Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

Abstract

BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

Interrogating the Genomic Landscape of Uterine Leiomyosarcoma: A Potential for Patient Benefit

“…However, TMB is not indicative of response across all cancer types [86], and "TMB high" cut-offs vary widely [87]. Moreover, as mentioned previously, some success with immunotherapy in uLMS has been observed [62,63,66].…”

“…Two case studies involving patients with metastatic uLMS reported dramatic reductions in tumour burden and symptomatic disease with immune checkpoint inhibitor therapy [62,63], yet clinical trials on small patient cohorts have as yet failed to show any response to anti PD-1 therapy in uLMS [64,65]. However, in a basket study of doublet immunotherapy involving nivolumab and ipilimumab for four cycles followed by maintenance nivolumab [66], two patients had complete response and a third showed a partial response out of the five uLMS patients enrolled. This observation requires further investigation.…”

Perioperative and palliative systemic treatments for biliary tract cancer

“…The Australian trial CA209-538 examined the chemotherapy-free combination regimen of ipilimumab and nivolumab and yielded an ORR of 23% (all partial responses), however with a relatively modest mPFS of 2.9 months and mOS of 5.7 months. 61 …”

Disparity in the era of personalized medicine for epithelial ovarian cancer

“…Although OCS demonstrate a copy number high phenotype in 15/17 cases, 104 PD-L1 expression and CD8+ T-cell infiltration are a feature of this disease, 105 with whole exome sequencing of a single OCS sample demonstrating the presence of multiple tumour specific neo-antigens. 106 Within the CA209-538 study, one PR and one SD were reported in five patients with OCS who received treatment with nivolumab and ipilimumab 107 with an additional case report of a PR in recurrent OCS following treatment with pembrolizumab. 108…”