PHERGain: Adapted-Response Trial Guides Treatment With Dual HER2 Blockade Alone

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The phase II PHERGain trial, which employed a response-adapted strategy in the treatment of early-stage, HER2-positive breast cancer, has shown promising results for the selective use of HER2 blockade and de-escalation of chemotherapy.1 Nearly all patients assigned to skip chemotherapy prior to surgery for early-stage, HER2-positive breast cancer were without a recurrence at 3 years.

The noncomparative randomized study, whose results were reported at the 2023 ASCO Annual Meeting,1 used a response-adapted design to identify early responders by fluorine-18–fluorodeoxyglucose (F-18–FDG)–positron-emission tomography (PET) and pathologic complete responders after neoadjuvant therapy who might be effectively treated with trastuzumab and pertuzumab, minus the standard chemotherapy.

“The 3-year invasive disease–free survival in the group of patients treated with this adapted design was 95.4%. Unfortunately, we had nine metastatic events, but this compares amazingly well with what we might expect with the standard of care of chemotherapy, trastuzumab, and pertuzumab,” said Javier Cortés, MD, PhD, of the Ramón y Cajal University Hospital, Madrid. “This strategy identifies about one in three patients with HER2-positive, early-stage breast cancer who can safely omit chemotherapy, with significantly reduced toxicity.”

This strategy identifies about one in three patients with HER2-positive, early-stage breast cancer who can safely omit chemotherapy, with significantly reduced toxicity.
— Javier Cortés, MD, PhD

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Of 86 patients who never received chemotherapy, 1 had a recurrence of cancer (a locoregional ipsilateral recurrence, not metastasis). The 3-year invasive disease–free survival rate of 95.4% (P < .001) met the study’s primary endpoint.

Study Rationale

HER2 inhibition plus chemotherapy has become the standard of care for HER2-positive, early-stage breast cancer, with dual HER2 blockade with trastuzumab and pertuzumab, plus chemotherapy, as an effective escalation strategy for patients at high risk for disease recurrence. However, there is now evidence that dual anti-HER2 therapy alone, without chemotherapy, may also be associated with improved survival and achievement of high pathologic response rates—comparable to those observed with dual HER2 blockade plus chemotherapy.

The question is which patients would be suitable for this scaled-down approach. The answer may lie with response-adapted clinical trials such as PHERGain. The PHERGain trial employed early metabolic evaluation with PET imaging to recognize patients with an increased probability of a pathologic complete response, Dr. Cortés noted.

About PHERGain

PHERGain enrolled patients from 45 European centers who had HER2-positive, stage I to IIIA breast cancer and whose tumors were at least 1.5 cm. Approximately half the patients had lymph node–positive disease, about two-thirds had hormone receptor–positive disease, and more than three-quarters were immunohistochemistry (IHC) 3+ for HER2 status.

Patients in PHERGain received either HER2 blockade plus chemotherapy—docetaxel, carboplatin, trastuzumab, and pertuzumab—or HER2 therapy alone with trastuzumab and pertuzumab. For the first phase of treatment, patients were randomly assigned 1:4 to the following groups: 

  • Group A: HER2 blockade plus chemotherapy (TCHP): docetaxel, carboplatin, trastuzumab, pertuzumab for two cycles (n = 71)
  • Group B: HER2 blockade alone (PH): pertuzumab, trastuzumab for two cycles (n = 285).

After two cycles of the assigned treatment, patients underwent total-body F-18–FDG–PET scans. Patients were considered PET responders if the scan showed a reduction in breast lesions of at least 40% from baseline (patients found to have metastases will be analyzed later). Thereafter, groups A and B followed this path:

  • Responders in the HER2 blockade–alone group (group B) continued with dual HER2 blockade for six more cycles (with the addition of endocrine therapy if indicated). 
  • Nonresponders in the HER2 blockade–alone group (group B) were switched to the TCHP group for six more cycles. 
  • Regardless of response, patients assigned to the HER2 blockade plus chemotherapy group (group A) remained there regardless for four more cycles of TCHP.

Upon completion of chemotherapy, patients underwent surgery and were assessed for pathologic complete response. The original TCHP group then switched over to receive adjuvant PH for 12 cycles. In the original PH (HER2 blockade alone) group, patients with complete responses received 10 cycles of adjuvant PH, whereas those without a pathologic complete response switched over to adjuvant TCHP for six cycles plus PH for four cycles. Patients with hormone receptor–positive disease in all arms also received adjuvant endocrine therapy.

The primary endpoints focused on group B: the HER2 blockade–alone arm. The first was pathologic complete response in PET responders (ypT0/isN0), and the second was 3-year invasive disease–free survival in that arm.

Primary Endpoints Met

The primary results were published in 2021 in The Lancet Oncology.2 The new analysis tracked patients for 3 years after they underwent surgery, calculating outcomes for 63 patients in group A and 267 patients in group B (the focus of this report).


  • The PHERGain trial in patients with early-stage, HER2-positive breast cancer aimed to identify patients for whom dual HER2 blockade, without chemotherapy, may be sufficient.
  • In the adapted-response (ie, the HER2 blockade–alone) group, nearly 80% of patients achieved a response by PET; the 3-year invasive disease–free survival rate was 95.4%.
  • In 37% of PET responders, a complete pathologic response was also achieved. Thus, this group never received any chemotherapy, yet their 3-year invasive disease–free survival rate was 98.8%.

A response on PET imaging was achieved after two cycles of HER2 blockade without chemotherapy by 79.6% of patients in that arm, and a pathologic complete response after surgery was achieved by 37.9% (P < .001, based on a null hypothesis of ≤ 20% rate); this 37.9% of patients never received chemotherapy. The pathologic complete responses were observed in patients with both HER2 IHC 2+ and IHC 3+, in patients with stage II and stage III disease, and in patients with hormone receptor–positive and –negative tumors, Dr. Cortés reported.

The co-primary endpoint of 3-year invasive disease–free survival was met, as just 12 patients experienced an event, although 15 events were expected. This translated into a 3-year invasive disease–free survival rate of 95.4% (P < .001), a result that is “in line with that reported using the combination of chemotherapy and HER2-targeted therapies for the same patient population,” Dr. Cortés pointed out.

There were 86 patients in the HER2 blockade–alone group (group B) who achieved both a PET response and a pathologic complete response, qualifying them for skipping chemotherapy. Only one of these patients experienced an event (a regional recurrence), yielding a 3-year invasive disease–free survival rate of 98.8% for that patient subgroup.

Group A, who were treated with dual HER2 blockade plus chemotherapy, experienced more grade ≥ 3 treatment-related adverse events (61.8%) than group B altogether (32.9%); rates were much higher for both these groups than for the group B patients who did not require chemotherapy (1.2%). For these three subsets, treatment-related adverse events leading to treatment discontinuation were seen in 8.8%, 2.1%, and 2.1%, respectively. 


DISCLOSURE: The study was funded by Roche and sponsored by MEDSIR. Dr. Cortés reported financial relationships with Roche, Celgene, AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Cellestia, Seattle Genetics, Erytech, Athenex, Polyphor, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, MEDSIR, and Nektar Pharmaceuticals.


1. Cortés J, Pérez-García JM, Ruiz-Borrego M, et al: 3-year invasive disease-free survival of the strategy-based, randomized phase II PHERGain trial evaluating chemotherapy de-escalation in human epidermal growth factor receptor 2-positive early breast cancer. 2023 ASCO Annual Meeting. Abstract LBA506. Presented June 2, 2023. 

2. Pérez-García JM, Gebhart G, Ruiz Borrego M, et al: Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): A multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol 22:858-871, 2021.

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