Abstract 1309P
Background
Preclinically, radiation induces immunogenic cell death (ICD) and acts in synergy with immune checkpoint inhibitors (ICIs). The alpha emitter Ra-223 increased antigen expression and stress response and induced ICD markers in cancer cell lines, including lung. Radiotherapy combined with ICI (eg pembrolizumab) showed synergistic antitumor responses in patients (pts) with NSCLC. We assessed whether the potentially complementary mechanism of actions of Ra-223 and pembrolizumab would result in greater efficacy in pts with NSCLC and bone metastases.
Methods
In this open-label, multicenter study (NCT03996473), pts aged ≥18 years with stage IV NSCLC and ≥2 bone metastases received Ra-223 55 kBq/kg every 6 weeks (≤6 injections) + pembrolizumab 200 mg every 3 weeks (≤35 cycles). The study included a safety run-in (phase I) and a planned efficacy expansion (phase II) for 2 cohorts: treatment-naive pts with baseline programmed cell death ligand-1 (PD-L1) tumor protein score (TPS) ≥50% and ICI-refractory pts with any PD-L1 TPS.
Results
Recruitment started on March 6, 2020, and phase I data are available for 8 pts (all ICI refractory), of whom 6 were evaluable for dose-limiting toxicity (DLT); 1 pt discontinued before starting therapy and 1 pt withdrew consent after cycle 1. No DLTs occurred. All pts who started treatment (n=7) had treatment-emergent AEs (TEAEs) (Table), which were mostly mild or moderate. Severe TEAEs included grade (G) 4 rectal hemorrhage and G 5 kidney failure in 1 pt and G 5 respiratory failure in 1 pt, considered unrelated to study drugs. All pts discontinued study treatment. Best overall response was stable disease in 1 pt, not evaluable in 1 pt, and progressive disease in 5 pts.
Conclusions
No dose-limiting toxicities or safety signals were observed for Ra-223 + pembrolizumab in pts with NSCLC and bone metastases. The combination did not appear to demonstrate improved clinical benefit for ICI-refractory pts. Table: 1309P
Baseline characteristics and outcomes of radium-223 + pembrolizumab in NSCLC (N=7)
| Age range, years | 49-78 |
| Male/female ratio | 2/5 |
| PD-L1 TPS, n | |
| <50% | 6 |
| ≥50% | 1 |
| Prior therapies received, range | 1-3 |
| Ra-223 injections received, range | 1-4 |
| Pembrolizumab infusions received, range | 1-9 |
| Best overall response, n | |
| Stable disease | 1 |
| Progressive disease | 5 |
| Not evaluable | 1 |
| TEAEs, n | 7 |
| Leading to dose modification | 3 |
| Leading to discontinuation | 0 |
| Serious | 2 |
Clinical trial identification
NCT03996473.
Editorial acknowledgement
David Murdoch, BSc (Hons), and Sara Black, ISMPP CMPP™, from OPEN Health, London, UK, provided medical writing support.
Legal entity responsible for the study
Bayer AG, Berlin, Germany, was responsible for study governance, coordination, and running.
Funding
Bayer AG, Berlin, Germany.
Disclosure
M. Reck: Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Amgen; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: AstraZeneca; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: BMS; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Lilly; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Mirati; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Merck; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: MSD; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Novartis; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Pfizer; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Roche; Financial Interests, Personal, Other, Honoraria for Lectures and Consultancy: Samsung Bioepis. K. Mileham: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Merck. L. Paz-Ares: Financial Interests, Personal, Other, Personal fees: BMS; Financial Interests, Personal, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: MSD; Financial Interests, Personal, Other, Personal fees: Lilly; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Other, Personal fees: Blueprint; Financial Interests, Personal, Other, Personal fees: Bayer; Financial Interests, Personal, Other, Personal fees: Mirati; Financial Interests, Personal, Other, Personal fees: Amgen; Financial Interests, Personal, Other, Personal fees: Jansen; Financial Interests, Personal, Other, Personal fees: Sanofi; Financial Interests, Personal, Other, Personal fees: PharmaMar. N. Viñolas: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Other, Travel grants and Other Honoraria: BMS; Financial Interests, Personal, Other, Travel grants and Other Honoraria: MSD; Financial Interests, Personal, Other, Travel grants and Other Honoraria: Roche; Financial Interests, Personal, Other, Travel grants and Other Honoraria: Boehringer Ingelheim; Financial Interests, Personal, Other, Travel grants and Other Honoraria: AstraZeneca; Financial Interests, Personal, Other, Travel grants and Other Honoraria: Lilly. L. Decoster: Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Invited Speaker: MSD. A. Estival: Financial Interests, Personal, Other, Conferences and Travel expenses: Lilly; Financial Interests, Personal, Other, Conferences and Travel expenses: PharmaMar; Financial Interests, Personal, Other, Conferences and Travel expenses: Bayer; Financial Interests, Personal, Other, Conferences and Travel expenses: MSD; Financial Interests, Personal, Other, Conferences and Travel expenses: BMS; Financial Interests, Personal, Other, Conferences and Travel expenses: Roche; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: PharmaMar. M. Sebastian: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: BMS; Financial Interests, Personal, Other, Personal fees: MSD; Financial Interests, Personal, Other, Personal fees: Boehringer Ingelheim; Financial Interests, Personal, Other, Personal fees: CureVac; Financial Interests, Personal, Other, Personal fees: BioNTech; Financial Interests, Personal, Other, Personal fees: Amgen; Financial Interests, Personal, Other, Personal fees: Janssen-Cilag; Financial Interests, Personal, Other, Personal fees: Novartis; Financial Interests, Personal, Other, Personal fees: Takeda; Financial Interests, Personal, Other, Personal fees: Sanofi-Aventis; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Other, Personal fees: Merck. H. Chen: Financial Interests, Personal, Full or part-time Employment: Bayer. M. Chisamore: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. V.J. Wagner: Financial Interests, Personal, Full or part-time Employment: Bayer. A. Wagner: Financial Interests, Personal, Full or part-time Employment: Bayer. All other authors have declared no conflicts of interest.