Long-term Results of a Phase I/II Trial of Nelfinavir with Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer

Abstract

The objective of this Phase I/II trial was to determine the response rate by RECIST and the median overall survival (OS) of concurrent chemoradiation (CT-RT) in combination with the radiosensitizer nelfinavir in locally advanced non-small cell lung cancer (LA-NSCLC) compared to historical controls. Nelfinavir (Dose Level (DL) 1: 625 mg PO BID, DL2:1250 mg PO BID) was administered for 7 to 14 days prior to and during concurrent CT-RT to patients (pts) with biopsy confirmed unresectable IIIA and IIIB NSCLC. 23 patients (65.7%) had stage IIIA disease; 11 patients (31.4%) had stage IIIB disease; 1 patient (2.9%) had a mediastinal recurrence after resection of early stage disease. Median age was 60 years for all patients. Nineteen patients (54.2%) were male, 16 (45.7%) were female. Ten patients (28.6%) had adenocarcinoma, 16 patients (45.7%) had squamous cell carcinoma; 9 patients (25.7%) had poorly differentiated carcinoma. Patients were treated with concurrent CT-RT to a dose of 66.6/1.8Gy and cisplatinum and etoposide. DLTs were defined as any treatment related Grade 4 hematologic toxicity requiring a break in therapy or non-hematologic Grade ≥ 3 toxicity except esophagitis and pneumonitis. Protocol specified criteria for compliance included receiving greater than 80% of the prescribed RT treatments and 70% of the prescribed nelfinavir doses. Thirty-five patients were enrolled and met protocol-specified criteria for compliance, 5 at DL1 and 30 at DL2. Two patients were enrolled and did not meet protocol-specified compliance criteria are excluded from this analysis. No DLTs were observed. The recommended phase II dose of nelfinavir was 1250 mg PO BID. Median follow-up for all patients was 6.8 years and minimum follow-up for survivors was 5 years. No Grade 4 or higher non-hematologic toxicities were observed. Of the non-hematologic toxicities: 10 patients (28%) experienced Grade 3 esophagitis/dysphagia/dehydration; 4 patients (11.4%) experienced Grade 3 nausea; 3 patients (8.5%) experienced Grade 3 anorexia; 3 patients (8.5%) experienced Grade 3 fatigue; and 1 patient (3%) experienced grade 3 diarrhea and 1 patient (3%) experienced grade 3 dyspnea. 33 of the 35 patients had evaluable post-treatment CT with RECIST response rate of 94% and (31/33) stable disease rate of 6% (2/33). The cumulative incidence of local failure as site of first failure was 20%, with the median time to failure not reached (NR). The cumulative incidence of distant failure as site of first failure was 51%, with the median time to distant failure of 15.8 months. The median progression-free survival was 12 months. The median OS for all patients was 40 months; 5 year OS was 37%. Nelfinavir administered with concurrent CT-RT is associated with acceptable toxicity and very promising local control, overall response rate, and survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of chemo-RT in this disease.