All-RAS Testing in Metastatic Colorectal Cancer: Just the First Step

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Sebastian Stintzing, MD

Heinz-Josef Lenz, MD

Alan Venook, MD

The overall survival of more than 30 months in both arms [of CALGB/SWOG 80405] sets a new benchmark for patients with metastatic colorectal cancer, which was achieved across a broad clinical trials network and suggests that the results apply in a variety of practice settings.

—Heinz-Josef Lenz, MD

Now that clinicians know to “think beyond KRAS” in metastatic colorectal cancer—and test for all RAS mutations, not just those in exon 2—it seems this is still not sufficient for selecting the best drugs. At the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, a proffered paper session was devoted solely to discussing the efficacy of monoclonal antibodies in the first-line setting for patients with all-RAS wild-type colorectal cancer.

Updated or extended analyses of the FIRE-3 trial and Cancer and Leukemia Group B (CALGB)/SWOG 80405 provided food for thought and fodder for discussion. The two phase III trials compared treatment approaches for chemotherapy plus cetuximab (Erbitux), which targets the epidermal growth factor receptor (EGFR), or bevacizumab (Avastin), directed against the vascular endothelial growth factor (VEGF). Which strategy is optimal remains an unresolved issue.

Updated FIRE-3 All-RAS Analysis

While FIRE-3 demonstrated an overall survival gain with cetuximab added to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan), this was a secondary endpoint. RECIST response rate was the primary endpoint and was not different between the arms. Progression-free survival also did not differ between the two regimens.1

At the ESMO meeting, Sebastian Stintzing, MD, of the University of Munich in Germany, presented an independent radiologic review of the data. The study compared cetuximab and bevacizumab in combination with FOLFIRI in 592 patients with KRAS exon 2 wild-type colorectal cancer. Extended RAS analysis was performed on, and outcome data available for, 400 patients deemed to have all-RAS wild-type disease.2

“The independent [computed tomography (CT)] review demonstrated a significantly higher objective response rate in FOLFIRI-plus-cetuximab–treated patients, compared to those receiving FOLFIRI plus bevacizumab,” Dr. Stintzing reported. Response rates were 72.0% with cetuximab vs 56.1% with bevacizumab (P = .003).

FOLFIRI plus cetuximab also was associated with greater early tumor shrinkage, defined as ≥ 20% change in diameter on the first CT image (6 weeks): 68.2% vs 49.1% (P = .0005). In both treatment arms, overall survival was significantly longer in patients who obtained early tumor shrinkage.

Median depth of response (percentage of maximal tumor shrinkage at the nadir, compared to baseline) was 48.9% in the cetuximab arm and 32.3% in the bevacizumab arm (P < .0001), and this also correlated with survival, Dr. Stintzing reported.


In patients with surgically resected colorectal cancer who demonstrate no evidence of disease, disease-free survival can exceed 5 years, according to Alan Venook, MD, of the University of California, San Francisco, who presented a subset analysis of CALGB/SWOG 80405.3

He reported the outcomes of 180 patients who underwent resection with the potential of cure, following neoadjuvant chemotherapy with cetuximab or bevacizumab plus FOLFIRI or FOLFOX (leucovorin/5-FU/oxaliplatin), per physician’s choice.

Of these patients, 132 at some point after surgery were deemed as having no evidence of disease. The median overall survival for this selected population of patients was 65 months, “almost 5½ years,” Dr. Venook reported.

“It is key to note that of those rendered free of disease, 81 (60%) got cetuximab as their biologic and fewer got bevacizumab. Though we see their median overall survival is the same (67 months with bevacizumab and 64 months with cetuximab), more patients went on to potentially curative resection on cetuximab. The difference is not statistically significantly different, but numerically higher, and we don’t know why at this point,” he said.

“One thing this is not due to is response rate,” he continued. Investigator-assessed responses (not yet audited) were higher with cetuximab (66% vs 57%). “This is not surprising to us in the field, and is validated by FIRE-3,” he noted. The differences were only seen among patients treated with FOLFOX, which in accordance with North American practice included three-quarters of the patients.

