Confusion persists about the best choice of frontline therapy for patients with metastatic colorectal cancer (mCRC) after a landmark clinical trial that was conceived a decade ago to answer that question concluded without a superiority finding, according to a panel of internationally recognized experts in gastrointestinal oncology.

” is that physicians can choose which treatment strategy would work best for each patient: either cetuximab (Erbitux) or bevacizumab (Avastin) with either FOLFOX or FOLFIRI.

Both agents are FDA-approved for frontline therapy in combination with chemotherapy.

The phase III CALGB/SWOG 80405 study demonstrated that combining either of the targeted agents with chemotherapy resulted in a comparable survival benefit of approximately 29 months among patients with KRAS wild-type mCRC.

“The 30,000-foot view is that we have overall survival of 29 months in both arms of a study that was done across the US and Canada in many sites,” said Alan P. Venook, MD, during the panel discussion. “The survivorship is much better than what we’ve seen before. That’s exciting. Now, the devil is in the details in figuring out how we can improve on it.” Venook presented the results of 80405 during a plenary session at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in June. It was the first ASCO plenary session to focus on CRC in years, noted Johanna C. Bendell, MD, who served as moderator for the Peer Exchange discussion.

The 80405 study was designed to evaluate the overall survival (OS) of patients with advanced CRC who were treated with either FOLFOX or FOLFIRI and then randomized to cetuximab, bevacizumab, or both. Since the trial was initiated, the cetuximab/bevacizumab arm was dropped based on worse outcomes with dual-targeted therapy.

As the trial design incorporated the investigator’s choice of the frontline chemotherapy regimen, the ultimate question asked by the study was a biologic one: What’s better—anti-EGFR therapy or an anti- VEGF therapy? Cetuximab targets EGFR, while bevacizumab targets VEGF.

Originally, KRAS mutations were not considered and the protocol was amended to look specifically at KRAS wild-type patients. Overall, 80405 was an enormous undertaking, incorporating a number of correlative studies.

In the final trial, 1137 patients with treatment-naïve mCRC, KRAS wild-type status at exon 2 codons 12 and 13, and performance status 0-1, were randomized 1:1 to cetuximab (n = 578) or bevacizumab (n = 559). At a median follow-up of 24 months, OS was equivalent in both arms—29 months for bevacizumab and 29.9 months for cetuximab (HR, 0.925; 

 = .34). “Overall survival exceeding 29 months in both arms really establishes a new benchmark for the treatment of patients with CRC,” Venook said. Median progression-free survival (PFS) was also equivalent for both antibodies at 10.8 months in patients receiving bevacizumab compared with 10.4 months in the cetuximab group (HR, 1.04; 

= .55). Toxicities with both agents were in line with those previously reported.

The take-home message is that survival is longer than ever in mCRC and that there is no right answer regarding which biologic to choose for treatmentnaïve, KRAS-wild-type patients, the panelists indicated. Most impressive in these patients, who were mostly borderline or initially unresectable, was the subset of approximately 10% of patients who were able to later undergo potentially curative surgery.

At ASCO, Venook also presented quality of life (QoL) data.

 EORTC QLQ-C30 and Dermatology-Specific QoL instruments were used and compliance was more than 90%. After a 9-month follow-up period, QoL was equivalent for both agents, but trended in favor of bevacizumab (

 = .056). The difference was largely driven by dissatisfaction with cetuximab-associated skin rash. However, this dissatisfaction diminished over time; the rash itself abates and patients presumably understand the association between severe skin toxicity and treatment benefit.

The findings from 80405 add complexity to the data accumulating for this patient population. The FIRE-3 study, conducted in a similar setting in patients with KRAS wild-type tumors, showed equivalence in response rate or PFS for bevacizumab versus cetuximab, according to results presented at the 2013 ASCO annual meeting.

 However, OS was significantly prolonged with cetuximab compared with bevacizumab (28.7 months vs 25.0 months; P = .017). This OS advantage was seen 1 year after the completion of onstudy therapy.

As a consequence, many practice patterns were changed to favor cetuximab, based on the secondary endpoint of OS, noted Axel Grothey, MD. He said the benefit was enhanced in an all-RAS analysis from the FIRE-3 trial. That analysis, which included KRAS and NRAS genes, demonstrated a wider OS advantage of about 7.5 months for cetuximab, according to data presented at the 2013 European Cancer Congress.

