November 24, 2015
On November 24, 2015, the U.S. Food and Drug Administration granted approval to necitumumab (PORTRAZZA, Eli Lilly and Company) in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC). Necitumumab is not indicated for treatment of non-squamous NSCLC.
Necitumumab is a recombinant human IgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands.
Approval was based on superior overall survival (OS) for patients who were randomly allocated to necitumumab in combination with gemcitabine and cisplatin (GC) compared to GC alone in an open-label, multicenter, multinational, randomized trial in patients with metastatic squamous NSCLC who had not received prior therapy for metastatic disease (N=1093). Patients received necitumumab 800 mg by intravenous infusion on days 1 and 8, gemcitabine 1250 mg /m2 on days 1 and 8 plus cisplatin 75mg/m2 on day 1 of each 3-week cycle (N=545) or GC alone (N=548). The major efficacy outcome was OS. Progression-free survival (PFS) and overall response rate (ORR) were also assessed. Necitumumab in combination with GC demonstrated a statistically significant improvement in OS and PFS as compared with GC alone. Median OS was 11.5 months (95% CI: 10.4, 12.6) for patients assigned to necitumumab plus GC and 9.9 months (95% CI: 8.9, 11.1) for those assigned to GC alone [HR 0.84, 95% CI (0.74, 0.96); p-value = 0.01)]. Median PFS was 5.7 months for patients assigned to necitumumab plus GC and 5.5 months for those assigned to GC alone [HR=0.85, 95% CI (0.74, 0.98); p-value 0.02]. No difference in ORR between arms was observed with an ORR of 31% (95% CI: 27, 35) for necitumumab plus GC and 29% (95% CI: 25, 33) for GC alone, p-value 0.40.
Lack of efficacy of necitumumab in combination with pemetrexed and cisplatin (PC) for the treatment of patients with metastatic non-squamous NSCLC was determined in a randomized, open-label, multicenter trial. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive necitumumab plus PC or PC alone. The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the necitumumab arm. Addition of necitumumab to PC did not improve OS [HR=1.01; 95% CI (0.84, 1.21); p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the necitumumab plus PC arm and 32% in the PC alone arm).
The most common adverse reactions (all grades) observed in necitumumab-treated patients at rate of greater than or equal to 30% and greater than or equal to 2% higher than GC alone arm were rash and hypomagnesemia. Serious and clinically significant adverse events include hypomagnesemia, venous and arterial thromboembolic events, dermatologic toxicities, infusion reactions, and increased toxicity and increased mortality in patients with non-squamous NSCLC. Death attributed to cardiovascular events or sudden death was reported in 3% of the patients in the necitumumab plus gemcitabine and cisplatin arm. Health care providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after necitumumab administration. Withhold necitumumab for grade 3 or 4 electrolyte abnormalities.
The recommended dose of necitumumab is 800 mg as an intravenous infusion over 60 minutes on days 1 and 8 of each 3-week cycle.
Full prescribing information is available: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).