Crossover Cohort Supports Combination Use of Tucatinib Plus Trastuzumab in HER2+ mCRC


Tucatinib as monotherapy and in combination with trastuzumab supported further investigation of the regimens in patients with metastatic HER2-positive colorectal cancer.

Patients with metastatic HER2-positive colorectal cancer (CRC) initially treated with tucatinib (Tukysa) monotherapy who later crossed over to receive doublet therapy with trastuzumab (Herceptin) experienced increased radiographic response rates further supporting the regimen’s use in this setting, according to updated data from cohort C of the phase 2 MOUNTAINEER trial (NCT03043313).1

John H. Strickler, MD, associate professor of medicine and a medical oncologist at Duke University School of Medicine, presented the data at the 2022 ESMO Congress.

Prespecified analyses for cohort C included objective response rate (ORR) by 12 weeks and disease control rate (DCR) by blind independent committee review (BICR); confirmed ORR by BICR for patients who crossed over from the monotherapy to combination regimen; and safety.

Among the 30 patients treated with tucatinib, ORR by 12 weeks was 3.3% (95% CI, 0.1%-17.2%) and DCR was 80.0%. Overall, cohort C was comprised of patients with 1 partial response (PR; 3.3%), 23 instances of stable disease (SD; 76.7%), and 4 occurrences of progressive disease (PD; 6.7%).

In total, 28 patients crossed over to the combination regimen, inducing a confirmed ORR of 17.9% (95% CI, 6.1%-36.9%) and DCR of 82.1%. Among patients who crossed over, 5 (17.9%) had PRs, 18 (64.3%) had SD, and 5 (17.9%) had PD.

In cohort C, 93.3% of patients experienced any-grade adverse events (AEs), including 26.7% with grade 3 or higher events. Three patients reported with serious AEs. The most common AEs with tucatinib included diarrhea (33.3%), abdominal pain (20.0%), and fatigue (20.0%), all of which were grade 1 or 2. The most common grade 3 or higher AEs were increased aspartate/alanine aminotransferase (AST/ALT; 6.7% each).

Among patients who crossed over to the combination regimen, 82.1% of patients reported any-grade AEs, with 21.4% experiencing grade 3 or higher events. Two patients had serious AEs. The most common AE was diarrhea (35.7%), of which all events were grade 1 or 2. Also in this group, the most common grade 3 or higher AEs include ALT/AST increase (7.1% and 10.7%, respectively). Two patients in the crossover group discontinued treatment because of AEs.

“Tucatinib monotherapy and tucatinib plus trastuzumab after crossover were well tolerated and consistent with the known safety profiles,” Strickler said.

The multicenter, open-label, randomized trial aimed to evaluate tucatinib in combination with trastuzumab or as a single agent among 117 patients with metastatic or unresectable HER2-positive CRC. Patients were divided into 3 cohorts:

  • Cohort A received oral tucatinib at 300 mg twice daily in combination with a loading dose of intravenous trastuzumab at 8 mg/kg followed by 6 mg/kg every 3 weeks thereafter (n = 45);
  • Cohort B included the global expansion of patients randomized to the combination regimen (n = 41); and
  • Cohort C comprised patients who received 300 mg oral tucatinib twice daily (n = 31).

Patients treated with tucatinib monotherapy could cross over for radiographic progression or stable disease by 12 weeks to the combination regimen.

ORR by RECIST v1.1 criteria per BICR in cohorts A and B served as the primary end point. Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability of the combination regimen.

To be eligible, patients had to have second-line or beyond metastatic CRC; HER2-positive disease per local immunohistochemistry, in situ hybridization, or next-generation sequencing; RAS wild-type mutations; measurable disease per RECIST 1.1; and prior treatment with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody.

At the ESMO World Congress on Gastrointestinal Cancer hosted in July 2022, full results from the pivotal trial were presented for cohorts A and B.2

Full trial results showed an ORR of 38.1% (95% CI, 27.7%-49.3%) in patients who received tucatinib in combination with trastuzumab. Moreover, patients experienced a median DOR of 12.4 months (95% CI, 8.5-20.5), a median PFS of 8.2 months (95% CI, 4.2-10.3), and a median OS of 24.1 months (95% CI, 20.3-36.7).

The most common treatment-emergent adverse events (TEAEs) in the combination arm were diarrhea (grade 1 or 2, 60.5%; grade 3, 3.5%), fatigue (grade 1 or 2, 41.9%; grade 3, 2.3%), nausea (grade 1 or 2, 34.9%), and infusion-related reaction (grade 1 or 2, 20.9%). The most common grade 3 or higher AE was hypertension (7.0%).

Treatment discontinuation occurred in 5.8% of patients because of AEs; however, no AE-related deaths were reported.

As a next step, Strickler noted that the combination of tucatinib and trastuzumab is being further investigated in the ongoing, randomized, global, phase 3 MOUNTAINEER-03 trial (NCT05253651), designed to evaluate the efficacy of the combination regimen plus fluorouracil, leucovorin, and oxaliplatin, or mFOLFOX6, compared with standard-of-care, first-line therapy for metastatic HER2-positive CRC.


  1. Strickler JH, Cercek A, Siena S, et al. Additional analyses of MOUNTAINEER: A phase II study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol. 2022;33(suppl 7):LBA27. doi:10.1016/annonc/annonc1089.
  2. News Release. 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. Published July 2, 2022. Accessed September 12, 2022.
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