Final results of a phase I “RadVax” trial of hypofractionated radiation combined with pembrolizumab in patients with metastatic solid tumors.
Authors: Lukens John Nicholas , Mick Rosemarie , Huang Alexander Chan Chi , Han Nicholas , Farwell Michael , Mitchell Tara C. , Amaravadi Ravi K. , Schuchter Lynn Mara , Berman Abigail T. , O'Hara Mark H. , Maity Alisha , Miller David , Minn Andy , Vonderheide Robert H. , Wherry E. John , Maity Amit 
Published: June 2021

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Background: Many patients treated with anti-PD-1 therapy do not show a clinical response. Preclinical studies suggest that adding hypofractionated radiotherapy (HFRT) to anti-PD1 can increase the efficacy of immunotherapy through several mechanisms including increased antigen presentation. We conducted a prospective trial testing the combination of pembrolizumab and HFRT in patients with metastatic solid tumors. Methods: This prospective single-institution phase I trial tested pembrolizumab in combination with HFRT in patients with metastatic cancers (NSCLC, melanoma, pancreas, breast, others) and an ECOG performance status of 0-1. Melanoma and NSCLC patients were required to have progression of disease on anti-PD1, having received ≥ 2 doses of anti-PD1 and progression documented by RECIST v1.1. Patients were required to have an index lesion ≥1 cm that was amenable to HFRT and at least one other lesion that was not irradiated and could be followed for response using RECIST criteria. Pembrolizumab 200 mg IV every 3 weeks was administered beginning 1 week prior to the first fraction of radiation. The HFRT dose was 8 Gy x 3 fractions or 17 Gy x 1 fraction, determined by randomization during the Expansion phase. The primary objective was the safety of HFRT combined with pembrolizumab, with dose-limiting toxicity (DLT) defined as Grade ≥ 3 non-hematological toxicity related to the combination of Pembrolizumab and HFRT. The secondary objective was the radiographic response of metastatic lesions outside the radiation field as measured by RECIST. Results: 59 patients aged 27-90 years (median 60) were enrolled from March 2015 to December 2018 (24 in the Safety Phase and 35 in Expansion Phase). 40 patients (67.7%) had treatment-related AEs, of which 4 were grade 3 and none were grade 4. One patient experienced hepatitis, classified as DLT. While most patients did not have a radiologic response, in patients with metastatic melanoma, 7 of 16 (43.8%, exact 95% CI 19.8-70.1%) had an objective response to HFRT + pembrolizumab, including 3 complete and 4 partial responses. Responses are durable with 3/3 complete responders alive with no progression, and 3/4 partial responders alive with 2 having no evidence of progression. Among melanoma patients, only 2 of 7 (29%) responders received ipilimumab prior to enrollment, compared to 8 of 9 (89%) non-responders (p = 0.035). An increase in Ki67+ PD-1+ non-naïve CD8 T-cells was observed in the blood 2 weeks after HFRT, but the magnitude did not correlate with likelihood of response. Responses were observed after either 17 Gy x 1 fraction or 8 Gy x 3 fractions, with no difference in response rate by fractionation. Conclusions: This study suggests that HFRT administered with concurrent pembrolizumab is associated with acceptable toxicity and that in patients with metastatic melanoma progressing on anti-PD-1 therapy, this approach yields an ORR of 44%. Clinical trial information: NCT02303990.