A. Craig Lockhart, MD, MHS, professor and associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses dual-immunotherapy strategies in colorectal cancer (CRC).

Data have shown that combination immunotherapy could be successful in a subset of patients with CRC, says Lockhart. Microsatellite instability—high tumors are immunogenic, and combination therapy has been evaluated in these patients as a means to enhance response rates.

At the 2018 ESMO Congress, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a good overall response rate and progression-free survival benefit with manageable toxicity in treatment-naïve patients with metastatic MSI-H/mismatch repair-deficient tumors. Subsequent follow-up from the phase II CheckMate-142 trial showed a robust and durable clinical benefit in this patient population. Although the study was relatively small, the regimen could potentially be considered for use in the frontline setting, concludes Lockhart.

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Dr. Lockhart on Dual-Immunotherapy Strategies in CRC

A. Craig Lockhart, MD, MHS, professor and associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses investigational strategies targeting the RAS/RAF/MEK/ERK pathway in colorectal cancer (CRC).

While probably not true in biology, the RAS/RAF/MEK/ERK pathway appears to be vertical in schematic drawings, says Lockhart. Research has shown that blocking 1 part of the pathway can prompt an escape mechanism to develop in another part of the pathway. For example, if MEK is blocked, an escape mechanism could develop through ERK, explains Lockhart.

Therefore, investigators are trying to develop treatment strategies that block the pathway at multiple nodes. This strategy showed success in 

-mutant animal models when the combination of cetuximab (Erbitux) and vemurafenib (Zelboraf) was used, says Lockhart. Subsequently, those data were reproduced in human studies with the addition of irinotecan.

Additional studies are looking at targeting EGFR and MEK simultaneously; however, dual blockade of these pathways may result in overlapping toxicities, such as skin rashes and diarrhea, adds Lockhart. Although it will be challenging to develop lasting blockade strategies due to escape mechanisms and synergistic toxicity, it is a worthwhile area of research, concludes Lockhart.

Dr. Lockhart on Strategies for Targeting the RAS/RAF/MEK/ERK Pathway in CRC

A. Craig Lockhart, MD, MHS, professor, associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses next steps for regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) in metastatic colorectal cancer (mCRC).

Immunotherapy has generated a lot of excitement in oncology. As such, there is a lot of interest in investigating combinations with immunotherapy. There is also evidence indicating that TKIs could enhance the immune microenvironment, leading to enhanced responses. Combinations of the like with regorafenib and TAS-102 may have the same effect, says Lockhart.

In addition, the optimal sequence of these agents is under evaluation. For example, in the ongoing phase II REVERCE trial, patients with KRAS exon 2 wild-type mCRC will be randomized to receive sequential therapy with regorafenib followed by cetuximab (Erbitux) or the reverse sequence following standard chemotherapy, says Lockhart. Such studies will have to be supplemented with biomarker analysis before the paradigm changes, he concludes.

A. Craig Lockhart, MD, MHS

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Dr. Lockhart on Dual-Immunotherapy Strategies in CRC

Dr. Lockhart on Strategies for Targeting the RAS/RAF/MEK/ERK Pathway in CRC

Dr. Lockhart on Next Steps for Regorafenib and TAS-102 in mCRC