Is Salvage Regorafenib or Enhanced Immunotherapy Optimal for Refractory Colon Cancer?

Andrea Cercek, MD, and Neil Segal, MD, PhD, both with Memorial Sloan Kettering Cancer Center (New York, NY), offered different stances on the optimal salvage therapy for refractory colon cancer at the Great Debates and Updates in Gastrointestinal Malignancies Meeting (March 23, 2018; New York, NY).

Dr Cercek began the debate by arguing that regorafenib and TAS-102 are the only approved agents for the treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Regorafenib—an oral multikinase inhibitor targeting multiple tumor pathways—was assessed in the CORRECT study (The Lancet; January 2013;381[9863]:303-312), in which patients with mCRC were treated with regorafenib or placebo after failure with standard therapy. Results of the study showed that patients receiving regorafenib benefited from improved overall survival (OS; 6.4 vs 5.0 months, respectively) and progression-free survival (PFS; 1.9 VS 1.7 months) compared with patients receiving placebo. Regorafenib was associated with frequent grade 3 adverse events (ie, skin reactions, fatigue, diarrhea, hypertension, and rash), Dr Cercek noted.

Dr Cercek also presented data from the global, randomized, phase III trial (RECOURSE), which showed that TAS-102 is associated with a significant improvement in PFS and OS in patients with mCRC previously treated with two or more prior regimens. Among the most frequently observed adverse events in patients receiving TAS-102 were neutropenia (38%) and leukopenia (21%).

Dr Cercek went on to explain that no trials involving immunotherapy in MSS mCRC have shown benefit, but the question of whether this treatment approach is harmful has yet to be determined. She referenced an article published in The New England Journal of Medicine (2013) titled, “PD-1 Blockade in Tumors With Mismatch-Repair Deficiency” that may suggest single-agent pembrolizumab may offer limited toxicity in patients with mismatch repair-proficient colorectal cancer. New strategies in this population will involve turning MSS tumors into immunogenic tumors, and to utilize combination approaches. The first potential immune-modifying combination for patients with MSS mCRC is atezolizumab plus cobimetinib, she noted.

In her concluding remarks, Dr Cercek asserted that MSS colorectal cancers are immune-void and non-responsive to anti-PD/L1 alone, and no current data support the use of immunotherapy in MSS mCRC outside of a clinical trial. Regorafenib and TAS-102 are the only FDA-approved therapies for OS benefit in this population.

Dr Segal was next to speak, and he took the side of enhanced immunotherapy as the optimal salvage therapy for refractory colon cancer. While regorafenib and TAS-102 have demonstrated survival benefits in these populations, he acknowledged, there are a few early-stage trials that indicate immunotherapeutic options may offer superior outcomes with less of a toxicity burden.

One such study (NCT01988896) is a phase Ib examination of atezolizumab plus cobimetinib in patients with locally advanced or metastatic solid tumors. In 23 patients receiving this combination regimen, the median PFS was 2.3 months and the 1-year OS was 61%. Additionally, grade 3/4 adverse events were significantly decreased for patients receiving the combination compared with those receiving regorafenib for the same disease (data for the latter patients presented in the CORRECT study).

Dr Segal also shared an ongoing trial (COTEZO IMblaze370), which is investigating efficacy and safety of cobimetinib plus atezolizumab and atezolizumab monotherapy vs regorafenib in patients with metastatic colorectal adenocarcinoma. Patients will receive treatment until disease progression or unacceptable toxicity. Researchers are hopeful that results of this trial will further support the use of immuno-agents in the salvage treatment of refractory colorectal cancer.

As his take home points, Dr Segal argued that enhanced immunotherapy is compelling, based on early phase trial data, and considering later line therapies. Further phase III data is pending for cobimetinib plus atezolizumab, he noted.—Zachary Bessette