Strategies emerge for chemotherapy de-escalation in HER2-positive breast cancer

Two studies presented during the ASCO20 Virtual Scientific Program show the potential to de-escalate chemotherapy in the setting of dual HER2 blockade for patients with HER2-positive breast cancer. In the PHERGAIN trial, researchers showed that early evaluation of metabolic response using ¹⁸F-FDG PET/CT could help identify patients who will develop a pathologic complete response (pCR) to dual HER2 blockade alone, potentially allowing them to avoid chemotherapy [1].

The PHERGAIN trial, presented by Javier Cortés, MD, PhD, of the Vall d´Hebron Institute of Oncology, in Barcelona, included 356 patients with stage I-IIIA HER2-positive breast cancer. They were randomly assigned 1:4 to receive docetaxel and carboplatin along with trastuzumab and pertuzumab (TCHP; Arm A, 71 patients), or trastuzumab and pertuzumab without chemotherapy but with endocrine therapy in the presence of an estrogen receptor–positive tumor (Arm B, 285 patients). The Figure outlines the study schema.

Patients underwent a PET scan after two cycles of therapy; in Arm B, responders (defined as a SUV_max reduction of at least 40%) received six cycles of dual HER2 blockade (trastuzumab/pertuzumab with endocrine therapy), while nonresponders received six cycles of the TCHP regimen. Following surgery, PET responders in Arm B who achieved a pCR received dual HER2 blockade for up to 1 year, meaning they never received chemotherapy; those without a pCR received TCHP followed by dual HER2 blockade.

A total of 79.6% of those evaluated by PET imaging were responders. Of those, 37.9% achieved a pCR, which Dr. Cortés said meant that the null hypothesis can be rejected (p < 0.001). The pCR rate among patients in Arm B who were nonresponders was 25.9%.

In all 285 patients in Arm B, the pCR rate was 35.4%; in Arm A, where all patients received chemotherapy, it was 57.7% (p < 0.01). In Arm A, 65.6% of those who were responders on the PET scan achieved a pCR, compared with 10% of those who were nonresponders (p < 0.01).

There were no significant differences with regard to breast-conserving surgery between the two arms, or between PET responders and nonresponders.

In Arm A, 58.8% of patients had a grade 3/4 treatment-related adverse event (AE); in Arm B nonresponders, who also received chemotherapy, that rate was 44.6%. In contrast, only 1.3% of PET responders in Arm B had such an AE. No patients who did not receive chemotherapy discontinued treatment due to an AE.

Depending on results from an ongoing evaluation of 3-year invasive disease-free survival (iDFS), Dr. Cortés said, “this strategy could select a group of HER2-positive early breast cancer patients who would not need chemotherapy.”

Sara A. Hurvitz, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, was the discussant for the abstract. She highlighted the “outstanding” adverse event rate in those who did not receive chemotherapy. “I think PET imaging after several cycles of therapy is very promising to assess the tumor responsiveness,” she said, adding that it will be important to see the iDFS rate.

Figure. PHERGAIN Study Design [1]

Abbreviations: C, carboplatin; D, docetaxel; EBC, early breast cancer; ETx, endocrine therapy (letrozole post-menopausal/tamoxifen pre-menopausal) adjuvant ETx up to 3 years from surgery; PET, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography; H, trastuzumab SC; HER2, human epidermal growth factor receptor 2; iDFS, invasive disease-free survival; MRI, magnetic resonance imaging; P, pertuzumab IV; R, randomization; TCHP, trastuzumab, pertuzumab, docetaxel, and carboplatin.^ⱡAll hormonal receptor-positive patients will receive ETx concomitantly with PH (except on chemotherapy).*PET Responders: RECIST responders after cycle 2 with SUVmax reduction ≥40%*Pathological complete response (ypT0/isN0)

 

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   1. Cortes J, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract

Posted on 8 September 202029 February 2024