1259O - A randomized phase II study of osimertinib with or without bevacizumab in advanced lung adenocarcinoma patients with EGFR T790M mutation (West Japan Oncology Group 8715L)

Background

Although several studies demonstrated that EGFR-TKI plus anti-angiogenic therapy would be a promising treatment strategy in EGFR-mutated lung adenocarcinoma patients, these evidences were from the first-generation EGFR-TKI. Preclinical study showed the potential of this combination in EGFR T790M mutated model. Thus, to explore the efficacy and safety of osimertinib (Osi) in combination with bevacizumab (Bv) among advanced lung adenocarcinoma patients with EGFR T790M mutation is intriguing.

Methods

Advanced lung adenocarcinoma patients who progressed with prior EGFR-TKI (other than third generation TKI) and acquired EGFR T790M mutation were randomized to Osi (80mg, p.o., everyday) or Osi+Bv (15mg/kg, div, every 3 weeks) in a 1:1 ratio. Primary endpoint was progression-free survival (PFS). Secondary endpoints consisted of overall response rate (ORR), time to treatment failure (TTF), overall survival (OS) and safety (Trial Identifier, UMIN000023761). Based on the hypothesis that Osi+Bv will provide a 0.55 improvement in PFS over Osi alone with median PFS of 9 months, the planned sample size was 80 to provide a power of 80% at two-sided significance level of 20%.

Results

Between Aug 2017 and Sep 2018, 81 patients were randomized (41 in Osi and 40 in Osi+Bv). Of those, median age was 68 (range, 41-82); male, 41%; c-stage III/IV/recurrence, 7/70/22%; PS 0/1, 46/54%; with brain metastasis, 26%; prior history of cytotoxic chemotherapy; 21%. Baseline characteristics were similar between the arms. Although ORR was better in Osi+Bv than Osi (68 % vs 54%), median PFS was shorter in Osi+Bv (9.4 months vs 13.5 months, HR 1.44 [95%CI, 1.00-2.08], p = 0.20). Median TTF was also shorter in Osi+Bv (8.4 months vs 11.2 months, HR 1.54, p = 0.12) and OS was similar (median not reached vs 22.1 months, p = 0.96). In Osi+Bv arm, common adverse events ≥Gr 3 were proteinuria (23%), hypertension (20%) and infection (10%).

Conclusions

Compared with Osi, Osi+Bv failed to show prolongation of PFS in advanced lung adenocarcinoma patients with EGFR T790M mutation.

Clinical trial identification

UMIN000023761.

Editorial acknowledgement

Legal entity responsible for the study

West Japan Oncology Group.

Funding

AstraZeneca K.K.

Disclosure

Y. Toi: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Ono Pharmaceutical. H. Hayashi: Honoraria (self), Research grant/Funding (self): AstraZeneca K.K.; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim Japan Inc.; Honoraria (self): Bristol-Myers Squibb Co. Ltd.; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Eli Lilly Japan K.K.; Honoraria (self): MSD K.K.; Honoraria (self), Research grant/Funding (self): Ono Pharmaceutical Co. Ltd.; Honoraria (self): Pfizer Japan Inc.; Honoraria (self): Shanghai Haihe Biopharm; Honoraria (self): Kyorin pharmaceutical co. ltd; Honoraria (self): Novartis Pharma K.K. ; Honoraria (self): Taiho Pharmaceutical Co. Ltd. D. Fujimoto: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical. M. Tachihara: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim,; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Olympus; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical. N. Furuya: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): Kyowa Kirin; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical. J. Shimizu: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Chugai Pharmaceutical. N. Katakami: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Japan Pharmaceutical Association. K. Azuma: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical. N. Miura: Honoraria (self): Nippon Boehringer Ingelheim Co., Ltd,; Honoraria (self): Ono Pharmaceutical Co. Ltd; Honoraria (self): Taiho Pharmaceutical Co., Ltd. K. Nishino: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): F. Hoffmann-La Roche Ltd; Honoraria (self): Novartis; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Pfizer. S. Teraoka: Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical Co.,Ltd. S. Morita: Honoraria (self): AstraZeneca K.K.; Honoraria (self): Bristol-Myers Squibb Company; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Eli Lilly Japan K.K.; Honoraria (self): MSD K.K.; Honoraria (self), Research grant/Funding (self): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self): Ono Pharmaceutical Co. Ltd.; Honoraria (self): Pfizer Japan Inc.; Honoraria (self): Taiho Pharmaceutical Co. Ltd. K. Nakagawa: Honoraria (self), Research grant/Funding (self): AstraZeneca K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (self): Astellas Pharma Inc.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Takeda Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant/Funding (self): MSD K.K.; Honoraria (self), Research grant/Funding (self): Taiho Pharmaceutical Co.,Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Ono Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant/Funding (self): Bristol-Myers Squibb Company; Honoraria (self), Research grant/Funding (self): Nippon Boehringer Ingelheim Co.,Ltd.; Honoraria (self), Research grant/Funding (self): Eli Lilly Japan K.K.; Honoraria (self), Research grant/Funding (self): Novartis Pharma K.K.; Honoraria (self): SymBio Pharmaceuticals Limited.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer Japan Inc.; Honoraria (self), Research grant/Funding (self): Chugai Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant/Funding (self): Daiichi Sankyo Co., Ltd.; Honoraria (self), Advisory/Consultancy: KYORIN Pharmaceutical Co.,Ltd.; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Roche Diagnostics K.K.; Honoraria (self): Nippon Kayaku Co.,Ltd.; Honoraria (self), Research grant/Funding (self): Bayer Yakuhin, Ltd; Honoraria (self), Research grant/Funding (self): Merck Biopharma Co., Ltd.; Honoraria (self), Research grant/Funding (self): AbbVie Inc.; Research grant/Funding (self): Kissei Pharmaceutical Co.,Ltd.; Research grant/Funding (self): Kyowa Hakko Kirin Co.,Ltd; Research grant/Funding (self): Otsuka Pharmaceutical Co., Ltd. N. Yamamoto: Honoraria (self), Research grant/Funding (self): AstraZeneca K.K.; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (self): Chugai Pharmaceutical; Honoraria (self), Research grant/Funding (self): Eli Lilly; Honoraria (self), Research grant/Funding (self): MSD; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (self): Ono Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant/Funding (self): Pfizer; Research grant/Funding (self): Astellas Pharma Inc; Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Daiichi Sankyo; Research grant/Funding (self): Takeda Pharmaceutical; Research grant/Funding (self): Taiho Pharmaceutical; Research grant/Funding (self): Terumo Corporation; Research grant/Funding (self): Toppan Printing Co., Ltd. All other authors have declared no conflicts of interest.