Many hoped the 80405 trial would confirm the FIRE-3 results, but the findings were not upheld, noted Grothey. At this point, both trials highlight the equivalent efficacy of two treatment options for patients with mCRC.

“It’s reassuring that we have two great study arms with outcomes that we didn’t consider possible when the trial was started in terms of duration of survival,” said Grothey. “I think it’s great. We have choices. We can adjust our treatments and we can use 80405 as a treasure trove to dive into more detailed analysis.”

Several studies suggest the importance of expanded RAS analysis beyond the KRAS tests typically conducted, according to Tanios Bekaii-Saab, MD.

He said another 10% to 15% of patients with traditional KRAS wild-type tumors have other RAS mutations and do not seem to derive benefit from an EGFR inhibitor.

“More concerning was the suggestion that, for some of these patients, if you give them the EGFR inhibitor, that their outcome ends up worse,” said Bekaii-Saab. “We may actually be inducing harm.”

Thus, clinicians should consider expanding RAS analysis beyond KRAS exon 2, to exons 2, 3, 4, and then NRAS, to optimize the use of EGFR inhibitors in patients with mCRC, said Bekaii-Saab.

Given the level of added benefit seen across several studies, extended RAS testing should become mandatory, believes Grothey. Despite this need, some community oncologists still do not have capacity to run extended testing, particularly since insurers and payers do not require it as part of the prescreening process, noted Bekaii-Saab.

Al B. Benson III, MD, added that patients want to understand the continuum of their care and what their options will be over time.

“Currently, you can’t adequately do that unless you know the RAS testing results. One reason this is now an NCCN guideline that’s heavily emphasized is that if we are going to maximize benefit, and importantly, patient selection—whether you’re going to give anti-EGFR first line, second line, third line&mdash;it is a continuum. Your goal should be to offer your patient options over time as much as possible. And, when we do this, we’re seeing a profound effect on outcome.” Charles D. Blanke, MD, believes the oncology community did not move quickly enough to consider the original RAS wild-type data in managing patients.

In addition, he noted that the discussion about RAS testing applies not only to cetuximab but also to panitumumab (Vectibix), an EGFR antagonist that is indicated for the treatment of wild-type KRAS mCRC.

Amid the discussion of molecular testing and targeted therapies, several Peer Exchange panelists noted that treatment renders some patients suitable for curative surgery, and that clinicians should keep this option in mind. In additional analysis of 80405 presented at the 2014 ESMO Congress in September,

 more patients who had been treated with cetuximab were able to achieve NED (no evidence of disease) status with surgery. Although these results were not available when the Peer Exchange roundtable took place, the potential for surgery was among the topics of discussion.

The possibility for some of these patients to go on to surgery goes back to continuum of care and guidelines, noted Benson. “We should be looking for these individuals in our trials. When an oncologist first sees a patient, it may not be clear whether they’re resectable. They may be very reluctant to go right to surgery. You want to see whether the tumor is chemosensitive.

This just adds to the importance of looking for a subset of patients who can enjoy really impressive survival.”

The 80405 protocol mandated that investigators designate whether treatment was curative or palliative. An initial surgical consult was included and many patients had a second surgical opinion at first disease assessment. “It’s not clear whether this made the difference,” said Venook. “It’s very unusual to see, across many centers, that patients were considered for things that many wouldn’t have done before.”

Blanke added, “If all we did was raise awareness, it would be good enough. I still see patients coming to me who had failed first-line therapy with a solitary progressing liver metastasis and the consideration of surgery is not even raised.”

Future analysis of 80405 will continue to inform practice for years to come, the panelists suggested. CRC is poised on the edge of an explosion of biologically derived therapies, believes Blanke. The next step will be to further personalize care.

			Venook AP, Niedzwiecki D, Lenz HJ, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s (suppl; abstr LBA3).

			Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial [published online July 31, 2014]. Lancet Oncol. 2014;15(10):1065-1075.

			Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/ NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as firstline treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract LBA17.

			Venook A, Niedzwiecki D, Lenz H, et al. CALGB/SWOG 80405: Analysis of patients undergoing surgery as part of treatment strategy. Presented at: ESMO Congress 2014; September 26-30, 2014. Abstract LBA10.

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Confusion persists about the best choice of frontline therapy for patients with metastatic colorectal cancer (mCRC) after a landmark clinical trial that was conceived a decade ago to answer that question concluded without a superiority finding

Lauren Zoeller

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