MOUNTAINEER and DESTINY-CRC01 Trials Expand Second-Line Options for HER2+ mCRC

Alaa Muslimani, MD

Updated findings from the pivotal phase 2 MOUNTAINEER (NCT03043313) and DESTINY-CRC01 (NCT03384940) trials have not only provided two more effective regimens for the treatment of patients with HER2-positive metastatic colorectal cancer (mCRC) but have inspired several ongoing investigations in this space. Such research could address the lack of effective first-line treatment options for this patient population, according to Alaa Muslimani, MD.

“For HER2-positive mCRC, we [now] have 2 very important trials that [will] change the way we treat this patient [population],” said Muslimani, who is a staff hematologist/oncologist at Levine Cancer Institute, Atrium Health in Charlotte, North Carolina. “We will hopefully have more trials [in this space] in the future.”

The safety and efficacy of tucatinib (Tukysa) and trastuzumab (Herceptin) in patients with chemotherapy-refractory, RAS wild-type, HER2-positive unresectable or metastatic CRC was evaluated in the MOUNTAINEER trial. At median follow-up of 20.7 months, patients receiving the doublet had a 38.1% overall response rate (ORR) and median duration of response (DOR) of 12.4 months. Treatment discontinuation occurred in 5.8% of patients, and no treatment-related deaths were reported.¹

The regimen was subsequently granted FDA approval on January 19, 2023, as a second-line treatment for this population.² Its potential use in the first-line setting for mCRC is being evaluated in the ongoing, randomized, phase 3 MOUNTAINEER-03 trial (NCT05253651).³

Similarly, final analysis from the DESTINY-CRC01 trial of fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated the agent’s durability and activity in HER2-positive mCRC. In cohort A, patients with HER2 positivity (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH] positive) experienced an ORR of 45.3%, with a median DOR of 7 months. The safety profile was consistent with previously reported data on the agent. Notably, treatment-related interstitial lung disease (ILD) was observed in 8 patients.⁴

Continued investigation of the agent’s efficacy and safety is ongoing in the phase 2 DESTINY-CRC02 trial (NCT04744831) in HER2-overexpressed advanced or metastatic CRC.⁵

In an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on gastrointestinal (GI) cancers, Muslimani discussed the significance of the phase 2 DESTINY-CRC01 and MOUNTAINEER-03 trials on HER2-positive mCRC treatment in the second line, efforts to expand the use of these agents in earlier disease settings, and the need for more robust clinical data and larger investigations for this population.

OncLive: What key trials have contributed to treatment advances in HER2-positive mCRC?

Muslimani: My presentation [highlighted] two important [studies on] new treatments for HER2-positive CRC. One [was] presented at the 2022 Gastrointestinal [Cancers] Symposium, and the second one was presented at the 2022 ESMO World Congress on Gastrointestinal Cancer. Both were very important trials [that] will change the way we treat [patients with] this malignancy.

[Between] 2% and 5% of [patients with mCRC are HER2 positive]. [HER2 is] usually associated with worse prognosis [because] those patients are resistant to EGFR antibodies. Before these two trials, only a few trials [were evaluating] a small number of patients [with HER2-positive mCRC], and there was no real standard of care [for] this patient [population]. The National Comprehensive Cancer Network [currently] recommends treating these patients [with] a [HER2-targeted] therapy in the second line, but there is no [specific] FDA-approved first-line therapy [for these patients].

Could you provide the rationale for evaluating tucatinib plus trastuzumab in the MOUNTAINEER study? What results were seen with this combination for patients with HER2-positive mCRC?

The MOUNTAINEER trial was a phase 2 study of tucatinib in combination with trastuzumab for HER2-positive mCRC. This is the largest trial so far for HER2-positive mCRC. Tucatinib is [a] TKI, and we know that it’s very effective in other types of HER2-positive solid tumors, such as breast cancer. This is the first trial [where the regimen was tested] for mCRC. In this trial, the investigators combined tucatinib and trastuzumab for patients with HER2-positive mCRC after they progressed on first-line therapy.

The data showed that the ORR [with this regimen] was about 38.1% after a median follow-up of 20.7 months, which is very promising. This is the highest [ORR] we’ve seen so far from any of our previous regimens we’ve used [in this population]. The progression-free survival [PFS] was about 8.2 months, and the overall survival [OS] was 24.1 months.

[The combination] was tolerable for patients, and [there were] no major adverse effects [(AEs) or] deaths in the trial. The main [AEs] were GI toxicity, decreased appetite, diarrhea, and nausea. There were no reports of cardiac toxicity, which is usually an issue with trastuzumab. The [treatment] discontinuation [rate in] this trial was [around] 5%. [Based on these data], the combination has the potential to become a standard of care [in the] second line for patients with HER2-positive mCRC.

