The approval was based findings from the phase 3 SQUIRE trial.
The FDA has approved Portrazza (necitumumab) in combination with Gemzar (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 3 SQUIRE trial.
In the 1,093-patient study, the addition of the fully human IgG1 anti-EGFR monoclonal antibody Portrazza to Gemzar and cisplatin improved overall survival (OS) by 1.6 months, which was equivalent to a 16 percent reduction in the risk of death. Progression-free survival (PFS) was improved by 15 percent 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 Portrazza 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, 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 3 study, patients were randomized to received Gemzar plus cisplatin with Portrazza (545 patients) or placebo (548 patients). Portrazza was administered at 800 mg on day 1 and 8 every 3 weeks. In both arms, Gemzar 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 Portrazza.
Baseline characteristics were balanced between the two arms. The median age of patients was 62 years, the majority of patients were white (84 percent), and most had smoked (91 percent). The most frequent metastatic site was the lung (83 percent). 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 Portrazza arm versus 9.9 months with the chemotherapy alone. The one-year OS rate was 48 percent versus 43 percent and the two-year OS rate was 20 percent compared with 17 percent, for the Portrazza and chemotherapy arms, respectively.
The median PFS with Portrazza was 5.7 versus 5.5 months for chemotherapy alone. The PFS rate at 6 months was 45 percent with Portrazza and 37 percent with chemotherapy alone.
The ORR was 31 percent in the Portrazza arm and 29 percent with the chemotherapy alone. The disease control rate (ORR plus stable disease) was 82 percent in the Portrazza group compared with 77 percent in the chemotherapy arm. The median time to treatment failure with Portrazza was 4.3 months versus 3.6 months with chemotherapy alone.
Grade ≥3 adverse events (AEs) were apparent in 72 percent of patients treated with Portrazza versus 62 percent with chemotherapy alone. Grade ≥3 AEs that occurred significantly more often in the Portrazza/chemotherapy arm were hypomagnesemia (9 percent vs 1 percent), skin rash (4 percent vs less than 1 percent), and venous thromboembolic events (5 percent vs 3 percent).
Serious AEs occurred in 48 percent of patients in the Portrazza arm versus 38 percent with Gemzar and cisplatin alone. Adverse events leading to discontinuation of treatment occurred at a rate of 31 percent in the Portrazza/chemotherapy arm and 25 percent in the chemotherapy alone arm. The incidences of adverse events with an outcome of death were 12 percent and 11 percent, 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, 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 Portrazza."
A phase 1/2 study is currently assessing Portrazza in combination with Gemzar and cisplatin as a first-line therapy for patients with stage 4 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 Portrazza, including nab-paclitaxel and carboplatin.
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.