Pancreatic cancer is one of the deadliest types of tumors, and the number of diagnosed cases continues to rise each year. The disease is often difficult to diagnose early, and as a result, pancreatic cancer is often diagnosed in an advanced stage when the cancer has metastasized. In addition, pancreatic cancer usually contain a variety of mutations, which often means a single targeted therapy isn’t enough to stop the disease by itself.[1]

For patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the five-year survival rate is less than 5%. Hence, without a doubt, this means that pancreatic cancer remains one of the most crucial challenges in oncology and is predicted to become the second leading cause of cancer death in the United States by 2040. [1].

In the metastatic setting, while combination chemotherapy reliably offers tumor control and clinical stabilization, both standard regimens of gemcitabine plus nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) are limited in response durability and incur toxicity. Thus, new treatment strategies for this disease are urgently needed.

Meeting unmet needs
Researchers from the Parker Institute for Cancer Immunotherapy (PICI) and its collaborative network of researchers, including from the University of Pennsylvania, presented during the annual meeting of American Society of Clinical Oncology (ASCO), held June 3 – 7, 2022 and published in Nature Medicine, shows that certain patients with pancreatic cancer who may be more likely to benefit from combination treatment regimens consisting of immunotherapy and chemotherapy.[2][3]

This translational work identified biological signals in the blood and tumor that may uncover which patients have longer survival after these combination treatment regimens. The goal of this research is to one day predict via a simple test ahead of time whether a patient stands to benefit from a particular chemo-immunotherapy regimen.

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Incidence of pancreatic cancer
Each year, approximately 60,000 people are diagnosed with pancreatic cancer and the prognosis is typically poor. For the subset of patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the disease studied in the Phase II clinical trial, known as the PRINCE study, a collaborative research effort designed to work towards advancing more efficacious therapies that can create durable response, and ultimately remission, the five-year survival rate is less than 5%[3].

The findings are part of a recent analysis of data from the PRINCE trial, co-funded by PICI the Cancer Research Institute in collaboration with Apexigen, and designed on the basis of decades of research by lead Principal Investigator Robert Vonderheide, M.D., D.Phil., and others at the University of Pennsylvania. The trial involved seven PICI network institutions and uncovered various predictive biomarkers associated with longer overall survival for a subset of mPDAC patients.[4]

New data from the PRINCE clinical trial, which evaluated the combination of standard-of-care chemotherapy (gemcitabine + nab-paclitaxel) and nivolumab, a PD-1 inhibitor, and/or sotigalimab, an experimental antibody that is an agonist of the CD40 protein being developed by Apexigen, could aid patient selection in future chemo-immunotherapy studies.

Explorative analyses
As part of exploratory analyses, PICI researchers discovered distinct biosignatures associated with survival for the nivolumab-chemotherapy and sotigalimab-chemotherapy treatment arms, which reflect each immunotherapy’s distinct mechanisms of action. Few biomarkers predicted survival in patients receiving the sotigalimab-nivolumab- chemotherapy regimen.

Results from 105 paricipating patients was analyzed for efficacy.  This data showed that the primary endpoint of 1-year overall survival (OS) was met for nivolumab-chemotherapy (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotigalimab in combination with chemotherapy (48.1%, P = 0.062, n = 36) or for sotigalimab in combination with nivolumab and chemotherapy (41.3%, P = 0.223, n = 35).[2][3]

Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR) and safety. The explorative analyses showed that Treatment-related adverse event (TRAE) rates were similar across arms. In addition, multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivolumab-chemotherapy and sotigalimab in combination with chemotherapy.[2][3]

Survival after nivolumab-chemotherapy correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T-cells at baseline. The investigators also noted that survival after sotigalimab in combination with chemotherapy correlated with greater intratumoral CD4 T-cell infiltration and circulating differentiated CD4 T-Cells and antigen-presenting cells. However, a patient subset benefitting from sotigalimab-nivolumab- chemotherapy regimen was not identified. Collectively, the investigators concluded that this analyses suggest a potential treatment-specific correlation of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemo-immunotherapy trials.[2][3]

Not be appropriate for all PDAC patients
“While the data from the trial suggest that these treatment regimens may not be appropriate for all PDAC patients, we uncovered various predictive biomarkers from the circulation and tumor that may correlate with longer survival and warrant further study,” said Lacey Padron, Ph.D., Vice President, Informatics at PICI and lead study author.

