Evidence Is Changing Colorectal Cancer Treatment Landscape

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Key colorectal cancer studies presented at this year’s ASCO Annual Meeting are changing the treatment landscape in this disease, according to Michael Overman, MD, of The University of Texas MD Anderson Cancer Center, who reviewed the data at the Best of ASCO San Diego meeting. The mix included several studies of targeted agents likely to expand options for metastatic disease. It also included promising studies on prognostic markers in stage II/III disease, and a disappointing one on managing colorectal cancer liver metastases.

Bevacizumab Continued Beyond Progression

The randomized phase III TML study assessed continuation of bevacizumab (Avastin)—an inhibitor of vascular endothelial growth factor (VEGF)—with new, second-line chemotherapy beyond first progression in 814 patients with metastatic colorectal cancer.1 Patients who continued bevacizumab had better progression-free survival (5.7 vs 4.1 months, HR = 0.67, P < .0001) and overall survival (11.2 vs 9.8 months, HR = .83, P = .0211). Adverse events were not increased with continuation.

“I do think that the FDA will likely have a label change for bevacizumab based on these data,” Dr. Overman predicted. “At present, the label says that bevacizumab is approved for first- or second-line treatment.… I think this will probably change, and it will be first- and second-line use going forward.”

Novel Targeted Agents Present Mixed Picture

The randomized phase III VELOUR trial tested addition of ziv-aflibercept (Zaltrap)—a fusion protein just approved by the FDA that binds VEGF-A, VEGF-B, and placental growth factor—to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) in 1,226 patients with metastatic colorectal cancer after failure of an oxaliplatin regimen.2 The investigators found improved overall survival with aflibercept vs placebo (13.5 vs 12.1 months, HR = 0.82, P = .003).

Only 28% of patients had previously received bevacizumab. “Though similar efficacy was seen in that subgroup, the study was not powered to answer that question within this subgroup,” Dr. Overman commented. Some chemotherapy-related adverse events were increased with added aflibercept.

“With the caveats of a cross-trial comparison, my sense is that aflibercept activity is similar to bevacizumab, but I do think the toxicities are more pronounced,” he said. “My question would be, what is the role of aflibercept in clinical practice? With the TML data, I think it’s uncertain. Clearly the TML findings actually apply better to the population that we see here—the majority of the patients in the front line receive bevacizumab in the United States.”

The phase III CORRECT trial randomly assigned 760 patients with progressive metastatic colorectal cancer despite standard therapy (including bevacizumab) 1:2 to placebo or regorafenib—an oral tyrosine kinase inhibitor with VEGFR2 and other targets.3 Regorafenib yielded better median progression-free survival (1.9 vs 1.7 months, HR = 0.49, P < .000001) and overall survival (6.4 vs 5.0 months, HR = 0.77, P = .005) (see sidebar, “Progression-free Survival Curve for Regorafenib Hints at Subgroup Effect”).

However, the response rate was merely 1%, Dr. Overman noted. “This agent does not give you responses. If you have a patient who has symptomatic pain from a metastatic site, you should palliate that prior to giving regorafenib.”

Progression-free survival was similar across subgroups. Certain adverse events were more common with regorafenib, but health-related quality of life did not differ.

“I think this will become a new standard of care for chemorefractory metastatic colorectal cancer,” he predicted. “It has not been approved at present, though it is undergoing FDA review.”

The phase III X-PECT trial randomly assigned 468 patients with refractory metastatic disease to placebo or perifosine—which inhibits the PI3K-Akt/PKB pathway and interrupts signal transduction at the cell membrane—each combined with capecitabine (Xeloda).4

The investigators found no significant improvement in progression-free survival or overall survival, which Dr. Overman speculated was related to issues arising in the transition from the earlier phase II trial to the phase III trial.

Summing up, he said, “I think we will be having new indications and drugs come into play. The benefits are modest,” at about 1.5 months’ gain in overall survival, “though real. These benefits are probably going to be very expensive.… We desperately need biomarkers to guide optimal use of these agents.”

Adding Erlotinib to Maintenance

The randomized phase III DREAM (OPTIMOX3) trial tested bevacizumab with vs without erlotinib (Tarceva)—an epidermal growth factor receptor (EGFR) inhibitor—as maintenance therapy after bevacizumab-containing first-line chemotherapy in 446 patients with metastatic colorectal cancer.5 Addition of erlotinib improved progression-free survival (5.75 vs 4.57 months, HR = 0.73, P = .005).

 However, “for practice, I don’t think [this trial] is applicable,” Dr. Overman commented. “It’s thought-provoking and interesting and surprising,” given previous studies. “But there are a lot of unanswered questions here.” For example, there was no KRAS mutation analysis, and some previous studies have found that combined VEGFR and EGFR inhibition, at least with chemotherapy, is harmful.

