A large multicenter phase III trial has found that the addition of figitumumab, a monoclonal antibody directed at insulin-like growth factor type 1 receptor (IGF-1R), to standard first-line chemotherapy for non-small cell lung cancer (NSCLC) does not improve overall survival and increases the risk for severe toxicities-even for patients with non-adenocarcinoma histology. Figitumumab is a monoclonal antibody that targets the insulin-like growth factor-1.

The trial was shut down early because of an increased number of deaths related to figitumumab therapy, but a subset analysis offers clues about which patients are likely to experience toxicities with the treatment.

In the study, treatment with paclitaxel and carboplatin with the addition of 20 mg/kg of figitumumab was compared to chemotherapy alone in a population of patients that was comprised largely of patients with squamous cell carcinoma. "The bottom line with respect to toxicity in this study is that the addition of figitumumab to chemotherapy is more toxic than chemotherapy alone," said Alan Sandler, MD, Professor of Medicine and Chief of the Hematology and Medical Oncology Division at the Oregon Health & Science University's Knight Cancer Institute. Dr. Sandler presented the study's results at the Best of ASCO Meeting in San Francisco.¹

Subset Analysis

Results of the study indicated that the overall survival of patients who received figitumumab in addition to chemotherapy was worse than for those who received chemotherapy alone-8.5 vs 10.3 months. Serious adverse effects (including those that resulted in fatalities) in the figitumumab arm of the study included asthenia, dehydration, hyperglycemia, hemoptysis, and cardiac events, Dr. Sandler said. However, a subset analysis of patient outcomes based on subjects' levels of circulating IGF-1 sheds some light on who is most at risk for toxicities from the drug and offers a suggestion of who might benefit, Dr. Sandler noted.

Higher circulating levels of IGF-1 have been associated with increased risk of cancer death. Lower levels have been linked to increased risk of heart failure and myocardial events in previous studies, Dr. Sandler noted.

In the subset analysis, patients with circulating levels of IGF-1 of greater than 1 ng/mL experienced improved outcomes-including increased overall survival-with the addition of figitumumab to chemotherapy. Yet those patients with less than 1 ng/mL were more likely to have an increased risk of toxicity and death when treated with the drug. However, because provision of samples for pharmacodynamics was optional, only 125 patients were included in the analysis of patients with levels of IGF-1 greater than 1 ng/mL, and only 324 samples with levels of free IGF-1 less than 1 ng/mL were analyzed.

"For patients with higher IGF levels, the addition of figitumumab to chemotherapy actually looks better than chemotherapy alone-although the numbers are small, and you can't make any definitive statements from these findings," Dr. Sandler said.  Patients with higher levels of IGF-1 who received figitumumab had an overall survival of 10.2 months, compared to 7 months with chemotherapy alone. Further, grade 5 (ie, fatal) adverse events were less likely in patients with higher levels of circulating IGF-1 than in those with lower levels (4.6% vs 8.6%), he noted. In patients with lower levels of IGF-1, the addition of figitumumab also negatively impacted overall survival compared to those who received chemotherapy alone (7 vs 10.3 months)

Past and Future Studies

A previous single-arm phase II study, published in the Journal of Clinical Oncology in 2009,² indicated that figitumumab in combination with paclitaxel and carboplatin produced an overall response rate of 64% in patients with squamous cell NSCLC. There is also a theoretical basis for using figitumumab in squamous cell lung carcinoma, because these cancers have been found to have high IGF-1 receptor expression, Dr. Sandler said.

Yet results of the phase III trial led the researchers to conclude that the potential benefit of adding figitumumab to chemotherapy in non-adenocarcinoma NSCLC may be compromised by the monoclonal antibody's side effects. They recommended additional research to verify whether figitumumab may have benefits for those with higher levels of IGF-1 and more risks for patients with low levels.

Figitumumab might be considered for additional study as an addition to chemotherapy in squamous cell cancer patients, but just in those patients whose circulating IGF-1 level is greater than 1 ng/mL, Dr. Sandler added. ■

References

1. Jassem J, Langer CJ, Karp DD, et al: Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer. Best of ASCO San Francisco. Abstract 7500. Presented July 17, 2010, by Alan Sandler, MD.

2. Karp DD, Paz-Ares LG, Novello S, et al: 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 27:2516-2522, 2009.