Safety and efficacy of avelumab plus carboplatin in patients with metastatic castration-resistant prostate cancer in an open-label Phase Ib study.

BACKGROUND: Single-agent PD-1/PD-L1 inhibitors have shown limited efficacy in unselected mCRPC. The evidence of a survival benefit with sipuleucel-T and ipilimumab, provides a rationale to study further increasing immunogenicity in mCRPC through combinations. METHODS: Safety and efficacy avelumab plus carboplatin was investigated in a single-arm Phase Ib study in mCRPC, progressing to at least one taxane and one androgen-receptor inhibitor. The primary endpoint was safety. Secondary endpoints included PSA/radiographic responses, progression-free survival (PFS) and overall survival (OS). Germline/somatic mutation analysis was performed. RESULTS: In total, 26 patients were included. Patients were heavily pretreated: 76.9% received ≥3 and 42.3% ≥4 prior lines. A DNA damage repair (DDR) alteration was found in three patients (11.5%). The safety profile was acceptable with 73% Grade 3-4 treatment-related adverse events. PSA response rate ≥50% was seen in 7.7% of patients. The objective response rate was 17.6%, including one complete response (5.9%). Two of these responders had a known DDR alteration (one BRCA2, one ATM). The median response duration was 6 months. Median radiographic PFS was 6.6 months (95% CI 4.28-9.01), and median OS 10.6 months (95% CI 6.68-NR). CONCLUSIONS: Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.

Phase I study of sunitinib in combination with gemcitabine and capecitabine for first-line treatment of metastatic or unresectable renal cell carcinoma.

BACKGROUND: The combination of gemcitabine plus capecitabine and sunitinib (GCS) shows activity in metastatic renal cell carcinoma (mRCC). We tested the multitargeted "chemo-switch" regimen as first-line treatment in patients with mRCC. METHODS: We assessed the maximum tolerated dose and antitumor activity of GCS in treatment-naïve, advanced mRCC patients. Treatment consisted of intravenous gemcitabine on days 1 and 8, oral capecitabine twice daily on days 1-14, and oral sunitinib daily for six 21-day cycles, followed by sunitinib monotherapy at the investigator's discretion. Dose level 0 (DL0) was gemcitabine 1,000 mg/m(2) per day plus capecitabine 650 mg/m(2) per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000 mg/m(2) per day plus capecitabine 850 mg/m(2) per 12 hours plus sunitinib 37.5 mg/day. RESULTS: Sixteen patients were enrolled. At DL1, two of four patients had dose-limiting toxicity (DLT; grade 3 diarrhea and grade 4 thrombocytopenia). The dose was reduced to DL0 when only 1 of 12 patients experienced DLT (grade 3 diarrhea, grade 3 mucositis, and grade 3 thrombocytopenia). Dose reductions were frequent (58% of patients), and only seven patients were able to receive the three drugs for more than three cycles. One patient achieved a complete response, three had partial responses, and the best response for four was stable disease. CONCLUSION: The safety profile of the combination does not seem manageable in this patient population. No further development of the combination is recommended.