Exploring Benefits of Multitargeted Therapy for Metastatic Colorectal Cancer and Gastrointestinal Stromal Tumours

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PRIORITY PRESS - 37th European Society of Medical Oncology Congress (ESMO)

Vienna, Austria / September 28 – October 2, 2012

Vienna - Progress continues to occur in the treatment of metastatic colorectal cancer. Improved recognition of the complexities of tumour signalling networks have led to the realization that inhibition of a single pathway is unlikely to achieve tumour control. Studies reported at ESMO support the hypothesis that multitargeted systemic agents will lead to better outcomes by blocking more of the pathways that allow tumours to evade treatment.

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

A large volume of laboratory and clinical evidence has demonstrated that genetic mutations ingrain tumours with adaptive capabilities related to proliferative signalling, angiogenesis, evasion of growth suppressors, invasion, metastasis, replicative immortality and resistance to cell death.

The multiplicity of adaptive resistance options in metastatic colorectal cancer (mCRC) poses a great therapeutic challenge according to Dr. Heinz-Josef Lenz, University of Southern California, Los Angeles. To succeed with treatment we must “block many exits in order to impact the traffic on the signal transduction network in colon cancer cells.”

Key Findings

Updated results of the CORRECT trial presented at ESMO revealed some of the potential benefits of multitargeted signal inhibition in mCRC. It demonstrated a sustained survival benefit for regorafenib in patients with heavily pretreated mCRC.

In typifying the multikinase inhibitor, Dr. Lenz explained that it has activity against RET, murine VEGF receptor 2, KIT, VEGF receptor 1, PDGF receptor beta, B-RAF, and, to a lesser extent, FGF receptor 1 among others. Collectively, the multiple targets of regorafenib are involved in proliferation, signalling in the tumour microenvironment and neo-angiogenesis.

The first preplanned interim analysis, reported in January at the ASCO GI meeting, showed a median overall survival (OS) of 6.4 months for regorafenib vs. 5 months for placebo (P<0.0052), leading to early termination of the study. The updated analysis confirmed the survival benefit, as the median OS remained at 6.4 and 5.0 months respectively, representing a 21% difference in the mortality hazard (HR 0.79, P=0.0038).

The initial results showed that this agent was generally well tolerated and the analysis revealed no new or unusual adverse events. “Regorafenib is the first oral multitargeted tyrosine kinase inhibitor (TKI) with proven activity in mCRC, improving OS in patients who progress on standard therapies,” stated Prof. Eric Van Cutsem, University Hospitals Gasthuisberg, Leuven, Belgium. “The benefit is sustained over time, with manageable side effects. Regorafenib represents a new potential standard of care for patients with chemo-refractory metastatic disease.” The survival benefit was consistent across all subgroups, he added.

The most common treatment-emergent adverse events (AEs) of the multitargeted TKI arm, for all grades and grade 3, respectively, were hand-foot syndrome (46.6%, 16.6%), fatigue (47.4%, 9.2%), hypertension (27.8%, 7.2%), diarrhea (33.8%, 7.0%) and rash or skin desquamation (26%, 5.8%).

Prof. Van Cutsem emphasized that many patients with mCRC fail standard treatments, and in this setting, there has been no salvage therapy available. Patients in this trial had good performance status despite disease progression.

Another finding of interest is the improved survival beyond progression in mCRC with continuation of the VEGF inhibitor bevacizumab. In this phase III trial, 184 patients with unresectable mCRC were randomized to second-line chemotherapy (CT) (FOLFOX or FOLFIRI) alone or with bevacizumab 5 mg/kg q2 weeks (Masi et al. Abstract LBA17).

After a median follow up of 18 months, median PFS was 4.97 months for CT alone and 6.77 months for those on added bevacizumab (HR=0.65; 95% CI, 0.48-0.89; P=0.0062). Stratification factors, age and sex taken into account confirmed the increased PFS with bevacizumab (HR=0.70; 95% CI, 0.50-0.97; P=0.032). The OS data are still immature and the AE profile was consistent with previously reported data.

Discovering, Blocking More Pathways

A study involving a preclinical model suggested the existence of yet another adaptive mechanism by which CRC might acquire resistance to treatment. Activation of regulatory T-cells (Treg) may interfere with the immune system’s anti-tumour response. In vitro studies have shown that VEGF-A directly induces Treg proliferation. Whether inhibition of VEGF or VEGF receptor has a role in preventing the interference has remained unclear, according to Dr. Magali Terme, Hôpital Européen Georges-Pompidou, Paris, France.

