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FDA: Cancer Treatment Improves Survival But Raises Blood Clot Risk

Necitumumab associated with fatal cardiopulmonary arrest and/or sudden death

The experimental lung cancer drug necitumumab (Eli Lilly) improved overall survival (OS) by an average of 1.6 months, but it also increased the risk of sometimes fatal blood clots, according to a preliminary review by the FDA.

The review was posted 2 days ahead of a July 9 meeting of the agency’s Oncologic Drugs Advisory Committee, which will discuss the new treatment and recommend whether it should be approved.

Necitumumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) and blocks interaction between EGFR and its ligands. Eli Lily is seeking initial approval of necitumumab in combination with gemcitabine and cisplatin for use in the first-line treatment of patients with locally advanced or metastatic squamous non–small-cell lung cancer (NSCLC).

Efficacy data for the proposed indication were based on results from the SQUIRE trial, an open-label, randomized, controlled, international study in 1,093 patients with advanced squamous NSCLC who had not received prior chemotherapy for metastatic disease. The patients were randomly assigned to receive either necitumumab with gemcitabine and cisplatin (N + GC; n = 545) or gemcitabine and cisplatin alone (GC; n = 548). The study’s primary efficacy endpoint was OS. Key secondary endpoints included progression-free survival (PFS) and the overall response rate (ORR).

The addition of necitumumab to GC resulted in a 1.6-month improvement in OS, which was statistically significant. Median OS was 11.5 months in the N + GC arm compared with 9.9 months in the GC arm (hazard ratio [HR], 0.84; P = 0.012). Median PFS was 5.7 months in the N + GC arm compared with 5.5 months in the control arm (HR, 0.85; P = 0.02). ORRs were 31% and 29% (P = 0.40) in the N + GC and GC arms, respectively.

Safety information was derived from a second randomized, controlled study (INSPIRE) of necitumumab in patients with advanced non-squamous NSCLC who had not received prior chemotherapy for metastatic disease. The patients were randomly assigned to receive either necitumumab with pemetrexed and cisplatin (N + PC) or pemetrexed and cisplatin alone (PC). The study was terminated prematurely at the request of the data monitoring committee because of an imbalance in the number of deaths attributed to potential thromboembolic events (TEs) and deaths of all causes observed in the N + PC arm compared with the PC arm. At the time of the study closure, 633 patients out of 947 planned were enrolled. There was no difference in OS between the two groups based on the available data (median OS, 11.3 months vs.11.5 months in the treatment and control arms, respectively; HR, 1.01).

In the SQUIRE trial, grade-3 or greater necitumumab-related adverse events (AEs) included hypomagnesemia (9%), skin rash (7%), and hypersensitivity/infusion reaction (0.4%). Fatal cardiopulmonary arrest and/or sudden death were observed in 2.2 % of the patients in the N + GC arm compared with 0.5 % in the control arm. The rates of TEs were higher in the necitumumab-containing arms in both the SQUIRE and INSPIRE trials. The incidence of grade-3 or greater TEs in the treatment and control arms was 9% versus 5% in the SQUIRE trial and 11% versus 6% in the INSPIRE trial. The most common venous TEs, some fatal, included pulmonary emboli and deep-vein thrombosis, whereas the most common arterial TEs included myocardial infarction and cerebrovascular accidents.

An FDA briefing document concluded: “Although the safety profile of necitumumab is noted to be similar to what is known for other anti-EGFR mAbs, the increased number of TE events in this already high-risk population is of concern.”

Sources: Reuters; July 7, 2015; and FDA Briefing Document; July 7, 2015.


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