Ongoing Trials Aim to Remove Carboplatin from TCHP and Reduce Treatment Cycles in HER2+ Breast Cancer

Paolo Tarantino, MD

Within the past decade, the HER2-positive breast cancer landscape has demonstrated significant improvements. However, coming off the heels of the 2025 ASCO Annual Meeting, data from the phase 2 CompassHER2 pCR trial (NCT04266249) and the phase 3 neoCARHP study (NCT04858529) have potentially helped move the HER2-positive breast cancer treatment paradigm towards a less intensive chemotherapy regimen.

Currently, the neoadjuvant combination of a taxane, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta; TCHP) represents the standard of care (SOC) in the HER2-positive breast cancer landscape. This was established following data from the phase 2 TRYPHAENA study (NCT01358877) and the phase 3 KRISTINE trial (NCT02131064), which both evaluated neoadjuvant TCHP in patients with HER2-positive breast cancer. In particular, data from TRYPHAENA revealed that neoadjuvant pertuzumab plus trastuzumab, given concurrently with an anthracycline-based or concurrently with a carboplatin-based chemotherapy regimen, demonstrated a lower incidence of left ventricular systolic dysfunction.1 Additionally, findings from KRISTINE determined that neoadjuvant THCP showed a significant increase in the rate of patients achieving a pathologic complete response (pCR) compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab in patients with stage II to III HER2-positive breast cancer.2

Nevertheless, this SOC has continuously been challenged by ongoing trials, ultimately determining whether carboplatin can be omitted from the TCHP regimen and patients can instead receive a taxane with trastuzumab and pertuzumab (THP).

“[The HER2-positive breast cancer treatment paradigm] has shifted. It’s moving, and it keeps on moving,” Jason A. Mouabbi, MD, an assistant professor in the Department of Medical Breast Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive®. “Right now, not only are we going towards using less chemotherapy, but also fewer cycles. The idea is, if [patients with] HER2-positive [breast] cancer are going to respond well, they respond well from the first treatment. Therefore, you don’t need to do 6 cycles of therapy; you can get away with 4 cycles.”

neoCARHP: Saying Goodbye to Carboplatin in TCHP?

Among patients with untreated, stage II to III HER2-positive breast cancer in the neoCARHP trial (n = 774), THP demonstrated a non-inferior pCR rate and improved tolerability at a dosing schedule of 3 weeks compared with TCHP.3 Of note, in patients treated with THP (n = 382), 64.1% achieved a pCR compared with 65.9% in those treated with TCHP (n = 384), representing a difference of –1.8%( 95% CI, –8.5% to 5.0%; P = .0089). Furthermore, 78.2% of patients with ER-negative and/or progesterone receptor (PR)–negative, HER2-positive breast cancer achieved a pCR following THP (n = 142) vs 77.8% of those in the TCHP arm (n = 144) for a difference of 0.4% (95% CI, –9.2%-10.0%). In a similar trend, among those with ER-positive and/or PR-positive, HER2-positive breast cancer, 55.8% vs 58.8% of patients achieved a pCR from the THP (n = 240) and TCHP (n = 240) arms, respectively, representing a difference of –3.0% (95% CI, 11.7%-5.9%). In patients whose breast tumors and nodes were examined, 91.9% (95% CI, 88.7%-94.2%) vs 94.8% (95% CI, 92.1%-96.6%) of patients treated with THP and TCHP, respectively, achieved complete or partial responses.

“The neoCARHP trial was a randomized, phase 3, non-inferiority study designed to determine whether the omission of carboplatin from standard neoadjuvant therapy would compromise efficacy in patients with early-stage HER2-positive breast cancer,” Yara Abdou, MD, explained in an interview with OncLive®. “The primary end point was pCR, and the study was powered to assess whether THP was non-inferior to the more intensive TCHP regimen. The results demonstrated that THP alone met the pre-specified non-inferiority criteria, with pCR rates that were statistically comparable to those achieved with the addition of carboplatin.”

Abdou is an assistant professor of medicine in the Department of Medicine in the Division of Oncology and a leader of the Breast Cancer Clinical Trial Program at the University of North Carolina School of Medicine at Chapel Hill.

