Trastuzumab Plus Pertuzumab Provides Sustained iDFS Benefit in HER2+ Breast Cancer

A chemotherapy-free, ¹⁸fluorine-fluorodeoxyglucose (¹⁸F-FDG)–PET-based, pathologic complete response (pCR)–adapted treatment regimen comprising trastuzumab (Herceptin) in combination with pertuzumab (Perjeta) with or without endocrine therapy was safe and generated a high 3-year invasive disease-free survival (iDFS) rate in patients with HER2-positive early breast cancer, meeting a coprimary end point of the phase 2 PHERGain trial (NCT03161353).

Findings from a second analysis published in The Lancet showed that at a median follow-up of 43.3 months (range, 0.0-63.0) and a data cutoff of November 4, 2022, the 3-year iDFS rate among patients who received trastuzumab plus pertuzumab with or without oral endocrine therapy was 94.8% (95% CI, 91.4%-97.1%; P = .001). Three-year iDFS outcomes were similar regardless of hormone receptor (HR) status, lymph node status, and HER2 protein expression. Furthermore, the estimated 3-year disease-free survival (DFS) and distant disease-free survival (DDFS) rates in the chemotherapy-free arm were 94.8% (95% CI, 91.4%-97.1%) and 96.5% (95% CI, 94.3%-98.8%), respectively.

“This strategy-based, randomized, noncomparative, multicenter, open-label, phase 2 study showed that an ¹⁸F-FDG-PET-based, pCR-adapted strategy can identify a group of patients with HER2-positive early breast cancer who can safely omit chemotherapy and receive exclusive dual HER2 blockade with trastuzumab and pertuzumab,” senior study author Antonio Llombart-Cussac, MD, PhD, chairman of the Medical Oncology Service at the University Hospital Arnau de Vilanova in Valencia, Spain, and coauthors, wrote in the paper.

The international, open-label PHERGain trial enrolled female patients aged 18 years or older with previously untreated, centrally confirmed, HER2-positive, stage I to IIIA invasive, operable breast cancer with 1 or more 18F-FDG-PET-evaluable lesions. Patients were also required to have an ECOG performance status of 0 or 1, a left ventricular ejection fraction of 55% or greater, and adequate organ function. Patients were excluded from the study if they had stage IV/metastatic disease, bilateral breast cancer, or had received prior treatment for the invasive breast cancer they presented with at study enrollment.

Patients were randomly assigned 1:4 to receive either intravenous (IV) docetaxel (Taxotere) at 75 mg/m2 plus IV carboplatin at an area under the curve of 6 mg/mL per minute, subcutaneous trastuzumab at a fixed dose of 600 mg, and IV pertuzumab at an 840-mg loading dose followed by 420 mg maintenance doses (TCHP; group A) or trastuzumab plus pertuzumab with or without oral endocrine therapy every 3 weeks (group B). Patients in group B with HR-positive disease received oral letrozole (Femara) at 2.5 mg daily or oral tamoxifen (Nolvadex) at 20 mg per day if they were postmenopausal or premenopausal/perimenopausal, respectively. Patients underwent centrally reviewed PET at baseline and after 2 treatment cycles. Patients in group A received 6 cycles of docetaxel plus carboplatin concurrently with trastuzumab and pertuzumab regardless of on-treatment 18F-FDG-PET results. Patients in group B received treatment based on their on-treatment PET results: PET responders, defined as those with a 40% or greater reduction of the SUVmax from baseline to on-treatment 18F-FDG-PET, continued to receive trastuzumab plus pertuzumab with or without endocrine therapy for 6 cycles, and PET nonresponders switched to receive 6 cycles of TCHP.

Patients who discontinued the neoadjuvant phase of the study treatment were allowed to initiate another neoadjuvant therapy or undergo surgery outside of the trial. Surgery consisted of breast conservation or mastectomy with either sentinel lymph node biopsy or axillary dissection, and was conducted 2 to 6 weeks after the last cycle of neoadjuvant therapy.

Following surgery, ¹⁸F-FDG-PET responders in group B who did not achieve a pCR received 6 more cycles of TCHP. All patients in groups A and B completed a maximum of 18 cycles of trastuzumab plus pertuzumab in the absence of progressive disease, unacceptable toxicity, patient withdrawal, or investigator decision to withdraw the patient. Patients received adjuvant endocrine therapy and radiotherapy according to HR status and institutional practices, respectively.

