Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.

INTRODUCTION: Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140). MATERIALS AND METHODS: Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive. RESULTS: The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients). CONCLUSION: ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.

Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer.

PURPOSE: Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m(2)) and carboplatin (area under the concentration-time curve, 6 mg · min/mL) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles. The primary end point was overall survival (OS). RESULTS: Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio [HR], 1.18; 95% CI, 0.99 to 1.40; P = .06); median progression-free survival was 4.7 months (95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P = .27); the objective response rates were 33% and 35%, respectively. The respective rates of all-causality SAEs were 66% and 51%; P < .01). Treatment-related grade 5 adverse events were also more common with figitumumab (5% v 1%; P < .01). CONCLUSION: Adding figitumumab to standard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued.