FDA Approves Necitumumab for Squamous NSCLC

Richard Pazdur, MD

The FDA has approved necitumumab (Portrazza) 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), based findings from the phase III SQUIRE trial.

In the 1093-patient study, the addition of the fully human IgG1 anti-EGFR monoclonal antibody necitumumab to gemcitabine and cisplatin improved overall survival (OS) by 1.6 months, which was equivalent to a 16% reduction in the risk of death. Progression-free survival (PFS) was improved by 15% with the triplet therapy.

The FDA approval follows an informal recommendation from the Oncologic Drugs Advisory Committee in July 2015. Following a discussion on the clinical trial results from the SQUIRE trial, the consensus of the panel was that the benefits of necitumumab were modest, yet clinically significant.

“Lung cancer tumors can be varied, so treatment options need to be tailored to the specific type of lung cancer in the patient,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval provides certain patients with squamous cell lung cancer a new option that may extend survival.”

In the phase III study, patients were randomized to receive gemcitabine plus cisplatin with necitumumab (n = 545) or placebo (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 OS, with secondary outcome measures focused on progression-free survival (PFS) and objective response rate (ORR).

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 48% versus 43% and the 2-year OS rate was 20% compared with 17%, 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 PFS rate at 6 months was 45% with necitumumab and 37% with chemotherapy alone.

The ORR was 31% in the necitumumab arm and 29% with the chemotherapy alone (P = .40). The disease control rate (ORR plus stable disease) was 82% in the necitumumab group compared with 77% in the chemotherapy arm (P = .043). The median time to treatment failure with necitumumab was 4.3 months versus 3.6 months with chemotherapy alone.

Grade ≥3 adverse events (AEs) were apparent in 72% of patients treated with necitumumab versus 62% with chemotherapy alone. Grade ≥3 AEs that occurred significantly more often in the necitumumab/chemotherapy arm were hypomagnesemia (9% vs 1%), skin rash (4% vs <1%), and venous thromboembolic events (5% vs 3%).

Serious AEs occurred in 48% of patients in the necitumumab arm versus 38% with gemcitabine and cisplatin alone. Adverse events leading to discontinuation of treatment occurred at a rate of 31% in the necitumumab/chemotherapy arm and 25% in the chemotherapy alone arm. The incidences of adverse events with an outcome of death were 12% and 11%, respectively.

"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."

A phase I/II study is currently assessing necitumumab in combination with gemcitabine and cisplatin as a first-line therapy for patients with stage IV squamous NSCLC. The primary endpoint of the first portion of the study is dose-limiting toxicities (NCT01763788). Additionally, trials are planned to assess different chemotherapeutics in combination with necitumumab, including nab-paclitaxel and carboplatin (NCT02392507).

Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763—774.