“The maintenance arm was nonstandardized—fluoropyrimidines are the standard maintenance therapy for colorectal cancer,” Dr. Overman added. “I do not believe this study changes that in any regard.”

Perioperative Chemotherapy for Liver Metastases

Investigators reported long-term survival results in the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial, which evaluated perioperative chemotherapy for liver metastases of colorectal cancer.6 A total of 364 patients with up to four potentially resectable liver metastases were randomly assigned to surgery or to FOLFOX4 (leucovorin, 5-FU, oxaliplatin), surgery, and more FOLFOX4.

Previously reported results showed better progression-free survival with chemotherapy (35% vs 28%, HR = 0.79, P = .058). But updated results, after a median follow-up of 8.5 years, showed no significant difference in overall survival.

“This is kind of a sobering study. What it means for us is that we are going to have to go back and really rethink what we are doing here a little bit,” Dr. Overman commented. “I think the benefit of perioperative chemotherapy in colorectal cancer liver metastases is less than perceived.”

New Tools for Postresection Prognostication

In the first of a trio of validation studies, investigators validated the Oncotype DX colon cancer recurrence score in 892 patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial with stage II or III disease treated with adjuvant 5FU/leucovorin alone or with additional oxaliplatin.7 The score performed well at predicting 5-year recurrence risk across patients dually stratified by stage and treatment arm (P < .001).

“You get a relative benefit that appears fairly similar across the board, but as your risk [rises], you get more absolute benefit. So could you find some low-risk patients who don’t get much added benefit from oxaliplatin? In some sense that’s possible,” Dr. Overman commented. “I don’t think this is really ready for us to be using.… But it’s kind of an interesting concept.”

A second study validated the ColoPrint classifier in 227 patients with stage II colon cancer having T3 disease with microsatellite stability (see sidebar, “Is Microsatellite Instability Status Also Predictive in Stage II Disease?”).8 The 3-year recurrence-free survival was 92% in the low-risk group and 80% in the high-risk group (P = .02).

“This is the intermediate group, the one for which we have kind of a challenge as far as what to do,” Dr. Overman observed. “This was statistically significant—more so than any clinical variables—and a fairly nice separation…” But ColoPrint requires frozen tissue, and “it’s kind of challenging right now to have this done.”

“Oncotype DX and ColoPrint…have had nice validation done. And I think in context of other risk factors such as [microsatellite instability] and other kinds of classic high-risk factors, they can be used to help guide the discussion,” he said. “But they don’t trump all these other factors.”

A third study validated microRNA-21, which is associated with multiple oncogenic processes, in 520 patients with stage II colon cancer.9 Higher microRNA-21 in relation to nuclear density predicted poorer cancer-specific survival (HR = 1.41, P < .001). However, it was not as strong a predictor as T4 stage or perforation.

“It appears to be an independent new marker,” Dr. Overman said. “How’s it going to help us? I’m not quite sure it’s ready to be incorporated or used right now … though it is interesting and novel in that it is a micro RNA.” ■

Disclosure: Dr. Overman has received research support from Amgen, Roche, and Bristol-Myers Squibb; and is on the advisory board and lectures for Sanofi-Aventis and Roche.


1. Arnold D, Andre T, Bennouna J, et al: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). 2012 ASCO Annual Meeting. Abstract CRA3503. Presented June 3, 2012.

2. Allegra CJ, Lakomy R, Tabernero J, et al: Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. 2012 ASCO Annual Meeting. Abstract 3505. Presented June 3, 2012.

3. Van Cutsem E, Sobrero AF, Siena S, et al: Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). 2012 ASCO Annual Meeting. Abstract 3502. Presented June 3, 2012.

4. Bendell JC, Ervin TJ, Senzer NN, et al: Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). 2012 ASCO Annual Meeting. Abstract LBA3501. Presented June 3, 2012.

5. Tournigand C, Samson B, Scheithauer W, et al: Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. 2012 ASCO Annual Meeting. Abstract LBA3500. Presented June 3, 2012.

6. Nordlinger B, Sorbye H, Glimelius B, et al: EORTC liver metastases intergroup randomized phase III study 40983: long-term survival results. 2012 ASCO Annual Meeting. Abstract 3508. Presented June 3, 2012.

7. O’Connell M, Lee M, Lopatin M, et al: Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox). 2012 ASCO Annual Meeting. Abstract 3512. Presented June 1, 2012.

8. Salazar R, Tabernero J, Moreno V, et al: Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients. 2012 ASCO Annual Meeting. Abstract 3510. Presented June 1, 2012.

9. Kjaer-Frifeldt S, Hansen T, Nielsen BS, et al: The prognostic importance of miRNA-21 in stage II colon cancer: a population-based study. 2012 ASCO Annual Meeting. Abstract 3513. Presented June 1, 2012.

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