Investigators Uncover PDAC Biosignatures Linked With Better Responses to Chemoimmunotherapy

Until recently, adequate treatments for pancreatic ductal adenocarcinoma (PDAC) were lacking since treatment efficacy with available chemotherapeutics was generally poor overall compared with that seen in other tumor types. Some advances, such as the FDA approval of olaparib (Lynparza) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated PDAC,¹ have moved the field forward but represent viable options for only a small subset of patients with the disease.

Added to that, PDAC is refractory to standalone immunotherapy due to an immunosuppressive microenvironment, leaving investigators to hypothesize about viable ways to overcome these immunologically cold tumors.

“The big challenge in patients with advanced pancreatic cancer is that we can’t get immunotherapy to work as well as it has for patients with other types of diseases,” Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, said at the recent 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in an interview with CancerNetwork^®. “There are [currently] no clear indications for immunotherapy in pancreatic cancer.”

Vonderheide and fellow investigators from the Parker Institute for Cancer Immunotherapy presented data from the phase 1/2 PRINCE trial (NCT03214250) evaluating gemcitabine and nab-paclitaxel (Abraxane) plus various immunotherapeutic options.² Three experimental arms included treatment with the PD-1 inhibitor nivolumab (Opdivo), the experimental CD40 agonist monoclonal antibody sotigalimab (formerly APX005M), or a combination of both agents. Previous results of the trial were published in Lancet Oncology in 2021 and demonstrated promising safety and potential activity of chemotherapy plus sotigalimab with or without nivolumab in this patient population.³

At 2022 ASCO meeting, Vonderheide offered insights into the biosignatures associated with survival after each chemoimmunotherapy regimen, shedding further light onto the immuno-pharmacodynamic effects of each treatment on different patients. Of note, pretreatment liquid and tumor biomarkers were predictive of overall survival with chemoimmunotherapy.

What was the rationale for assessing distinct biosignatures in patients with metastatic pancreatic cancer?

The first aspect [of this study] was to understand what the challenges [investigators were] facing in the laboratory, and we had 2 main observations. One is that we needed to do more than simply [administer checkpoint inhibitors]. There were other pathways to test that would more robustly generate T cells, which were missing. And the second part is, surprisingly, immunotherapy and chemotherapy do work well together [in this population]. Chemotherapy can kill some tumor cells, maybe not enough to cure a patient, but it acts as a vaccine that solves one of the problems for patients with this disease in that we need to get the immune system started in the first place. We took those observations to this clinical trial called PRINCE.

What do you feel were some of the most standout findings of this research?

First, we reported that we met the primary end point [of 1-year OS] in patients who were treated with standard chemotherapy with the addition of nivolumab. This hasn’t been shown before. We also saw activity and just missed statistical significance with chemotherapy combined with a novel agonist to CD40 [P = .062]. There are 2 good possibilities with chemoimmunotherapy which, of course, is useful in other tumor types and now we have an idea that it might be beneficial in pancreas cancer. More importantly was that for each of those combinations, we were able to identify specific biomarkers that indicate which patients are more likely to respond to which therapy using a large translational research approach. [These markers are] distinct by arm. A biomarker-predicting response to chemotherapy/nivolumab can’t predict response to chemotherapy/sotigalimab, and vice versa. In fact, it appears there are different types of patients whom we can identify now—not by a tumor biopsy, sequencing, or some of the more traditional approaches to precision oncology—but rather taking a sample of blood and studying the immune subsets by flow cytometry and other techniques. To us, that represents a novel approach for precision oncology, particularly in pancreatic cancer, where we need to do better.

How do you foresee this research impacting the treatment of patients with pancreatic cancer?

The current findings are promising. They’ve generated a lot of hypotheses. The obvious next step is to validate what we observed prospectively. If that’s true, we’re now looking at a novel approach to treating patients who we meet with metastatic pancreas cancer. [We must] first understand what their immune health is or what the status of their immune system is when we meet them, and then precisely direct them to particular chemoimmunotherapy combinations that are appropriate for their particular immune health. For one thing, it increases the chances, we would hope, of better long-term survival. But it also avoids treating patients with combinations that aren’t effective and have toxicities.

Are there any strong, multidisciplinary implications from this research?

The manuscript reporting these findings [is authored by] several dozen people who come from all walks of life, including laboratory science, immunology, data science, machine learning, and clinical science. It took that large group, which the Parker Institute brought together by design, to combine basic discovery, translational research, clinical trials, and biomarker discovery.

How do you foresee this being implemented in a multidisciplinary team?

Imagine our tumor boards where teams sit around a table and think about a particular patient [and their] genetic data. Now imagine an immune tumor board or a combination board where we look at all the data, including immune data, to understand if a particular patient has a certain level of immune health and is appropriate for a certain type of immunotherapy. That’s starting to happen, but we see the possibility for this becoming a standard part of patient care in the future.

What do you hope that your colleagues take away from our conversation?

One is that we need to be persistent and rigorous about improving therapies for patients with pancreatic cancer. The second is that not every patient with pancreas cancer should be treated the same. Different types of chemoimmunotherapy are just an example where we apply the notion of precision oncology. The third [is that we now know] what it takes for these large-scale, multi-omics studies to reveal biomarkers. The number of patients needed, the number of samples, and the types of biostatistics and bioinformatics analyses are quite challenging [to obtain]. Sometimes we think it’s straightforward to do it. Having lived that experience, it is intense. Not every assay is feasible or produces what you want. There are unexpected turns, but it can be done.

References

1. FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. News. FDA. December 27, 2019. Accessed July 8, 2022. https://bit.ly/3nQBWRq
2. Padrón LJ, Maurer DM, O’Hara MH, et al. Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer. J Clin Oncol. 2022;40(suppl 16):4010. doi:10.1200/JCO.2022.40.16_suppl.4010
3. O’Hara MH, O’Reilly EM, Varadhachary G, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 2021;22(1):118-131. doi:10.1016/S1470-2045(20)30532-5