At the end of the day, this trial doesn’t provide me the comfort of saying that the risk-benefit is a favorable one.
—Tito Fojo, MD
I certainly think the survival benefit is modest, but it’s real.
—Deborah Armstrong, MD
The U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) favored the approval of necitumumab in combination with gemcitabine and cisplatin for use in first-line treatment of patients with locally advanced or metastatic squamous non–small cell lung cancer (NSCLC).
In an unusual move, the FDA did not ask ODAC to vote on approval at its July 9 meeting. Instead, Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said he was more interested in the committee’s discussion weighing the therapy’s risks and benefits.
Necitumumab is a recombinant human immunoglobulin G1 monoclonal antibody designed to block the ligand-binding site of the human epidermal growth factor receptor (EGFR) 1.
Clinical Trial Data
In this randomized phase III trial supporting the drug’s efficacy, called SQUIRE, the addition of necitumumab to gemcitabine/cisplatin for patients with squamous NSCLC who had not received prior chemotherapy for metastatic disease resulted in a statistically significant improvement in median overall survival (hazard ratio [HR] = 0.84 [95% CI = 0.74–0.96], P = .01), the primary endpoint of the study. The median overall survival was 11.5 months in the group that received necitumumab compared with 9.9 months in the patients who received gemcitabine/cisplatin alone.
The median progression-free survival was 5.7 months in the necitumumab arm compared with 5.5 months in the control arm (HR = 0.85 [95% CI = 0.74–0.98], P = .02). There was no statistically significant difference in objective response rate (31% vs 29%).
The study enrolled 1,093 patients from 26 countries. The SQUIRE trial included a patient population typical of one seen in clinical practice. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were eligible for inclusion in the trial. Notably, 55% of patients had metastases to more than two organ systems.
A second randomized phase III trial, INSPIRE, provided additional safety data. Patients with advanced nonsquamous NSCLC who had not received prior chemotherapy for metastatic disease received either necitumumab with pemetrexed (Alimta) and cisplatin, or pemetrexed and cisplatin alone. The data monitoring committee recommended that enrollment in the study be stopped prematurely due to an imbalance in the number of deaths attributed to thromboembolic events and deaths of all causes observed in the necitumumab arm compared with the control arm. There was no difference in overall survival.
The safety profile of necitumumab generally is consistent with the adverse events observed with the class of anti-EGFR antibodies, according to the FDA’s analysis. In SQUIRE, significant adverse events of grade 3 or greater included hypomagnesemia (9%), skin rash (7%), and hypersensitivity/infusion reaction (0.4%) Fatal cardiopulmonary arrest or sudden death was observed in 2.2% of the patients receiving necitumumab compared with 0.5% in the control arm.
The incidence of thromboembolic events was higher in the necitumumab-containing arms in both SQUIRE and INSPIRE. The incidence of grade 3 or higher thromboembolic events was 9% vs 5% in SQUIRE and 11% vs 6% in INSPIRE. The most common venous thromboembolic events, some fatal, were pulmonary emboli and deep vein thrombosis, whereas the most common arterial thromboembolic events were myocardial infarction and cerebrovascular accidents.
Eli Lilly and Company proposed drug labeling to address the safety issues, including recommending that prophylactic anticoagulation be used according to current guidelines, monitoring of serum electrolytes prior to each necitumumab injection and for 8 weeks following treatment completion, and using electrolyte repletion as necessary.
Approval Decision Expected Later This Year
First-line treatment of metastatic squamous NSCLC has not changed in about 20 years, since the introduction of gemcitabine, even as molecularly targeted therapies have resulted in survival improvements for patients with nonsquamous NSCLC. Five-year survival of squamous NSCLC stands at less than 5%.
In a round-robin discussion, it appeared that about 10 or 11 of the 12 ODAC members favored approval of necitumumab.
“While there is a very modest benefit, this is a population that needs options,” said ODAC consumer representative Virginia Mason, RN, BSN, Executive Director and President of the Inflammatory Breast Cancer Research Foundation, West Lafayette, Indiana. “If I could be assured that people are going to have good monitoring and good discussions about the risk-benefits, I can feel comfortable with this moving forward.”
“I certainly think the survival benefit is modest, but it’s real,” said ODAC Chairperson Deborah Armstrong, MD, Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. “When I talk to the patients who are going on trials, they all want a magic bullet or a home run, but frankly we tend to build in small baby steps and move forward that way, and this would have to be considered one of those.”
Tito Fojo, MD, Director of the Medical Oncology Fellowship Program at the National Cancer Institute, questioned whether the drug offered a positive risk-benefit profile. “At the end of the day, this trial doesn’t provide me the comfort of saying that the risk-benefit is a favorable one. It sure would be nice to have better data and additional data,” he said.
ODAC provides the FDA with independent expert advice and recommendations, but the Agency makes the final decision regarding approval. The FDA plans to make that decision on necitumumab by the regulatory deadline later this year, Dr. Pazdur said.
“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, Senior Vice President, Product Development and Medical Affairs for Lilly Oncology. “We believe necitumumab with gemcitabine and cisplatin represents 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.” ■
Disclosure: Drs. Pazdur, Armstrong, Fojo, and Gaynor reported no potential conflicts of interest.