Tucatinib regimen extends PFS in advanced HER2-positive breast cancer
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Key takeaways:
- Patients achieved median PFS of 9.5 months with tucatinib vs. 7.4 months with placebo.
- Tucatinib-treated patients experienced higher rates of nausea, diarrhea and elevated liver enzymes.
The addition of tucatinib to ado-trastuzumab emtansine significantly improved PFS among patients with unresectable locally advanced or metastatic HER2-positive breast cancer, according to study findings.
The addition of tucatinib (Tukysa, Seagen) to ado-trastuzumab emtansine (Kadcyla, Genentech) also increased risk for certain adverse events, an interim analysis of the randomized phase 3 HER2CLIMB02 trial presented at San Antonio Breast Cancer Symposium showed.
Background and methods
Tucatinib — a highly selective HER2-directed tyrosine kinase inhibitor — is approved for use in combination with trastuzumab and capecitabine for previously treated HER2-positive locally advanced or metastatic breast cancer.
The agent also has been shown to delay disease progression in the central nervous system.
“For patients with brain metastases, such a drug can make a significant difference,” Sara A. Hurvitz, MD, FACP, professor and head of the division of hematology and oncology in the department of medicine at University of Washington and senior vice president of the clinical research division at Fred Hutch Cancer Center, said in a press release. “HER2-positive breast cancer has a predilection to spread to the brain and, when this occurs, prognosis is poor. Few options exist for the successful management of breast cancer brain metastases, making this an area of unmet need.”
The HER2CLIMB02 trial included 463 patients with previously treated, unresectable locally advanced or metastatic HER2-positive breast cancer. Patients with previously treated stable, progressing or untreated brain metastases not requiring immediate local therapy were included.
Researchers randomly assigned 228 patients to 21-day cycles of 300 mg twice-daily tucatinib plus 3.6 mg/kg ado-trastuzumab emtansine once every 3 weeks. The other 235 patients received placebo plus ado-trastuzumab emtansine.
PFS by investigator assessment served as the primary endpoint. Secondary endpoints included safety, OS and objective response rate among the overall population, as well as PFS and OS among the subset of patients with brain metastases at baseline.
Median follow-up was 24.4 months.
Findings
Results showed median PFS of 9.5 months (95% CI, 7.4-10.9) with tucatinib vs. 7.4 months (95% CI, 5.6-8.1) with placebo, corresponding to a 24.1% (HR = 0.75; 95% CI, 0.6-0.95) reduction in relative risk for disease progression or death.
Among those with brain metastases (44.1%), researchers observed median PFS of 7.8 months with tucatinib combination vs. 5.7 months with placebo (HR = 0.64; 95% CI, 0.46-0.89).
“After HER2CLIMB, the HER2CLIMB02 trial is only the second large placebo-controlled randomized trial to be reported for HER2-positive breast cancer with this type of study design,” Hurvitz told Healio. “Both studies have demonstrated significant benefits with using tucatinib [for] patients with brain metastases.”
The confirmed ORR was numerically higher among those in the tucatinib group (42% vs. 361.%).
OS data remained immature; however, at data cutoff, the difference between the tucatinib and placebo groups had not reached statistical significance (median, not reached vs. 38 months; HR = 1.23; 95% CI, 0.87-1.74). Follow-up is ongoing, Hurvitz said.
“The addition of tucatinib was associated with an increased rate of certain side effects, including gastrointestinal symptoms of nausea and diarrhea, and elevations in liver enzymes, for which monitoring is needed,” she added.
Treatment-emergent adverse events leading to death occurred among three patients (1.3%) in the tucatinib group and two patients (0.9%) in the control group.
Implications
The data demonstrate that adding tucatinib to ado-trastuzumab emtansine extends time to disease progression for this patient population, Hurvitz told Healio.
“The benefits were especially notable [among] patients with brain metastases — a patient subset with a particularly poor prognosis,” she said.
