Closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology.
—Jacek Jassem, MD, PhD
The vast majority of non–small cell lung cancer (NSCLC) patients present with advanced disease, and many will develop metastases after primary curative therapy. Until recently, despite its low efficacy, chemotherapy remained the only treatment modality in metastatic NSCLC. Within the past decade, the management of advanced NSCLC has dramatically changed as a result of the development of several targeted anticancer agents. Currently, some of them constitute standard of care in this malignancy and have replaced chemotherapy in genetically selected patients. The most effective compounds include the small epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib, gefitinib (discontinued in the United States), and afatinib (Gilotrif) and the ALK inhibitors crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (investigational).
However, the activity of these treatments, as well as the activity of the anti–vascular endothelial growth factor (VEGF)-A antibody bevacizumab (Avastin), is virtually restricted to lung adenocarcinoma. Molecular features of other subtypes of NSCLC, particularly squamous cell carcinoma, are far less defined.
In the absence of validated targetable alterations, there are virtually no approved targeted therapies specific for squamous cell carcinoma; for more than a dozen years, patients with squamous cell carcinoma have been receiving the same, barely effective conventional chemotherapy.
Squamous cell carcinoma is the second most common pathology subtype of lung cancer, comprising 20% to 30% of newly diagnosed NSCLC in the United States and a greater proportion in Europe and Asia. Thus, closing this therapeutic gap between two main lung cancer subtypes remains one of the sore needs of contemporary oncology.
Targeting the IGF Pathway
The insulin-like growth factor (IGF) pathway is one of the most extensively studied signaling pathways in cancer. IGF-1 and its receptor, IGF-1R, have been implicated in tumor cell proliferation, survival, and invasiveness. IGF-1R protein expression has been detected in 40% to 80% of NSCLC specimens and appears to be more common in squamous cell carcinoma. Hence, the IGF pathway was considered a promising therapeutic target in this subtype.
These hopes were heightened when a randomized phase II study demonstrated that the addition of figitumumab, a fully human anti-IGF-1R G2 monoclonal antibody, to a standard chemotherapy doublet (carboplatin/paclitaxel) resulted in a higher response rate and trends for superior progression-free survival and overall survival. Most important, a subgroup analysis of this study indicated a particularly high benefit of figitumumab in squamous cell carcinoma patients.
Based on these data, and in view of a strong preclinical rationale for targeting IGF-1R, a phase III study was enthusiastically launched for patients with nonadenocarcinoma histology (mostly squamous cell carcinoma), a group with a particular need of new successful therapies.1 The study—reported by Langer and colleagues in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post—was terminated early after a planned interim analysis demonstrated a hazard ratio that crossed the futility boundary favoring the control arm—an outcome that was an unpleasant surprise and a great disappointment.
Reasons for Failure
The reasons for this failure are unclear and can only be speculated upon. First, a reanalysis of the preceding phase II study did not confirm its promising results, leading to their retraction.2 Hence, inhibition of the target by figitumumab may not be strong enough to induce disease response in nonadenocarcinoma patients, a likely explanation in view of negative results of a parallel phase III study (ADVIGO 1018, a combination of figitumumab with erlotinib in a similar population).
Indeed, IGF-1R signaling may activate other downstream signaling pathways (for example mTOR), and some of them may become constitutively activated to overcome disruption of the IGF-1R axis. Most likely, owing to the genetic complexity of lung cancer, targeting of multiple signaling pathways may be necessary to induce a therapeutic effect.
Second, despite there being a clearly defined therapeutic target, this study did not use predictive biomarkers for patient selection. Notably, there are very few molecularly targeted anticancer therapies that are effective in unselected patient populations. A post hoc biomarker analysis of our study showed no overall survival difference in a subset of patients with elevated (> 120 ng/mL) baseline total IGF-1 serum levels and an apparently detrimental effect of figitumumab in patients with low IGF-1, constituting around two-thirds of the tested population. Importantly, IGF-1 levels did not correlate with treatment outcomes in patients receiving chemotherapy alone, suggesting specific predictive value of this biomarker for figitumumab treatment.
Unfortunately, at the time the phase III study was developed, these correlations had not been analyzed in serum samples collected from patients participating in the phase II study. Therefore, no biomarker-based patient selection was employed.
Another factor that might have contributed to the negative results of our study was an unexpectedly high toxicity (not reported in the phase I/II studies) of figitumumab. IGF-1R shares structural homology with the insulin receptor; thus, its inhibition (likely as a class effect) may affect vital physiologic functions. Interestingly, low baseline total IGF-1 serum level not only identified patients with detrimental effect of figitumumab, but was also a marker of its particularly high toxicity.
Although Pfizer has decided to terminate the figitumumab program in NSCLC, these observations may be exploited in the clinical development of other IGF-1R inhibitors. ■
Disclosure: Dr. Jassem reported no potential conflicts of interest.
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.
Dr. Jassem is Head of the Department of Oncology and Radiotherapy, Medical University of Gdańsk. Dr. Jassem was an investigator in and is an author of the article reporting the phase III trial of figitumumab.
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...