The coprimary end points of PHERGain were pCR in all patients in group B who were PET responders after 2 treatment cycles, as per local assessment, and 3-year iDFS among patients in group B who underwent surgery per protocol.

Between June 26, 2017, and April 24, 2019, 356 patients from 45 hospitals across 7 countries were randomly assigned to group A (n = 71) or group B (n = 285). Across both groups, 66% of patients had HR-positive disease, 48% of patients had lymph node involvement, and 76% of patients had clinical stage II disease. In total, 96% and 99% of patients in groups A and B, respectively, received at least 1 study drug. No patients are still receiving treatment. Among these patients, 89% and 94% in groups A and B, respectively, proceeded to surgery.

PHERGain met its first coprimary endpoint at the first planned analysis. In total, 80% of patients in group B were ¹⁸F-FDG-PET responders, 37.9% (95% CI, 31.6%-44.5%; P < .0001 vs the historical rate) of whom achieved a pCR.²

The most common event observed in the 3-year iDFS analysis was distant recurrence (3%, n = 8).1 Seven of the 8 patients with distant recurrence did not achieve a pCR, 5 were 18F-FDG-PET responders, 6 had node-positive disease, and 2 had stage II node-negative disease. The remaining iDFS events in group B were locoregional ipsilateral relapse (n = 3), second primary non-breast cancer in the ovary (n = 2), and death due to suicide (n = 1).

Among the group B ¹⁸F-FDG-PET responders who achieved a pCR and did not receive chemotherapy during study treatment (n = 86), the estimated 3-year iDFS rate was 96.4% (95% CI, 92.4%-100%). In this population, 3 iDFS events occurred: 1 locoregional ipsilateral relapse and 2 second, non-breast, primary ovarian cancers. Investigators reported no distant recurrence events, and 85 of the 86 patients were free of breast cancer relapse at 3 years post-surgery.

Among the patients in group A who underwent per-protocol surgery (n = 63), the estimated 3-year iDFS, DFS, and DDFS rates were all 98.3% (95% CI, 95.1%-100%). One death occurred in group A, which was attributed to a distant recurrence event.

In groups A and B, respectively, the estimated 3-year event-free survival rates were 98.4% (95% CI, 95.3%-100%) and 93.5% (95% CI, 90.7%-96.5%), and the estimated 3-year overall survival rates were 98.4% (95% CI, 95.3%-100%) and 98.5% (95% CI, 97.1%-100%).

Among the 351 patients included in the safety analysis, 81% of those in group A (n = 55/68) and 86% of those in group B (n = 244/283) received all scheduled cycles of study treatment. The safety analysis included 90% of the group B 18F-FDG-PET responders with pCR (n = 77/86), 88% of the group B 18F-FDG-PET responders without pCR (n = 124/141), and 77% of the group B 18F-FDG-PET nonresponders (n = 43/56). A total of 9% and 2% of patients in groups A and B, respectively, discontinued treatment.

Investigators observed no new safety signals. The most common adverse effects (AEs) among patients who received neoadjuvant or adjuvant chemotherapy were diarrhea, fatigue, stomatitis, anemia, neutropenia, and alopecia. The most common AEs among patients who did not receive chemotherapy as part of the trial treatment were fatigue and diarrhea.

The most common grade 3 or higher hematologic treatment-emergent AEs (TEAEs) were anemia (group A, 7%; group B, 7%), neutropenia (28%; 11%), thrombocytopenia (4%; 4%), and febrile neutropenia (21%; 13%). The most common grade 3 or higher nonhematologic TEAEs were fatigue (group A, 16%; group B, 7%), diarrhea (10%; 6%), nausea (0%; 2%), stomatitis (9%; 1%), alopecia (1%; 1%), vomiting (1%; 2%), and rash (1%; < 1%).

Patients in group A experienced numerically higher rates of TRAEs (62%) and serious AEs (28%) than those in group B (33% and 14%, respectively). 18F-FDG-PET responders with pCR in group B exhibited the lowest incidence of grade 3/4 TRAEs (1%) and no serious AEs.

“Our study offers a new therapeutic alternative to be considered in our daily clinical practice that enables a significant reduction of toxicity for this patient population without compromising efficacy,” the authors concluded.

References

1. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet. 2024;403(10437):1649-1659. doi:10.1016/S0140-6736(24)00054-0
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. 2021;22(6):858-871. doi:10.1016/S1470-2045(21)00122-4