare, Eli Lilly and Company, Genexine, Janssen, Menarini, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube; personal fees and non-financial support from Takeda; and non-financial support from Blueprint Medicine, outside the submitted work.

Huzhang Mao, Ling Gao, Sameera R. Wijayawardana, Rebecca R. Hozak, and Bo H. Chao: Current or past employees and minor shareholders of Eli Lilly and Company.

David Planchard: Personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly and Company, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, outside the submitted work; and clinical trials research (as Principal investigator or co-investigator): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo.

©2020 American Association for Cancer Research.

Figures

Figure 1.

A. Confirmed best response based on tumor burden. Investigator-assessed best percentage change in tumor size from baseline is shown for each patient whose disease was assessable by RECIST 1.1 criteria. Patients (x-axis) are color-coded according to best overall response. B. Tumor response over time in treated patients. Tumor response over duration on treatment (A) and percent change in tumor size from baseline over analysis time (B) are shown for each patient, color-coded by best overall response. C. Confirmed Best Overall Systemic Response. CI, confidence interval; CNS, central nervous system; CR, complete response; N, number of patients in population; n, number of patients in specified category; NE, non-evaluable; PD, progressive disease; PR, partial response; SD, stable disease. Response criteria were from RECIST 1.1 and were investigator-assessed. Confidence intervals are based on the Clopper-Pearson method. aOne patient did not have post baseline tumor assessment.

Figure 2.. Progression-free survival.

Data are shown for A) all patients; and B) baseline CNS metastasis categories. The curves and medians (90% CI) were estimated using the Kaplan-Meier method. --, not available; CI, confidence interval; CNS, central nervous system; N, number of patients in population; n, number of patients in specified category; PFS, progression-free survival.

Figure 3.

A. T790M (Detectable vs. Undetectable on Y axis) in circulating tumor DNA over time (3 time points, along X axis) and correlation with best overall response (color coded) and progression-free survival (ordered along Z axis by descending PFS). B. EGFR- Exon 19 deletion or Exon 21 L858R mutation in circulating tumor DNA similarly presented over time and correlation with best overall response and progression-free survival. Plasma samples were collected for assessment of circulating tumor DNA at baseline, during treatment (Cycle 4 Day 1 or Cycle 7 Day 1), and post progression (30-day follow-up). Genetic alterations were assessed by Guardant 360® next-generation sequencing. Patients are color-coded according to best overall response. BOR, best overall response; CR, complete response; n, number of subjects in the specified category; NE, non-evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 3.

A. T790M (Detectable vs. Undetectable on Y axis) in circulating tumor DNA over time (3 time points, along X axis) and correlation with best overall response (color coded) and progression-free survival (ordered along Z axis by descending PFS). B. EGFR- Exon 19 deletion or Exon 21 L858R mutation in circulating tumor DNA similarly presented over time and correlation with best overall response and progression-free survival. Plasma samples were collected for assessment of circulating tumor DNA at baseline, during treatment (Cycle 4 Day 1 or Cycle 7 Day 1), and post progression (30-day follow-up). Genetic alterations were assessed by Guardant 360® next-generation sequencing. Patients are color-coded according to best overall response. BOR, best overall response; CR, complete response; n, number of subjects in the specified category; NE, non-evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 4.. Kaplan-Meier plot of progression-free survival by loss or retention of the EGFR- Exon 19 deletion or Exon 21 L858R mutation in circulating tumor DNA.

The curves and medians (95% CI) were estimated using the Kaplan-Meier method. Loss or retention of the EGFR activating mutation is defined as being undetectable or detectable, respectively, in on-treatment ctDNA samples, as only samples detectable for EGFR activating mutations at baseline are included for this analysis. Plasma samples were collected for assessment of circulating tumor DNA at baseline and during treatment (Cycle 4 Day 1 or Cycle 7 Day 1). Note: In the subgroup of 8 patients with on-treatment loss of EGFR activating mutations, 6 had Exon 19 deletion, and 2 had L858R at baseline, whereas in the subgroup of 8 patients with retained EGFR activating mutations on treatment, 5 had Exon 19 deletion, and 3 had L858R at baseline. In addition, there were 4 patients with CNS metastasis and 4 patients without in each subgroups of on-treatment loss or retained EGFR activating mutations. Responder: CR or PR as BOR. Non-responder: SD as BOR. BOR, best overall response; CR, complete response; PR, partial response; SD, stable disease.