Oncologist Kristen K. Ciombor, M.D., holds a wealth of experience in clinical investigation of therapies for metastatic colorectal cancer (CRC) and recently served as a co-author of the Society for Immunotherapy of Cancer guidelines for GI cancers.
Ciombor also helped lead the MOUNTAINEER study – which reported promising results for the now-FDA-approved combination of tucatinib plus trastuzumab for HER2-positive metastatic CRC.
Here, Discoveries in Medicine speaks with Ciombor about ongoing developments in using genetic biomarkers to help direct CRC treatment, including successes and prudent opportunities ahead.
Immunotherapy and MSI
Discoveries: Microsatellite instability (MSI) is a great predictive marker of success with immunotherapies. These agents have moved from the refractory setting into standard first-line therapy for metastatic MSI high CRC. What’s next for targeting this marker?
Ciombor: We’ve had exciting wins in this area over the past 10 years. Many patients with stage 4 metastatic MSI high colon cancer now receive immunotherapy in the first-line setting, and this can lead to a functional cure in some patients. We don’t typically think of this outcome with chemotherapy alone.
We’re now evaluating immunotherapies in earlier stage MSI high disease and, in general, we’re seeing that the earlier the disease stage, the better the patients respond. I’m leading a national trial evaluating whether combination immunotherapies in patients with MSI high stage 2 or 3 rectal cancer can allow them to avoid the standard treatments such as chemotherapy, radiation and surgery.
However, because MSI is a rare biomarker in CRC, found in about 5 percent of patients in the metastatic setting and 10 to 15 percent of earlier stage disease, the million-dollar question is how to apply immunotherapies to patients with microsatellite stable disease.
Discoveries: There’s a lot of ongoing research on this front. What are the most promising avenues?
Ciombor: There are some encouraging results from trials looking at the combination of a targeted agent with immunotherapy to make the tumors immunologically ‘hot,’ but, interestingly, it doesn’t work across the board. Patients with metastatic CRC but with no metastases to the liver appear to have more benefit from this approach.
The MOUNTAINEER Trials
Discoveries: The results from the MOUNTAINEER study have led to much optimism about better treating HER2-positive CRC. What work is ongoing to expand the reach of tucatinib plus trastuzumab within CRC?
Ciombor: The neat thing about that combination is it’s extremely well tolerated, with strong tumor shrinkage rates and a long duration of response – much longer than traditional chemotherapy. It’s such welcome news for patients who have had multiple lines of chemotherapy again and again, with nothing working.
The MOUNTAINEER-03 study is now looking at that combination with the chemotherapy backbone FOLFOX (5-fluorouracil and oxaliplatin) as a first-line treatment in patients with HER2-positive metastatic CRC, and this study will be open at Vanderbilt soon. We hope it improves survival for these patients.
Lessons Along the Way
Discoveries: While helping to lead trials for therapies that target genetic biomarkers, what are key lessons you’ve learned along the way?
Ciombor: One key lesson is that while you may have a place to start in learning from other cancers how to target an alteration, it’s not always a guarantee that one way to target is equivalent across cancer types. These adjustments seem to be particularly unique for colon cancer.
Take BRAF for example. Our melanoma colleagues have been studying and targeting BRAF for a long time and it’s now largely considered to be a tumor agnostic biomarker. Pairing a BRAF and MEK inhibitor is successful in melanoma, cholangiocarcinoma, and others. We tried the same in colon cancer and found that it didn’t work. We’ve having more success combining a BRAF and EGFR inhibitor.
“It’s not always a guarantee that one way to target is equivalent across cancer types.”
Similarly, in lung cancer, a KRAS G12C inhibitor as a monotherapy is effective. But in colon cancer, you need to inhibit not only KRAS but also EGFR.
There are different compensatory pathways in colon cancer, and in many GI cancers, and you must hit the pathways at different points.
Genetic Testing, Upfront
Discoveries: What do you view as being the biggest challenge ahead in biomarker selected therapies?
Ciombor: As a result of this great progress, there’s even more importance placed on getting molecular testing done when patients are first diagnosed.
We’re pursuing processes at Vanderbilt to streamline the use of that data for treatment and clinical trial matching. Genetic testing results are one of the first things that we look for because they can dramatically change what therapies patients receive and dramatically improve outcomes.