Although the implications of utilizing TCHP in HER2-positive breast cancer have set a solid foundation, data from the CompassHER2 pCR and neoCARHP trials could potentially set a new precedent, Mouabbi asserted.

“[Removing carboplatin from THP could be] a game changer because in clinical practice right now, the standard of care is to use TCHP in the US. If we [can use this regimen] without carboplatin, that’s big,” he said. “Our patients tolerate THP so much better than TCHP, so I truly think those results are ready for prime time, and they’re going to be shaping up the care from today. They’re not going to be streamlined until we have the event-free survival data from the CompassHER2 pCR study. However, a lot of doctors, including myself, think this will be practice-changing, and I’m ready to drop the carboplatin. [Overall,] The consensus seemed to have shifted away from carboplatin, and we’ve been ready to make that change.”

CompassHER2 pCR: De-escalating Neoadjuvant THP in HER2-Positive Breast Cancer

Secondary results from the non-randomized CompassHER2 pCR trial revealed that in patients who were treated with at least 1 dose of THP in the overall population (n = 2141), 43.8% (95% CI, 41.6%-45.9%) achieved a pCR.4 Notably, those with estrogen receptor (ER)–negative disease (n = 774) achieved a pCR rate of 63.7% (95% CI, 60.2%-67.1%), and those with ER-positive disease (n = 1337) achieved a pCR rate of 32.5% (95% CI, 30%-35%). Of note, higher pCR rates were significantly associated with clinicopathologic factors, including ER 0 or ER-positivity of 70% or less, HER2 immunohistochemistry (IHC) 3+ compared with HER2 IHC 2+/ISH positive, and receiving weekly paclitaxel vs docetaxel once every 3 weeks.

“The primary goal of CompassHER2 pCR was to determine whether a de-escalated neoadjuvant regimen of 4 cycles of THP could achieve a meaningful 3-year recurrence-free survival [RFS] rate in patients with stage II or III, node-negative HER2-positive breast cancer,” Abdou said. “The study was designed to explore whether a shorter, less intensive approach could effectively treat select patients without compromising long-term outcomes. If successful, this strategy could help reduce overtreatment and improve quality of life by minimizing unnecessary toxicity.”

Paolo Tarantino, MD, a research fellow in the Department of Medicine at the Dana-Farber Cancer Institute in Boston, Massachusetts, highlighted the significance of these data and further, the role genomic and molecular testing could play in the realm of HER2-positive breast cancer.

“The biology of the tumor drove the activity of THP. [Although] we still don’t have survival data from these patients, and follow-up is currently ongoing, we know that more than 40% of the patients [in the overall population] can achieve a pCR within only 12 weeks with a very well tolerated treatment,” he said in an interview with OncLive®. “[These data are] very promising and align with other data in this field, which suggest we may already consider this regimen in the clinic. [THP] is abbreviated and milder, compared with TCHP, which is considered a standard regimen for this disease that includes 18 weeks [of treatment] and carboplatin, so it’s a much tougher regimen. THP, instead, proved to be highly effective in terms of [leading to] pCRs and is very well tolerated.”

The Importance of Genomic and Molecular Testing in HER2-Positive Breast Cancer

With an array of treatment options in the HER2-positive breast cancer space, including monoclonal antibodies, antibody-drug conjugates, and TKI inhibitors, assays are crucial to inform decisions based on pCR, which could help identify whether less intensive treatment is better, Tarantino noted. “Importantly, the recurrence risk score tells you the chances of the tumor recurring—this [genomic test] does help in those situations,” he explained. “HER2DX involves an ERBB2 signature that [determines whether] the tumor is predicted to be HER2-positive. In the future, this will be helpful because, even with IHC and FISH, we’re still not perfect at predicting which tumors are HER2-positive or HER2-negative.”

The HER2DX genomic test integrates data regarding immune responses, luminal differentiation, HER2 expression, with clinical factors, and tumor cell proliferation, and provides precise information to help guide treatment decisions.5 Specifically, the genomic test analyzes 27 genes and incorporates clinical characteristics, such as tumor and nodal stage, to determine 3 key scores, including long-term prognosis, the likelihood of achieving a pCR, and HER2 mRNA expression.

