A multi-center team of researchers may have found a novel application for the protease inhibitor nelfinavir mesylate (Viracept, Pfizer) in patients with locally advanced non small-cell lung cancer (NSCLC). 

Their phase 1/2 clinical trial concluded that administration of nelfinavir with concurrent chemoradiotherapy was well tolerated and boasted promising long-term local control and survival in 35 patients with the disease.

Reporting in JAMA Oncology, the investigators noted that local failure after chemoradiotherapy significantly contributes to mortality in patients with locally advanced NSCLC. “One approach to improve local control,” they wrote, “is through targeted radiosensitization of the tumor.”

To help determine the viability of this approach, the investigators --  led by Ramesh Rengan, MD, PhD, currently a Professor of Radiation Oncology at the University of Washington School of Medicine -- sought to evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of nelfinavir mesylate, when administered concurrently with chemoradiotherapy in patients with locally advanced NSCLC (NCT00589056). The objective of the study’s phase two portion was to estimate the objective response rate, local and distant failure rates, and overall survival of the novel combination.

A total of 35 patients (19 men; median age 60 years) were enrolled and met protocol-specified criteria for adherence in the prospective, open-label, single-group, single-institution phase 1/2 trial. All of the patients -- who presented between June 29, 2007, and February 22, 2012 -- had biopsy-confirmed unresectable stage IIIA/IIIB locally advanced NSCLC. 

The participants were all treated with oral nelfinavir mesylate, in doses of either 625 mg twice daily (n=5) or 1250 mg twice daily (n=30), for seven to 14 days before and during concurrent chemoradiotherapy. The investigators measured a number of endpoints, including graded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors (version 1.1).

Median follow-up for all patients was 6.8 years, with a minimum five years of follow-up for all survivors. Data were analyzed as of May 9, 2017. 

Among 33 patients with evaluable post-treatment computed tomographic scans, the investigators observed an objective response rate of 94% (31/33; 95% confidence interval: 86%-100%). 

It was also found that the cumulative incidence of local failure was 39% (95% CI: 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI: 6.2-17.1 months). 

Median overall survival for all patients was 41.1 months (95% CI: 19.0-63.1 months), while the five-year mean overall survival rate was 37.1%.

“The benchmark median survival rate for patients with stage III lung disease is about 28 months,” Dr. Rengan said in a statement. “The median survival that we saw was 41 months, and about 35% of patients were still alive at 120 months – 10 years out from treatment – long-term survival.”

No dose-limiting toxic effects were observed. Similarly, no non-hematologic toxic effects of grade 4 or greater were observed. 

These findings, the investigators said, suggest that treatment with nelfinavir and concurrent chemoradiotherapy is associated with acceptable toxic effects and a promising efficacy profile in unresectable locally advanced NSCLC, and may enhance the efficacy of chemoradiotherapy.

“This is an intervention that appears to improve the local control of lung cancer after radiotherapy, which seems to have driven an improvement in overall clinical outcome for these patients,” Rengan said. “Compared with historical data of patients with this disease who received chemotherapy and radiation, our outcomes were favorable. We are certainly interested to pursue a randomized trial.”