Ramucirumab Extends Survival in Metastatic CRC, a Bit

Nick Mulcahy

January 14, 2015

The new angiogenesis inhibitor ramucirumab (Cyramza, Lilly) showed a survival benefit in patients with metastatic colorectal cancer who had stopped responding to initial therapy in the international phase 3 trial known as RAISE.

The results suggest that second-line therapy in colorectal cancer could be a new indication for the drug, which is already approved in the United States for use in stomach cancer and lung cancer.

Ramucirumab is a vascular endothelial growth-factor receptor 2 (VEGFR) antagonist, and is seen as a successor to the first angiogenesis inhibitor, bevacizumab (Avastin, Roche /Genentech).

The new data, which are the first proof of efficacy for ramucirumab in colorectal cancer, were discussed during a presscast held in advance of the 2015 Gastrointestinal Cancers Symposium in San Francisco.

When added to standard second-line chemotherapy, ramucirumab prolonged life by 6 weeks, compared with standard chemotherapy alone, reported lead author Josep Tabernero, MD, from the Vall d'Hebron Institute of Oncology in Barcelona, Spain.

One and half months is not a long time.

"One and half months is not a long time," acknowledged presscast moderator Smitha S. Krishnamurthi, MD, from Case Western Reserve University in Cleveland, about the survival benefit.

Clinicians would like to see the results "be even stronger," she said.

Nevertheless, Dr Krishnamurthi is enthusiastic. "It's always exciting to have a new active drug for our patients," she said.

"Advanced colorectal cancer is an incurable disease, and it is particularly difficult to treat after initial therapy stops working," Dr Tabernero said in a press statement.

It's always exciting to have a new active drug.

Dr Krishnamurthi pointed out that the 6 week survival benefit seen with ramucirumab is "similar" to that seen with other second-line treatments.

She told reporters during the presscast that the most commonly used second-line treatment for metastatic colorectal cancer is bevacizumab plus an irinotecan-based chemotherapy. This means that clinicians continue bevacizumab after a first-line failure, but change the chemotherapy.

In the United States, bevacizumab and ziv-aflibercept are approved by the US Food and Drug Administration for use in combination with chemotherapy in the second-line treatment of metastatic colorectal cancer. In addition, regorafenib is approved as a standalone therapy for patients with previously treated metastatic colorectal cancer.

The RAISE results offer clinicians yet another choice, said Dr Krishnamurthi and Dr Tabernero, although they both pointed out that ramucirumab is not yet approved for use in colorectal cancer.

Significant Improvement in Survival

Patients in the RAISE study were treated with FOLFIRI (folinic acid, fluorouracil, and irinotecan), a standard regimen for colorectal cancer. In addition, they received either intravenous ramucirumab 8 mg/kg or placebo every 2 weeks until disease progression, unacceptable toxicity, or death. All 1072 patients had failed first-line treatment with bevacizumab and another standard chemotherapy (oxaliplatin plus a fluoropyrimidine).

Median overall survival, the study's primary end point, was longer in the ramucirumab group than in the placebo group (13.3 vs 11.7 months; = .0219). This translates into a hazard ratio (HR) of 0.84, which means that the addition of ramucirumab reduced the risk for death by 16%.

Progression-free survival, a secondary end point, was also better in the ramucirumab group than in the placebo group (5.7 vs 4.5 months; P = .0005). This means that the addition of ramucirumab reduced the risk for progression by 21% (HR, 0.79).

Dr Tabernero said that there was a "consistent" treatment effect in patient subgroups, including KRAS mutant and wild-type tumors.

The results "clearly demonstrate" that the "sustained inhibition of the angiogenesis" from first-line to second-line therapy for metastatic colorectal cancer improves survival, Dr Tabernero explained.

Ramucirumab plus FOLFIRI was more toxic than placebo plus FOLFIRI.

Table. Adverse Events of Grade 3 or Higher

Adverse Event Ramucirumab Group, % Placebo Group, %
Neutropenia 38.4 23.3
Hypertension 11.2 2.8
Diarrhea 10.8 9.7
Fatigue 11.5 7.8


However, Dr Tabernero said that ramucirumab plus FOLFIRI was "well tolerated" and noted that, overall, the "adverse events were manageable."

The study was funded by Eli Lilly. Some of the study authors report financial ties to industry, including Lilly. Dr Krishnamurthi has disclosed no relevant financial relationships.

2015 Gastrointestinal Cancers Symposium (GICS): Abstract 512. To be presentedJanuary 17, 2015.


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