John H. Strickler, MD, highlights key findings from the MOUNTAINEER trial and addresses the possibility of moving the combination up to the first line setting.
The accelerated approval of tucatinib (Tukysa) plus trastuzumab (Herceptin) by the FDA marks a transformation in the treatment paradigm for patients with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer (mCRC) that has progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.1
Data from the phase 2 MOUNTAINEER (NCT03043313) trial supported the approval, which showed that at a median follow-up of 20.7 months, the combination elicited an overall response rate (ORR) of 38% (95% CI, 28%-49%) in patients (n=84) with 3 patients achieving a complete response per blinded independent central review (BICR). The median duration of response (DOR) was 12.4 months (95% CI, 8.5-20.5). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.2-10.3) and median overall survival (OS) was 24.1 months (95% CI, 20.3-36.7).2,3
“This is an exciting breakthrough for patients in that we now have a regimen that’s well tolerated with high response rates where we’re seeing durable disease control,” John H. Strickler, MD, said. “This was largely tested in the third-line setting and later and certainly, with this approval, it will be a standard of care option.”
In an interview with OncologyLive®, Strickler, an associate professor of medicine at Duke Cancer Center in Durham, North Carolina, highlighted key findings from the MOUNTAINEER trial and addresses the possibility of moving the combination up to the first line setting.
It’s been known for many years that patients with HER2-positive, RAS wild-type mCRC benefit from anti-HER2 therapies. This has been part of our National Comprehensive Cancer Network guidelines for many years. But, to date, we’ve not had any FDA approvals. This can create access problems for our patients and mean that those who have HER2-positive disease are sometimes not able to get treatment with these as off-label treatments. The approval improves access to a highly active regimen for patients with HER2-positive mCRC.
Trastuzumab has been approved for many years. It’s now off patent and is accessible through biosimilars. It’s an antibody that binds to HER2 and prevents activation of the HER2 receptor.
Tucatinib is a relatively new molecule, it’s an oral small molecule that’s highly selective for HER2. The main advantage of tucatinib is that it selectivity decreases some of the off target [adverse] effects [AEs] that other tyrosine kinase inhibitors have, so lower rates of rash, diarrhea, and other AEs. It’s a highly selective anti-HER2 regimen, which improves tolerability.
MOUNTAINEER was a global, open-label phase 2 trial. It enrolled patients who had progressed on standard chemotherapy [and] all patients had HER2-positive disease by local testing. That could have been immunohistochemistry, [fluorescence in situ hybridization] FISH, or next-generation sequencing. This initially started as an investigator-sponsored trial and all patients were enrolled in cohort A, which was the combination of tucatinib and trastuzumab. Based on very favorable results that we reported in 2019, the study was expanded with a randomization to either tucatinib and trastuzumab or tucatinib alone.
We found that the response rate for patients receiving the combination of tucatinib and trastuzumab confirmed by BICR was 38%. That compares very favorably to tucatinib by itself, [which] had a response rate of 3% [in MOUNTAINEER], though in that group of patients the disease control rate was high—most patients achieved stable disease with a disease control rate of 80%. The response rate was high, but also what was impressive about this data is that the [median] PFS exceeded 8 months and [the median] OS exceeded 2 years.
In a refractory setting where patients have limited treatment options available with response rates to standard-of-care therapies at 1% to 2% and [a median] PFS closer to 1.8 months, we’ve shown that a highly selective, well-tolerated regimen can generate higher response rates, high levels of disease control, and improve survival based on this trial. What’s also impressive is that when patients respond to this regimen, they have quite durable responses; the median DOR exceeded a year which is impressive given this highly refractory group of patients.
What’s exciting is it’s a break from chemotherapy. It’s a chemotherapy-free regimen and, increasingly, clinicians who get accustomed to the tucatinib/trastuzumab combination will wonder why they’re not giving this earlier to patients. There will be a desire to bring this regimen up into earlier lines so that patients are spared chemotherapy entirely and getting that clinical benefit and tolerability. Though the current FDA approval is for those patients who have progressed on all standard chemotherapy, you’ll see a lot of interest in years to come about bringing a well-tolerated and highly active regimen to our patients earlier in their treatment course.
MOUNTAINEER-03 [NCT05253651] is an exciting trial that’s been launched. [It] is a global, open-label phase 3 trial. Based on the activity we've seen for tucatinib and trastuzumab alone, there's strong interest in bringing this all the way up to the front line and the MOUNTAINEER-03 trial is designed to do that.
Patients will be randomized either to the combination of [modified] FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin], tucatinib, and trastuzumab or standard-of-care first-line therapy, with the primary end point [of] PFS. If this study is positive, it will redefine our treatment algorithm for patients with HER2-positive disease. It’s a very important study, one that we’re hoping will enroll well, [and] it reinforces the need for us to check HER2 status very early in the disease course because we want our patients to get access to these therapies and be able to participate in these trials.
We’re excited about MOUNTAINEER and the fact that this is a new standard of care for patients with HER2-positive disease. But, we know that there are patients with HER2-positive disease who don’t benefit from these highly selective anti-HER2 regimens. One group of patients that we’re interested in reaching are those [with] resistance mutations. Typically, a patient with HER2-positive disease [who]also [has] a KRAS mutation would not benefit from an anti-HER2 regimen.
[At Duke] we are launching a trial to take standard conventional chemotherapy, TAS-102, and combine it with tucatinib and trastuzumab in patients who have both HER2-positive disease [and] a built-in resistance mutation. It’s a way to potentially bring these targeted therapies to a new group of patients.