MOUNTAINEER-03 Aims to Confirm Efficacy of Tucatinib/ Trastuzumab/mFOLFOX6 in mCRC

In an interview with Targeted Oncology, Tanios Bekaii-Saab, MD, FACP, discussed the methods and design of the MOUNTAINEER-03 trial and its role following the positive data observed from MOUNTAINEER.

The combination of tucatinib (Tukysa), trastuzumab (Herceptin), and 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the first-line for patients with HER2-positive metastatic colorectal cancer (mCRC) is being evaluated in the phase 3 MOUNTAINEER-03 trial (NCT05253651).

This trial is a follow-up from the positive phase 2 MOUNTAINEER trial (NCT03043313), which looked at tucatinib in combination with trastuzumab in this patient population.

At a median follow-up of 20.7 months (interquartile range, 11.7-39.0), the combination led to a confirmed objective response rate of 38.1% (95% CI, 27.7%-49.3%) in patients. Moreover, complete responses were seen in 3.6% of patients while partial responses were observed in 35%. Responses to the combination were durable and the median duration of response was 12.4 months (95% CI, 8.5-20.5). Based on these data, the combination of tucatinib and trastuzumab was approved by the FDA in January 2023.

Now in the global, open label, randomized, phase 3 MOUNTAINEER-03 study, investigators are evaluating tucatinib, trastuzumab, and modified FOLFOX6 compared with the standard-of-care treatment for patients with frontline HER2-positive mCRC. The primary end point of the trial is progression-free survival per RECIST v1.1 with secondary end points of overall survival and confirmed objective response.

“If MOUNTAINEER-03 is positive, it will essentially open the doors for global approval for tucatinib and trastuzumab added to FOLFOX6 in HER2-positive colorectal cancer. That’s the first element that would come from this study,” said Tanios S. Bekaii-Saab, MD, FACP, in an interview with Targeted OncologyTM.

In the interview, Bekaii-Saab, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, medical oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona, discussed the methods and design of the MOUNTAINEER-03 trial and its role following the positive data observed from MOUNTAINEER.

Targeted Oncology: What is important to note about the MOUNTAINEER-03 study?

Bekaii-Saab: The data that led to the MOUNTAINEER-03 trial were from a study called MOUNTAINEER, which looked at the role of tucatinib added to trastuzumab in patients with HER2-amplified metastatic colorectal cancer. HER2 is present and amplified in about 3%-4% of all [patients] with metastatic colorectal cancer. HER2 seems to be 1 of the major drivers of carcinogenesis in colorectal cancer. Of interest to us are mostly those RAS wild-type HER2-amplified tumors, which represent about 70% of all the HER2-amplified tumors.

Early clinical data suggested that the dual targeting of HER2-targeting agents have yielded responses in 30% or so range. Essentially, that led to the development of the idea of taking tucatinib, which is a highly potent oral agent for HER2 and does not have some of the [negative] aspects of lapatinib [Tykerb], and it is more specific. You would imagine less off-target toxicities, which was of interest to us. Then combining that with trastuzumab. There were some preclinical data suggesting that you would see nice trends with the combination of the tucatinib and trastuzumab in HER2-positive preclinical models. That led to MOUNTAINEER, which was initiated as a study evaluating tucatinib and trastuzumab. Cohort A started with limited sites. The Mayo Clinic research consortium helped take it through and then it got the interest of the manufacturer of tucatinib and it ultimately led to a company-sponsored study adding 2 cohorts, B and C, randomized to tucatinib and trastuzumab vs tucatinib.

What were the findings of the MOUNTAINEER study?

[MOUNTAINEER] ended up being a positive study with interesting results for the combination of tucatinib and trastuzumab in refractory patients. There was about a 40% response rate and a duration of response that went above a year, and survival that was close to 2 years. That is the basis for the FDA to approve the combination in this setting. These interesting results always lead me to ask the question, “Can we move those agents to the first-line and induce even better results?” If [the disease is] hit early and hit hard, it is likely to yield even further improvements than when you hit it a little bit later, at least, that’s where we find a lot of different targets. It makes sense to take this from the refractory setting to earlier settings. That essentially led us to MOUNTAINEER-03.

What can you tell us about the MOUNTAINEER-03 study in this patient population?

At a high level, MOUNTAINEER-03 is a global, randomized, open-label, phase 3 trial. It is the largest ever phase 3 trial or trial period in HER2-positive metastatic colorectal cancer. This will take first-line patients with metastatic colorectal cancer and they will be assessed for HER2-positivity centrally. They have to be RAS wild-type since we know the RAS-mutated tumors don’t respond as well. Patients will be randomized to tucatinib, trastuzumab, and chemotherapy vs FOLFOX6 plus/minus the biologic of choice.

The primary end point of the study is progression-free survival. We expect tucatinib and trastuzumab, or other targeted therapies, to be available, so patients who may not have received them in the earlier cycle can cross over to them. It will make it very difficult to assess survival as the primary end point, although we still hope that survival is superior with moving those agents sooner rather than using them later. [Overall survival will] be essentially a secondary end point.

This study will need to accrue about 400 patients. It’s a major lift for a rare patient population, but that is what we’re excited about. MOUNTAINEER-03 is a global, randomized, phase 3 study that will hopefully move HER2 targeted therapies into the first-line.

What are the next steps for research in the MOUNTAINEER-03 study?

If MOUNTAINEER-03 is positive, it will essentially open the doors for global approval for tucatinib and trastuzumab added to FOLFOX6 in HER2-positive colorectal cancer. That’s the first element that would come from this study. Following this, we need to start understanding, if this ends up being positive and approved, then we [have to] start looking at those patients with lower expression of HER2. Those have not been included in most studies.

We do have a study led by John Strickler, MD, that’s going on through our research consortium that is looking at trastuzumab and tucatinib and added to TAS-102 in refractory patients [NCT05356897]. Those patients are who we expect to be of lower expression or have resistance mutations. [This study is to] hopefully understand more fully the role of adding those 2 agents to chemotherapy in patients who are less likely to respond just to the 2 agents. This could, if it shows signals, move into a larger study. Then, 1 of the points of interest is if we find the MOUNTAINEER-03 study to be positive, which we’re hoping it ends up being positive and leads to a new standard in the metastatic setting, how can we then move this into the earlier stages and understanding that 2%-3% of patients will amplify HER2. Therefore, they may benefit from the addition of a biologic earlier on.

These studies have to be designed. We’ve done that with BRAF-v600 mutations now moving to the adjuvant setting. We’ve done that with MSI-high moving to the adjuvant setting, and I think this would be the natural transition to take this into the earlier stages. You do see additional responses. One would wonder if in rectal cancer where there is a small proportion of patients with HER2-amplified tumors, if we start exploring new adjuvant strategies with dual HER2-targeting and chemotherapy. It opens up a whole wide net of questions to ask.

What unmet needs still exist in this space?

One of the main elements, and we’re working hard with a lot of the samples we obtained on MOUNTAINEER, is to try to understand mechanisms of resistance. What would be the drivers for resistance for HER2-targeted strategies? Then as we identify them, we start understanding the potential for follow-up of targeted strategies to reverse some of these patterns of resistance. A lot of this work will be done and hopefully will lead to rationally designing future studies as follow-up studies to primary HER2 targeting, or even in combination, to try to counter these elements of resistance. There’s a lot of work that still needs to be done, but I think we have a good start. I think what will follow is that we will hopefully keep moving those 40% patients to 50%, 60%, and hopefully to almost everyone responding once we understand the full picture.

1. Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of TUKYSA® (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. Press release. Seagen. July 2, 2022. Accessed January 23, 2023.