De-Escalation of Therapy Remains a Focus for Early-Stage HER2+ Breast Cancer

Studies investigating the reduction or elimination of chemotherapy from treatment regimens for patients with early-stage HER2-positive breast cancer could help continue to identify those who would benefit most from the de-escalation of therapy, according to Francisco Javier Esteva, MD, PhD.

“Now we are trying to de-escalate chemotherapy by not just removing the anthracyclines, but even removing the taxane. Carboplatin is still a controversial area, but we are trying to find patients who may not need any chemotherapy. That takes time; this is not something you can do [quickly] since we are dealing with a stage of disease that can be cured, and it's hard to compromise [treatment] from the beginning. You have to show that patients are cured, and then we can de-escalate safely,” said Esteva following a presentation on HER2-positive breast cancer at an OncLive^® State of the Science Summit^™ on breast cancer.

In an interview with OncLive, Esteva discussed the management of early-stage HER2-positive breast cancer with a focus on de-escalation strategies, emphasized the ongoing efforts to de-escalate chemotherapy without compromising effective treatments, and expanded on the ongoing debate regarding the role of carboplatin in this setting. Esteva is the interim chief of the Division of Hematology/Oncology and chief of Breast Medical Oncology at Lenox Hill Hospital, and director of Breast Medical Oncology at Northwell Health’s Western region in New York, New York.

OncLive: Could you provide a brief overview of the current standard of care for patients with early-stage HER2-positive breast cancer?

Esteva: In patients with stage I HER2-positive breast cancer, we generally do surgery first and then offer patients weekly paclitaxel and trastuzumab [Herceptin], with trastuzumab given for 1 year.

For patients with stage II or stage III [disease], we use a taxane with or without carboplatin, plus trastuzumab and pertuzumab [Perjeta] in the neoadjuvant setting, based on the phase 2 NeoSphere trial [NCT00545688], where patients received a taxane plus trastuzumab and pertuzumab, and the phase 2 TRYPHAENA trial [NCT00976989], where patients received trastuzumab plus pertuzumab, docetaxel, and carboplatin. The pathologic complete response [pCR] rates were quite high [in both studies]. Patients who achieve a pCR then continue to trastuzumab and pertuzumab for up to 1 year, and for patients who have residual disease [after neoadjuvant therapy], we generally treat them with ado-trastuzumab emtansine [Kadcyla; T-DM1].

Could you expand potential de-escalation strategies for treatment regimens using docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with early-stage HER2-positive breast cancer?

One of the studies we discussed at this meeting was the phase 2 PHERGain study [NCT03161353] presented at the 2023 ASCO Annual Meeting by Javier Cortes, MD, PhD, [of the International Breast Cancer Center, Pangaea Oncology, Quiron Group, in Barcelona, Spain].¹ In this study, patients with stage II or stage III breast cancer were treated in 2 different groups. The first group [group A] received standard docetaxel, carboplatin, trastuzumab, and pertuzumab. Regardless of the response, the first group received 2 cycles of treatment followed by a PET scan, then continued with 4 additional cycles before surgery.

In a second group of patients [group B], those who had response [as assessed by] PET scan after 2 cycles of trastuzumab and pertuzumab without chemotherapy continued with trastuzumab and pertuzumab. If there was no response by PET, they were switched to docetaxel, carboplatin, trastuzumab, and pertuzumab. Then at the time of surgery, if the patient achieved a pCR, they continued with trastuzumab and pertuzumab alone.

There was a group of patients that received only monoclonal antibody therapy—trastuzumab and pertuzumab—from the beginning, had a PET response, went to surgery, had a pCR, and did not receive chemotherapy. Out of the initial 285 patients [in this group], 79.6% of them achieved a PET response. At the time of surgery, 37.9% of PET responders had a pCR after surgery and did not require chemotherapy. The interesting thing they reported was a 3-year invasive disease–free survival rate of 95.4% [in group B], so these were extremely good results.

