Strategy may enable some patients with HER2-positive breast cancer to avoid chemotherapy
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Key takeaways:
- The PHERGain trial met its second primary endpoint with a 3-year invasive DFS rate of 95.4%.
- The adaptive response strategy “might identify 30% of patients who may be cured without the need for chemotherapy.”
CHICAGO — A chemotherapy de-escalation strategy involving dual HER2 blockade resulted in high rates of 3-year invasive DFS among patients with HER2-positive early breast cancer, according to study results presented at ASCO Annual Meeting.
The findings appeared consistent with those of studies that explored a combination of neoadjuvant chemotherapy and dual HER2-targeted treatments, with no unexpected safety signals.
“This strategy might identify 30% of patients who may be cured without the need for chemotherapy and only be treated with the combination of trastuzumab [Herceptin, Genentech], pertuzumab [Perjeta, Genentech] and endocrine therapy, if appropriate,” Javier Cortés, MD, PhD, of the International Breast Cancer Center in Madrid and the faculty of biomedical and health sciences in the department of medicine at Universidad Europea de Madrid, said during a presentation.
Background, methodology
Improved patient outcomes with targeted therapies for HER2-positive breast cancers have prompted researchers to investigate various chemotherapy de-escalation strategies.
The randomized phase 2 PHERGain trial evaluated one such strategy in HER2-positive early breast cancer based on early metabolic response to neoadjuvant trastuzumab and pertuzumab by PET/CT and pathologic response.
Researchers randomly assigned 356 patients with centrally-confirmed, stage I to stage IIIA HER2-positive breast cancer in a 1:4 ratio to chemotherapy plus trastuzumab and pertuzumab (group A, n = 71) or two cycles of trastuzumab and pertuzumab with or without endocrine therapy (group B, n = 285).
Patients in group B who achieved a PET response could receive another six cycles of trastuzumab and pertuzumab, and those who did not could receive six cycles of chemotherapy plus trastuzumab and pertuzumab. After surgery, those who achieved pathologic complete response (pCR) could remain on the chemotherapy-free regimen, whereas those who did not could receive chemotherapy added to trastuzumab and pertuzumab.
A previous analysis of the trial showed 86 of 227 PET responders achieved a pCR (37.9%, 95% CI, 31.6-44.5).
At ASCO, Cortes presented results of the second primary endpoint: 3-year invasive DFS among patients in group B who underwent surgery.
Results
The trial met the secondary primary endpoint, with a 3-year invasive DFS rate of 95.4% (95% CI, 92.8-98). Twelve invasive DFS events occurred after median follow-up of 43.3 months (range, 2.4-63). These consisted of eight distant recurrences, three locoregional ipsilateral recurrences and one unrelated death with no recurrence.
A subgroup analysis of the 86 PET responders who achieved a pCR and did not receive chemotherapy showed a 3-year invasive DFS rate of 98.8% (95% CI, 96.3-100), with only one invasive event (locoregional ipsilateral recurrence).
Group A had a higher rate of grade 3 of higher treatment-related adverse events (61.8% vs. 32.9%) and serious adverse events (27.9% vs. 13.8%) than group B. Patients in group B who did not receive chemotherapy had the lowest incidence of grade 3 or higher treatment-related adverse events (1.2%) and no serious adverse events.
No patients died of causes related to treatment.
Perspective
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Elisa Krill-Jackson, MD
The PHERGain trial challenges us to de-escalate therapy in appropriate patients using personalized medicine and real-time response to therapy to adjust treatment.
This trial has a number of unique features, including using a non-chemotherapy treatment of only targeted agents in the experimental arm and using PET to assess responsiveness and adjusting therapy accordingly. I think this is a remarkable advancement in safely treating our patients to achieve the highest chance of cure with the least toxicity.
Given the large volume of data regarding pCR in the standard-of-care group, the trial could be randomized 1:4 with a larger experimental group, allowing a smaller sample size. The population of patients reflects well the real-world population we see in our clinics.
The standard-of-care approach had a 2 percentage-point higher distant DFS rate and 3 percentage-point higher invasive DFS rate than the full experimental arm. This approach makes it difficult in patients with a clinical complete response who go on to have surgery and do not have a pCR to determine who may benefit from additional adjuvant therapy with TDM-1 (Kadcyla, Genentech), as shown in the KATHERINE trial, and therefore may somewhat jeopardize these patients’ outcomes.
These findings are exciting and may allow more than a third of patients with HER2-positive disease to avoid the toxicity of chemotherapy, but we need more data before applying this strategy in the clinic. We need biomarkers, including clinical and genomic analysis, to allow us to predict which patients have the highest chance of obtaining a pCR.
Reference:
von Minckwitz G, et al. N Engl J Med. 2019:doi:10.1056/NEJMoa1814017.
University of Miami Miller School of Medicine
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Cortés J, et al. Abstract LBA506. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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