Background

Tumour Protein 53 (TP53) plays a role in angiogenesis by regulating vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2). In patients (pts) with EGFR+ NSCLC, TP53 mutations, notably on exon 8, are associated with poorer outcomes of EGFR tyrosine kinase inhibitor treatment and may be involved in primary resistance. We evaluated the relationship between TP53 status and outcomes in RELAY.

Methods

Pts with untreated metastatic EGFR+ NSCLC received oral ERL (150 mg/day) with either intravenous RAM (10 mg/kg) or placebo (P+ERL) every 2 weeks. This exploratory analysis consisted of 386 pts with any mutation detected at baseline by Guardant 360 next-generation sequencing. The primary endpoint was PFS. Secondary and exploratory endpoints included overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. TP53 status was assessed in relation to outcomes and treatment-emergent gene alterations at progression.

Results

TP53 mutations were detected in 46% of White and 42% of Asian pts and was similar for EGFR exon 19 and exon 21 mutations (∼43%). Other pt and disease characteristics and concurrent gene alterations were comparable between TP53 mutant (mt) and wildtype (wt) tumors. Irrespective of treatment, pts with TP53 mutations, notably on exon 8, had worse outcomes than pts with TP53wt. In all pts, RAM+ERL improved PFS and DoR, while ORR (78% to 82%) and DCR (95% to 97%) were similar. OS data were immature. Safety was comparable between TP53mt and wt subgroups. Treatment-emergent T790M mutation rates at progression were higher in TP53mt (33% to 39%) than TP53wt tumors (19% to 21%) regardless of treatment. Table: 1209P

Outcomes according to TP53 status

Conclusions

The addition of RAM to ERL showed consistent benefit in both TP53wt and TP53mt EGFR+ NSCLC, suggesting that the RELAY regimen is a suitable first-line treatment option for pts with EGFR+ NSCLC irrespective of TP53 status.

Clinical trial identification

NCT02411448.

Editorial acknowledgement

Declan O’Dea, PhD, of Eli Lilly and Company provided medical writing and editorial support.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

