Tukabrutinib plus trastuzumab has a benefit in HER2+ metastatic colorectal cancer (mCRC).

Additional analyses based on the Phase 2 MOUNTAINEER trial (NCT04262466) further support the early use of tucatinib (Tukysa) in combination with trastuzumab (Herceptin) as the optimal treatment strategy
for previously treated HER2-positive metastatic colorectal cancer (mCRC).
John H.
Strickler, M.
D
.

Updated results for trial cohort C, presented at ESMO 2022, showed an overall response rate (ORR) of 3.
3% (95% CI, 0.
1% to 17.
2 %) in patients receiving tukabrutinib monotherapy (n = 30), with one patient experiencing a partial response
.
76.
7% of patients reported stable disease with a disease control rate (DCR) of 80%.

The protocol allowed for crossover, with an ORR of 17.
9% (95% CI, 6.
1% to 36.
9%) of the 28 patients who continued the combination therapy, 5 with a partial response, and 18 patients with stable disease, with a DCR of 82.
1%.

The safety data showed that both tucatinib monotherapy and combination therapy were well tolerated by patients, and the results were consistent
with the safety profile of tucatinib.
In cohort C, 26.
7% of patients present with a grade 3 or higher AE.

Grade 3 or higher adverse effects (AEs)
after crossover, new onset, or worsening were reported in 21.
4% of patients.

[Although] tucatinib [alone] has a low ORR, the DCR is surprisingly high [at] 80 percent," said
Strickler, associate professor of medicine at Duke University School of Medicine and medical oncologist at Duke Cancer Center.
"We also found that by adding trastuzumab to tukabrutinib, we can turn non-responders into responders
.
[This indicates] The optimal [treatment] strategy for HER2-positive mCRC [individuals] is a combination of tucatinib and trastuzumab
at the beginning of [treatment].
This [combination] produced the highest response rate, showed excellent disease control, and [resulted in] a median response lasting more than a year
.
" ”

In an interview with OncLive®, Strickler discusses key safety and efficacy data for MOUNTAINEER, the ongoing investigation these findings have sparked, and the potential benefits
of anti-HER2 therapy in this patient population.

OncLive®: What is the rationale for evaluating dual HER2-targeted therapy in patients with RAS wild-type mCRC in the MOUNTAINEER trial?
Strickler: HER2 [overexpression] occurs in about 3% of mCRC patients, and we found rates as high as 10% or more
of patients with wild-type disease of RAS and BRAF.
The tyrosine kinase inhibitor tucatinib is a highly selective oral therapy that has shown activity
in preclinical xenograft models of other tumor types (e.
g.
, breast cancer) and HER2-positive CRC.
It is important to note that the combination of trastuzumab and tukabrutinib is a potent tumor growth inhibitor and is more effective
than trastuzumab or tukatinib alone.

PLEASE EXPAND MOUNTAINEER'S TRIAL DESIGN AND PATIENT POPULATION
.

MOUNTAINEER IS AN OPEN-LABEL, GLOBAL PHASE 2 STUDY
.
It recruited patients with RAS wild-type mCRC who had made advances
in previous [fluoropyrimidine], oxaliplatin, irinotecan, and anti-VEGF [monoclonal] antibody therapy.
All patients enrolled had HER2-positive disease by local testing, possibly immunohistochemistry, FISH [fluorescence in situ hybridization], or next-generation sequencing [NGS].

These patients were initially enrolled in Cohort A, a pilot cohort
using tukabrutinib and trastuzumab.
Based on very favorable results from initial experience, the study was expanded
.
Randomization
was present when the study was extended to cohort B (tukabrutinib/trastuzumab combination) or cohort C (tukabrutinib itself).

Resources:

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):S1394.
doi:10.
1016/j.
annonc.
2022.
08.
023