3-year invasive disease-free survival (iDFS) of the strategy-based, randomized phase II PHERGain trial evaluating chemotherapy (CT) de-escalation in human epidermal growth factor receptor 2-positive (HER2[+]) early breast cancer (EBC).

Abstract

LBA506 Background: PHERGain is assessing the feasibility of a CT-free treatment based on a dual HER2 blockade with trastuzumab and pertuzumab (HP) in patients (pts) with HER2[+] EBC using a PET-based, pathologic complete response (pCR)-adapted strategy. In an earlier analysis of this study, a total of 227 (79.7%) of 285 pts included in group B were PET-responder (RX), of whom 86 of 227 (37.9%, 95% CI, 31.6 to 44.5; p<0.0001) achieved a pCR, reaching the first primary endpoint (Perez-Garcia JM, Lancet Oncol 2021). Methods: Details of the trial design and study population have been previously reported. Here, we present the results of the second primary endpoint, 3-year iDFS, among pts included in group B who underwent surgery based on an intent-to-treat (ITT) analysis. In brief, group B included centrally-confirmed, stage I-IIIA, HER2[+] EBC pts that were initially treated with HP (± endocrine therapy), introducing CT in pts without PET response after two treatment cycles and/or pCR. The binomial design tested the null hypothesis that the true 3-year iDFS rate was ≤89.0% against the alternative that the 3-year iDFS was >95%. We estimated that enrolling 284 pts in group B would provide 80% power at a nominal level of one-sided α of 0.025, assuming a 25% dropout rate. Results: Between June 26, 2017 and April 24, 2019, 356 pts were randomly assigned (71 pts in group A and 285 pts in group B) and 63 (89.0%) and 267 (93.7%) pts proceeded to surgery in groups A and B, respectively. In group B, the 3-year iDFS rate for the ITT population was 95.4% (95% CI, 92.8 to 98), meeting the second primary endpoint (p<0.001). After a median follow-up of 43.3 months (range, 2.4-63.0), a total of 12 iDFS events were reported, including eight distant recurrences (3.0%), three locoregional ipsilateral recurrences (1.1%), and one non-related death (0.4%). Among group B/PET-RX pts with pCR that did not receive CT as part of study treatment (n = 86), only one patient had an invasive event (locoregional ipsilateral recurrence) for a 3-year iDFS rate of 98.8% (95% CI, 96.3 to 100.0). Treatment-related adverse events (AEs) and serious adverse events (SAEs) were higher in pts allocated to group A than to group B (grade ≥3, 61.8% vs. 32.9% [p<0.001]; SAEs, 27.9% vs. 13.8% [p=0.01]). Group B/PET-RX pts with pCR presented the lowest incidence of treatment-related grade ≥3 AEs (1.2%) without any SAEs. No treatment-related deaths were reported. Conclusions: Among HER2[+] EBC pts, a PET-based, pCR-adapted strategy was associated with a substantial 3-year iDFS. These results appear comparable to those reported in several studies for the combination of neoadjuvant CT and dual HER2 blockade. This strategy identifies about a third of HER2[+] EBC pts who may safely omit CT with significantly reduced toxicity. Clinical trial information: NCT5732164 .

HER2-Positive Early Breast Cancer: Time for Ultimate De-Escalation?

“…A total of 36% of patients in the chemotherapy-free cohort achieved a pCR, compared to 91% in the paclitaxel plus trastuzumab/pertuzumab group. After a median follow-up of 60 months, there were numerical but not significant differences between the treatment groups regarding survival endpoints (5-year iDFS: 98% [95% CI [84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] in the chemotherapy group vs. 87% [95% CI [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] in the chemo-free group, HR 0.32, 95% CI 0.07-1.49; p = 0.15; relapse-free survival: 98% [95% CI [84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] vs. 89% [95% CI 79-94], HR 0.41, 95% CI 0.09-1.91; p = 0.25); distant DFS: 98% [95% CI…”

“…Another approach to optimized patient selection was tested in the PHERGain trial. Here, imaging tools were used to identify patients who are likely to benefit from de-escalated neoadjuvant treatment [ 85 , 86 ]. In this study, 356 patients with HER2-positive tumors were randomly allocated to two cycles of conventional TCHP regimen (docetaxel/carboplatin/trastuzumab/pertuzumab) vs. chemo-free trastuzumab/pertuzumab, combined with endocrine treatment in triple-positive patients.…”

“…However, when all patients in the experimental arm were considered, the iDFS was lower than in the standard arm (95.4% vs. 98.3%), despite the fact that all patients with non-pCR after chemo-free therapy were recommended six courses of TCHP after surgery. The study is ongoing and OS data are pending, but nevertheless PET imaging seems to be a promising tool to distinguish responders from non-responders [ 85 , 86 ].…”

HER2+ Early Breast Cancer: From Escalation via Targeted and Post-Neoadjuvant Treatment to De-Escalation

“…Subsequently, CTx-free adjuvant treatment (H + P) was administered to patients with pCR, while those with non-pCR additionally received CTx. 3-year iDFS in patients who were initially randomized to H + P and then underwent response-guided therapy was 95.4% (98.8% in those who never received CTx) and 98.3% in patients on continuous neoadjuvant CTx+H+P therapy followed by adjuvant H + P [54]. Another marker of early response is a low cellularity in on treatment biopsies (alone or in combination with Ki67 decrease or other cellular markers) which has been shown to be associated with pCR or survival in several trials (PAMELA [NCT01973660], WSG-TP-II [NCT03272477], WSG-ADAPT-HR+/HER2+, and WSG-ADAPT-HER2+/HR- [47, 49, 55, 56]).…”

Breast Cancer Outcome: What Have We Achieved

“…In addition, the recently presented PHERGain trial assessed the feasibility of a chemotherapy-free treatment with a dual HER2+ blockade only by using a PET scanbased judgement of early response after two cycles. This strategy identified about one third of HER2+ early breast cancer patients who may safely omit chemotherapy with significantly reduced toxicity [3]. Despite these impressive results, the omission of chemotherapy in HER2+ responders is not yet standard of care.…”