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Smitha S. Krishnamurthi, MD

Wafik S. El-Deiry, MD, PhD, FACP

Leonard B. Saltz, MD

We want to offer patients all we can, because these agents [biologics] tend to be well tolerated and they can be combined with chemotherapy.

—Smitha S. Krishnamurthi, MD
I cannot think of a human being in whom I might consider second-line ramucirumab in colorectal cancer, because I don’t have any reason to believe it is meaningfully different from either bevacizumab or aflibercept.

—Leonard B. Saltz, MD

Commenting on the RAISE study at a press briefing held during the 2015 Gastrointestinal Cancers Symposium, moderator Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, acknowledged that improvements of 1 to 2 months in progression-free and overall survival appear modest. However, she said, “We want to offer patients all we can, because these agents [biologics] tend to be well tolerated, and they can be combined with chemotherapy.”

Study discussant Wafik S. El-Deiry, MD, PhD, FACP, an American Cancer Society Professor and Deputy Director and Program Leader at Fox Chase Cancer Center, Philadelphia, indicated that RAISE is the third major study to show an overall survival benefit for antiangiogenic therapy in the second line, after first-line chemotherapy plus bevacizumab (Avastin). The TML trial evaluated bevacizumab plus FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) or FOLFOX (leucovorin, 5-FU, oxaliplatin) in the second line and ­VELOUR evaluated ziv-aflibercept (Zaltrap) plus FOLFIRI.

“Though the study designs were not the same, the outcomes appear similar,” he said. Overall survival was improved by approximately 1.5 months in each trial, with the addition of an antiangiogenic agent.

Future Study

Randomized comparisons and studies of antiangiogenic combinations would be the next step, and the following were Dr. El-Deiry’s suggestions for future study:

  • Ramucirumab (Cyramza) plus FOLFIRI vs bevacizumab plus FOLFIRI in the second-line setting after FOLFOX plus ­bevacizumab
  • Ramucirumab plus FOLFIRI in patients who have received prior FOLFOX therapy without ­bevacizumab
  • Ramucirumab plus FOLFIRI vs anti–epidermal growth factor receptor (EGFR) plus FOLFIRI in the second line in the wild-type KRAS population
  • Single-agent ramucirumab in patients who cannot tolerate chemotherapy
  • Ramucirumab or ramucirumab-plus-capecitabine maintenance
  • Ramucirumab plus FOLFIRI vs ziv-aflibercept plus FOLFIRI in the second line after prior ­FOLFOX or FOLFOX plus bevacizumb

“We also need biomarkers to predict response, and in 2015, we also need to assess and compare financial toxicities of these regimens,” he concluded.

Cost Considerations

Colorectal cancer specialist ­Leonard B. Saltz, MD, of Memorial Sloan Kettering Cancer Center, commented to the speakers that ramucirumab and ziv-aflibercept in the second-line colorectal cancer setting are “equivalent,” yet “ramucirumab [would be] more than double the cost" of ziv-aflibercept and bevacizumab in colorectal cancer. He estimated that comparison at $12,000 vs $5,000.

“I cannot think of a patient in whom the use of second-line ramucirumab would be appropriate, given the other alternatives,” Dr. Saltz said. He added that the trial showed a survival benefit over the control arm, but not over current standard care.

Dr. El-Deiry responded that clinical trials in colorectal cancer will offer the opportunity to “determine what the niche will be for this drug, should there be one,” adding that “outside of a clinical trial, it is not appropriate to use this drug.”

Open Discussion

Dr. Tabernero defended the “clean design” of the study “in a very homogeneous population” and its ability to demonstrate an effect in this population. “Whether the price for this effect [is fair] is an open discussion,” he said.

In an interview with The ASCO Post, Dr. Saltz elaborated on his concerns about the potential cost of ramucirumab for second-line colorectal cancer treatment.

“I cannot think of a human being in whom I might consider second-line ramucirumab in colorectal cancer, because I don’t have any reason to believe it is meaningfully different from either bevacizumab or aflibercept,” he said.

When ziv-aflibercept debuted, Dr. Saltz advocated against using this drug, due to its modest benefit at a high cost, but he indicated that the cost has since been lowered to bring it almost on a par with bevacizumab. “Ramucirumab is more than double the price of those two,” he emphasized.

A ‘Different Story’

Another expensive drug in colorectal cancer—regorafenib (Stivarga)—is “a different story,” he said, “because as limited as it may be, it’s used third line after other regimens fail.” Neither ramucirumab nor ziv-aflibercept offers a new line of therapy, he emphasized.

He noted Dr. El-Deiry’s proposal for additional trials but predicted these will not happen, since they lack financial incentives.

“The interesting question is whether the data from RAISE will justify a compendium listing for ramuciru-
mab, which does not consider the cost of drugs,” he said. “Probably, yes. But there is no reason to think that it will be anything other than an expensive regimen with no benefit. It may become an option for American oncologists, but personally I believe it is irresponsible to use it.” ■

Disclosure: Drs. Krishnamurthi, El-Deiry, and Saltz reported no potential conflicts of interest.


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