First- and second-line treatments of HER2-positive metastatic breast cancer have become the standard of care based on solid gains in overall survival, but the prevalence of resistance to these agents is increasing; up to 55% of patients will ultimately develop brain metastases. According to a pair of studies presented at the 2020 European Society for Medical Oncology (ESMO) Breast Cancer Virtual Meeting, however, new anti-HER2 therapies in the late-line setting focused on brain involvement may change early-line treatment paradigms in the near future.
In a phase II study,1 fam-trastuzumab deruxtecan-nxki (T-DXd) demonstrated efficacy in patients with HER2-positive metastatic breast cancer who had stable, treated brain metastases at baseline—similar to its efficacy in the overall population. In a phase III trial,2 the addition of tucatinib vs placebo to trastuzumab and capecitabine significantly improved survival in patients with untreated or previously treated, progressing brain metastases.
Brain metastases are no longer a limitation for systemic treatment of HER2-positive metastatic breast cancer.— Antonio Llombart-Cussac, MD, PhD
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Discussant of these two abstracts, Antonio Llombart-Cussac, MD, PhD, of the Universidad Catolica Valencia, Spain, called the activity of T-DXd “astonishing,”3 adding that “brain metastases are no longer a limitation for systemic treatment of HER2-positive metastatic breast cancer. In addition, tucatinib in combination with trastuzumab and capecitabine is the new standard third-line treatment, and T-DXd may change paradigms of treatment.”
Trastuzumab Deruxtecan
Guy Jerusalem, MD, PhD, Head of the Breast Unit at Centre Hospitalier Universitaire du Sart-Tilman, Liège, Belgium, presented a subgroup analysis of the DESTINY-Breast01 study.1 This open-label, multicenter, phase II trial evaluated T-DXd, an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.
Results published in TheNew England Journal of Medicine showed that T-DXd (5.4 mg/kg every 3 weeks) was associated with a confirmed objective response rate of 60.9%, a median duration of response of 14.8 months, and a median progression-free survival of 16.4 months.4 All patients enrolled on study (n = 184) had received prior treatment with ado-trastuzumab emtansine (T-DM1). T-DXd was approved for the treatment of unresectable and/or metastatic breast cancer after at least two prior anti-HER2 regimens in the United States or after prior chemotherapy in Japan.
Among 40 patients without brain lesions at baseline who had progressive disease, just two patients had new brain lesions, and both were late events.— Guy Jerusalem, MD, PhD
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In the subgroup analysis presented during the ESMO meeting, Dr. Jerusalem focused on patients with central nervous system (CNS) involvement at the time of enrollment (n = 24). Patients were included in the study if they had brain metastases that were treated, asymptomatic, or did not require therapy to control symptoms. Prior treatment, including radiation, surgery, steroids, and/or anticonvulsants, was completed at least 60 days before randomization, said Dr. Jerusalem, who noted brain imaging was performed every 6 weeks for patients with a history of brain metastases.
As Dr. Jerusalem reported, patients in the CNS subgroup were heavily pretreated, with a median of six prior treatments. Nevertheless, T-DXd demonstrated efficacy in patients who had stable, treated brain metastases at baseline—similar to its efficacy in the overall population. The confirmed objective response rate was 58.3% in the CNS subgroup and 60.9% for all patients, and the disease control rate was 91.7% in the CNS subgroup and 97.3% for the overall population.
Surprisingly, the median duration of response was actually longer for patients with brain metastases than for all patients (16.9 months vs 14.8 months), and patients with brain metastases had improved progression-free survival as well (18.1 months vs 16.4 months).
“Of note, disease progression in the brain was found in just 8% of patients,” said Dr. Jerusalem. “And among 40 patients without brain lesions at baseline who had progressive disease, just two patients had new brain lesions, and both were late events.”
Finally, Dr. Jerusalem reported that the safety profile in the CNS subgroup was consistent with the non-CNS subgroup and overall population.
