Reports

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PRIORITY PRESS - 48th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2012

Chicago - New data extend the period in which inhibition of angiogenesis improves control of metastatic colorectal cancer (mCRC). The latest in a series of studies have indicated therapies targeted at tumour growth signalling, including the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways, produce meaningful improvements in outcome without substantially diminishing quality of life. The studies are significant because they bring mCRC closer to the concept of a chronic rather than terminal disease that may eventually be controlled indefinitely. In some of the most recent clinical trials, most patients with mCRC, who once had a median survival measured in months, are now achieving a median survival >2 years.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Several large trials presented here at ASCO 2012 delivered new milestones in the outcome of mCRC attributed to targeted therapies. In the phase III TML trial, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab produced a significant improvement in overall survival (OS) when continued past first progression into second-line therapy. In the DREAM trial, presented as a late-breaker, the addition of erlotinib, a tyrosine kinase inhibitor (TKI) associated with epidermal growth factor receptor (EGFR), was found to significantly improve progression-free survival (PFS) in unresectable mCRC patients already receiving chemotherapy plus bevacizumab. In the CORRECT trial, the oral multikinase inhibitor regorafenib demonstrated activity after all approved standard therapies had failed. All three studies have the potential to change current standards for care.

Referring to the results of the TML study, “The OS advantage makes this a very positive trial,” stated Dr. Alan P. Venook, University of California, San Francisco. In discussing these results, he suggested that a label revision to include an indication for use after first-line progression might be expected.

Persistent Activity in Second-line Therapy

In the TML trial, 820 patients with unresectable mCRC who progressed within 3 months after discontinuing a first-line oxaliplatin- or irinotecan-based chemotherapy were randomized to receive second-line chemotherapy with or without bevacizumab. In the second-line regimen, which was anchored with an agent not used previously, bevacizumab was administered in a dose of 2.6 mg/kg/week. The primary end point was OS. Secondary end points included PFS and safety. Most of the 220 participating treatment centres were in Europe.

The advantage of bevacizumab for the OS primary end point was significant with a hazard ratio (HR) of 0.81 (95% CI, 0.69-0.94; P=0.0062) in an unstratified analysis and HR 0.83 (0.71-0.97; P=0.0211) in a stratified analysis. The absolute benefit of about 6 weeks (9.8 vs. 11.2 months) was called “both clinically and statistically significant” by the senior author, Dr. Dirk Arnold, Hubertus Wald Tumour Centre, Hamburg, Germany. The 33% relative advantage for PFS (HR 0.67; 95% CI, 0.58-0.78; P<0.0001), was almost exactly the same whether stratified or unstratified.

The safety and tolerability of bevacizumab in second-line therapy was on the same order previously reported in first-line therapy. While the proportion of patients with grade ≥3 adverse events (AEs) were slightly greater in the VEGF inhibitor group (64% vs. 58%), the rate of serious AEs was slightly lower (32% vs. 34%). Treatment discontinuation for AEs was 16% in the bevacizumab group vs. 9% in the other group, but a survey of specific grade ≥3 side effects did not reveal substantial differences. The most common grade ≥3 AE in the bevacizumab-treated group was diarrhea, but at 10%, the incidence was only slightly greater than the 8% incidence in the other group.

The TML trial confirms the hypothesis that suppression of angiogenesis is effective for controlling tumour growth at both early and advanced stages of disease, according to Dr. Arnold, who said these results lay the foundation for a new model of treatment “that involves suppression of angiogenesis through multiple lines of chemotherapy to improve tumour control.”

Rationale for Double Inhibition of Pathways

In the DREAM study, the results were nearly as compelling even though an OS advantage has not yet been shown. In DREAM, 700 patients with previously untreated and unresectable mCRC were randomized to maintenance therapy with bevacizumab alone or added to the TKI erlotinib. All had received an induction therapy with FOLFOX, XELOX or FOLFIRI that included bevacizumab. PFS was the primary end point although OS was included among secondary end points. The trial included participating centres in France, Canada and Austria.