How will the ongoing phase 3 MOUNTAINEER-03 trial build on findings from the phase 2 MOUNTAINEER study in mCRC?

[Trastuzumab and tucatinib elicited] a positive response in HER2-positive breast cancer and have shown efficacy in HER2-positive mCRC. [Investigators are] now opening the phase 3 MOUNTAINEER-03 study [NCT05253651], which will be a very important study. It’s comparing tucatinib and trastuzumab [plus] mFOLFOX vs mFOLFOX with and without bevacizumab [Avastin] or cetuximab [Erbitux] in the frontline. They investigators are trying to enroll 400 patients. [This trial will help] us understand this type of tumor, and [potentially] move this therapy [into the] first-line setting for these patients.

Turning to the DESTINY-CRC01 trial, what was notable about the trial design and patient population in this study?

The DESTINY-CRC01 trial [evaluated] trastuzumab deruxtecan in patients with HER2-positive mCRC. We know this drug is very effective in other types of solid tumors, such as HER2-positive breast cancer. This is a unique trial, because it is the first in this type of malignancy [to] allow [for] previous exposure to HER2[-targeted] treatments. It started as a 3-armed trial of patients with HER2-positive, [RAS]/BRAF wild-type [disease]. Most of these patients were heavily pretreated [with] two or more lines of therapy. Usually, these patients have no effective treatments at this [stage]. We focused on the arm that included patients who were [categorized as] HER2 positive, with an IHC score of 3+ or an IHC of 2+ with positive ISH. This is the only arm [in which] this drug showed efficacy.

Please discuss the efficacy and safety data that were reported from this trial.

In this trial, the ORR [in cohort A] was about [45.3%], but the disease control rate, which is important in this line of therapy, was 83%. Even patients who did receive prior HER2-directed treatment showed responses to trastuzumab deruxtecan. This trial also showed a [median] PFS [of] 6.9 months. At the time of [initial] reporting, the median OS was not reached in this population.

We know that this drug [can] cause some lung toxicity. Two deaths were caused by drug-related pneumonitis. Other AEs reported in this trial included neutropenia, which is] expected because these patients are heavily pretreated. There was also drug-related GI toxicity. The authors did recommend close monitoring of patients for any signs of lung toxicities, and treatment [cessation followed by] high-dose steroid [administration] at the first indication [of] pneumonitis.

The trial concluded that trastuzumab deruxtecan showed a median PFS of 6.9 months [in this cohort]. About 6.4% [of patients] reported ILD related to this drug [in the primary analysis], [including 2] deaths. These findings support the potential use of trastuzumab deruxtecan [for] heavily pretreated patients with advanced HER2-positive mCRC.

What unanswered questions remain in mCRC, and how might they be addressed going forward?

Not all HER2-positive solid tumors act the same. In the [DESTINY-CRC01 trial], patients who were [borderline] HER2 [positive with] an IHC of 2+ [and negative ISH] did not respond to trastuzumab deruxtecan, [unlike] patients with breast cancer [with the same profile]. We still don’t have strong trials for first-line therapy in mCRC, which the [phase 3] MOUNTAINEER-03 will [attempt to ameliorate].

[Additionally], it seems patients with HER2-positive mCRC do worse than other [HER2-positive] tumor types. For example, there is a higher risk of brain metastases in HER2-positive mCRC.

[Lastly], trials [in this space] still enroll a small number of patients compared with other [studies of] HER2-positive solid tumors. In the future, we hope to have more trials for our patients and [to better] understand the biology of HER2 in mCRC.

What is your main message for colleagues based on this presentation?

In general, it’s a very exciting time for CRC oncologists because there are a lot of new data and treatment options for our patients. The phase 3 MOUNTAINEER-03 trial [in] the first-line setting will [soon] open at our institution. [As] the largest institution in the greater Charlotte [area], Atrium Health is actively involved in a lot of phase 1, 2, and 3 trials, especially for CRC.

Disclosure: Dr Muslimani reports serving in an advisory role for Seagen.

References

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. News release. Seagen. July 2, 2022. Accessed April 12, 2023. https://investor.seagen.com/press-releases/news-details/2022/
2. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. Seagen. January 19, 2023. Accessed April 12, 2023. https://investor.seagen.com/press-releases/news-details/2023/
3. A study of tucatinib with trastuzumab and mFOLFOX6 versus standard of care treatment in first-line HER2+ metastatic colorectal cancer (MOUNTAINEER-03). Clinicaltrials.gov. Updated April 5, 2023. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT05253651
4. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 4):119). doi:10.1200/JCO.2022.40.4_suppl.119
5. Trastuzumab deruxtecan in participants with HER2-overexpressing advanced or metastatic colorectal cancer (DESTINY-CRC02). Clinicaltrials.gov. Updated February 24, 2023. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT04744831