LBA70 - OSIRAM-1: A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer (TORG1833)

Background

Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram).

Methods

Previously untreated patients with advanced NSCLC and EGFR mutations were randomized to receive Osi daily with or without Ram every 2 weeks. Eligibility included asymptomatic and/or treated brain metastases. Stratification was based on gender and mutation type (exon 19 del, L858R). The primary endpoint was progression free survival (PFS) assessed by central radiologic review.

Results

Between November 2018 and April 2020, 122 patients (Osi+Ram arm: 59, Osi arm: 63) were enrolled. With a median follow up of 36.0 months (m), median PFS was 20.0 m for Osi+Ram arm and 24.0 m for Osi arm, resulting in a hazard ratio of 1.054 (95% CI 0.674-1.648, p = 0.82). The overall response rate was 77.2% and 79.3%, with a median duration of response of 24.7 m and 25.1 m in the Osi+Ram and Osi arms respectively. Notable grade 3 or higher adverse events (≥10%) included CK elevation (13%) in Osi arm, neutropenia (10%) and hypertension (17%) in Osi+Ram arm. Pneumonitis of any grade occurred in 9% and 16% of Osi+Ram and Osi arms. Median treatment durations for Osi and Ram were 18.8 (0.5-49.7) and 4.6 (0.5-40.7) m in the Osi+Ram arm, and 17.4 m in the Osi arm. The treatment period of Ram was shorter compared to previous studies. In a post hoc analysis, PFS favored the Osi+Ram combination among patients with brain metastasis (n=34) with a hazard ratio of 0.655 (95% CI 0.296-1.451).

Conclusions

While both treatment arms demonstrated long-term effects with acceptable toxicity, this study did not reveal an advantage of the Osi+Ram combination over Osi monotherapy in improving PFS. It’s noteworthy that conducted period during the COVID-19 pandemic, and the suboptimal administration of Ram may have influenced the outcome. jRCT2080224085

Clinical trial identification

jRCT2080224085 2021.11.12.

Editorial acknowledgement

Legal entity responsible for the study

Thoracic Oncology Research Group (TORG).

Funding

Eli Lilly and Company.

Disclosure

Y. Nakahara: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Taiho, Chugai; Financial Interests, Personal, Research Grant: JSPS KAKENHI, The Japan Lung Cancer Society; Financial Interests, Institutional, Research Funding: Takeda. T. Kato: Financial Interests, Personal, Advisory Board, speaker, consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, speaker: Pfizer, Amgen, Janssen; Financial Interests, Personal, Other, consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, consultancy, speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis, Bristol-Meyers Squibb, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: BeiGene, Glaxo; Financial Interests, Personal, Advisory Board, Steering Committee: Roche; Financial Interests, Personal, Full or part-time Employment, Family member: Eli Lilly; Financial Interests, Institutional, Local PI: Chugai, MSD, Pfizer, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biophama, Haihe Biopharma, Blueprint Medicines, Turning Point, BeiGene, Daiichi Sankyo, Gilead, GSK, Janssen, Bayer, Takeda; Financial Interests, Institutional, Steering Committee Member, Local PI: AstraZeneca. M. Tamiya: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Amgen; Financial Interests, Personal, Advisory Board: Pfizer. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. N. Furuya: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Chugai, Bristol Myers Squibb, Taiho, Pfizer Japan, Novartis. A. Ono: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: Janssen Research & Development. Y. Takiguchi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Daiichi Sankyo, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Lilly, Pfizer, Novartis, Kyowa Kirin International, MSD, Eisai, Takeda, Amgen; Financial Interests, Personal, Other, Member of Ethics Committee: Oncolys BioPharma; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Lilly, Chugai Pharma, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: MSD Oncology, AstraZeneca, AbbVie. S. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Ono, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono, Bristol Myers Squibb, Taiho, Eli Lilly, Pfizer, Boehringer Ingelheim, Takeda; Financial Interests, Research Grant: AstraZeneca, Chugai. K. Watanabe: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, Boehringer Ingelheim, Merck, MSD, Takeda Pharmaceutical. T. Tokito: Financial Interests, Personal, Invited Speaker: AstraZeneca, Ono Pharmaceutical, MSD Oncology, Bristol Myers Squibb, Boehringer Ingelheim; Financial Interests, Personal, Other, lecture fee: Chugai Pharma, Nippon Kayku. N. Seki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Eli Lilly, AstraZeneca, MSD, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Daiichi Sankyo, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Kyowa Kirin, Merck; Financial Interests, Institutional, Research Grant: Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Boehringer Ingelheim, Eisai, Daiichi Sankyo, Shionogi. T. Shukuya: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Novartis, Amgen, Pfizer, Bristol-Myers squibb, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Otsuka pharmaceutical, Eisai, Kyowa Kirin, Life technologies, Eli Lilly, Takeda Pharmaceutical, Nippon Kayaku; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, MSD; Financial Interests, Institutional, Coordinating PI: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. Y. Shibata: Financial Interests, Personal, Other, Honoraria: Pfizer, Takeda, Bristol-Myers Squibb, Merck, AstraZeneca, Chugai, Ono, Eli Lilly; Financial Interests, Institutional, Local PI: MSD, Novartis, Blueprint Medicines, Chugai. T. Kozuki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Beohringer Ingelheim, Merck Biophama, Nippon Kayaku, Novartis, Takeda Pharmaceutical Co., Bayer, Sawai, Amgen; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AbbVie; Financial Interests, Institutional, Local PI: Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Kyowa Hakko Kirin, Merck Biophama, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Pfizer, Labcorp Development Japan. H. Okamoto: Financial Interests, Institutional, Research Grant: MSD, Taiho, Bristol Myers Squibb. All other authors have declared no conflicts of interest.