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SAN FRANCISCO -- Patients with progressive metastatic colorectal cancer had modest but statistically significant improvement in overall survival and progression-free survival (PFS) with second-line ramucirumab (Cyramza) and chemotherapy, investigators reported here.

The addition of ramucirumab to chemotherapy led to a median overall survival (OS) of 13.3 months versus 11.7 months with FOLFIRI plus placebo. The median PFS was 5.7 months with ramucirumab compared with 4.5 months with placebo. All of the patients had progressed during or after first-line treatment with chemotherapy plus bevacizumab (Avastin).

Ramucirumab was associated with higher rates of neutropenia, fatigue, hypertension, and thrombocytopenia, which investigators considered manageable, as reported here at the Gastrointestinal Cancers Symposium.

"The trial met its primary endpoint, demonstrating a statistically significant improvement in overall survival for ramucirumab and FOLFIRI versus placebo and FOLFIRI," said , of Vall d'Hebron University Hospital in Barcelona, Spain. "We observed consistent survival benefits across subgroups.

"Ramucirumab, in combination with FOLFIRI, was well tolerated in patients with metastatic colorectal cancer. Overall, the adverse events were considered manageable."

In a separate study, Chinese investigators found that the angiogenesis inhibitor famitinib extended PFS in patients with previously treated, advanced metastatic colorectal cancer.

Ramucirumab

In colorectal cancer, tumor growth involves multiple molecules and signaling pathways, including vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), which mediate tumor angiogenesis. Both VEGF and VEGFR2 are established therapeutic targets in colorectal cancer, as reflected in the approved indication for bevacizumab, Tabernero noted.

Ramucirumab is an anti-VEGFR2 antibody that targets the receptor's extracellular domain to prevent ligand binding and receptor activation. The drug was FDA approved for the treatment of advanced gastric cancer or adenocarcinoma of the gastroesophageal junction last year.

Investigators in a multicenter, randomized clinical trial evaluated the efficacy and safety of adding ramucirumab to standard second-line chemotherapy (FOLFIRI) for patients with colorectal cancer that had progressed during or after first-line treatment with bevacizumab, oxaliplatin, an a fluoropyrimidine.

All patients received FOLFIRI chemotherapy and were randomized to ramucirumab or placebo. Assigned treatment continued until disease progression or development of unacceptable toxicity. The primary endpoint was OS.

Data analysis included 1,072 patients. Half the patients in each treatment group had KRAS-mutant tumors and three-fourths of the patients had first-line progression-free intervals of 6 months or greater.

The efficacy data of a 1.6-month difference in OS favoring ramucirumab achieved statistical significance (P=0.0219), as did the 1.2-month improvement in PFS (P=0.0005). The objective response rate was 13.4% with ramucirumab and 12.5% with placebo, and the disease control rates were 74.1% and 68.8% for ramucirumab and placebo, respectively. Neither outcome achieved statistical significance.

The overall relative dose intensity of ramucirumab and placebo was similar. Patients in both groups received a median of eight cycles of all components of therapy, and the median duration of therapy was similar between groups for all components. About 55% of patients in both arms received post-treatment anticancer therapy.

Almost all patients in both treatment groups had one or more treatment-emergent adverse events. Grade 3-plus adverse events occurred more often in the ramucirumab arm (79.0% versus 62.3% for FOLFIRI and placebo).

The incidence of grade 3-plus neutropenia differed between treatment groups (38.4% with ramucirumab versus 23.3% with placebo), as did the incidence of grade 3-plus fatigue (11.5% versus 7.8%), hypertension (10.8% versus 2.8%), and thrombocytopenia (3.0% versus 0.8%). Febrile neutropenia (any grade) occurred in 3.6% of the ramucirumab group and 2.7% in the placebo group.

Famitinib

Chinese investigators found that famitinib extended PFS by about 6 weeks in patients with previously treated, advanced metastatic colorectal cancer. The drug targets multiple factors involved in tumor angiogenesis, including VEGFR2, c-Kit, and platelet-derived growth factor.

In a trial involving 70 patients with advanced disease, treatment with famitinib resulted in a disease control rate of 34.5%, including four confirmed partial responses and three unconfirmed partial responses, said Rui-hua Xu, MD, of in Guangzhou.

Given the lack of treatment options beyond second line in metastatic colorectal cancer, the findings supported a rationale for evaluating famitinib in advanced metastatic colorectal cancer.

Xu reported findings from a trial involving 154 patients with advanced, metastatic colorectal cancer, randomized 2:1 to famitinib monotherapy or placebo. The treatment groups were well matched. The patients had received at least two prior regimens for metastatic colorectal cancer, although investigators did not have complete information on the patients' treatment history. Xu noted that FOLFIRI, FOLFOX, cetuximab, and bevacizumab are available in China.

The primary endpoint was PFS, and the data showed that patients in the famitinib arm had significant improvement (median PFS of 2.8 versus 1.5 months, P=0.0034). The disease control rate (response plus stable disease) also favored the famitinib arm (57.58% versus 30.91%, P=0.0023). OS did not differ between treatment groups.

In general, famitinib was well tolerated, and the overall incidence of adverse events was about 10% in the famitinib and placebo groups.

'Financial Toxicity'

Invited discussant , of Fox Chase Cancer Center in Philadelphia, agreed with Tabernero's assessment that ramucirumab improves OS and PFS in patients with metastatic colorectal cancer that has progressed during or after bevacizumab plus chemotherapy. However, he questioned whether famitinib has a role in advanced metastatic colorectal cancer, given the results reported by Xu were less favorable than what has been reported with other third-line therapies.

During the discussion that followed the presentations, , of Memorial Sloan Kettering Cancer Center in New York City raised the issue of "financial toxicity," questioning whether the benefits observed with ramucirumab are worth the drug's high cost, roughly double that of bevacizumab.

Speaking to El-Deiry and Tabernero, Saltz asked, "Can you think of a patient in whom use of ramucirumab in second-line colon cancer would be appropriate, given the other alternatives? Personally, I can't."

"I think without understanding better who is likely to respond and who is not likely to respond, it is very hard to come up with an answer to that question," El-Deiry responded. "I think within the context of clinical trials, before any of these drugs are approved, there is still an opportunity to figure out what the niche ultimately will be, if there is one. Within the context of clinical trials, there is less worry about financial toxicity, but obviously it is a question in clinical practice."

"Outside of a clinical trial, is there an appropriate use of this clinical agent, given it’s more than double the price?" Saltz asked.

"I don’t think we know, and I don’t think it would be appropriate to use this agent outside of a clinical trial,” said El-Deiry.

Tabernero said he agrees “in general” with Saltz’s comments, adding that if use of an expensive drug expands to broader application in prevalent diseases, “an adjustment of the price” should be considered.

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