Eli Lilly and Company announced that the US Food and Drug Administration (FDA) has approved Portrazza (necitumumab injection for intravenous use, 800 mg/50 ml), in combination with gemcitabine and cisplatin, as the first biologic for the first-line treatment of people with metastatic squamous non-small cell lung cancer (NSCLC). Portrazza is not indicated for treatment of nonsquamous NSCLC.

Metastatic squamous NSCLC is a difficult-to-treat form of lung cancer with few treatment options. The five-year survival rate for patients with metastatic disease is less than five percent.

"We have seen advances in lung cancer in the last 20 years, but not for the initial treatment of patients battling metastatic squamous non-small cell lung cancer. This is a complex disease and there is an urgent need for effective, first-line treatments," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology.

"The approval of Portrazza is an important step forward that reaffirms Lilly's commitment to discovering new treatments that respond to the needs of individual patients."

Portrazza has been granted Orphan Drug designation by the FDA. Orphan drug status is given in the US by the FDA's Office of Orphan Products Development (OOPD) to medicines that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.

The Portrazza approval is based on the results of SQUIRE, an open-label, randomized, multi-center phase III trial that compared first-line treatment with Portrazza in combination with gemcitabine and cisplatin to treatment with gemcitabine and cisplatin alone in patients with metastatic squamous NSCLC. The main outcome measure, or primary endpoint, was overall survival. Portrazza is not indicated for treatment of nonsquamous NSCLC. The labeling for Portrazza contains Boxed Warnings regarding cardiopulmonary arrest and hypomagnesemia.

"Lung cancer is an extremely complicated disease that requires a variety of therapy options so doctors can choose an appropriate treatment for each patient's unique circumstances," said Bonnie J. Addario, founder and chair of the Bonnie J. Addario Lung Cancer Foundation, and a lung cancer survivor.

"Today's approval represents progress for patients diagnosed with metastatic squamous non-small cell lung cancer, as each new therapy advances cancer care and gives patients hope for improved outcomes."

Lilly is committed to offering assistance programs for eligible patients receiving Portrazza, including a co-pay programme that allows qualified patients to pay no more than $25 per dose.

Portrazza, in combination with gemcitabine and cisplatin, is approved for the first-line treatment of people with metastatic squamous non-small cell lung cancer (NSCLC). Portrazza is not indicated for treatment of nonsquamous NSCLC. Portrazza is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis, or cell death. As demonstrated in preclinical studies, EGFR plays a role in the formation (tumorigenesis) and spread (metastasis) of tumours.

SQUIRE was an open-label, randomized, multi-center phase III trial that compared first-line treatment with Portrazza in combination with gemcitabine and cisplatin to treatment with gemcitabine and cisplatin alone in patients with metastatic squamous NSCLC. Patients on both arms of the study were allowed to receive a maximum of six cycles of chemotherapy. Patients on the Portrazza arm demonstrating at least stable disease continued to receive additional cycles of Portrazza until disease progression or unacceptable toxicity. The trial enrolled 1,093 people with stage IV squamous NSCLC, of which 91 per cent had a baseline performance status (PS) 0-1, and nine per cent had PS 2. Of patients enrolled, 91 per cent had metastatic disease at two or more sites. The SQUIRE study was conducted across 184 investigative sites in 26 countries.

SQUIRE was the first and only randomized phase III study conducted specifically in patients with metastatic squamous NSCLC to demonstrate a statistically significant improvement in overall survival over gemcitabine and cisplatin alone, specifically in the first-line setting. Portrazza combination therapy showed a statistically significant improvement in overall survival, the main outcome measure (HR 0.84; 95 per cent CI: 0.74-0.96; p=0.01), with a median overall survival of 11.5 months (95 per cent CI: 10.4-12.6) for the Portrazza arm, as compared to 9.9 months (95 per cent CI: 8.9-11.1) for those treated with gemcitabine and cisplatin alone. This translated to a 16 per cent reduction in risk of death. The percentage of deaths at the time of analysis was 77 per cent (418 patients) on the Portrazza arm and 81 per cent (442 patients) on the control arm. The significant survival improvement observed in SQUIRE was supported by a statistically significant improvement in progression-free survival (HR 0.85; 95 per cent CI: 0.74-0.98; p=0.02), with a median progression-free survival (PFS) of 5.7 months (95per cent CI: 5.6-6.0) on the Portrazza arm, as compared to 5.5 months (95per cent CI: 4.8-5.6) for those treated with gemcitabine and cisplatin alone. The percentage of events at the time of analysis was 79 per cent (431 patients) on the Portrazza arm and 76 per cent (417 patients) on the control arm. Overall response rate (ORR) was also assessed and there was no difference between arms, with an ORR of 31 per cent (95 per cent CI: 27-35) for the Portrazza plus gemcitabine and cisplatin arm and an ORR of 29 per cent (95 per cent CI: 25-33) for the gemcitabine and cisplatin arm (p=0.40).

Cardiopulmonary arrest or sudden death occurred in 15 (3 per cent) of 538 patients treated with Portrazza plus gemcitabine and cisplatin as compared to three (0.6 per cent) of 541 patients treated with gemcitabine and cisplatin alone in SQUIRE. Twelve of the 15 patients died within 30 days of the last dose of Portrazza and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within six months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in SQUIRE. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known. Hypomagnesemia occurred in 83 per cent of patients receiving Portrazza in combination with gemcitabine and cisplatin, as compared to 70 per cent of patients treated with gemcitabine and cisplatin alone. Hypomagnesemia was severe (grade 3 or 4) in 20 per cent of patients on the Portrazza plus gemcitabine and cisplatin arm, compared to seven per cent of patients on the gemcitabine and cisplatin alone arm. Because of these risks, the Portrazza Prescribing Information contains instructions about monitoring for electrolyte imbalances and treating as necessary. Portrazza labeling contains additional Warnings and Precautions for venous and arterial thromboembolic events (some fatal), dermatologic toxicities, infusion-related reactions, increased toxicity and increased mortality in patients with nonsquamous NSCLC, and embryofetal toxicity.

NSCLC is the most common type of lung cancer, and accounts for about 85 per cent of all lung cancer cases. Squamous NSCLC, which represents about 30 percent of all lung cancer cases, is a devastating, difficult-to-treat form of the disease. Patients face an imposing disease and symptom burden with very poor prognosis; the five-year survival rate for patients with metastatic disease is less than five percent. Until now, little progress has been made over the last two decades, particularly in the first-line setting, leaving a significant unmet medical need.