IGF Inhibitor Adds No Benefit, Potentially Harmful in Advanced NSCLC

A phase III trial of the insulin-like growth factor 1 receptor (IGF-1R) inhibitor figitumumab showed no benefit in survival outcomes when added to standard chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC). The study is likely the last attempt at development of figitumumab in NSCLC.

An earlier phase II study of the drug showed an improvement in objective response rate (ORR) with figitumumab over chemotherapy alone (54% vs 42%), which prompted the phase III study in first-line therapy for NSCLC. However, the phase II data were subsequently retracted following a re-analysis showing a lower ORR in both arms. The newly reported phase III results, from authors led by Corey J. Langer, MD, of the University of Pennsylvania in Philadelphia, were published online ahead of print on June 2 in the Journal of Clinical Oncology.

The study included a total of 681 patients who were randomized, and 671 who actually received treatment (338 in the figitumumab group, 333 in the chemotherapy group). Chemotherapy included paclitaxel and carboplatin. All patients had stage IIIB/IV or recurrent NSCLC with non-adenocarcinoma histology. Enrollment was closed early after an analysis showed futility and an increased incidence of serious adverse events with figitumumab.

The median overall survival with the study drug was 8.6 months compared with 9.8 months for chemotherapy alone, for a hazard ratio (HR) of 1.18 (95% confidence interval [CI], 0.99–1.40; P = .06). The median progression-free survival was 4.7 months with figitumumab and 4.6 months with chemotherapy, for an HR of 1.10 (95% CI, 0.93–1.32; P = .27). ORRs were 33% with figitumumab and 35% with chemotherapy alone.

Adverse events that occurred more frequently in the figitumumab group included hyperglycemia, diarrhea, decreased appetite, vomiting, and decreased weight. Grade 3/4 adverse events that were more common with the study drug included most of these, along with dehydration and fatigue. Treatment-emergent serious adverse events occurred in 66% of figitumumab patients and in 51% of chemotherapy patients, a significant difference (P < .01).

Treatment-related grade 5 adverse events occurred in 5% of study drug patients, significantly more than the 1% of chemotherapy patients (P < .01). These included hemoptysis, pneumonia, septic shock, and others.

“Unexpectedly, adding figitumumab to chemotherapy proved deleterious,” the authors wrote. Subgroup analyses suggested that low baseline IGF-1 levels could be a safety biomarker identifying patients for whom IGF-1R inhibition is more harmful. Further clinical development is not being pursued, the authors wrote, noting that the potential harm “may be a class effect and should be assessed in current and future trials examining IGF-1R inhibitors.”