With a median follow-up of 31 months, the PFS was significantly improved (5.8 vs. 4.6 months) for a 27% relative improvement (HR 0.73; 95% CI, 0.59-0.91; P=0.005) in the VEGF/TKI arm. The PFS from the start of the induction regimen was also significantly increased (10.22 vs. 9.23 months; P=0.0045). It is notable that the median OS in both arms of this study now exceeds 2 years even though the OS data are not yet sufficiently mature to document a significant difference between treatment arms.

“The data provide a clinical rationale for double inhibition of pathways involved in tumour proliferation,” reported the senior author of the DREAM study, Dr. Christophe Tournigand, Hôpital Saint-Antoine, Paris, France. He noted that the evidence of crosstalk between the VEGF and EGFR pathways was the basis for conducting this study. Previous studies in mCRC combining bevacizumab with cetuximab, an extracellular inhibitor of EGFR, had found unacceptable levels of toxicity. In contrast, there were no significant differences in the rate of grade ≥3 AEs when the 2 arms in this study were compared.

“There was an increase in diarrhea and in skin rash, but these tended to be tolerable,” reported Dr. Tournigand, who noted that the number of cycles of chemotherapy delivered in patients in the 2 targeted therapy groups was comparable.

Synergy Proof of Concept

The ASCO invited discussant, Dr. Chris R. Garrett, M.D. Anderson Cancer Center, Houston, Texas, cautioned that a change in practice should await evidence of a survival benefit with the bevacizumab/erlotinib combination. However, he called these data “a proof of concept of synergy” from inhibiting different pathways of angiogenesis and tumour proliferation.

In the CORRECT trial, 760 mCRC patients with progression within 3 months of their last regimen and no longer considered good candidates for standard regimens were randomized in a 2:1 ratio to regorafenib 160 mg once-daily or best supportive care (BSC). Regorafenib was administered daily for 3 weeks out of a 4-week cycle. Relative to BSC, the improvements in both PFS (HR 0.49; 95% CI, 0.42-0.58; P<0.00001) and OS (HR 0.77; 95% CI, 0.64-0.94; P=0.0052) were both highly significant.

“Comparable OS and PFS benefits were observed in exploratory subgroup analyses by region, age, time from diagnosis of mCRC to randomization, prior lines of treatment and KRAS status,” reported first author, Dr. Eric Van Cutsem, University of Leuven, Belgium. He noted that the most common grade ≥3 side effect was hand-foot syndrome, providing this agent with a high degree of tolerability in a challenging population.

In the context of these benefits, a study from Canada provided some surprising evidence that anti-angiogenesis agents are not being prescribed uniformly when patients are stratified by age. In data collected on 800 patients and presented by Dr. Matthew Chan, who is in training at the University of British Columbia, only 22% of those ≥70 years vs. 50% of those younger (P<0.001) were receiving an anti-angiogenesis agent with first-line mCRC therapy as indicated by current standard of care practices. Yet, OS advantages and the tolerability of anti-angiogenesis therapy appear to be similar in younger and older patients.

“We looked at the reasons why patients did not receive a particular regimen and the reasons in both arms were pretty similar,” reported Dr. Chan, referring to comorbidities or patient preference. Yet with a survival benefit anticipated in both older and younger patients, there is a strong rationale for urging use of anti-angiogenesis agents, which are relatively well tolerated, in both groups.

Summary

New data support the premise that mCRC survival can be extended by chronic anti-angiogenesis therapy. The significant survival advantage observed when bevacizumab was included in a second-line regimen among mCRC patients who also received this agent first-line confirms persistent and meaningful protection against tumour growth. These results move treatment toward a model in which mCRC is managed as a chronic disease. A proof-of-concept benefit of targeting other pathways of proliferation, such as EGFR, at the same time as VEGF, was introduced by the DREAM study that showed at TKI could be added to an anti-VEGF drug to improve disease control with a low risk of significant AEs. The studies are consistent with a changing orientation in mCRC management.