Tucatinib combination extends OS in HER2-positive breast cancer with brain metastases
Tucatinib plus trastuzumab and capecitabine extended OS among patients with brain metastases from HER2-positive breast cancer, according to findings from a randomized phase 3 study presented during the ASCO20 Virtual Scientific Program and simultaneously published in Journal of Clinical Oncology.
“Brain metastases are common in patients with HER2-positive metastatic breast cancer; however, evidence-based treatment options are limited as patients with active brain metastases have been excluded from virtually all prior registration trials in breast cancer,” Nancy U. Lin, MD, PhD, medical oncologist in the department of medical oncology at Dana-Farber Cancer Institute, told Healio. “In the phase 1 program for tucatinib [Tukysa, Seattle Genetics], central nervous system activity was observed in patients with brain metastases, which led to inclusion of [patients with brain metastasis] in HER2CLIMB. In this abstract, we analyzed the large subset of patients with brain metastases enrolled in the trial.”
Tucatinib — an investigational oral tyrosine kinase inhibitor that is highly selective for HER2 — has demonstrated antitumor activity in preclinical models of HER2-positive breast cancer, as well as in intracranial tumor models.
The global, double-blind HER2CLIMB trial included patients with locally advanced or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab (Herceptin, Genentech), pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech).
Researchers randomly assigned patients 2:1 to tucatinib dosed at 300 mg or placebo twice daily in combination with trastuzumab — dosed at 6 mg/kg once every 21 days, with a loading dose of 8 mg/kg on day 1 of the first cycle — and capecitabine, dosed at 1,000 mg/m² twice daily on days 1 to 14 of each 21-day cycle.
In the current study, Lin and colleagues analyzed a subset of HER2CLIMB participants (n = 291) with brain metastases, including 198 from the tucatinib group and 93 from the control group.
Investigators used RECIST version 1.1 for baseline brain metastases efficacy analyses. They assessed central nervous system PFS and OS among all patients with brain metastases, as well as intracranial-confirmed objective response rate and intracranial duration of response among those with measurable intracranial disease.
Results showed the triplet combination conferred a 68% reduction in risk for CNS progression compared with the control regimen (median CNS PFS, 9.9 months vs. 4.2 months; HR = 0.32; 95% CI, 0.22-0.48). Researchers also reported a 42% reduction in the risk for death in the triplet therapy group vs. the control group (median OS, 18.1 months vs. 12 months; HR = 0.58; 95% CI, 0.4-0.85).
Patients in the triplet therapy group demonstrated a higher intracranial-confirmed ORR (47% vs. 20%) and a longer median intracranial duration of response (6.8 months vs. 3 months) than those in the control group.
In a subset of patients (n = 30) who continued on the tucatinib regimen after local treatment and until second disease progression, researchers observed a 67% (HR = 0.33; 95% CI, 0.11-1.02) reduced risk for second progression or death.
Median PFS from randomization was 15.9 months in the triplet therapy group vs. 9.7 months in the control group (HR = 0.292; P = .009). Median time from first CNS progression to second progression or death was 7.6 months in the triplet therapy group vs. 3.1 months in the control group (HR = 0.332; P = .02).
“This is the first randomized trial in breast cancer to demonstrate a statistically significant and clinically meaningful prolongation of OS with systemic therapy in patients with brain metastases, including those with active and progressive brain metastases,” Lin told Healio. “We are planning additional analyses focused on patients with brain metastases included in HER2CLIMB and hope to present the findings at upcoming meetings.” – by Jennifer Southall
References:
Lin NU, et al. Abstract 1005. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Lin NU, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.00775.
Disclosures: Seattle Genetics funded this study. Lin reports consultant/advisory roles with Daiichi Sankyo, Genentech/Roche, Novartis, Puma Biotechnology and Seattle Genetics; research funding from Genentech, Merck, Pfizer and Seattle Genetics; and patents, royalties and other intellectual property from Jones & Bartlett and Up-to-Date. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Breast cancer has the second highest incidence of brain metastases among all cancers, second only to lung cancer. Risk and incidence of brain metastases varies based on breast cancer subtype. Those with HER2-positive disease have a 50% chance over their lifetime to develop brain metastases, so this is a high unmet clinical need. A review of select trials that only enrolled patients with HER2-positive brain metastases show their time on standard therapy ranges from less than 2 months to about 5 months with current options.
In addition to the commonly allowed population of patients with brain metastases that were treated and stable, HER2CLIMB also allowed patients with untreated brain metastases and those who were treated and were progressing at time of trial entry.
HER2CLIMB met all endpoints, with a 46% reduction in risk for progression or death, a 34% improvement in OS among all comers and a 52% improvement in PFS among patients with brain metastases. At 1 year, no patients on capecitabine and trastuzumab alone remained progression free, but one-quarter of those receiving tucatinib remained on trial. These data led to the approval of tucatinib in April in the setting of at least one prior anti-HER2 therapy.
An analysis of survival in HER2CLIMB broken down just by patients with brain metastases shows an OS benefit in all comers, with an improvement from 12 months to 18.1 months. In the group with active brain metastases — either untreated or treated and progressing — we again see an OS improvement from 11.6 months to 20.7 months.
We know up to 50% of our patients with HER2-positive disease will develop brain metastases, especially if they have risk factors such as tumors of at least 2 cm or node-positive disease. Younger patients — those aged 40 years and younger — also are at increased risk.
We need to be thinking about prevention, not just reacting when metastases are there. If we use CNS-active drugs earlier, could we prevent some of these brain metastases? Could we evaluate tucatinib in a high-risk adjuvant setting defined by tumor characteristics or an adequate response to neoadjuvant therapy? And what about leptomeningeal disease? These patients have a worse prognosis than those with brain metastases, and I am happy to see there is such a trial ongoing.
I would be remiss if I didn’t capitalize on HER2CLIMB’s success and clear demonstration of the advantage of using a heterogenous patient population in a clinical trial to encourage us to broaden eligibility criteria. When we use overly restrictive entry criteria, we limit the patients that can help us move treatments forward. We fail to capture the real-world population that eventually will go on to use these drugs, and we exclude many subgroups of patients who need more options, including those with brain metastases, older patients, and patients with a history of infection such as hepatitis or HIV.
Perspective
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Tucatinib is a total game changer for patients with HER2-positive metastatic breast cancer who also have brain metastases. In this subgroup, the addition of tucatinib made a large difference, including a hefty impact on OS. Tucatinib will be the standard of care for all patients with brain metastases and HER2-positive metastatic breast cancer regardless of the line of therapy. In addition, this is the only study I am aware of that included patients with completely untreated brain metastases. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases.
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Lin NU, et al. Abstract 1005. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.