Matching patients with pancreatic cancer to therapies based on genomic alterations in their tumors may be beneficial. In the retrospective Know Your Tumor trial, patients with alterations who were treated with targeted agents lived longer than those treated with standard therapies.

Recently published results suggest that matching patients with pancreatic cancer to therapies based on genomic alterations in their tumors may be beneficial. In the retrospective Know Your Tumor trial, patients with alterations who were treated with targeted agents had better overall survival (OS) than those treated with standard therapies (Lancet Oncol 2020;21:508–18).

The trial, started in 2014 by the Pancreatic Cancer Action Network (PanCAN), aims to improve treatment for patients with pancreatic cancer by increasing molecular profiling of tumors. Patients enrolled in the trial undergo genomic testing, the results of which—along with prior treatment history—are used to develop a list of treatment options. The patients' physicians then decide the best course of treatment, and researchers follow patients' responses.

Initial trial results established the molecular landscape of the disease and indicated that patients with DNA damage–response mutations might benefit from platinum-based therapy (Clin Cancer Res 2018;24:5018–27; JCO Precis Oncol 2019 Oct 23 [Epub ahead of print]). In the most recent study, however, “we wanted to ask the question broadly: If patients were treated with the therapy that was appropriately matched to their actionable mutations, did they do better than if they didn't get matched therapy?” says lead author Michael Pishvaian, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, MD.

Pishvaian and his colleagues analyzed data from 1,082 patients who had molecular profiling. Overall, 26% of patients had actionable molecular alterations; 46 of them were treated with matched therapies, including off-label or experimental agents, whereas 143 received standard, unmatched drugs. The median OS was 2.6 years compared with 1.5 years, respectively.

“This shows that patients do have alterations and that they can benefit from specifically matched therapies,” Pishvaian says. “Our hope for the sake of pancreatic cancer is that we can start to carve out the 25% or so of patients with alterations and offer them the optimal therapy.” Other trials in pancreatic cancer are taking a similar approach, including PanCAN's Precision Promise trial and Cancer Research UK's Precision-Panc Platform.

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Pancreatic adenocarcinoma

Brian Wolpin, MD, MPH, of the Dana-Farber/Harvard Cancer Center in Boston, MA, who was not involved in the trial, says that physicians and researchers have been skeptical that targeted therapy could be beneficial in pancreatic cancer, but “this study and some of those that have come before it suggest that there are opportunities here for personalized treatment approaches.”

Wolpin notes the importance of findings confirming that microsatellite-unstable tumors may respond to immune checkpoint inhibitors; KRAS wild-type tumors may have other targetable driver mutations; and DNA damage repair–deficient tumors with mutations beyond BRCA1/2 may respond to PARP inhibitors or other agents.

However, given the trial's retrospective nature, it cannot definitively establish whether matched therapy improves OS. Thus, Wolpin stresses the need for randomized, prospective trials that focus on specific alterations and therapies. Indeed, Pishvaian and his team hope to launch an umbrella trial in which patients receive a drug based on actionable alterations.

For Eileen O'Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the trial, “the key take-home point is that there is a subset of patients in whom tumor-based mutation profiling is very important.” The findings, she emphasizes, reinforce the need for widespread genomic profiling—including germline and somatic testing—in all patients with pancreatic cancer to identify those with alterations.

O'Reilly says that researchers should now focus on making responses to targeted therapies deeper and more durable: “That's where an increased understanding of tumor biology and mechanisms of resistance will come in—understanding what combinations may be leveraged.”–Catherine Caruso

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©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.