ODAC supported the approval of necitumumab in combination with gemcitabine and cisplatin for the first-line treatment of patients with locally advanced or metastatic squamous nonâ€“small cell lung cancer.
Richard Pazdur, MD
The FDA’s Oncologic Drugs Advisory Committee (ODAC) supported the approval of necitumumab in combination with gemcitabine and cisplatin for the first-line treatment of patients with locally advanced or metastatic squamous non—small cell lung cancer (NSCLC), according to an informal poll conducted by Richard Pazdur, MD, at an advisory meeting.
Eli Lilly and Company completed a rolling submission to the FDA for necitumumab in the fourth quarter of 2014, based on findings from the phase III SQUIRE trial. ODAC was not asked to cast an official vote in favor or against the application for the EGFR antibody; instead, Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, sought the insight and thoughts on the application through discussion of the clinical trial results.
The consensus of the panel was that the benefits of necitumumab were modest, yet clinically significant, following a discussion of findings from the phase III SQUIRE and INSPIRE trials. Moreover, the panelists felt the benefits of necitumumab outweighed the risks associated with the drug. However, during the discussion, ODAC chairwoman Deborah K. Armstrong, MD, noted that none of the members of the advisory group were lung cancer experts.
Based on the FDA's standard review timeline, a decision on the necitumumab application was expected in the third quarter of 2015. During the hearing, Pazdur noted that the FDA planned to approve necitumumab for patients with squamous NSCLC prior to the set decision date.
"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," Richard Gaynor, MD, senior vice president, product development and medical affairs for Lilly Oncology, said in a statement. "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."
In the SQUIRE study, 1093 patients were randomized to received gemcitabine plus cisplatin plus necitumumab (n = 545) or gemcitabine plus cisplatin (n = 548). Necitumumab was administered at 800 mg on day 1 and 8 every 3 weeks. In both arms, gemcitabine was administered at 1250 mg/m2 on days 1 and 8 and cisplatin was administered at 75 mg/m2 on day 1. Those who responded in the investigational arm went on to receive single-agent necitumumab.
Baseline characteristics were balanced between the two arms. The median age of patients was 62 years, the majority of patients were white (84%), and most had smoked (91%). The most frequent metastatic site was the lung (83%).
The primary endpoint of the study was overall survival (OS), with secondary outcome measures focused on progression-free survival (PFS) and objective response rate (ORR). The study was designed to detect a hazard ratio (HR) for OS of 0.80 with a P value of 0.5.
After a follow-up of approximately 25 months, the median OS was 11.5 months in the necitumumab arm versus 9.9 months with the chemotherapy alone (HR = 0.84; 95% CI, 0.74-0.96; P = .012). The 1-year OS rate was 47.7% versus 42.8% and the 2-year OS rate was 19.9% compared with 16.5%, for the necitumumab and chemotherapy arms, respectively.
The median PFS with necitumumab was 5.7 versus 5.5 months for chemotherapy alone (HR = 0.85; 95% CI, 0.74-0.98; P = .02). The ORR was 31.2% in the necitumumab arm and 28.8% with the chemotherapy alone (P = .40). The disease control rate (ORR plus stable disease) was 81.8% in the necitumumab group compared with 77% in the chemotherapy arm (P = .043).
Outcomes were similar in an exploratory analysis by EGFR H-score. In those with an H score ≥200 (n = 374) there was a 25% improvement in OS with necitumumab. In those with a score less than 200 (n = 608), the benefit was 10%. For PFS, the HR score was not predictive, with 12% to 17% improvement across all scores.
"The SQUIRE trial is the largest trial reported for patients with advanced squamous cell carcinoma, and the therapeutic options that we do have are very limited," study author Martin Reck, MD, PhD, Head of Thoracic Oncology, Hospital Grosshansdorf, said at the 2015 ASCO Annual Meeting, when updated data were presented. "We observed a significant improvement in overall survival and progression-free survival in favor of the combination with necitumumab."
Grade ≥3 adverse events were apparent in 72.1% of patients treated with necitumumab versus 61.6% with chemotherapy alone. Adverse events leading to discontinuation of treatment occurred at a rate of 31.2% in the necitumumab/chemotherapy arm and 24.6% in the chemotherapy alone arm. The incidences of adverse events with an outcome of death were 12.3% and 10.5%, respectively.
Grade ≥3 adverse events that occurred significantly more often in the necitumumab/chemotherapy arm were hypomagnesemia (9.3% vs 1.1%), skin rash (7.1% vs 0.4%), and venous thromboembolic events (5.0% vs 2.6%).
"We do know that squamous cell patients are different than other lung cancer patients," Reck said. "They do have more comorbidities, they do have more symptoms, and treatment is a little more difficult in these patients."
In the ODAC discussion, representatives from Lilly Oncology recommended that the label for necitumumab should contain information on the risk of venous thromboembolic events, with extra caution advised for those with a history of events. Additionally, steps on the utilization of anticoagulants for those at high risk or with prior history should be incorporated into the label along with information on monitoring for electrolyte disturbances.
In addition to the SQUIRE trial, which was the basis for the application, the ODAC panel discussed findings from the phase III INSPIRE study, which was discontinued in 2011 following safety concerns. This study assessed pemetrexed plus cisplatin with or without necitumumab in patients with metastatic non-squamous NSCLC.
In this study, the addition of necitumumab did not improved OS compared with chemotherapy alone (HR = 1.01; 95% CI, 0.84-1.21). Additionally, an improvement in PFS was not seen with necitumumab (HR = 0.96; 95% CI, 0.8 0 -1.16). The ORR was also similar between the two arms (32% vs 31%).
In INSPIRE, there was an increased incidence of venous thromboembolic events in the necitumumab arm compared with chemotherapy (13% vs 8%). Additionally, according to an FDA briefing document, some of these events were fatal.