Abstract 1420TiP
Background
Preclinically, radiation induces immunogenic cell death (ICD) and acts in synergy with immune checkpoint inhibitors. Ra-223, a targeted alpha therapy approved for treatment of pts with metastatic castration-resistant prostate cancer, increased antigen expression and stress response and induced ICD markers in cancer cell lines of different origin, including lung. Radiotherapy combined with immune checkpoint inhibitors, including pembrolizumab, showed synergistic antitumor responses in pts with NSCLC. Combining Ra-223 with pembrolizumab may enhance antitumor responses as first-line treatment and overcome immune resistance in pts with bone-metastatic NSCLC progressing on immune checkpoint therapy.
Trial design
This open-label, phase 1/2 study will determine the tolerable dose of Ra-223 in combination with pembrolizumab, and the efficacy of this combination in 2 cohorts of pts aged ≥18 years with stage IV NSCLC, ≥2 bone metastases, ECOG PS 0–1 and adequate bone marrow/organ function. Cohort 1 will include pts with treatment-naïve metastatic NSCLC, programmed death-ligand 1 (PD-L1) tumor protein score ≥50% and no driver mutation. Cohort 2 will include pts, irrespective of PD-L1 score, who progressed on a prior immune checkpoint inhibitor, including pembrolizumab, and received the appropriate prior treatment in the presence of driver mutations. In phase 1, pts will receive Ra-223 55 kBq/kg q6w for ≤6 doses and 200 mg pembrolizumab q3w for ≤35 cycles. In the case of dose limiting toxicities (DLTs), Ra-223 dose may be reduced to 33 kBq/kg. The primary endpoint is to determine the recommended phase 2 dose (RP2D), based on DLTs and safety. In phase 2, pts in cohort 1, randomized 1:1, will receive Ra-223 at the RP2D and pembolizumab or pembrolizumab alone. Pts in cohort 2 will receive Ra-223 at the RP2D and pembrolizumab. The primary endpoint is objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Additional endpoints include ORR per immune RECIST (iRECIST), duration of response, disease control rate, progression-free survival (RECIST v1.1; iRECIST), overall survival and safety. Patient enrollment has started.
Clinical trial identification
NCT03996473.
Editorial acknowledgement
Dr Egle McDonald and Dr Shaun Villa of Cancer Communications and Consultancy Ltd, Knutsford, UK, provided editorial assistance.
Legal entity responsible for the study
Bayer Healthcare.
Funding
Bayer.
Disclosure
M. Reck: Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Serono; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche/Genentech; Advisory/Consultancy: AbbVie; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen. K.F. Mileham: Advisory/Consultancy: AstraZeneca; Speaker Bureau/Expert testimony: Merck; Honoraria (self): Takeda; Research grant/Funding (self): Celgene. L. Decoster: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Research grant/Funding (self): Boehringer Ingelheim; Research grant/Funding (self): Bristol-Myers Squibb. A. Estival: Honoraria (self), Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Lilly; Travel/Accommodation/Expenses: PharmaMar. E. Felip: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony: Guardant Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy, Speaker Bureau/Expert testimony: AbbVie; Advisory/Consultancy, Speaker Bureau/Expert testimony: Blueprint Medicines; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck KGaA; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: BerGenBio; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Medscape; Advisory/Consultancy, Speaker Bureau/Expert testimony: prIME Oncology; Advisory/Consultancy, Speaker Bureau/Expert testimony: Samsung; Advisory/Consultancy, Speaker Bureau/Expert testimony: Touchtime; Research grant/Funding (institution): Merck; Research grant/Funding (institution): EMD Serono; Officer/Board of Directors, Independent Member of the Board of Directors: GRIFOLS. L. Paz-Ares: Officer/Board of Directors: Genómica; Leadership role: Altum Sequencing; Honoraria (self): Adacap; Honoraria (self): Amgen; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Blueprint Medicines; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Eli Lilly; Honoraria (self): Incyte; Honoraria (self): Ipsen; Honoraria (self): Merck; Honoraria (self), Research grant/Funding (self): Merck Sharp and Dohme; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self): PharmaMar; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Takeda; Honoraria (self): Sysmex. M. Sebastian: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Celgene. N. Vinolas Segarra: Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Pierre Fabre; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: MSD. V. Surmont: Advisory/Consultancy: Roche; Advisory/Consultancy: Bristol-Myers Squibb. A. Wagner: Full/Part-time employment: Bayer. S.M. Galdy: Full/Part-time employment: Bayer. E.F. Smit: Advisory/Consultancy, Institution: Lilly; Advisory/Consultancy, Research grant/Funding (institution), Institution: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Institution: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution), Institution: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution), Institution: Bristol-Myers Squibb; Advisory/Consultancy, Institution: Merck KGaA; Advisory/Consultancy, Institution: MSD Oncology; Advisory/Consultancy, Institution: Takeda; Advisory/Consultancy, Research grant/Funding (institution), Institution: Bayer; Advisory/Consultancy, Institution: Regeneron; Advisory/Consultancy, Institution: Novartis; Advisory/Consultancy, Institution: Daiichi Sankyo; Advisory/Consultancy, Institution: Seattle Genetics. All other authors have declared no conflicts of interest.