[This treatment approach] is something that may not be ready for primetime in the United States, given that doing a PET scan after 2 cycles of treatment is not standard of care, but this study was something that really caught my attention. I'd love to explore these opportunities in the future.

What would it take for PET scans after 2 cycles of trastuzumab/pertuzumab to become standard of care in the United States?

This was a small study that started with 356 patients [between both arms]. They had to have a PET scan before [treatment] and a PET scan after 2 cycles. We would have to show similar findings in larger studies with larger populations to identify patients who may not need chemotherapy. This is not part of the [National Comprehensive Cancer Network] guidelines at the moment, and insurance companies may not support this type of testing outside of a clinical trial. Additional studies could help in that regard.

What are the benefits of the subcutaneous formulation of pertuzumab and trastuzumab with hyaluronidase-zzxf (Phesgo) for patients with HER2-positive breast cancer?

Trastuzumab and pertuzumab were given subcutaneously in the phase 3 FeDeriCa trial [NCT03493854]. Based on [data from] the FeDeriCa trial, there was no difference in terms of pharmacokinetics compared with intravenous [trastuzumab and pertuzumab]; the pCR was also the similar whether patients received trastuzumab and pertuzumab intravenously [IV] or subcutaneously.²

The [phase 2] PHranceSCa trial [NCT03674112] showed that patients preferred the subcutaneous formulation compared with [the standard] IV [administration]. The subcutaneous formulation is something we use a lot. This saves us a lot of time, and patients are quite happy.³

What is the importance of the renewed focus in de-escalation treatment?

We started with trastuzumab added to chemotherapy with anthracyclines or taxanes in the metastatic setting. The approval was with paclitaxel because there were cardiac toxicities when [trastuzumab] was used with the anthracyclines. Then in the adjuvant setting, the trastuzumab, pertuzumab, and docetaxel was similar in efficacy to anthracyclines, so we've basically removed anthracyclines from this therapy. That's the first de-escalation that took a few years. Now, we are using mostly trastuzumab, pertuzumab, and docetaxel [with or without carboplatin] in most of these patients, and it takes years to see the survival analysis.

There have been a lot of studies trying to de-escalate therapy since we have gotten such good results with trastuzumab and now with trastuzumab plus pertuzumab. For example, in the initial trials, trastuzumab was given for 1 year. There were several studies looking at 6 months [of trastuzumab] vs 1 year, and they're still not 100% conclusive. The standard of care remains 1 year [of trastuzumab]. However, some studies show that 6 months is probably enough [treatment] for some patients.

Where would you say you stand in terms of the carboplatin debate?

I'm not convinced carboplatin adds that much [benefit] to this regimen. The key is that taxane, [either with] weekly paclitaxel or docetaxel every 3 weeks, and then the main treatment of trastuzumab and pertuzumab. There are no randomized trials in the neoadjuvant setting or even in the adjuvant setting with [docetaxel plus trastuzumab and pertuzumab alone or with carboplatin]. There was a study in the metastatic setting comparing the two regimens, and there was no difference in response rates outside of HER2 therapies. Randomized trials with or without carboplatin have not shown significant improvements in survival.

I use [carboplatin] in patients at higher risk because the pCR rate may be a little bit higher, but not if it compromises their myelosuppression. What I consider the most important part of the backbone which is the taxane. I'm not a big fan of carboplatin in that setting.

References

1. Cortes J, Perez-Garcia JM, Ruiz-Borrego M, et al. 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). J Clin Oncol. 2023;41(suppl 17):LBA506. doi:10.1200/JCO.2023.41.17_suppl.LBA506
2. Tan AR, Im SA, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. doi:10.1016/S1470-2045(20)30536-2
3. O'Shaughnessy J, Sousa S, Cruz J, et al. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study. Eur J Cancer. 2021;152:223-232. doi:10.1016/j.ejca.2021.03.047