Finding Active Combinations Key to Advancing CRC Field, Expert Says

Hans-Joachim Schmoll, MD

Hans-Joachim Schmoll, MD

While the FDA approvals of the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) were significant developments in the field of colorectal cancer, the treatments are specifically indicated for those with microsatellite instability-high disease, which comprises 15% of patients. In an effort to move the treatment paradigm of metastatic colorectal cancer (mCRC) forward, investigators are currently exploring chemotherapy combinations, says Hans-Joachim Schmoll, MD.

Regarding chemotherapy, the final results and multivariate prognostic factor analysis of the phase II CHARTA study, which evaluated FOLFOX and bevacizumab (Avastin) with or without irinotecan, were presented at the 2017 ASCO Annual Meeting and 2017 World Congress on Gastrointestinal Cancer. The FOLFOX regimen has shown limited activity, prompting investigators to study it in combination with bevacizumab and irinotecan.

Results showed that FOLFOX plus irinotecan (FOLFOXIRI) and bevacizumab was superior to FOLFOX plus bevacizumab, which was previously demonstrated in the TRIBE study. In CHARTA, the progression-free survival (PFS) rate at 9 months was 56% versus 68% (P= .086) with FOLFOX plus bevacizumab versus FOLFOXIRI and bevacizumab, respectively. The median PFS was improved with the 4-drug combination at 12.0 months versus 9.8 months (HR, 0.7).

In an interview withTargeted Oncology, Schmoll, head of the Department of Oncology and Hematology, associate professor of internal medicine, at University Hospital Halle, discussed these updated CHARTA findings, the current role of chemotherapy in patients with metastatic CRC, and his predictions for the future CRC treatment landscape.

TARGETED ONCOLOGY:Could you provide a recap of the final results of the CHARTA trial?

Schmoll:CHARTA investigated the potential activity of a 4-drug regimen consisting of some standards in CRC management: FOLFOX plus bevacizumab with the addition of irinotecan. The question was, “Is it better in terms of response rate, PFS, and overall survival?” For that reason, we have treated 450 patients, and the primary endpoint of the study was improvement of the PFS at 9 months. The primary endpoint was met, meaning the PFS was increased at 9 months with the 4-drug regimen.

TARGETED ONCOLOGY:Has the role of chemotherapy evolved in any way in this landscape?

Schmoll:Chemotherapy is still there. We are now wondering how the chemotherapy triplet plus the VEGF inhibitor bevacizumab combination fare in relation to the cetuximab (Erbitux)- or EGFR inhibitor—based results. Based on our current knowledge of the 4-drug combination with bevacizumab, I would suggest that a patient with a RAS-wildtype and left-sided tumor, with liver or lung metastases, should probably undergo surgery to make long-term survival possible. Some patients should still [be treated with] the EGFR inhibitor, but you need to compare the data and see if you should just go for the FOLFIRI plus cetuximab, for example.

TARGETED ONCOLOGY:What is the biggest challenge in the treatment of patients with advanced CRC?

Schmoll:We need to have more active chemotherapies or targeted treatments—whatever it is, as long as it is active. We need more active combinations that can incite major responses in the majority of patients. Right now, we have a 60% to 70% response rate, but this is not enough. We need maximum responses to enable surgical resection of tumors, at least in those patients who have a specific biology—which is 50% of patients with liver or lung metastases.

Therefore, we must have more patients achieving major responses to follow-up with a residual tumor resection because these patients have a chance to be cured—not all, but at least a fraction of them. This means that all together, we need more active drug combinations and more intelligent ways of combining agents. Immunotherapy is only one part; the checkpoint inhibitors likely will work in some patients.

It is difficult in CRC, as there are not many good targets. HER2 is one of the targets. Currently, there is a screening study checking the value of the drugs in first-line setting. This is a way forward.

TARGETED ONCOLOGY:What else is taking place in the CRC field that is important to highlight?

Schmoll:At the moment, there are many interesting things in biology going on, which are demonstrating new ways to go forward. It is all very early and experimental, and there is nothing that can go into routine [practice] any time soon. If you compare the amount of information and new preclinical investigation with molecular data in CRC, it shows that we are really accelerating our understanding for the future.

Reference:

Schmoll HJ, Meinert FM, Cygon F, et al. CHARTA: FOLFOX/bevacizumab vs. FOLFOXIRI/bevacizumab in advanced colorectal cancer—Final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO.J Clin Oncol.2017;35(15):3533. doi: 10.1200/JCO.2017.35.15_suppl.3533.