In mice bearing experimental colorectal tumours, sunitinib (a multikinase inhibitor whose targets include VEGF receptor) and the anti-VEGF-A monoclonal antibody bevacizumab decreased Treg accumulation in mouse spleens and tumours, but masitinib (a kinase inhibitor not targeting VEGF receptors) did not.

In the peripheral blood of patients with mCRC compared with blood samples obtained from healthy volunteers, investigators found increased Treg proportion. Blood from patients treated with CT plus bevacizumab did not exhibit increased Treg proliferation, whereas samples from patients treated with CT alone continued to have enhanced Treg accumulation. “We identified a new mechanism by which VEGF-A induced by the tumour could stimulate Treg proliferation,” noted Dr. Terme. “Targeting VEGF-A or VEGF receptor is sufficient to inhibit Treg accumulation in both a mouse model of CRC and in patients with mCRC.”

Progress in GIST

Gastrointestinal stromal tumour (GIST) might also benefit from multitargeted therapy. The most common subtype of sarcoma, GIST has mutant kinase drivers in >90% of cases, stated Dr. George Demetri, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

At diagnosis, a patient with GIST has only one detectable mutation. Different patients harbour different mutations in KIT or PDGFRA. However, the tumours become addicted to signals from the mutant kinases and cannot survive without the signalling.

Treatment with the TKI imatinib has led to a 300% improvement in OS among patients with metastatic GIST. Some patients have rapid and dramatic responses to kinase inhibition, observed Dr. Demetri, who showed images of a patient whose formerly large, multicentric tumour had mostly disappeared after a month of imatinib therapy.

Different mutations exhibit differential behaviour, leading to variable failure rates with imatinib. For example, patients harbouring KIT mutant exon 11 have better survival compared to those with KIT mutant exon 9, but both confer a more favourable prognosis than does wild-type GIST. Currently, no therapeutic standard exists for patients whose disease progresses on imatinib and sunitinib.

Data from the GRID trial presented at ESMO reinforced previously reported evidence suggesting that regorafenib might help in patients who have progressive or refractory GIST. The study included 199 patients with GIST that had progressed on both imatinib and sunitinib. They were randomized 2:1 to regorafenib or placebo, and the primary end point was progression-free survival (PFS), reported Dr. Peter Reichardt, HELIOS Klinikum Bad Saarow, Germany.

Treatment with the novel TKI was associated with a median PFS of 4.8 months compared with 0.9 month for placebo-treated patients, confirming results originally reported earlier this year at the ASCO GI meeting. Dr. Reichardt also presented data from an analysis of patients who crossed over from the placebo group to regorafenib, as well as for a subgroup of patients who continued treatment with it after the randomized phase of the trial ended. The 56 patients who crossed over to regorafenib had a median PFS of 5.0 months and those originally allocated to the multitargeted TKI gained an additional median 4.5 months of freedom from progression.

“Post-progression, open-label regorafenib treatment showed sustained benefit,” Dr. Reichardt told delegates. “This suggests that continuous kinase inhibition after progression may benefit patients by slowing tumour progression.”

Pruritus Management

Pruritus is a common AE of TKI and anti-EGFR therapies, and although not serious, the associated itching can adversely affect patient quality of life.

Santini et al. suggested that the antiemetic aprepitant has efficacy for reducing treatment-emergent pruritus in patients receiving anti-EGFR or TKI therapy (Abstract 1550PD). The study involved 45 patients with solid tumours (mostly lung and CRC, among others) and itching associated with therapy. The group included 24 patients whose pruritus had proven refractory to treatment.

Investigators treated patients with aprepitant, following a schedule of 125 mg on day 1, 80 mg on day 3 and 80 mg on day 5. The refractory subgroup had a median baseline pruritus intensity of 8 on a 10-point visual analog scale (VAS). After 1 week of treatment, the median score had declined to 1 (P<0.0001).

In 21 patients who received aprepitant as initial therapy for pruritus, the median VAS score declined from 8 at baseline to 0 after a week of treatment. Overall, 41 of the 45 patients had a clinical response, defined as >50% reduction in pruritus score from baseline. The response was maintained without recurrence in all but 6 patients.


Increased recognition of tumours complex system of adaptive mechanisms led researchers to therapeutic strategies involving agents that inhibit multiple pathways to control tumour growth and spread. Multitargeted agents have shown promise as a step in the right direction toward better treatment of mCRC and GIST. Though seemingly modest at times, the incremental progress provides a base for another step forward. 

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