Pazopanib effective against progressive carcinoid tumors

CHICAGO — Pazopanib was associated with a significant improvement in PFS compared with placebo in patients with progressive carcinoid tumors, according to phase 2 data at the ASCO Annual Meeting.

During a presentation, Emily K. Bergsland, MD, professor of clinical medicine at the University of California, San Francisco, and associate director of education at the Helen Diller Family Comprehensive Cancer Center, said the study supports targeting the vascular endothelial growth factor (VEGF) signaling pathway as a treatment approach in this patient population.

“As all of you know, there have been a number of advances in the treatment of carcinoid tumors over the last several years,” she said. “Eventual resistance is the rule, however, and additional therapeutic strategies are needed in this disease.”

The VEGF pathway has already been established as a target in neuroendocrine tumors (NETs). In 2011, sunitinib (Sutent, Pfizer) became the first anti-VEGF agent for advanced pancreatic NETs, according to the manufacturer. However, Bergsland and colleagues reported that treatment options remain limited for patients with progressive NETs that develop outside of the pancreas.

“We know that VEGF and its receptors are expressed in GI and pancreatic NETs,” she said. “Leading up to this study, there had been pilot studies with small molecule tyrosine kinase inhibitors that have also suggested activity in carcinoid [tumors]... In waterfall plots for sunitinib and pazopanib [(Votrient, Novartis)], we had preliminary evidence for a cytostatic effect with these types of agents.”

For the phase 2 trial, Bergsland and colleagues further investigated the effects of pazopanib in patients with locally-advanced or metastatic low- or intermediate-grade NETs originating in the foregut, midgut, hindgut or other nonpancreatic site. The patients were randomly assigned to receive 800 mg of pazopanib daily (n = 97) or placebo (n = 74). Patients who were initially assigned to placebo had the option to crossover to open-label pazopanib upon disease progression.

All patients had measurable disease by RECIST and at least some radiographic evidence of progression within the past 12 months. Enrollment criteria excluded patients who previously received treatment with a VEGF inhibitor, though previous treatment with everolimus was acceptable. Prior somatostatin analog treatment was required for patients with a primary small-bowel cancer. These patients were allowed to receive concurrent somatostatin analog treatment if it was initiated more than 2 months before enrollment and progressive disease while on the treatment was documented.

The primary endpoint of the trial was PFS, which was determined by a central review. Secondary endpoints included OS, safety and quality of life (QOL).

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Over the course of the study, 49 patients in the placebo arm crossed over to receive pazopanib. As of February, two patients were still receiving placebo and six patients were receiving pazopanib, including two who crossed over from placebo. The median follow-up duration was 44 months.

Median PFS was 11.6 months among patients who received pazopanib and 8.5 months among those who received placebo (HR = 0.53). A preliminary OS analysis failed to demonstrate a significant difference between patients who received pazopanib and placebo (41.3 months vs. 42.4 months). However, most patients in the placebo arm crossed over to open-label pazopanib, which likely confounded the results, Bergsland said.

In both treatment arms, the best response was stable disease, which was experienced by 70% of patients who received pazopanib and 54% who received placebo. A higher proportion of evaluable patients in the pazopanib arm experienced some degree of tumor shrinkage compared with the placebo arm (55.3% vs. 30.9%).

The safety profile of pazopanib was consistent with previous reports, according to Bergsland. More patients in the placebo arm discontinued treatment due to disease progression or relapse compared with patients in the pazopanib arm (68% vs. 38%). In contrast, more patients in the pazopanib arm discontinued treatment due to adverse events and complications (30% vs. 12%).

Patients who received pazopanib were more likely to have a dose modification (34% vs. 10.8%) or drug hold during the treatment course (79.4% vs. 61.1%). Pazopanib was also associated with a higher rate of treatment-related grade 3/4 (60.7% vs. 20.8%) or grade 5 adverse events (2.2% vs. 0%). Notable grade 3 or higher adverse events included hypertension (26.9% for pazopanib vs. 4.2% for placebo), fatigue (7.9% vs. 2.8%), increased alanine aminotransferase (9% vs. 0%), increased aspartate aminotransferase (9% vs. 0%) and diarrhea (4.5% vs. 4.2%). Despite these findings, Bergsland said the overall QOL was similar between the treatment arms.

“This is the first randomized study suggesting the VEGF pathway is a valid target for therapy in carcinoid tumors. The potential benefit of pazopanib, however, needs to be considered in the context of its risk for toxicity,” she concluded. “Additional work is needed to identify the strategies for mitigating toxicity and/or selecting patients who are most likely to benefit. To this end, a number of predictive biomarker analyses are ongoing, including angiome profiling, an assessment of tumor growth rate and textural image analysis.” – by Stephanie Viguers

Reference:

Bergsland EK, et al. Abstract 4005. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.

Pfizer. Sutent receives U.S. FDA Approval for Advanced Pancreatic Neuroendocrine Tumors. https://www.pfizer.com/news/press-release/press-release-detail/sutent_receives_u_s_fda_approval_for_advanced_pancreatic_neuroendocrine_tumors. Accessed July 26, 2019.

Disclosure: Bergsland reports serving in leadership roles for MoreHealth; receiving stock and other ownership interests from MoreHealth; receiving honoraria from UpToDate; serving in consulting or advisory roles for Advanced Accelerator Applications and MoreHealth; receiving research funding on behalf of her institution from Lexicon, Merck and Novartis; and patents, royalties and other intellectual property from UpToDate.