Alimta Combination Fails Survival Objectives in Phase III Study

Eli Lilly announced that a combination regimen of their chemotherapy drug Alimta (pemetrexed injection) and bevacizumab (Avastin) failed to improve survival in late stage non-squamous non-small cell lung cancer (NSCLC) when compared with a standard chemotherapy regimen.

Lilly reported the results of the Phase III POINTBREAK trial, which are scheduled to be presented at the Chicago Multidisciplinary Symposium in Thoracic Oncology. In this trial, 939 patients with stage IIIB/IV non-squamous NSCLC with a performance status of either 0 or 1 were randomized to receive either the pemetrexed injection (500 mg/m²) plus carboplatin and bevacizumab (n = 472) or paclitaxel (200 mg/m²) plus carboplatin and bevacizumab with dexamethasone (n = 467). Patients in the pemetrexed arm whose disease did not progress after first-line treatment received pemetrexed and bevacizumab as maintenance therapy (n = 292), while patients in the control arm whose disease did not progress received maintenance bevacizumab (n = 298). The primary endpoint of the study was overall survival (OS) with progression-free survival (PFS) as a secondary endpoint.

The study found that patients in the pemetrexed arm achieved a median OS of 12.6 months compared with 13.4 months in patients in the control arm (hazard ratio [HR] = 1.00; P = .949), which Lilly reported had no statistical difference. A slight statistically significant improvement was observed in PFS, with patients in the pemetrexed arm achieving a median PFS of 6.0 months compared with 5.6 months in the control arm (HR = 0.83; P = .012). The overall response rate was 34.1% in the pemetrexed arm compared with 33.0% in the control arm, and the disease control rate was 65.9% in the pemetrexed arm compared with 69.8% in the control arm. These rates were not considered significantly different between the two arms.

Toxicities varied between the two arms, with patients in the pemetrexed arm having experienced significantly more drug-related grade 3 or 4 anemia (14.5%), thrombocytopenia (23.3%), and fatigue (10.9%) compared with the control arm. In the control arm, grade 3 or 4 rates of neutropenia (40.6%), febrile neutropenia (4.1%), and sensory neuropathy (4.1%) were significantly higher.

“Phase II results with this combination were promising and we were hoping to demonstrate an improvement in survival for non-squamous NSCLC patients, so we are disappointed with the results of this trial,” said Allen S. Melemed, MD, MBA, senior medical director with Lilly Oncology, in a statement. “POINTBREAK did show an improvement in progression-free survival, though this did not translate to an overall survival advantage.”

Pemetrexed injection was approved by the FDA in 2008 to treat non-squamous NSCLC when given in combination with cisplatin in the initial treatment of the disease. The POINTBREAK trial explored the use of the drug with bevacizumab instead of cisplatin and whether it could be given in a maintenance setting.