Radiotherapy Augments Pembrolizumab Responses and Outcomes in Metastatic Non-Small Cell Lung Cancer: Pooled Analysis of Two Randomized Trials

Background: In metastatic non-small cell lung cancer (mNSCLC), the clinical trials NCT02492568 and NCT02444741 are the only known randomized comparisons of pembrolizumab alone versus pembrolizumab combined with radiation therapy (RT). When the trials were analyzed individually, some potential benefit was observed in the combination therapy group, but the relatively small sample size of each trial limited the detection of potential differences in response rates and outcomes. Hence, we perform a pooled analysis of these two randomized trials to validate and explore whether whether RT improves mNSCLC patient responses to immunotherapy. Methods: This was a pooled analysis of two randomized trials (NCT02492568 and NCT02444741) of pembrolizumab with or without RT for mNSCLC. Endpoints included the out-of-field overall response rate (ORR) and disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and subgroup analysis of the different RT schemes. Findings- In all, 131 patients were analyzed (n=66 pembrolizumab; n=65 pembrolizumab/RT (iRT)). ORR was 21% in the pembrolizumab arm vs. 38% in the iRT arm (p=0.01); DCR was 53% in the pembrolizumab arm vs. 67% in the iRT arm (p=0.0009); PFS was 4.4 m vs 8.3 m (p=0.046); and OS was 9.2 m vs 19.2 m (HR 0.66; p=0.040). Ablative RT (24Gy/3 fractions and 50Gy/4 fractions) had better ORRs of 48% and 54%, respectively, compared to 18% for non-ablative RT (45Gy/15 fractions) (p<0.05, respectively). Interpretation: The addition of RT to immunotherapy significantly increased the ORR of unirradiated lesions and was additionally associated with significant improvements in PFS and OS. Ablative RT was associated with response rates significantly higher than those of non-ablative RT, possibly due to a detrimental effect of non-ablative RT on ALC. These hypothesis-generating findings require dedicated, large-volume, and randomized studies for corroboration. Funding Statement: Both MDACC and NKI trials were financially supported with an unrestricted grant by Merck Sharp & Dohme that included medication supply. Other support was provided by the Cancer Center Support (Core) Grant P30 CA016672 from the National Cancer Institute, National Institutes of Health, to The University of Texas MD Anderson Cancer Center. Declaration of Interests: Dr. Welsh has received grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Nanobiotix, Mavu Pharmaceuticals, and Checkmate Pharmaceuticals; has been on the scientific advisory boards for RefleXion Medical, Molecular Match, OncoResponse, CheckMate, Mavu, and Alpine Immune Sciences; is cofounder of Helios Oncology, Molecular Match, and OncoResponse; is an advisor for AstraZeneca, Merck, Molecular Match, Incyte, Aileron, and Nanobiotix; and has patents for MP470 (amuvatinib), MRX34 regulation of PD-L1, and an X-ray therapy technique to overcome immune resistance (MD Anderson Cancer Center has a trademark for RadScopal). Dr. Theelen has received grants from Merck Sharpe & Dohme and Astra Zeneca. Dr. Baas reports grants from Merck, BMS, Boehringer Ingelheim, Pfizer and Roche. Dr. Aerts reports personal fees and non-financial support from Merck, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Bayer, Roche and Astra Zeneca outside the submitted work; In addition, Dr. Aerts has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. The remaining authors declare no conflict of interest. Ethics Approval Statement: Both trials (NCT02492568 and NCT02444741) and this pooled analysis were approved by the relevant institutional review boards.