Combinations of chemotherapy and immunotherapy showed activity in patients with metastatic pancreatic cancer, according to findings from a national, randomized clinical trial led and sponsored by the Parker Institute for Cancer Immunotherapy. The results of the small trial were presented by Padrón et al at the 2022 ASCO Annual Meeting (Abstract 4010) and simultaneously published in Nature Medicine.
The researchers found that in 34 patients with advanced pancreatic cancer randomly assigned to receive the anti–PD-1 therapy nivolumab with two chemotherapy drugs, nab-paclitaxel and gemcitabine, had a 1-year survival rate of 57.7%, significantly greater than the historical average of 35% with chemotherapy alone. The findings also included the identification of immune system biomarkers associated with better outcomes. A second treatment of the CD40 agonistic antibody sotigalimab with chemotherapy also appeared more effective in a subgroup of patients, identified with a different set of biomarkers.
This study suggests there is benefit of combining immunotherapy and chemotherapy in patients with advanced pancreatic cancer and there may be ways to fine-tune treatment choices based on the ‘immune health’ of the patient.— Robert H. Vonderheide, MD, DPhil
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“This study suggests there is benefit of combining immunotherapy and chemotherapy in patients with advanced pancreatic cancer and there may be ways to fine-tune treatment choices based on the ‘immune health’ of the patient,” said senior study author Robert H. Vonderheide, MD, DPhil, the John H. Glick Abramson Cancer Center Professor and Director of the Abramson Cancer Center at Penn Medicine. “We now hope to evaluate these potential biomarkers in further trials to see if they’ll enable us reliably to identify patients who will respond best to this and other combination therapies. The most promising biomarkers were measured by a blood test of the immune system, not genetic sequencing, which opens the door for a new approach in precision oncology.”
The most common form of pancreatic cancer—pancreatic ductal adenocarcinoma—is commonly diagnosed only after it has become advanced or metastatic, and is also notoriously aggressive and difficult to treat effectively. Historically, only about 10% of patients who receive a pancreatic ductal adenocarcinoma diagnosis survive for 5 years, and patients newly diagnosed with metastatic pancreatic ductal adenocarcinoma usually live for less than 1 year even with optimal chemotherapy.
Standard chemotherapy regimens can arrest the growth of pancreatic ductal adenocarcinoma tumors, but only temporarily. Newer immune-targeted therapies, such as checkpoint blockade antibodies, have been strikingly effective against some other cancers, but almost entirely ineffective when used on their own against pancreatic ductal adenocarcinoma. However, an initial small clinical trial reported by Dr. Vonderheide’s team last year in The Lancet Oncology suggested that the addition of chemotherapy can substantially disrupt pancreatic tumors’ resistance to immunotherapy—making the combination more effective than either type of treatment on its own. In the new study, they tested that approach on a larger scale.
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The team randomly assigned a set of more than 100 patients with metastatic pancreatic ductal adenocarcinoma to receive a standard chemotherapy (gemcitabine/nab-paclitaxel) plus one of three immunotherapy regimens: an antibody treatment (nivolumab) targeting the immune “off switch” PD-1; a different antibody treatment (sotigalimab) that activates an immune “on switch,” CD40; and a combination of the anti–PD-1 and pro-CD40 treatments. The main goal of the study was to see if any of these combinations could improve the rate of survival over 1 year for these patients, compared to the historical rate of just 35% for patients who receive chemotherapy alone.
The researchers found that all three groups had 1-year survival rates higher than 35%: 57.7% for anti–PD-1 plus chemotherapy, 48.1% for pro-CD40 plus chemotherapy, and 41.3% for combination immunotherapy plus chemotherapy. Only the first of these results was statistically significant, although the study authors did note the study had rather small patient numbers.
Patients who received chemotherapy and both types of immunotherapy did not benefit any more than chemotherapy alone. The researchers suspect that the relatively poor results for the two-immunotherapy regimen may have resulted from an excessive activation of T cells that pushed the cells into an exhausted state.
The study authors concluded, “Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent pancreatic ductal adenocarcinoma chemoimmunotherapy trials.”
Participating clinical sites included Penn’s Abramson Cancer Center; Dana-Farber Cancer Institute; The University of Texas MD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; Stanford University; the University of California, Los Angeles; and the University of California, San Francisco.
Disclosure: Funding and/or immunotherapy doses were provided by the Cancer Research Institute, the Parker Institute for Cancer Immunotherapy, Bristol Myers Squibb, and Apexigen. For full disclosures of the study authors, visit coi.asco.org or nature.com.
