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The optimal treatment for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) and contraindication to cisplatin is uncertain. This trial (NCT03258554) tested the primary hypothesis that radiation therapy (RT) with concurrent and adjuvant durvalumab, a PD-L1 inhibitor, improves progression-free survival (PFS) compared to standard RT with cetuximab. This phase II/III randomized trial enrolled patients ≥ 18 years of age who had previously untreated AJCC 8th stage III-IVB SCC of the larynx, hypopharynx, oral cavity, p16- oropharynx/unknown primary (OPC/UP) or stage III and selected stage I-II p16+ OPC/UP, with a contraindication to cisplatin: ECOG performance status (PS) 2; renal or hearing impairment; peripheral neuropathy; age ≥ 70 with moderate/severe comorbidity; age < 70 with severe comorbidity. Favorable-risk p16+ HNSCC, PS >2, inadequate end-organ function, or active autoimmune disease were exclusion criteria. Patients were randomized 2:1 to RT (70 Gy, 35 fractions, 7 weeks) plus either: (arm A) durvalumab 1500 mg IV q4 weeks starting 2 weeks before RT (7 cycles) or (arm B) cetuximab 400 mg/m2 IV 1 week prior to RT then 250 mg/m2 weekly (8 cycles). The primary phase II endpoint was PFS with planned sample size of 234 randomized patients (69 PFS events, hazard ratio 0.65, 80% power, 1-sided alpha 0.20). The difference in PFS between arms was tested using a log-rank test. This study enrolled 190 patients (186 randomized; 123 arm A; 63 arm B) from Mar 2019-Jul 2021. Following planned interim futility analysis, the trial was temporarily closed to accrual, pending analysis based on total required phase II PFS events (met in Jun 2022). Median age was 72 years (59% ≥ 70). 95% had ≥ 3 comorbidities (median 5); 58% had T3-4; 49% had N2-3; 47% had p16+ OPC/UP. 87% in arm A and 89% in arm B completed RT. 89%/63% completed concurrent/adjuvant durvalumab and 81% completed ≥ 7 cycles of cetuximab. At median follow-up of 1.2 years, PFS was not improved and locoregional failure (LRF) was higher with durvalumab (Table). Grade ≥ 3 adverse events were 69%/79% for arm A/B. Grade ≥ 3 dysphagia, mucositis, and dermatitis rates were 22%/30%, 11%/20%, and 5%/13% for arm A/B, respectively. Novel eligibility criteria and feasibility of accrual were established. However, RT with durvalumab did not show a signal toward improved PFS and led to significantly worse LRF, compared to RT with cetuximab in HNSCC pts with a contraindication to cisplatin. The trial will not move to phase III. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): 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.Materials/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: A total of 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 of non-irradiated lesions 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.Conclusion: 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%. [ABSTRACT FROM AUTHOR]