In the CompassHER2 pCR study, investigators utilized the HER2DX genomic test to establish whether high or low HER2DX pCR scores would affect pCR rates.4 Notably, high HER2DX pCR scores were associated with an approximately 40% higher absolute pCR rate compared with a low HER2DX pCR score in patients with ER-negative and ER-positive, HER2-positive breast cancer.

“[HER2DX is] not completely foolproof; however, it’s less likely to get a pCR in patients who have a low HER2DX signature, which is excellent,” Mouabbi emphasized. “This can be used as a tool to escalate for the patient who has low HER2DX pCR scores because they are unlikely to achieve pCR, so you can do more for those patients. For patients with a high HER2DX signature, it could be [sufficient] to give them THP. [Utilizing HER2DX] is not currently standard of care in the United States [US]; in Europe, it is being utilized a lot more.”

Riding the Evolutionary Wave in HER2-Positive Breast Cancer

Within the past 10 years, the HER2-positive breast cancer treatment paradigm has seen significant shifts. A striking change included the recognition that patients with HER2-positive breast cancer can receive less treatment without affecting efficacy, Tarantino noted. Specifically, he explained that data from the phase 2 APT trial (NCT00542451) evaluating adjuvant paclitaxel and trastuzumab in node-negative, HER2-positive breast cancer, and the phase 2 ATEMPT trial (NCT01853748) assessing adjuvant T-DM1 compared with paclitaxel plus trastuzumab in HER2-positive breast cancer have contributed to this growing change. Additionally, another important finding that led to a positive change in the treatment paradigm was the understanding that patients should receive neoadjuvant treatment, except for those with tumors less than 15 cm, he stated.

“These are 2 very different paradigm changes. Giving less for patients with small tumors and giving more to patients with residual disease [before surgery] made our treatment so much more tailored and much more effective, but also overall better tolerated,” he said.

The utilization of de-escalation and escalation strategies has also increased within recent years; however, it’s key to emphasize the need for patient selection, Mouabbi added. Defining the appropriate patient population for these respective approaches is necessary, which is why utilizing more assays and genomic tests, such as HER2DX, has promising potential, he explained. “If [clinical pathological features, including age, stage, and nodal status are incorporated with genomics, we have a much better way to [determine] whether patients are appropriate for de-escalation or escalation,” he said. “That’s what the field is going to be moving toward in the very near future.”

Ongoing trials have made strides towards personalized treatment, along with treatment de-escalation in patients with lower-risk disease, which could one day set a new standard, Abdou said.

“These strategies are particularly promising for patients with stage I or II disease. However, broader adoption depends on the emergence of long-term outcome data and validated biomarkers that can reliably guide treatment intensity. There’s also growing momentum around chemo-free or ADC-based neoadjuvant regimens. Overall, we’re getting closer to being able to ‘right-size’ therapy using biologic tools, but prospective, randomized data will be key to unlocking that next phase of care,” Abdou said. “What’s most exciting is how these trials are redefining what ‘optimal’ treatment looks like, not just in terms of efficacy, but also in terms of patient experience. As oncologists, we are moving toward a more nuanced understanding of HER2-positive breast cancer, where biology, not just staging, guides treatment. The future of HER2-positive care is not just targeted—it’s tailored.”

References

1. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284. doi:10.1093/annonc/mdt182
2. Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018;19(1):115-126. doi:10.1016/S1470-2045(17)30716-7
3. Gao HF, Wu Z, Dong J, et al. De-escalated neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in HER2-positive early breast cancer (neoCARHP): a multicentre, open-label, randomized, phase 3 trial. J Clin Oncol. 2025;43(suppl 16):LBA 500. doi:10.1200/JCO.2025.43.17_suppl.LB
4. Tung NM, Zhao F, DeMichele A, et al. Predicting pathologic complete response (pCR) from clinicopathologic variables and HER2DX genomic test in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the EA1181/CompassHER2 pCR trial. J Clin Oncol. 2025;43(suppl 16):501. doi:10.1200/JCO.2025.43.16_suppl.501
5. Tolaney SM, Tung N, Wolff AC, et al. HER2DX genomic test in early-stage HER2-positive breast cancer. ESMO Open. 2024;9(12):103987. doi:10.1016/j.esmoop.2024.103987