Dual Immunotherapy in Stage 4 Pancreatic and Biliary Cancer

JAMA Oncology featured a single-institution case series by Dr Gretel Terrero and colleagues, in which the combination of ipilimumab and nivolumab was shown to be highly effective in patients with chemotherapy-resistant metastatic pancreatic or biliary cancer who had pathogenic inherited mutations leading to homologous recombination deficiency (HRD).

Approximately 3% to 10% of patients with pancreatic ductal adenocarcinoma, the most common pancreatic cancer subtype, have pathogenic germline variants (inherited mutations) leading to HRD. In addition, approximately 15% to 17% of this patient group have similar somatic (noninherited) genetic alterations involving BRCA1 and BRCA2 biallelic gene loss, resulting in a high tumor mutation burden and greater genomic loss of heterozygosity.

Immunotherapy in Pancreatic Cancer

The next generation of immunotherapies, immune checkpoint inhibitors, have been ineffective in unselected patients with pancreatic cancer. Given the molecular rationale for increased sensitivity to immunotherapies in patients with pancreatic cancer associated with HRD pathogenic germline variants (mutations in inherited cancer genes), this study investigated whether this subgroup was sensitive to immunotherapy strategies.

Study Details

The study included patients treated between April 2018 and February 2021 at the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, totaling 12 patients.

For HRD pathogenic germline variants:

• 4 patients carried BRCA1,
• 5 patients carried BRCA2, and
• 1 patient each carried RAD51C, RAD51D, and ATM mutations.

Most patients had disease resistant to platinum-based chemotherapy and PARP inhibitors.

Patients received 1 mg/kg ipilimumab (Yervoy) plus 3 mg/kg nivolumab (Opdivo) every 21 days for four cycles, followed by 480 mg nivolumab every 28 days.

Key Findings

• Four patients had a complete response (BRCA1 in 2,  BRCA2  in 1,  RAD51C in 1),
• one had a partial response (BRCA1 ), and
• two had stable disease ( BRCA1  and  ATM, respectively).
• An objective response rate of 42% and a disease control rate of 58% were observed.

Three of the four complete responders discontinued treatment after 2 years, and all these patients had no evidence of disease 11 to 41 months after treatment began.

The response in the patient with a partial response lasted 7.3 months. The 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 complete responders and two patients with progressive disease. Responders had a higher density of tumor-infiltrating lymphocytes and higher expression of chemokines (CCL4, CXCL9, CXCL10) known to enable interaction between adaptive effector immune cell groups.

Summary and Commentary

This case series shows that combined ipilimumab/nivolumab immunotherapy is effective in a selected group of pancreatic cancer patients with pathogenic inherited mutations in genes encoding HRD, which is responsible for DNA repair.

In addition, few or no infiltrating immune effector cells, low antigenicity, and multiple immunosuppressive factors in the pancreatic cancer tumor microenvironment were associated with a lack of response to immunotherapy.

Until recently, treatment with immunotherapies had shown no meaningful benefit in pancreatic cancer other than tumors with high microsatellite instability (MSI-H). This study demonstrated an association between germline HRD status and sensitivity to immune checkpoint inhibitors, and strengthened previous evidence linking BRCA1/2 variants with immunotherapy response in other tumors.