In a single-institution case series reported in a research letter in JAMA Oncology, Terrero et al found that the combination of ipilimumab and nivolumab was active in patients with chemotherapy-refractory metastatic pancreatic or biliary cancer with homologous recombination deficiency (HRD) pathogenic germline variants.
As stated by the investigators, “Approximately 3% to 10% of patients with pancreatic ductal adenocarcinoma have pathogenic germline variants leading to HRD, and approximately 15% to 17% have similar somatic alterations….[pancreatic ductal adenocarcinomas] with biallelic loss of BRCA1 and BRCA2 [have] a higher median tumor mutation burden and higher genomic loss of heterozygosity than wild-type tumors….Immune checkpoint inhibitors have been ineffective in unselected patients with [pancreatic ductal adenocarcinoma]. Given the molecular rationale for increased susceptibility to immune checkpoint inhibitors in patients with [pancreatic ductal adenocarcinoma] associated with HRD pathogenic germline variants, we investigated whether this subgroup may be sensitive to immunotherapy strategies.”
The study included 12 patients treated between April 2018 and February 2021 at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. HRD pathogenic germline variants consisted of BRCA1 in four patients; BRCA2 in five; and RAD51C, RAD51D, and ATM in 1 each. Most patients had platinum- and poly (ADP-ribose) polymerase (PARP) inhibitor–refractory disease. Patients received ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg every 21 days for four doses, followed by nivolumab at 480 mg every 28 days.
Complete response was observed in four patients (2 with BRCA1, 1 with BRCA2, 1 with RAD51C), partial response was observed in one (with BRCA1), and stable disease was observed in two (with BRCA1 and ATM, respectively), yielding an objective response rate of 42% and a disease control rate of 58%.
Among the four patients with complete response, three discontinued therapy after 2 years and all remained without evidence of disease at 11 to 41 months after starting therapy. Response persisted for 7.3 months in the patient with partial response. Durations of stable disease were 4.1 and 3.5 months.
Treatment-related adverse events were consistent with the known toxicity of ipilimumab/nivolumab.
Adequate archival biopsy results were available for two patients with complete response and two with progressive disease. Responders had a higher density of tumor-infiltrating lymphocytes and higher expression of chemokines (CCL4, CXCL9, CXCL10) known to enable trafficking of adaptive effector immune populations. As noted by the investigators, expression of these chemokines has been shown to correlate with a T-cell–inflamed phenotype in pancreatic ductal adenocarcinoma.
The investigators concluded, “This case series showed that ipilimumab/nivolumab therapy was associated with clinical benefit in a biomarker selected group of patients with [pancreatic ductal adenocarcinoma] and pathogenic germline variants in genes encoding for HRD, with pretreatment biopsy analysis supporting biological plausibility.”
The further stated, “Typically, [pancreatic ductal adenocarcinoma] is characterized by few or no infiltrating immune effector cells, low antigenicity, and multiple immunosuppressive factors in the tumor microenvironment. Treatment with immune checkpoint inhibitors has not shown meaningful benefit for [pancreatic ductal adenocarcinoma] except for microsatellite instability–high tumors. This study showed an association between germline HRD status and sensitivity to immune checkpoint inhibitors, advancing previous evidence of an association between BRCA1/2 variants in other tumors and immunotherapy response.”
Peter J. Hosein, MD, of the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by a grant from the National Institutes of Health and others. For full disclosures of the study authors, visit jamanetwork.com.
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