Ramesh Rengan, MD, PhD1,2; Rosemarie Mick, MS3; Daniel A. Pryma, MD4; et al
Question Is administration of the oral protease inhibitor nelfinavir mesylate improve clinical outcomes with concurrent chemoradiotherapy assoicated with improved clinical outcomes in locally advanced non–small cell lung cancer?
Findings This phase 1/2 clinical trial found that nelfinavir with concurrent chemoradiotherapy was well tolerated and had promising long-term local control and survival in 35 patients with locally advanced non–small cell lung cancer.
Meaning The addition of the putative radiosensitizer nelfinavir with concurrent chemoradiotherapy in patients with locally advanced non–small cell lung cancer may improve clinical efficacy and outcomes.
Importance Local failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non–small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor.
Objective To evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival.
Design, Setting, and Participants This prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors.
Interventions Oral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT.
Main Outcomes and Measures 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.
Results Thirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). 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); the 5-year mean (SE) overall survival rate was 37.1% (8.2%).
Conclusions and Relevance
This study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT.
Trial Registration ClinicalTrials.gov identifier: NCT00589056