Among the resected patients who achieved “no evidence of disease” status and were assessable, however, response rates were greater in the bevacizumab arm (82% vs 68%), though probably similar statistically, he said. Median disease-free survival for all resected patients was 16 months; median time to recurrence after randomization was 26 months and was similar for the two arms.

With the full RAS mutational analysis, the investigators observed that outcomes were much better when patients with all-RAS wild-type disease were rendered disease-free. For this group, median overall survival was 78 months, vs 48 months for patients with RAS ­mutations.

“Patients with mutations in KRAS or NRAS could still be rendered disease-free, but after that point, they did not do as well as the RAS wild-type patients,” Dr. Venook explained. “These differences are perhaps suggestive of a different biology,” he speculated.

“This subset of patients reaching [no evidence of disease] does well, and some do very well,” he concluded. “They appear more likely to reach [no evidence of disease] on cetuximab-containing regimens, but ultimately their outcomes are similar.”

From this dataset, the investigators will further characterize the tumors’ molecular profiles, exploring the depth of response, evaluating circulating tumor DNA, developing a model of curability, determining the prognostic impact of RAS mutations, and looking for differences between extreme responders and rapid ­progressors.

The answers are most likely to come, Dr. Venook suggested, by “combining, rather than contrasting, data sets across studies, including FIRE-3.”

Exploratory Analysis

Another analysis of CALGB/SWOG 80405 explored the treatment effect in patients with all-RAS wild-type colorectal cancer as determined by expanded RAS testing using BEAMing technology (beads, emulsion, amplification, magnetics). This sensitive test identifies mutant alleles with a prevalence ≥ 1% and can detect and enumerate mutant sequences down to a 1:10,000 ratio.

Outcomes were analyzed for 526 patients lacking any mutation in RAS and were presented at the ESMO meeting by Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.4

Using this highly accurate technology, the researchers found that 15% of patients originally identified as having KRAS wild-type disease had additional RAS mutations beyond exon 2. In the all-RAS wild-type sample, median progression-free survival was 11.3 months with bevacizumab/chemotherapy and 11.4 months with cetuximab/chemotherapy, and median overall survival was 31.2 and 32.0 months, respectively. As in the primary analysis,5 there was no significant advantage of one drug over the other in these comparisons.

“The overall survival of more than 30 months in both arms sets a new benchmark for patients with metastatic colorectal cancer, which was achieved across a broad clinical trials network and suggests that the results apply in a variety of practice settings,” Dr. Lenz said.

Commenting on this largest expanded RAS analysis with a head-to-head comparison in colon cancer, Dr. Lenz added, “First-line therapy should reflect the treatment goal and concern for potential side effects.”

He continued, “ With additional data such as dose intensity, treatment duration, location, tumor shrinkage, second-line therapies, and additional biomarkers for anti-EGFR and anti-VEGF therapies, we might better understand the differences between FIRE‑3 and CALGB/SWOG 80405.” ■

Disclosure: Dr. Stintzing has received honoraria from Amgen, Merck, Roche, Sanofi, and travel expenses from Amgen, Merck, Roche, and Sanofi. Dr. Venook has received research support from Genentech/Roche, BMS, Lilly, and Novartis. Dr. Lenz reported serving on the advisory boards of Genentech/Roche, MerckKG, EMD, and BMS.


1. 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. Lancet Oncol 15:1065-1075, 2014.

2. Stintzing S, Modest DP, Fischer von Weikersthal L, et al: Independent radiological evaluation of objective response rate, early tumor shrinkage, and depth of responses in FIRE-3 (AIO KRK-0306). ESMO Congress. Abstract LBA11. Presented September 29, 2014.

3. Venook A, Niedzwiecki D, Lenz H, et al: CALGB/SWOG 80405: Outcome of patients treated with curative intent. ESMO Congress. Abstract LBA10. Presented September 29, 2014.

4. Lenz H, Niedzwiecki D, Innocenti F, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FY/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with expanded ras analyses untreated metastatic adenocarcinoma of the colon or rectum. ESMO Congress. Abstract 501O. Presented September 29, 2014.

5. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014.

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