“This study was not designed to compare the efficacy and safety of the HER2CLIMB regimen (tucatinib/trastuzumab/capecitabine) to that of this regimen,” Hurvitz added. “Thus, selection between these two regimens will need to be individualized, taking into consideration the side effect profile of each regimen, patient’s wishes and prior treatment received.”
This study also was not designed to evaluate the benefits of this regimen compared with outcomes among patients treated with fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo), Hurvitz added.
“An ongoing study is evaluating trastuzumab deruxtecan in combination with tucatinib,” she said. “Tucatinib is also being evaluated in combination with ado-trastuzumab emtansine in the adjuvant setting in the COMPASSHER2-RD trial.”
References:
- Hurvitz S, et al. Abstract GS01-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
- Tucatinib plus trastuzumab emtansine may benefit patients with advanced or metastatic HER2-positive breast cancer (press release). Published Dec. 6, 2023. Accessed Dec. 6, 2023.
Perspective
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Published data show 50% to 60% of patients with HER2-positive metastatic breast cancer will develop brain metastases. That number likely will increase as more effective systemic agents are developed, so anything that can prevent brain metastases from arising would be an incredibly important advance.
HER2CLIMB-02 was designed to address that in a way. About 20% to 25% of patients in each treatment group had active brain metastases. Results showed a modest PFS improvement with the addition of tucatinib to T-DM1 in the overall cohort (9.5 months vs. 7.4 months). We saw a similar PFS improvement with that combination among patients with brain metastases (7.8 months vs. 5.7 months).
Median OS was a little over 3 years among those assigned T-DM1 alone, but it had not yet been reached in the combination group. The interesting question is why? One intriguing hypothesis is whether this relates to new brain metastases-specific survival?
The NEfERT-T trial compared the oral pan HER inhibitor neratinib (Nerlynx, Puma Biotechnology) plus paclitaxel vs. trastuzumab plus paclitaxel, and results showed median PFS of about 12 months in each group. However, incidence of brain metastases as a new site of progression was halved with neratinib. That is my hope in this trial, and I’m curious to see if that really happened.
We know from the initial HER2CLIMB study — which assessed the addition of tucatinib or placebo to trastuzumab and capecitabine — that progression of new brain metastases was delayed by up to a year with the tucatinib regimen. Maybe that is the reason why patients had improved survival with the HER2CLIMB-02 regimen, and I think that will be important to tease out.
Perspective
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Ado-trastuzumab emtansine (Kadcyla, Genentech [T-DM1]) used to be our second-line standard until fam-trastuzumab deruxtecan-nxki (Enhertu, AstraZeneca [T-DXd]) upended it very recently on the basis of the DESTINY-Breast03 trial. However, T-DM1 still can potentially be effective for these patients.
We don’t have much data on the efficacy of T-DM1 after T-DXd. For patients who progress on T-DXd, I often use the HER2Climb regimen, because this trial showed a clear PFS and OS benefit of adding the HER2-selective kinase inhibitor tucatinib to the established combination of capecitabine and trastuzumab, including for patients with active central nervous system metastases.
The HERCLIMB-02 trial enrolled patients treated with prior taxane/trastuzumab therapy. Researchers randomly assigned them to T-DM1 with either placebo or tucatinib.
Results showed a 24% reduction in progression events, and the regimen was reasonably well tolerated. I thought tolerability would be an issue because combining kinase inhibitors with chemotherapy has always been difficult, but the quality of life in this study was reasonable and supports use of this approach. However, this trial did not enroll patients with prior T-DXd or neratinib (Nerlynx, Puma Biotechnology), so these findings cannot be generalized to patients who progress on those agents.
What treatment we use after T-DXd is an open question right now. We don’t really have a standard. If patients are resistant to the topoisomerase I inhibitor payload, T-DM1 plus tucatinib could be further studied in this population. This is a newer antibody-drug conjugate with a new payload, augmented by a kinase inhibitor that is well tolerated, so I think we may see this become the new post-T-DXd recommendation.
References:
Hurvitz S, et al. Abstract GS01-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
Murthy RK, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1914609.
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Hurvitz S, et al. Abstract GS01-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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