In recent years, immunotherapy has revolutionized the field of oncology. Several malignancies in which immunotherapy has improved survival, such as melanoma, lung, and renal cell carcinoma, are well-vascularized, highly immunogenic, have a high mutational burden, and have a microenvironment conducive to immune cell survival and function.[24, 25] Despite encouraging results in other malignancies, immunotherapy has not demonstrated efficacy in the majority of PDAC patients. More recently, olaparib (a poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor) was approved for utilization in patients with metastatic pancreatic cancer. There was no difference in median survival as compared to placebo (18.9 months vs 18.1 months), but olaparib was associated with an greater progression-free survival (7.4 months vs 3.8 months). Of note, olaparib was only approved for patients with BRCA (breast cancer gene)-mutated pancreatic cancer, which accounts for just 5% of cases. The median survival of both arms in the aforementioned study were greater than the current analysis. To be included in this trial, patients had to complete 16 weeks of chemotherapy, likely preventing enrollment of patients with poor performance status or rapidly progressive disease. Therefore, these results are not broadly generalizable to the majority of patients with metastatic PDAC.
In our study, we report that the addition of immunotherapy to chemotherapy was associated with a survival advantage in patients with metastatic PDAC. Median overall survival was approximately 1.6 months longer in the IT-CT group. This is concordant with a recent report which demonstrated that the combination of immunotherapy and chemotherapy in the adjuvant setting was associated with improved survival compared to adjuvant chemotherapy alone (5-year overall survival: 30.3% vs 20.6%). The associated survival advantage among patients who received adjuvant IT-CT as compared to adjuvant CT was greater in magnitude relative to the findings in our study. We hypothesize that this discrepancy may be due to the effectiveness of treatments based on disease burden. For example, when compared to single-agent gemcitabine, FOLFIRINOX lead to a 19.4 month survival advantage in the adjuvant setting, but just a 4.3 month advantage in metastatic PDAC.[2, 5] It is possible that our current findings, as well as those reported in the adjuvant setting, are false positive results, attributable to randomness in a relatively small sample size or unappreciated confounders.
Numerous immune targets have been studied in PDAC. A phase II trial in patients with metastatic PDAC who failed first-line chemotherapy received durvalumab, a monoclonal antibody targeting PD-L1 (programmed death-ligand 1); however, this trial was terminated due to a response rate of 0%. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), another immune checkpoint, has been shown to downregulate immune responses. A single-arm clinical trial which combined ipilimumab (a CTLA-4 antagonist), nivolumab (a PD-1 (programmed cell death protein 1) antagonist), and radiation in patients with metastatic PDAC demonstrated an objective response rate of just 14% and a progression-free survival of 76 days. A recent phase I trial examining the safety of nivolumab, nab-paclitaxel, and gemcitabine in patients with advanced PDAC did not show a survival benefit as compared to historic survival data without nivolumab.
Deficiencies in mismatch repair with subsequent microsatellite instability (MSI) are often found in cancers and cause numerous genetic mutations, activating a patient’s anti-tumor immune response. A pivotal trial administered pembrolizumab (a PD-1 antagonist) to patients with metastatic cancer and demonstrated a disease control rate of 75% and a reported objective response rate of 62% in those with pancreatic cancer. A follow-up trial, which also administered pembrolizumab to MSI-high/mismatch repair-deficient advanced cancers, reported an objective response rate in tumors of pancreatic-origin of just 18% with progression-free and overall survival of two and four months, respectively. Importantly, only 1–2% of PDAC tumors are MSI-high and/or mismatch repair-deficient. It should be emphasized that the impact of immunotherapy on PDAC with MSI remains unproven, and the incidence of these tumors is extremely rare. One potential explanation for the discrepancy in effectiveness of immunotherapy relative to other cancers is due to the austere tumor microenvironment of PDAC, which includes a dense stromal compartment, low nutrient concentrations, and relative hypoxia.[15, 32] Patients’ immune cells, which immunotherapies rely upon, are likely less effective under these harsh conditions, since they are not well adapted to survive in this harsh environment.[32, 33] A recent study by our group demonstrated that among all active phase III trials in the United States, 37% targeted the immune system. While our data show that some patients benefit from immunotherapy, the two-year survival rate was just 7%. Thus, ongoing research efforts may want to investigate other potential targets.
Our study also highlights disparities in utilization of immunotherapy. We found that advanced age and greater comorbidity index were associated with a decreased utilization of IT. Higher level education and receiving treatment at an academic center were associated with increased IT utilization. Disparities in cancer are well-studied and previous reports have shown variations in therapies administered and survival based on race and socioeconomic status.[35, 36] Studies have recommended multiple strategies, including insurance reform, improved access to quality care with community outreach, improved access to novel therapies, increased emphasis on prevention and screening, and diversification of employees in the healthcare field, to reduce disparities in cancer care.[37–39] Previous reports identified that Black and Asian patients, those who live alone, were unmarried or did not have children, had government issued insurance, or had issues performing their activities of daily living were more likely to decline all treatment.[40, 41]
Although our study includes data on a large number of PDAC patients, there are limitations. Importantly, the use of immunotherapy is not common therefore the IT-CT treatment group is small in comparison to those who received CT alone. Based on limitations inherent to NCDB studies, including the lack of granularity of the data, we cannot comment on specific treatment details, such as the type of chemotherapy or immunotherapy received, whether the immunotherapy was part of a clinical trial, how many cycles of chemotherapy were completed, the genetic make-up of a patient’s tumor (BRCA mutation, MSI status, etc.), and why immunotherapy was administered (progression of disease, patient desire, clinical trial, etc.). Also, the NCDB only includes data on the first six months of treatment, therefore a subset of patients in the CT group may have received IT later in their treatment course. Details of a patient’s performance status are not recorded in the NCDB, thus Charlson-Deyo scores were used as a surrogate. The NCDB only receives data from Commission on Cancer-accredited hospitals and only captures 70% of cancer diagnoses. Therefore, these data cannot truly be generalized to all hospital systems and patients. We also cannot account for incorrect data within the database. Despite these limitations, our study reports a thorough analysis of the utilization of immunotherapy in patients with metastatic PDAC and demonstrates there may be a subset of patients who respond to immunotherapy.