M. Nishio: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly and Company; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo Healthcare; Financial Interests, Personal, Speaker’s Bureau: Merck Serono. L. Paz-Ares: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AZ; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Eli Lilly and Company; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Mirati; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Member of the Board of Directors: Altum sequencing; Financial Interests, Institutional, Principal Investigator: Alkermes; Financial Interests, Personal, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: IO Biotech; Financial Interests, Institutional, Principal Investigator: Janssen-Cilag International NV; Financial Interests, Institutional, Principal Investigator: Eli Lilly and Company; Financial Interests, Institutional, Principal Investigator: Merck Sharp & Dohme Corp.; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: PharmaMar; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Sanofi; Financial Interests, Institutional, Principal Investigator: Takeda; Financial Interests, Institutional, Principal Investigator: Tesaro. M. Reck: Financial Interests, Institutional, Other, Consulting Fees: Amgen; Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca; Financial Interests, Institutional, Other, Consulting Fees: Bristol Myers Squibb; Financial Interests, Institutional, Other, Consulting Fees: Boehringer Ingelheim; Financial Interests, Institutional, Other, Consulting Fees: Eli Lilly and Company; Financial Interests, Institutional, Other, Consulting Fees: Merck; Financial Interests, Institutional, Other, Consulting Fees: MSD; Financial Interests, Institutional, Other, Consulting Fees: Mirati; Financial Interests, Institutional, Other, Consulting Fees: Novartis; Financial Interests, Institutional, Other, Consulting Fees: Pfizer; Financial Interests, Institutional, Other, Consulting Fees: Roche; Financial Interests, Institutional, Other, Consulting Fees: Sanofi; Financial Interests, Institutional, Speaker’s Bureau: Amgen; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Institutional, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Institutional, Speaker’s Bureau: Eli Lilly and Company; Financial Interests, Institutional, Speaker’s Bureau: Merck; Financial Interests, Institutional, Speaker’s Bureau: MSD; Financial Interests, Institutional, Speaker’s Bureau: Mirati; Financial Interests, Institutional, Speaker’s Bureau: Novartis; Financial Interests, Institutional, Speaker’s Bureau: Pfizer; Financial Interests, Institutional, Speaker’s Bureau: Roche; Financial Interests, Institutional, Speaker’s Bureau: Sanofi; Financial Interests, Institutional, Advisory Board: Amgen; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board: Eli Lilly and Company; Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Mirati; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: Sanofi. K. Nakagawa: Financial Interests, Institutional, Funding: AstraZeneca K.K; Financial Interests, Institutional, Funding: Astellas Pharma; Financial Interests, Institutional, Funding: MSD K.K; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Nippon Boehringer Ingelheim Co., Ltd.; Financial Interests, Institutional, Funding: Novartis Pharma K.K; Financial Interests, Institutional, Funding: Pfizer Japan Inc.; Financial Interests, Institutional, Funding: Bristol Myers Squibb Company; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Funding: Merck Biopharma Co., Ltd.; Financial Interests, Institutional, Invited Speaker: Takeda; Financial Interests, Institutional, Invited Speaker: Taiho; Financial Interests, Institutional, Invited Speaker: SymBio; Financial Interests, Institutional, Invited Speaker: AbbVie Inc.; Financial Interests, Institutional, Invited Speaker: ICON Japan K.K; Financial Interests, Institutional, Invited Speaker: Kissei; Financial Interests, Institutional, Invited Speaker: Parexel International; Financial Interests, Institutional, Invited Speaker: EPS; Financial Interests, Institutional, Invited Speaker: Syneos Health; Financial Interests, Institutional, Invited Speaker: Pfizer R&D Japan G.K.; Financial Interests, Institutional, Invited Speaker: A2 Healthcare; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: CMIC Shift Zero; Financial Interests, Institutional, Invited Speaker: Kyowa Kirin; Financial Interests, Institutional, Invited Speaker: Bayer Yakuhin; Financial Interests, Institutional, Invited Speaker: EPS International; Financial Interests, Institutional, Invited Speaker: Otsuka Pharmaceutical; Financial Interests, Institutional, Invited Speaker: PRA Health Sciences; Financial Interests, Institutional, Invited Speaker: Covance Japan Inc.; Financial Interests, Institutional, Invited Speaker: Medical Research Support; Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Invited Speaker: PPD-SNBL; Financial Interests, Institutional, Invited Speaker: Japan Clinical Research Operations; Financial Interests, Institutional, Invited Speaker: Sysmex; Financial Interests, Institutional, Invited Speaker: AbbVie Inc.; Financial Interests, Institutional, Invited Speaker: Mochida Pharmaceutical; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting Fees: Astellas; Financial Interests, Personal, Other, Consulting Fees: Pfizer; Financial Interests, Personal, Other, Consulting Fees: Takeda; Financial Interests, Personal, Other, Consulting Fees: Eli Lilly Japan; Financial Interests, Personal, Other, Consulting Fees: Ono; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Roche Diagnostics; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan; Financial Interests, Personal, Invited Speaker: Nippon Kayaku; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: Bayer Yakuhin; Financial Interests, Personal, Invited Speaker: Merck Biopharma; Financial Interests, Personal, Invited Speaker: Nanzando; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis Pharma; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Personal, Invited Speaker: Medical Mobile Communications; Financial Interests, Personal, Invited Speaker: Yomiuri Telecasting; Financial Interests, Personal, Invited Speaker: Nikkei Business Publications; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Medicus Shuppan; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Care Net; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Medical Review; Financial Interests, Personal, Invited Speaker: Yodosha; Financial Interests, Personal, Invited Speaker: 3H Clinical Trial; Financial Interests, Personal, Invited Speaker: Thermo Fisher Scientific; Financial Interests, Personal, Invited Speaker: Hisamitsu; Financial Interests, Personal, Invited Speaker: Nichi-Iko; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: Kyorin; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan; Financial Interests, Personal, Invited Speaker: Pfizer Japan; Financial Interests, Personal, Invited Speaker: Kyorin; Financial Interests, Personal, Invited Speaker: Ono. E.B. Garon: Financial Interests, Institutional, Funding: Eli Lilly and Company; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Dynavax Technologies; Financial Interests, Institutional, Research Grant: Eli Lilly and Company; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Iovance Biotherapeutics; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: Neon; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Other, Consulting Fees: ABL-Bio; Financial Interests, Institutional, Other, Consulting Fees: Boehringer Ingelheim; Financial Interests, Institutional, Other, Consulting Fees: Bristol Myers Squibb; Financial Interests, Institutional, Other, Consulting Fees: Dracen Pharmaceuticals; Financial Interests, Institutional, Other, Consulting Fees: EMD Serono; Financial Interests, Institutional, Other, Consulting Fees: Eisai; Financial Interests, Institutional, Other, Consulting Fees: GlaxoSmithKline; Financial Interests, Institutional, Other, Consulting Fees: Merck; Financial Interests, Institutional, Other, Consulting Fees: Natera; Financial Interests, Institutional, Other, Consulting Fees: Novartis; Financial Interests, Institutional, Other, Consulting Fees: Regeneron; Financial Interests, Institutional, Other, Consulting Fees: Sanofi; Financial Interests, Institutional, Other, Consulting Fees: Shionogi; Financial Interests, Institutional, Other, Consulting Fees: Xilio. M. Ceccarelli: Financial Interests, Institutional, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. S.R. Wijayawardana: Financial Interests, Institutional, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Institutional, Stocks/Shares: Eli Lilly and Company. C. Visseren-Grul: Financial Interests, Institutional, Full or part-time Employment: Eli Lilly and Company. S. Novello: Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role: MSD; Financial Interests, Institutional, Advisory Role: Eli Lilly and Company; Financial Interests, Institutional, Advisory Role: Takeda; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Roche; Financial Interests, Institutional, Speaker’s Bureau: Amgen; Financial Interests, Institutional, Advisory Role: Sanofi; Financial Interests, Institutional, Advisory Role: BMS; Financial Interests, Institutional, Advisory Role: Beigene; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Institutional, Speaker’s Bureau: Beigene; Financial Interests, Institutional, Speaker’s Bureau: MSD; Financial Interests, Institutional, Speaker’s Bureau: Eli Lilly and Company; Financial Interests, Institutional, Speaker’s Bureau: Takeda; Financial Interests, Institutional, Speaker’s Bureau: Pfizer; Financial Interests, Institutional, Speaker’s Bureau: Roche; Financial Interests, Institutional, Speaker’s Bureau: Amgen; Financial Interests, Institutional, Speaker’s Bureau: Sanofi; Financial Interests, Institutional, Speaker’s Bureau: BMS.