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Doubts About Stroma-Targeting Agents in Pancreatic Cancer


Adding pegvorhyaluronidase alfa (PEGPH20) to treatment with nab-paclitaxel and gemcitabine (AG) did not improve survival in adults with previously untreated metastatic pancreatic ductal adenocarcinoma in a phase 3 trial.

The median overall survival was 11.2 months with PEGPH20 plus AG and 11.5 months with placebo plus AG. The median progression-free survival was 7.1 months in both treatment arms.

Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg Leuven and KU Leuven in Belgium, and colleagues reported these findings in the Journal of Clinical Oncology.

The authors explained that, in pancreatic ductal adenocarcinoma, “a dense fibrotic stroma (i.e., desmoplasia) surrounds the growing tumor mass, which can compress tumor vasculature within the microenvironment and increase interstitial pressure, impeding perfusion and delivery of systemic agents.”

PEGPH20 is an enzyme that degrades hyaluronan, a major component of the stroma. The researchers’ hypothesis was that PEGPH20 would weaken the stromal barrier and facilitate greater penetration of the AG combination into the tumor.

However, PEGPH20 failed to improve upon results with AG in this trial, which led Halozyme Therapeutics to halt further development of PEGPH20.

The negative findings in this trial, as well as the failure of other stroma-remodeling agents in pancreatic ductal adenocarcinoma, “collectively indicates the need to reevaluate this treatment strategy,” Dr. Van Cutsem and colleagues wrote.

“More preclinical and retrospective analyses are needed to better understand the failures of tumor stroma remodeling and whether and how it should continue to be pursued,” the authors added.

Phase 3 Results

The intent-to-treat analysis included 492 adults with previously untreated metastatic pancreatic ductal adenocarcinoma. All patients expressed high hyaluronan levels, as defined by at least 50% hyaluronan staining in the extracellular matrix from tumor samples.

There were 165 subjects randomized to receive placebo plus AG and 327 randomized to receive PEGPH20 plus AG. Baseline characteristics were similar between the treatment arms.

The overall response rate was 47% with PEGPH20-AG and 36% with placebo-AG. The median duration of response was 6.1 months and 7.4 months, respectively.

The overall survival analysis was performed after 330 deaths. There were no significant differences between the PEGPH20 and placebo arms with regard to median overall survival (11.2 months and 11.5 months, respectively; hazard ratio, 1.00, P = .97) or progression-free survival (7.1 months in both arms; HR, 0.97).

All patients experienced at least one treatment-emergent adverse event (AE). The most common AEs of any grade that were more frequent in the PEGPH20 arm than in the placebo arm (≥ 2%) were peripheral edema (61.8% vs. 33.3%), muscle spasms (51.4% vs. 9.6%), myalgia (28.9% vs. 14.7%), and arthralgia (19.4% vs. 11.5%).

Grade 3 or higher AEs that were more common with PEGPH20 (≥ 2%) included fatigue (16.0% vs. 9.6%), muscle spasms (6.5% vs. 0.6%), and hyponatremia (8.0% vs. 3.8%).

“[T]here were no apparent safety signals that affected study treatment exposure or survival,” the investigators noted.

Two Failed Trials

“We now have two failed clinical trials for PEGPH20. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough?” Nausheen Hakim, DO, of Northwell Health Cancer Institute in New York, and colleagues wrote in a commentary shortly after Halozyme released topline results from the phase 3 trial (Pancreas [Fairfax]. 2019;3[1]:e1-e4. doi: 10.17140/POJ-3-e010).

The second study the editorialists were referring to is a phase 1b/2 trial of PEGPH20 added to fluorouracil, leucovorin, irinotecan, and oxaliplatin (J Clin Oncol. 2019 May 1;37[13]:1062-9).

In this trial, the median overall survival was worse with PEGPH20 than without it, at 7.7 months and 14.4 months, respectively. The difference was probably due to the increased toxicity with the PEGPH20 regimen, which led to subjects receiving only half the number of chemotherapy cycles as the control group, Dr. Hakim and colleagues wrote.

“Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells but additional intrinsic factors at play,” the editorialists wrote. “It may indeed be a combination of stroma-modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.”

The phase 3 study was funded by Halozyme Therapeutics. The authors disclosed relationships with Halozyme and many other companies. The editorialists disclosed no conflicts of interest.

SOURCE: Van Cutsem E et al. J Clin Oncol. 2020 Jul 24;JCO2000590. doi: 10.1200/JCO.20.00590.

This article originally appeared on MDedge.com.

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