Researchers find PDAC biosignatures linked to better responses to chemoimmunotherapy

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

Additionally, PDAC is refractory to autonomic immunotherapy due to an immunosuppressive microenvironment, leaving researchers to speculate on viable ways to overcome these immunologically cold tumors.

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

Vonderheide and fellow researchers at the Parker Institute for Cancer Immunotherapy presented data from the Phase 1/2 PRINCE trial (NCT03214250) evaluating gemcitabine and nab-paclitaxel (Abraxane) along with various immunotherapeutic options.2 Three experimental arms included treatment with the PD-1 inhibitor nivolumab (Opdivo), the investigational CD40 agonist monoclonal antibody sotigalimab (formerly APX005M), or a combination of the two 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 the 2022 ASCO meeting, Vonderheide offered an overview of the biosignatures associated with survival after each chemoimmunotherapy regimen, further shedding light on the immunopharmacodynamic effects of each treatment on different patients. Of note, pretreatment fluid and tumor biomarkers were predictive of overall survival with chemoimmunotherapy.

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

The first aspect [of this study] was to understand what the challenges were [investigators were] face in the laboratory, and we had 2 main observations. First, we had to do more than just [administer checkpoint inhibitors]. There were other pathways to test that would more robustly generate T cells, which were missing. And the second part is, amazingly, immunotherapy and chemotherapy work well together. [in this population]. Chemotherapy can kill some tumor cells, maybe not enough to cure a patient, but it acts like a vaccine that solves one of the problems of patients with this disease in that we have to start the immune system first . We brought these observations to this clinical trial called PRINCE.

What do you think were the most remarkable findings of this research?

First, we reported that we had met the primary endpoint [of 1-year OS] in patients who have been treated with standard chemotherapy with the addition of nivolumab. This has not been shown before. We also found activity and just missed statistical significance with chemotherapy plus a new CD40 agonist [P = .062]. There are 2 good possibilities with chemoimmunotherapy which of course is useful in other types of tumors and now we have an idea that it might be beneficial in pancreatic cancer. More importantly, for each of these combinations, we were able to identify specific biomarkers that indicate which patients are most likely to respond to which therapy using a large-scale translational research approach. [These markers are] distinct by the arm. A predictive biomarker response to chemotherapy/nivolumab cannot predict the response to chemotherapy/sotigalimab, and vice versa. In fact, it seems that there are different types of patients that we can identify now – not by tumor biopsy, sequencing or some of the more traditional precision oncology approaches – but rather by taking a blood sample and by studying immune subsets by flow cytometry and other techniques. For us, this represents a new approach for precision oncology, especially in pancreatic cancer, where we need to do better.

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

Current findings are promising. They 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 new approach to treating patients we encounter with metastatic pancreatic cancer. [We must] first understand what their immune health is or what the state of their immune system is when we meet them, and then direct them precisely to particular chemoimmunotherapy combinations tailored to their particular immune health. On the one hand, it increases the chances of hopefully better long-term survival. But it also avoids treating patients with combinations that are ineffective and exhibit toxicities.

Are there strong and multidisciplinary implications of this research?

The manuscript reporting these discoveries [is authored by] several dozen people from all walks of life, including laboratory science, immunology, data science, machine learning, and clinical science. This large group, which the Parker Institute purposely brought together, had to combine fundamental discovery, translational research, clinical trials and the discovery of biomarkers.

How do you envisage this implementation 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 chart or a combination chart where we look at all the data, including the immune data, to understand if a particular patient has a certain level of immune health and is appropriate for a certain type of immunotherapy. It’s starting to happen, but we see the possibility of it becoming a standard part of patient care in the future.

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

First, we must be persistent and rigorous in improving therapies for patients with pancreatic cancer. The second is that not all patients with pancreatic cancer should be treated the same. Different types of chemoimmunotherapy are just one 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 biostatistical and bioinformatic analyzes are quite difficult [to obtain]. Sometimes we think it’s easy to do. To have lived this experience, it is intense. Not all tests are feasible or produce what you want. There are some unexpected turns, but it can be done.

References

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

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