Despite the many obstacles associated with treating and managing patients with metastatic colorectal cancer, the ongoing study of several novel agents has the potential to significantly improve the outcomes of these patients in the coming years. In this interview, Tanios Bekaii-Saab, MD, Professor of Medicine at the Mayo Clinic Cancer Center in Phoenix, Arizona, discusses strategies to optimize the management of metastatic colorectal cancer and the promising developments which may advance treatment of this disease in the future.
What are some of the most significant challenges of managing patients with metastatic colorectal cancer?
Tanios Bekaii-Saab, MD: One of the most significant challenges of managing patients with metastatic colorectal cancer is figuring out exactly what type of therapy we want to use first. As an example, we've seen some emerging data with microsatellite instability (MSI)–high colorectal cancer that seems to indicate that chemotherapy may not have much utility in about 30%-40% of patients. It suggests that those patients would do well, and could even have the equivalent of a cure, with pembrolizumab. Unfortunately, about 60% of patients, despite their MSI-high status, still do not appear to respond well to immunotherapy and experience challenges with chemotherapy.
Another challenge is the accumulation of toxicities with chemotherapy, specifically the neuropathy associated with oxaliplatin and the fatigue associated with irinotecan. Frankly, since patients are living longer overall, they're spending most of their lives on chemotherapy. Our understanding of where to establish a line for maintenance therapy has become clearer and clearer. We have published some data, and others have as well, suggesting that after three to four months of intensive chemotherapy, patients should go on maintenance therapy more simplified with oral cytarabine, with or without bevacizumab. We can do that only for select patients, because the data did not show a survival benefit versus taking a complete break from treatment.
The last challenge, and the most important one, is that 90%-95% of patients with colorectal cancer in the metastatic setting will die from their disease. The good news is that we're beginning to lower that percentage a little with patients who are potentially curable. It is key to identify the patients who may be amenable to resection because of oligometastatic or isolated metastatic disease, as they may be in the pool of potentially curable patients in the metastatic setting. All of these challenges are important, but I think we're starting to see a little bit clearer.
Do you have any advice for utilizing biomarkers to personalize treatment strategies for patients with metastatic colorectal cancer?
Dr. Bekaii-Saab: I think that every patient with metastatic colorectal cancer should, from Day 1 at the time of diagnosis, undergo biomarker testing. My advice is that now that these tests are widely available in the United States, every patient should get a complete profiling with next-generation sequencing. We're looking for a number of markers. We're looking for RAS, we're looking for BRAF, and we're looking for human epidermal growth factor (HER2) amplification. Very importantly, we're looking at some uncommon targets like NTRK fusions, RET fusions, and a number of other markers. These are important because they help us strategize.
As I said, patients with MSI-high disease will go directly on pembrolizumab but will skip chemotherapy; 40% of them will never see chemotherapy. With NTRK fusions, you can prepare for entrectinib or larotrectinib. For RET fusions, we now have agents that are available and showing remarkable responses. For HER2 amplification, we understand that those patients will have exposure to HER2-targeted therapy at some point in their journey, but HER2 amplification also tells us that patients are unlikely to respond to epidermal growth factor receptor (EGFR) inhibitors, so that excludes EGFR inhibitors for them. Having a RAS mutation also excludes EGFR inhibitors. For BRAF V600 and V600E mutations, there are agents specifically targeting these that are now part of our armamentarium. We're seeing G12C emerging as a target, with G12D following that. There's a lot going on in the biomarker setting, and it's very important to have this information from Day 1.
Is there any role for immune checkpoint inhibitors in the adjuvant setting?
Dr. Bekaii-Saab: There is currently no role for immune checkpoint inhibitors in the adjuvant setting. There is one study ongoing in the United States and soon in Germany, as well. The ATOMIC trial is assessing the role of atezolizumab in combination with chemotherapy in patients with stage III MSI-high disease. This study is ongoing, so we'll see where that goes. Beyond that study, though, combination chemotherapy remains the standard of care for high-risk MSI-high patients in the adjuvant setting. Overall, at this point in time, immune checkpoint inhibitors do not have a role in the adjuvant setting.
Do you have any advice for the optimal sequencing of treatment for patients with metastatic colorectal cancer?
Dr. Bekaii-Saab: We currently have so many options, and the data continue to suggest that the more our patients are exposed to multiple lines of therapy, the higher their likelihood is of surviving longer. It's important from Day 1 to think about sequencing and to ensure that patients are exposed to all active agents in order to optimize their survival. The decision of when to start chemotherapy, when to skip chemotherapy, and when to move on to a biologic agent depends on the biologic agents that are available to us and on the presence of targets or the absence thereof. This decision has become an integral part of how we optimize our treatment sequencing options in metastatic colorectal cancer, as well as how we integrate these agents into the treatment continuum.
Of the agents that are currently in clinical trials for metastatic colorectal cancer, which do you think are the most promising?
Dr. Bekaii-Saab: There are a lot of promising agents. I think the ones that are the closest to reaching the clinic are the HER2-targeted strategies. The MOUNTAINEER trial is investigating tucatinib plus with trastuzumab, a combination which is already used in breast cancer. It is on track to be reporting out hopefully sometime next year and may become a valid option for our patients with HER2-amplified tumors. Another agent is trastuzumab deruxtecan, which is approved in both gastric and breast cancers for HER2-amplified tumors. It could be a great fit beyond trastuzumab/tucatinib for patients with HER2-amplified colorectal cancer, as well.
The DESTINY-CRC02 trial has shown promise in this space, including in patients pre-exposed to HER2-targeted agents, so we're going to have quite a bit of activity in the HER2 setting. For BRAF V600E mutations, we've already established the value of encorafenib and cetuximab or panitumumab in refractory patients. The BREAKWATER study is essentially looking at the value of bringing this combination, plus or minus chemotherapy, to the first line. We already have pembrolizumab for MSI-high disease in the first-line setting, and there are studies looking at further amplifying the benefit from single-agent immunotherapy by doubling up on the immunotherapy or further. There's also quite a bit of activity in the microsatellite-stable space, although nothing has panned out so far.
Then there are a number of other agents in development: those targeting KRAS G12, G12C, G12D (which is coming down the pipeline), and others, as well. That's only the tip of the iceberg. A number of other promising agents are being developed as we speak. There's a lot of activity there, and the future continues to look bright for metastatic colorectal cancer.
About Dr. Bekaii-Saab
Tanios S. Bekaii-Saab, MD, is a Professor at the Mayo College of Medicine and Science. He is also the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center. Dr. Bekaii-Saab is the Vice Chair and Section Chief for Medical Oncology in the Department of Internal Medicine and the Medical Director of the Cancer Clinical Research Office at the Mayo Clinic. He specializes in the treatment of gastrointestinal cancers, including liver, pancreatic, esophageal, gallbladder, and colorectal cancers. His research focuses on the development of novel therapeutics and the utilization of personalized targeted strategies for patients with gastrointestinal cancers.
For More Information
Clinicaltrials.gov (2021). Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. NLM identifier: NCT03043313.