There are currently three large, international, phase III studies of T-DXd in HER2-positive breast cancer:
- DESTINY-Breast02: T-DXd vs standard of care after T-DM1
- DESTINY-Breast03: T-DXd vs T-DM1
- DESTINY-Breast04: T-DXd vs chemotherapy (in HER2-low–expressing disease).
Tucatinib Plus Trastuzumab and Capecitabine
Giuseppe Curigliano, MD, PhD, Associate Professor of Medical Oncology at the University of Milano and Head of the Division of Early Drug Development at the European Institute of Oncology in Italy, presented the results of the pivotal HER2CLIMB trial.2 This study randomly assigned patients with HER2-positive, metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1 to treatment with tucatinib vs placebo in combination with trastuzumab and capecitabine. Tucatinib is a U.S. Food and Drug Administration (FDA)-approved oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of EGFR.
Giuseppe Curigliano, MD, PhD
As Dr. Curigliano reported, HER2CLIMB is the first randomized trial completed in patients with HER2-positive metastatic breast cancer that included patients with untreated or previously treated progressing brain metastases. Patients were eligible for enrollment with or without evidence of brain metastases. The primary endpoint of the study was progression-free survival, according to Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review. Secondary endpoints included overall and progression-free survival in patients with brain metastases and confirmed overall survival in patients with measurable disease.
The median number of lines of previous treatment was four for the overall population and three for the metastatic setting, said Dr. Curigliano. This is similar to patient characteristics seen in real-world clinical practice, he added.
Tucatinib in combination with trastuzumab and capecitabine significantly improved progression-free and overall survival, according to Dr. Curigliano, who noted the addition of tucatinib reduced the risk of death by 34% compared with trastuzumab and capecitabine alone. At 2 years, the estimated overall survival was 45% in the tucatinib arm and 27% in the control arm, with a median overall survival of 21 months with tucatinib and 17.4 months with placebo.
“This is an unprecedented result for patients receiving this type of treatment,” said Dr. Curigliano. “In patients with brain metastases, the results are exciting, because there is a 52% reduction in the risk of disease progression or death with tucatinib vs placebo.”
According to Dr. Curigliano, the tolerability profile and low treatment discontinuation rate also allowed for continued HER2 inhibition until disease progression in heavily pretreated patients.
Tucatinib in combination with trastuzumab and capecitabine received approval by the FDA for patients with and without brain metastases who have received one or more prior anti–HER2-based regimens in the metastatic setting. “This combination has the potential to become a new standard of care in this patient population,” Dr. Curigliano concluded.
DISCLOSURE: Dr. Llombart-Cussac reported financial relationships with MedSIR, Initia-Research, Eisai, Celgene-BMS, Lilly, Pfizer, Roche, Novartis, MSD, Tesaro-GSK, Roche, Pierre Fabre, Genomic Health, AstraZeneca, Foundation Medicine, and Agendia. Dr. Jerusalem reported financial relationships with Daiichi Sankyo, Novartis, Roche, Pfizer, Lilly, Amgen, BMS, AstraZeneca, AbbVie, MedImmune, and Merck KGaA. Dr. Curigliano has received advisory/speaker and/or consulting fees from MSD, Mylan, Daiichi Sankyo, Lilly, Pfizer, Merck, Foundation Medicine, Samsung, Celltrion, Seattle Genetics, NanoString, Roche, Novartis, BMS, and Ellipsis and also has received institutional funding from Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, MedImmune, and Bayer.
REFERENCES
1. Jerusalem G, Park YH, Yamashita T, et al: CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. 2020 ESMO Breast Cancer Virtual Meeting. Abstract 138O. Presented May 23, 2020.
2. Curigliano G, Murthy RK, Loi S, et al: Tucatinib vs placebo added to trastuzumab and capecitabine in previously treated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). 2020 ESMO Breast Cancer Virtual Meeting. Abstract 137O. Presented May 23, 2020.
3. Llombart-Cussac A: Discussion: HER2[+] MBC late lines and brain involvement: Crossing the rubicon. 2020 ESMO Breast Cancer Virtual Meeting. Invited discussion of Abstracts 138O and 137O. Presented May 23, 2020.
4. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.
