Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associated director for clinical research, at the University of Colorado Cancer Center, discusses where future research should focus in metastatic colorectal cancer (mCRC).

Patients with refractory mCRC are experiencing a significantly prolonged median overall survival due to the progress that has been made, says Lieu. However, the field has not hit the ceiling of therapeutic development, and many patients need better treatment options, he adds.

One of the major areas of research right now is immunotherapy. However, immunotherapy has not been shown to be effective for the 95% of patients with mCRC who are microsatellite stable (MSS) or mismatch repair (MMR)-proficient. Over time, more immunotherapies will be tested in clinical trials for this group of patients to see whether the benefit of immunotherapy can extend beyond those with microsatellite instability. Even if immunotherapy shows signals of activity in patients with MSS/MMR-proficient tumors, Lieu foresees the greatest impact being made among small biomarker-directed subgroups.

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Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associated director for clinical research, at the University of Colorado Cancer Center, discusses where future research should focus in metastatic colorectal cancer.

Dr. Lieu Discusses the Focus of Future Research in mCRC

Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associated director for clinical research, at the University of Colorado Cancer Center, discusses the rationale for combined MEK, VEGF, and PD-1 inhibition in microsatellite stable (MSS) colorectal cancer (CRC).

One of the main challenges in pursuing immunotherapy in MSS CRC is that immune cells are not close to the tumor or inside the tumor, says Lieu. Therefore, a lot of work has gone into figuring out how to bring immune cells to the tumor.

An emerging strategy is to use 2 targeted therapies—binimetinib (Mektovi) and bevacizumab (Avastin)&mdash;to bring more immune cells to the tumor. The addition of a PD-1 inhibitor may further increase this activity, leading to synergistic antitumor activity, explains Lieu. Right now, the MEK inhibitor binimetinib, is being tested in combination with the VEGF inhibitor bevacizumab, and the PD-1 inhibitor pembrolizumab. The safety lead-in of the trial has already been completed and has shown some promising results. Now, the regimen is being moved to a phase II trial, concludes Lieu.

Dr. Lieu Discusses the Rationale for Combined MEK/VEGF/PD-1 Inhibition in CRC

Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associate director for clinical research, at the University of Colorado Cancer Center, discusses the predictive value of 

 V600E mutations in metastatic colorectal cancer (mCRC).

 V600E mutations comprise approximately 5% to 10% of the population with mCRC. This mutation is associated with a poor prognosis due to the aggressive biology of the disease and lack of effective therapies. Historically, some patients with this mutation have an overall survival (OS) that is about one-third of what is normally expected.

However, results from a safety lead-in of the BEACON study were recently published in the 

. The study looked at the combination of a MEK inhibitor, a BRAF inhibitor, and an EGFR inhibitor: binimetinib (Mektovi), encorafenib (Braftovi), and cetuximab (Erbitux). Investigators noted a response rate of approximately 48%.

Based on these results, investigators launched the phase III study, where patients were randomized to receive the triplet versus standard chemotherapy and an EGFR inhibitor. Data from the trial, which were presented at the 2019 World Congress on Gastrointestinal Cancers, showed a significant improvement in OS with the triplet versus cetuximab and an irinotecan-containing regimen.

The regimen is currently listed in the National Comprehensive Cancer Network (NCCN) guidelines. It's important that providers test for this mutation and that they know that not only is it prognostic, but it could also be predictive of benefit from this treatment, concludes Lieu.

Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associate director for clinical research, at the University of Colorado Cancer Center, discusses the predictive value of BRAF V600E mutations in metastatic colorectal cancer (mCRC).

Dr. Lieu on the Predictive Value of BRAF V600E Mutations in mCRC

Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associate director for clinical research, at the University of Colorado Cancer Center, discusses investigational immunotherapy strategies in metastatic colorectal cancer (mCRC).

The phase III IMblaze370 trial tested the combination of the MEK inhibitor cobimetinib (Cotellic) and the PD-L1 inhibitor atezolizumab (Tecentriq), versus atezolizumab alone or regorafenib (Stivarga) alone in the third-line setting. However, the trial was negative; there was no arm that did statistically significantly better than the others, says Lieu. Notably, the combination of cobimetinib and atezolizumab was not shown to be superior to regorafenib, which is the current standard of care.

An ongoing phase II trial at the University of Colorado is testing a similar strategy with MEK and PD-1 inhibition. In the trial, investigators are looking at the combination of the MEK inhibitor binimetinib (Mektovi), the VEGF inhibitor bevacizumab (Avastin), and the PD-1 inhibitor pembrolizumab (Keytruda) in patients with microsatellite stable CRC. Because this trial is still accruing, investigators will have to wait some time before the results are revealed.

Dr. Lieu on Investigational Immunotherapy Strategies in mCRC

Christopher Lieu, MD, director, GI Medical Oncology Program and deputy associated director for clinical research, at the University of Colorado Cancer Center, discusses HER2-directed therapy for patients with colorectal cancer (CRC).

HER2 is a gene that is well-known in breast cancer, for which there are many targeted therapies on the market. Additionally, there are data with this gene in gastric cancer that is now starting to be collected in CRC, says Lieu. However, the use of HER2-directed therapy for patients with 

-amplified CRC is still in early stages of research. Early data suggest that patients who have 

-amplified CRC may not receive any benefit from anti-EGFR therapy. Therefore, there are ongoing studies looking at the addition of anti-HER2 therapy in patients with refractory metastatic CRC (mCRC).

Specifically, the ongoing SWOG 1613 trial is looking at the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) in patients who had previously received treatment for 

-amplified mCRC. It is important that providers are aware that such a clinical trial is available, says Lieu. Notably, the trial does allow patients to crossover, therefore patients will have the opportunity to be exposed to the experimental treatment.

Christopher Lieu, MD

Articles

Dr. Lieu Discusses the Focus of Future Research in mCRC

Dr. Lieu Discusses the Rationale for Combined MEK/VEGF/PD-1 Inhibition in CRC

Dr. Lieu on the Predictive Value of BRAF V600E Mutations in mCRC

Dr. Lieu on Investigational Immunotherapy Strategies in mCRC

Dr. Lieu on HER2-Directed Therapy in CRC