Weighing the Benefit-Risk Profile of Necitumumab in Lung Cancer

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The recombinant human IgG1 monoclonal antibody necitumumab in combination with gemcitabine (Gemzar) and cisplatin as first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) may help improve survival. However, adding this agent to gemcitabine and cisplatin also increases the risk of thromboembolic events (TEs), according to a preliminary review by the US Food and Drug Administration (FDA).

On July 9, 2015, the FDA’s Oncologic Drugs Advisory Committee (ODAC) issued a review on this experimental lung cancer drug that showed that adding this agent increased the incidence of TEs when combining all the clinical trial data. The review showed that most common venous TE events (some fatal) were pulmonary emboli and deep vein thrombosis. The most common arterial TEs were myocardial infarction and cerebrovascular accidents. 

"We are encouraged by the Committee's constructive discussion on the benefit-risk profile of necitumumab as few advances have been made over the past two decades in the first-line treatment of advanced squamous NSCLC, leaving a significant unmet medical need," said Richard Gaynor, MD, who is senior vice president of product development and medical affairs for Lilly Oncology, Indianapolis. "We believe necitumumab with gemcitabine and cisplatin represent a meaningful advance in the search for a new first-line treatment option and look forward to working closely with the FDA as they continue their review."

Necitumumab is designed to block the ligand binding site of the human epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. The FDA is expected to make a decision on Lilly's biologics license application for necitumumab within the next 5 months.

Currently, the 5-year survival rate for patients with metastatic lung cancer is less than 5% and little progress has been made over the last 2 decades, particularly in the first-line setting. In an open-label, randomized, controlled phase III trial, necitumumab as part of first-line therapy in patients with stage IV squamous non-small cell lung cancer (SQUIRE) showed a improvement in overall survival (OS).  Researchers reported that the median OS was 11.5 months in the necitumumab plus gemcitabine and cisplatin group compared to 9.9 months in the gemcitabine and cisplatin alone group.

In the necitumumab arm, the number of patients with at least one grade 3 or worse adverse event was higher (72% vs 62%) when compared to the control arm, and the same was true for the incidence of serious adverse events (48% vs 38%). More patients in the necitumumab arm had grade 3/4 hypomagnesaemia (9% vs 1%).

Overall, Lilly researchers found that the safety profile of necitumumab with gemcitabine and cisplatin was acceptable and in line with expectations, but two questions remain by the FDA:

• Do the efficacy and safety results of SQUIRE in squamous cell NSCLC support a positive benefit: risk assessment of necitumumab in combination with gemcitabine/cisplatin in the proposed population?
• Do the INSPIRE trial results in the nonsquamous NSCLC population impact the benefit-risk assessment of necitumumab for squamous NSCLC?

References:

• US Food and Drug Administration. (2015). FDA Briefing Document Oncologic Drugs Advisory Committee Meeting.
• P&T Community. (2015). FDA: Cancer Treatment Improves Survival But Raises Blood Clot Risk.