Phase II Trial of First-Line Durvalumab and Chemotherapy in Patients With Extra-Pulmonary Small Cell Carcinoma

Prospective randomized trials are lacking in extensive-stage or metastatic extra-pulmonary small cell carcinoma (EPSCC). As a result, treatment for EPSCC is largely extrapolated from SCLC studies.

This single-arm phase II trial enrolled patients with EPSCC to investigate the activity of first-line durvalumab (1500 mg every 3 wk) and 4 to 6 cycles of chemotherapy (either cisplatin or carboplatin) with etoposide, followed by maintenance durvalumab 1500 mg every 4 weeks until disease progression. All had comprehensive genomic profiling of an archival tumor specimen, using Illumina TruSight Tumour 170, Illumina TSO500, or Foundation Medicine. The primary end point was progression-free survival (PFS) at 12 months. Key secondary end points were objective response rate, overall survival, and prognostic biomarkers, including tumor mutational burden (ACTRN12621001225808).

A total of six participants were enrolled (target: n = 16). The trial closed early due to slow accrual. The primary disease sites were the bladder, colon, gall bladder, esophagus, and pancreas. After a median follow-up of 20.5 months, the rate of PFS at 12 months was 17% (95% confidence interval [CI]: 1%-52%), median PFS was 4.9 months (95% CI: 2.0-12.5 mo), and median overall survival was 8.8 months (95% CI: 6.41-not-estimable). The objective response rate was 50% (95% CI: 19%-81%). No new safety signals were observed. Common mutations were microsatellite stability, RB1 and TP53 mutations. Tumor mutational burden ranged from 2.4 to 20.5 mutations per megabase.

In this small prospective study, chemotherapy-durvalumab produces responses comparable to historical chemotherapy outcome, but without clear improvement in durability. Early closure due to slow accrual highlights the challenges of conducting trials in EPSCC. These findings should be considered descriptive and hypothesis generating. This study reveals that durvalumab plus chemotherapy is safe and has some activity in rare small cell cancers outside the lung, but benefits are modest and short lived. Current treatment remains largely chemotherapy based, highlighting the urgent need for larger, collaborative research efforts to find more effective options for these patients.