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Emotions High in Criticisms & Defense of CALGB 80405 Colorectal Cancer Study

Carlson, Robert H.

doi: 10.1097/01.COT.0000471639.31650.9b


BARCELONA, Spain—The lead author of the CALGB 80405 metastatic colorectal cancer trial was called to task here at the ESMO World Congress on Gastrointestinal Cancer for important data still to come, more than a year after overall survival and progression-free survival data were presented at the ASCO 2014 Annual Meeting (Abstract LBA 3, OT 7/10/14 issue).

The additional data—on response rate, subsequent treatments, and treatment duration/dose intensity—are awaited by researchers eager to understand why the overall survival results in that study were different from those in the similar European FIRE 3 trial (Heinemann et al: Lancet 2014;15:1065-1075), even though both tested the same regimens in the first-line treatment of metastatic colorectal cancer.

CALGB 80405 showed equivalent overall survival and progression-free survival between its two study arms:

  • The anti-VEGF agent bevacizumab plus FOLFIRI (folinic acid [leucovorin], fluorouracil, and irinotecan) versus the anti-EGFR agent cetuximab plus FOLFIRI;
  • The FIRE 3 trial showed equivalent progression-free survival for its two arms, but overall survival with cetuximab-FOLFIRI was superior to that of bevacizumab-FOLFIRI.

In his update on CALGB 80405 here, the lead author, Alan P. Venook, MD, Professor of Medical Oncology and Translational Research at the University of California, San Francisco, although acknowledging that work is still to be done, defended the trial's conclusions: “We need to move that into the manuscript; we have to audit all medical records for missing information, and do a data sweep,” he said in his presentation.



Venook said more events have occurred and he could have updated the major findings in each arm, but he felt this would not be productive. So rather than put out another set of slides with updated data, that information will be in the forthcoming published manuscript.

“We have a lot of work to do,” he said at the conclusion of his presentation. “I am not happy to report that we have been unable to complete the data sweep or refine the data, but it is out of my hands and in the hands of the cooperative group. Hopefully in the next three to six months we will have a manuscript and fill in the blanks you are appropriately waiting for us to fill in.”

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Discussant: ‘Key Issue is Relevance’

The Discussant for the presentation here, Alberto F. Sobrero, MD, Head of the Department of Medical Oncology at Ospedale San Martino in Italy, reiterated the point that it is not possible to predict whether CALBG 80405 will change clinical practice because important data are missing. He said he could say, though that the data do have internal validity and internal consistency.

Discussant ALBERTO F

Discussant ALBERTO F

Still, he questioned whether there was external consistency because of the discordance with FIRE 3.

“The key issue is relevance—the CALGB 80405 data cannot be said to be relevant because the data are too early. We do not have the entire picture of patient characteristics; we have no data on compliance, on second-line treatment, or sequential treatment.”

Sobrero said that for the time being, with the data that have been presented, he could grant the fact that the CALGB trial shows clinical benefit, “simply because, if the two treatments are similar, then you would go for the FOLFIRI-bevacizumab arm because of the lack of skin toxicity [that occurs frequently with cetuximab]. But I cannot come to that conclusion because I don't know the data.”

Turning to FIRE 3, Sobrero said that trial “is causing me grief,” because the FIRE trialists failed to include survival as a major endpoint. The primary endpoint of the study was objective response rate, with secondary endpoints of progression-free survival and overall survival.

“How that mistake could have been made I do not understand,” he said.

Sobrero also said he was “unhappy with FIRE 3” because it shows a difference in overall survival but not in progression-free survival.

Nevertheless, he said FIRE 3 shows external validity as its outcomes are similar to those in the Phase II PEAK (Panitumumab Efficacy in Combination with mFOLFOX6 Against bevacizumab plus mFOLFOX6 in mCRC subjects with wild-type KRAS tumors) trial (Schwartzberg et al: JCO 2014;32:2240-2247) in which progression-free survival was similar but overall survival was improved with the anti-EGFR agent panitumumab plus FOLFOX versus bevacizumab with FOLFOX (leucovorin, fluorouracil, oxaliplatin).

Because of the “huge clinical benefit shown [with cetuximab], FIRE 3 is practice changing,” Sobrero said.

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‘The FIRE 3-CALGB 80405 Era’

Sobrero summarizing his take on the current situation in first-line metastatic colorectal cancer treatment following both of these trials, in what he called the FIRE 3-CALGB 80405 era.

Considerations for treatment with bevacizumab have not changed, he said: It has good efficacy in first- and second-line therapy, and is easy to use with little toxicity. Companion chemotherapy is not a big issue, although there is no single-agent activity.

Considerations for anti-EGFR therapy have not changed either, he added: It has good efficacy in first- and third-line therapy, and has single-agent activity. Companion chemotherapy is an issue, but anti-EGFR therapy can be combined with oxaliplatin. The RAS testing needed before treatment causes delays, and skin toxicity is still a major problem.

“What has changed is my conclusion,” Sobrero said. “While waiting for the CALGB full report—and I may change my mind—in general, anti-EGFR agents in [patients with] RAS wild-type are more efficacious than anti-VEGF treatment in first-line colorectal cancer.

“I'm not saying better; I'm saying more efficacious, meaning science—p values and so on.”

Sobrero said he was uneasy with this conclusion, but said it is driven by his conviction that “the data are the data.

“And if you cannot change the data, then you should change the way you thought before.”

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Venook Responds to Concerns

In an interview after the session, Venook responded to some of Sobrero's concerns: “There's a lot of distinction being made between CALGB 80405 and FIRE 3, and the major issue to me is: Why did the bevacizumab arm in FIRE 3 not do as well as the CALGB 80405 bevacizumab arm?”

There has been a lot of discussion about whether 80405 had depth of response or early time to tumor shrinkage in the cetuximab arm, and how that might have affected results, he said. “The fact is, the cetuximab patients in 80405 did exactly as they did in both the panitumumab arm in PEAK, and in the cetuximab arm in FIRE 3. The difference is in how the bevacizumab patients did in those other studies.

“I suspect it's because of an asymmetry in the second and subsequent treatment lines. In the FIRE 3 data they've looked at the subsequent lines, and there is a very different outcome in subsequent treatment, as you'd expect, because there's no difference in progression-free survival.

“But there is a big survival difference, and [the researchers] attribute that to some biological phenomenon whereby the prior cetuximab makes the sequence important, and the patients get greater benefit from subsequent therapy. So in fact, the treatments subsequently aren't equal.”

CALGB 80405's primary endpoint was overall survival, Venook noted, as opposed to FIRE 3, which had investigator-adjudicated response rate as the primary endpoint. “There has never been a Phase III study that showed no progression-free survival advantage that then led to a survival advantage,” he said. “So for many reasons FIRE 3 is just an outlier. If I were the folks in FIRE 3, I'd be wondering why the bevacizumab patients did poorly, as opposed to the patients in 80405.”



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‘More Important to Understand than to Say Not Valid’

Venook said it is more important to understand the CALGB 80405 results than to suggest that the study is not valid: “That's not exactly what Dr. Sobrero said, but it is approximately what he said.”

Venook acknowledged Sobrero's point that important CALGB 80405 data are yet to be analyzed. “There is a lot left to be done—subsequent treatment needs to be clear, and certainly we don't have BRAF status in all patients—that's a function of the cooperative group and how much resource we can put to it.”

But he said he also thought some of the missing data, such as depth of response and early time-to-treatment response, would not matter since those data were the same in both CALGB 80405 study arms.

“And our endpoint was overall survival, and that's a pretty hard data point.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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