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Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial.
JAMA Oncol 2019JO

Abstract

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.

Authors+Show Affiliations

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia. currently, Department of Radiation Oncology, University of Washington School of Medicine, Seattle.Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania School of Medicine, Philadelphia.Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia.Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia. Medical Affairs and Clinical Research, Elekta, Atlanta, Georgia.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia.Division of Hematology-Oncology, Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio.Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore.Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia.Division of Thoracic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31436839

Citation

Rengan, Ramesh, et al. "Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: a Phase 1/2 Trial." JAMA Oncology, 2019.
Rengan R, Mick R, Pryma DA, et al. Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial. JAMA Oncol. 2019.
Rengan, R., Mick, R., Pryma, D. A., Lin, L. L., Christodouleas, J., Plastaras, J. P., ... Maity, A. (2019). Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial. JAMA Oncology, doi:10.1001/jamaoncol.2019.2095.
Rengan R, et al. Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: a Phase 1/2 Trial. JAMA Oncol. 2019 Aug 22; PubMed PMID: 31436839.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial. AU - Rengan,Ramesh, AU - Mick,Rosemarie, AU - Pryma,Daniel A, AU - Lin,Lilie Leming, AU - Christodouleas,John, AU - Plastaras,John P, AU - Simone,Charles B,2nd AU - Gupta,Anjali K, AU - Evans,Tracey L, AU - Stevenson,James P, AU - Langer,Corey J, AU - Kucharczuk,John, AU - Friedberg,Joseph, AU - Lam,Sarah, AU - Patsch,Dana, AU - Hahn,Stephen M, AU - Maity,Amit, Y1 - 2019/08/22/ PY - 2020/08/22/pmc-release PY - 2019/8/23/entrez PY - 2019/8/23/pubmed PY - 2019/8/23/medline JF - JAMA oncology JO - JAMA Oncol N2 - 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. SN - 2374-2445 UR - https://www.unboundmedicine.com/medline/citation/31436839/Clinical_Outcomes_of_the_HIV_Protease_Inhibitor_Nelfinavir_With_Concurrent_Chemoradiotherapy_for_Unresectable_Stage_IIIA/IIIB_Non_Small_Cell_Lung_Cancer:_A_Phase_1/2_Trial_ L2 - https://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2019.2095 DB - PRIME DP - Unbound Medicine ER -