In the first phase III trial assessing the combination of an insulin-like growth factor 1 receptor (IGF-1R) inhibitor with chemotherapy as first-line treatment for advanced nonadenocarcinoma non–small cell lung cancer (NSCLC), the addition of the fully human immunoglobulin G2 monoclonal antibody figitumumab to paclitaxel/carboplatin did not improve overall survival over chemotherapy alone. The study, reported by Corey J. Langer, MD, of University of Pennsylvania, and colleagues in Journal of Clinical Oncology, was stopped early due to futility and an increased frequency of serious adverse events, including treatment-related death, in patients receiving figitumumab.¹

When the trial was begun, it was thought that IGF-1R played a role in squamous cell NSCLC, in which it is more commonly expressed than in adenocarcinoma, and analysis of phase II data suggested increased efficacy of figitumumab in patients with this histology. A randomized phase II study in patients with treatment-naive advanced NSCLC showed improved objective response rate with the addition of figitumumab to full-dose paclitaxel/carboplatin (54% vs 42%). However, the failure of the phase III trial prompted a thorough review of the phase II data, which were subsequently retracted when reanalysis showed lower response rates in both groups.²

Study Details

In the open-label phase III trial, 681 patients with stage IIIB/IV or recurrent NSCLC with nonadenocarcinoma histology from 25 countries were randomly assigned between April 2008 and September 2009 to receive figitumumab at 20 mg/kg plus paclitaxel at 200 mg/m² and carboplatin at area under the concentration-time curve = 6 mg • min/mL (n = 342) or paclitaxel/carboplatin alone (n = 339) once every 3 weeks for up to six cycles. The primary endpoint was overall survival.

The figitumumab and chemotherapy groups were generally balanced for age (median, 62 years in both), sex (76% and 77% male), ethnicity (78% and 80% white, 16% and 17% Asian), Eastern Cooperative Oncology Group performance status (0 in 33% and 34%, 1 in 66% and 64%), disease stage (IIIB in 11% and 12%, IV in 88% in both), smoking status (10% never in both, 42% current in both), histology (squamous cell in 86% and 85%, large cell in 8% in both, adenosquamous in 4% and 6%), and prior treatment (surgery in 21% and 18%, radiation in 13% and 11%, and adjuvant chemotherapy in 4% in both).

No Benefit

After median follow-up of 23.1 months, median overall survival was 8.6 months in the figitumumab-plus-chemotherapy group vs 9.8 months in the chemotherapy-alone group (hazard ratio [HR] = 1.18, P = .06). One-year overall survival rates were 34% vs 39%. The effect of figitumumab on overall survival was similar across subgroups for sex, performance status, nonsquamous histology, smoking status (never, current), stage, and HbA1c < vs ≥ 5.7%.

Exploratory analysis based on baseline total IGF-1 with a cutoff of 120 ng/mL indicated that median overall survival was 7.0 vs 10.4 months in figitumumab recipients and 10.1 vs 9.4 months in chemotherapy-alone recipients patients with low vs high IGF-1. Overall survival was significantly shorter for figitumumab vs chemotherapy patients with low IGF-1 (HR = 1.37, P = .01) and did not differ between patients with higher IGF-1 (HR = 0.93, P = .67).

Hyperglycemia appears to be a class effect of IGF-1R inhibition. Median overall survival was 8.7 months in the figitumumab group and 10.2 months in the control group (HR =1.07, P = .65) among patients with baseline HbA1c < 5.7% and 8.2 vs 9.7 months (HR = 1.26, P =. 05) in those with HbA1c ≥ 5.7%.

Median progression-free survival was 4.7 vs 4.6 months (HR = 1.10, P = .27). Objective response rates were 33% vs 35%.

Adverse Events

Adverse events of any grade that were more common in the figitumumab plus chemotherapy group included decreased appetite (38% vs 23%), diarrhea (30% vs 14%), vomiting (25% vs 14%), hyperglycemia (23% vs 5%), and decreased weight (20% vs 9%). Grade 3 or 4 adverse events that occurred more frequently in the figitumumab group included hyperglycemia (12% vs 1%), fatigue (8% vs 4%), decreased appetite (7% vs 2%), dehydration (6% vs <1%), and diarrhea (5% vs 1%).

Serious adverse events occurred in 66% of the figitumumab group vs 51% of the chemotherapy group (P < .01) and were considered possibly related to treatment in 22% vs 12%. Apart from disease progression events, the most common serious adverse events were pneumonia (6% vs 4%), dehydration (4% vs 1%), asthenia (3% vs 1%), and hyperglycemia (3% vs < 1%). Adverse events led to discontinuation of figitumumab in 7% of patients and to discontinuation of chemotherapy in 9% of patients in each group.

Treatment-Related Deaths

Grade 5 adverse events not related to disease progression occurred in 13% vs 10% of patients (P = .22), with the most common in figitumumab patients being pulmonary hemorrhage and pneumonia (2% each). Grade 5 adverse events were considered to be treatment-related in 5% of figitumumab patients vs 1% of chemotherapy patients (P < .01); those observed in the figitumumab group consisted of hemoptysis, pneumonia, unknown cause reported only as death, septic shock, cardiorespiratory arrest, decrease of performance status, neutropenic sepsis, toxicity to various agents, renal failure, hemorrhage, and hypovolemic shock and those in the chemotherapy-alone group consisted of unknown cause reported as death, pneumonia, septic shock, and dehydration.

Baseline IGF-1 was not related to overall frequency or type of adverse events. However, grade 5 adverse events were more likely to occur among figitumumab patients with lower vs higher IGF-1 levels (56% vs 38%), with no such difference in risk observed in the chemotherapy group. As stated by the investigators, “Although additional studies are required, these data suggest that low baseline total IGF-1 may be a safety biomarker that identifies a subset of patients for whom IGF-1R inhibition is particularly harmful.”

Rates of adverse events did not vary markedly by HbA1c level, but the rate of grade 3 or 4 events among patients with no grade 5 events was slightly lower in those with baseline levels <5.7% in the figitumumab group (30% vs 36%; 33% vs 35% in chemotherapy group).

The investigators concluded:

[T]hough the phase II trial suggested an [objective response rate] advantage for adding figitumumab to standard chemotherapy in advanced NSCLC, our current phase III study involving nonadenocarcinoma patients failed to show any benefit and unexpectedly suggested a possible detrimental effect. This may be a class effect and should be assessed in current and future trials examining IGF-1R inhibitors. Further clinical development of figitumumab is not being pursued. ■

Disclosure: The study was supported by a grant from the National Cancer Institute and by Pfizer. Dr. Langer reported a consultant or advisory role with and research funding from Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.

References

1. Langer CJ, Novello S, Park K, et al: 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. J Clin Oncol 32:2059-2066, 2014.

2. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: Phase II study of the anti–insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 30:4179, 2012.