“We are encouraged by the data and believe chemoimmunotherapy combinations may improve outcomes for some patients with metastatic PDAC. Following up on these results, the scientific community can work to better understand who is most likely to benefit and why.”

“The PRINCE trial illustrates how this groundbreaking clinical research fostered collaboration between clinicians, researchers, nonprofits and industry, with the goal of bringing innovative treatments to patients faster,” said Ute Dugan, M.D., Ph.D., Chief Medical Officer of PICI.

First step
The study authors conclude that the Phase Ib/II study is a first step toward characterizing which patients may derive clinical benefit from these chemoimmunotherapy regimens by having identified potential biomarkers that can now be validated prospectively to determine if this allows for minimally invasive biomarker-enrichment designs for chemoimmunotherapy treatment in metastatic PDAC.

“The identification of signals that may help predict clinical outcomes for pancreatic cancer patients receiving combination treatment with chemotherapy and immunotherapy has significant potential to save more lives, as oncologists will be better equipped to design optimal treatment plans for their patients based on the presence or absence of these signals,” said Jill O’Donnell-Tormey, Ph.D., Chief Executive Officer and Director of Scientific Affairs at the Cancer Research Institute.

Unique challenges
“While scientific and medical advances in immunotherapy are helping to turn cancer into a curable disease for many patients, pancreatic cancer presents unique challenges that deserve the attention of the greatest scientific minds,” said William Hoos, cancer research and collaboration lead at 1440 Foundation, a nonprofit that funds innovative pancreatic cancer research and collaboration, including support for the REVOLUTION study of novel immunotherapy combinations in pancreatic cancer, at PICI.

“The potential for a biomarker selection strategy to identify the right immunotherapy combination for each patient holds potential for progress in pancreatic cancer. These new findings suggest next steps for researchers, and hope for pancreatic cancer patients and their families. We look forward to continued progress in this promising field.”

“The presentation [during the annual meeting of the American Society of Clinical Oncology] and publication of these results in pancreatic cancer underscore PICI’s commitment to advancing our understanding of the toughest tumor types,” said John Connolly, Ph.D., Chief Scientific Officer of PICI.

“This shared knowledge can help patients, clinicians and researchers, alike, combat this deadly disease,” Connolly concluded.

Clinical trial
Safety and Efficacy of APX005M With Gemcitabine and Nab-Paclitaxel With or Without Nivolumab in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma – NCT03214250.

Highlights of prescribing information
Oxaliplatin (Eloxatin®; Sanofi) [Perscribing Information]
Irinotecan (Camptosar®; Pfizer) [Prescribing Information]
Fluorouracil (Adrucil®; Teva) [Prescribing information]
Levoleucovorin (Fusilev®; Aceotech Biotech) [Prescribing information]
Gemcitabine (Gemzar® Eli Lilly & Co) [Perscription Information]
Nab-paclitaxel (Abraxane®; Bristol-Myers Squibb) [Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb) [Prescribing Information]

[1] Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021 Apr 1;4(4):e214708. doi: 10.1001/jamanetworkopen.2021.4708. PMID: 33825840; PMCID: PMC8027914.
[2] Padrón LJ, Maurer DM, O’Hara KM, O’Reilly EM, Wolff RA, Wainberg ZA, Ko AH, 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 40, 2022 (suppl 16; abstr 4010) | DOI 10.1200/JCO.2022.40.16_suppl.4010
[3] Padrón LJ, Maurer DM, O’Hara MH, O’Reilly EM, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma., et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med. 2022 Jun 3. doi: 10.1038/s41591-022-01829-9. Epub ahead of print. PMID: 35662283.
[4] Survival Rates for Pancreatic Cancer. Early Detection, Diagnosis, and Staging. American Cancer Society. Online. Last accesses on June 4, 2022.

Featured image: Networking over lunch at the inaugural Trainee & Early Career Luncheon during the 58th annual meeting of the American Society of Clinical Oncology (ASCO), held June 3 – 7, 2020 in Chicago, Il. Photo courtesy: © 2022 ASCO/Scott Morgan. Used with permission.

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