Cyramza yields a modest survival benefit in second-line NSCLC
| Jun 3, 2014
By Greg Wolfe and Neesha Suvarna
Cyramza™ (ramucirumab, IMC-1121B; Eli Lilly) is a human IgG1 monoclonal antibody directed against the extracellular domain of VEGFR-2. It was recently approved by the Food and Drug Administration (FDA) for advanced gastric cancer or gastroesophageal junction adenocarcinoma. On February 19, 2014, Lilly announced via press release that the REVEL trial was positive for both overall survival (OS) and progression-free survival (PFS) benefit. Results from the randomized, double-blind, placebo-controlled Phase III REVEL trial (NCT01168973) were reported at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). The trial evaluated docetaxel with or without Cyramza in squamous or non-squamous Stage IV non-small cell lung cancer (NSCLC) patients following disease progression after one prior platinum-based therapy.
Patients in the REVEL trial, were randomized to receive docetaxel (75 mg/m2IV Day 1 of a 21-day cycle) plus either Cyramza (10 mg/kg IV Day 1 of a 21-day cycle, n=628) or placebo (n=625) until disease progression or unacceptable toxicity. The primary endpoint was OS, and secondary endpoints included PFS, overall response rate (ORR) and quality of life. REVEL met its primary endpoint with a modest improvement in median OS (10.5 months for Cyramza plus docetaxel versus 9.1 months for docetaxel alone (HR = 0.857; p=0.0235)). The addition of Cyramza to docetaxel improved OS in patients with squamous and non-squamous histologies. The ORR was 22.9% for Cyramza plus docetaxel and 13.6% for the docetaxel arm (p<0.001). Median PFS was 4.5 months for Cyramza plus docetaxel versus 3.0 months for docetaxel (HR=0.762; p<0.0001).
Treatment-emergent Grade 3 or higher adverse events (AEs) were reported in 78.9% of patients in the Cyramza plus docetaxel arm and 71.8% of patients in the docetaxel arm. The most common Grade 3 or higher treatment emergent AEs in the Cyramza/docetaxel arm compared to docetaxel alone arm included neutropenia (48.8% vs. 39.8%), febrile neutropenia (15.9% vs. 10.0%), fatigue (14.0% vs. 10.5%) and hypertension (5.6% vs. 2.1%). Pulmonary hemorrhage (any grade; all patients) was reported in 2.1% vs. 1.6% of patients but was slightly more in squamous patients (3.8% vs. 2.4%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%).
Docetaxel is commonly preferred as second-line therapy for patients with NSCLC. These results demonstrate that addition of Cyramza to docetaxel improves median OS by 1.4 months, but at the same time it increases toxicities including neutropenia, febrile neutropenia and hypertension. Recent ASCO recommendations suggest that clinically relevant improvements in OS should be on the order of four months for NSCLC with a hazard ratio of less than 0.8. It is obvious that the REVEL results did not clear this bar; however, there are some positives with Cyramza trial.
REVEL is the first Phase III study to show that the addition of a biologic to standard chemotherapy improves survival compared to chemotherapy alone in second-line NSCLC. In addition, Cyramza was active in squamous NSCLC, where treatment options are more limited. The increased toxicity in REVEL was modest, similar to the toxicity profile observed when Cyramza was combined with paclitaxel in the RAINBOW trial in gastric cancer. Lilly has announced their plans for a regulatory submission for Cyramza for NSCLC in 2014 based upon the REVEL results. Will the REVEL data be sufficient to convince the regulatory authorities to approve Cyramza for NSCLC? If it is approved will physicians utilize Cyramza with such modest clinical benefit? Time will tell.
 Perol, LBA8006, ASCO 2014