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FDA Approves Second-Line Ramucirumab for mCRC

Josep Tabernero, MD

In the pivotal phase III study, the VEGFR-2 inhibitor ramucirumab in combination with FOLFIRI extended overall survival (OS) by 1.6 months and progression-free survival (PFS) by 2.2 months compared with FOLFIRI alone in patients with mCRC. Josep Tabernero, MD, presented findings from the study at the 2015 Gastrointestinal Cancers Symposium.

"Ramucirumab is an effective new treatment option for second-line treatment [of mCRC], including patients with poor prognosis," Tabernero, director of the Vall d'Hebron Institute of Oncology in Barcelona, Spain, said when the data were presented. "The RAISE trial clearly demonstrates that sustained inhibition of the angiogenesis from first-line to second-line mCRC therapy improves survival in a clinically representative mCRC population."

In the phase III trial, 1072 patients with mCRC who progressed on or after first-line treatment with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomized to receive FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) plus ramucirumab (n = 536) or placebo (n = 536). In the investigational arm, patients received intravenous ramucirumab at 8 mg/kg every 2 weeks.

The median age of patients was 62 years, with approximately 50% harboring a KRAS mutation. The time to disease progression after beginning first-line therapy was ≥6 months for approximately 75% of patients. A small portion of patients (17.2% to 17.7%) had liver only metastasis. The primary endpoint of the study was OS, with PFS and objective response rate (ORR) as secondary outcomes measures.

Median OS with ramucirumab was 13.3 versus 11.7 months with placebo (HR = 0.84; 95% CI, 0.73-0.98; P = .0219). OS favored ramucirumab across all subgroups. For patients in North America (N = 286), the HR for OS was 0.75 in favor of ramucirumab over placebo (95% CI, 0.57-0.98).

The HR for survival in female patients was 0.74 (95% CI, 0.59-0.91), favoring ramucirumab, and 0.95 for male patients (95% CI, 0.78-1.14). In total, 247 female patients received ramucirumab compared with 210 in the placebo arm.

In general, outcomes favored ramucirumab in patients with a greater burden of metastatic lesion. The HR for survival for patients with liver-only metastases was 0.96 favoring ramucirumab (95% CI, 0.68-1.37).

Median PFS with ramucirumab was 5.7 versus 4.5 months with placebo (HR = 0.79; 95% CI, 0.70-0.90; P = .0005). The HR for PFS in North America was 0.73 in favor of ramucirumab (95% CI, 0.57-0.93). The HR for PFS in female patients was 0.75 (95 % CI, 0.62-0.91).

A statistically significant difference in ORR was not observed between the two arms. With ramucirumab the ORR was 13.4% versus 12.5% with placebo (P = .6336). The stable disease rate was 60.6% versus 56.3% for ramucirumab and placebo, respectively.

The most common all-grade adverse events with ramucirumab versus placebo were neutropenia (58.8% vs 45.6%), fatigue (57.7% vs 52.1%), hypertension (25.7% vs 8.5%), and thrombocytopenia (28.4% vs 13.6%). The most common grade ≥3 adverse events were neutropenia (38.4% vs 23.3% with placebo) and hypertension (10.8% vs 2.8%). The rate of febrile neutropenia was comparable between the two arms at 3.6% and 2.7% in the ramucirumab and placebo arms, respectively.

Adverse events of special interest included bleeding or hemorrhage, which occurred in 43.9% of patients treated with ramucirumab versus 22.7% with placebo. Additionally, 17% of patients treated with ramucirumab had proteinuria compared with 4.5% in the placebo arm. Ramucirumab is approved with a Boxed Warning regarding hemorrhage, gastrointestinal perforation, and impaired wound healing.

The application for ramucirumab in mCRC was reviewed and approved by the FDA within just nine weeks, according to the manufacturer of the drug, Lilly Oncology. Prior applications for the drug were reviewed within a six-month timeframe.

In 2014, ramucirumab was approved as a single-agent and in combination with paclitaxel as a treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma. The label for ramucirumab was expanded in December 2014 to include the treatment of patients with metastatic non-small cell lung cancer in combination with docetaxel. Ramucirumab continues to be explored in clinical trials in combination with chemotherapy across various types of cancer.

"Cyramza now has approvals in advanced or metastatic forms of three of the world's most common and deadly cancers--gastric, non-small cell lung, and colorectal--with four FDA approvals received in just over a year," Sue Mahony, PhD, senior vice president and president, Lilly Oncology, said in a statement. "This progress is encouraging and supports our ongoing development program for Cyramza. Achieving today's milestone is another example of Lilly's commitment to people living with gastrointestinal cancers."


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