HER2-Directed Therapies Continue to Shape Improved Breast Cancer Outcomes

Debu Tripathy, MD

As the treatment of HER2 in breast cancer becomes better defined, the HER2-directed antibody trastuzumab (Herceptin) has earned a place as a standard agent in several stages of HER2-positive disease, and additional HER2-targeted drugs may build on historical treatment successes achieved with this agent, according to Debu Tripathy, MD.

“The early studies of trastuzumab in [patients with] very low-risk cancer, stage I cancers, had shown, in general, better outcomes... However, we know in [patients] with high-risk disease, trastuzumab is helpful, so one of the dilemmas is: How can we de-escalate treatment in these patients?” Tripathy said during a presentation at the 41st Annual Miami Breast Cancer Conference.¹

In the presentation, Tripathy provided insights on the management of HER2-positive breast cancer, including the evolving role of trastuzumab in this population, data for the combination of trastuzumab and pertuzumab (Perjeta), and how trastuzumab compares with ado-trastuzumab emtansine (T-DM1; Kadcyla).

Tripathy is a professor and chairman in the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Trastuzumab Enters the HER2-Positive Breast Cancer Scene

Historically, when HER2 amplification was found to be a poor prognostic factor in breast cancer, therapeutic research aimed to develop agents that targeted the HER2 ligand, Tripathy began.

“It is truly a sign of oncogene addition in the sense that therapies for HER2-positive breast cancer, even after resistance, continue to focus on targeting HER2,” Tripathy said. “[Targeting HER2 has] maintained [an] ability to drive responses.”

Tripathy noted that current treatment strategies for patients with HER2-positive breast cancer include therapeutic de-escalation, especially for patients with early-stage or stage I disease. However, appropriate and selective therapeutic escalation must also be considered for patients at high risk for disease recurrence.

Trastuzumab is a 95% human IgG1 antibody that activates antibody-dependent cytotoxicity and binds to the HER2 antigen. “As a humanized antibody, [trastuzumab] is able to activate the immune system but not develop an antibody reaction itself, since it’s not a foreign protein,” Tripathy explained.

Early-stage trials with adjuvant trastuzumab that were conducted in patients with HER2-positive breast cancer demonstrated reduced recurrence rates in patients who were randomly assigned to receive trastuzumab. Findings from a pooled analysis by the Early Breast Cancer Trialists’ Collaborative Group of adjuvant trastuzumab in patients with early-stage, HER2-positive breast cancer mirrored those early research findings. The 10-year recurrence rates were 22.9% with trastuzumab vs 31.9% with control regimens, and the 10-year breast cancer mortality rates were 14.7% and 21.1%, respectively.²

“The results are better now…with the addition of other antibody therapies,” Tripathy noted.¹

The single-arm, phase 2 APT trial (NCT00542451) investigated trastuzumab plus paclitaxel in patients with 1- to 3-cm/node-negative HER2-positive breast cancer.3 The 5-year disease-free survival (DFS) rate was 96.3% (95% CI, 94.4%-98.3%), and the 7-year DFS rate was 93.3% (95% CI, 90.4%-96.2%).

“On this basis, [trastuzumab] has now been adopted as the standard of care [SOC] for patients with stage I breast cancer,” Tripathy emphasized.¹

T-DM1 Challenges Trastuzumab As a Tolerable ADC

To further de-escalate breast cancer therapy, the phase 2 ATEMPT trial (NCT01853748) compared toxicities and estimated DFS differences between trastuzumab plus paclitaxel (n = 114) and T-DM1 (n = 383) in patients with stage I HER2-positive breast cancer.4 The 3-year DFS rate in the T-DM1 arm was 97.8% (95% CI, 96.3%-99.3%). Although this trial was not powered to evaluate the efficacy of trastuzumab plus paclitaxel, the 3-year DFS rate in this arm was 93.4% (95% CI, 88.7%-98.8%).

In the T-DM1 arm, the rates of symptomatic congestive heart failure and asymptomatic left ventricular ejection fraction declines were low, at 0.8% and 1.3%, respectively. In the trastuzumab arm, these values were 0.9% and 6.1%, respectively. Importantly, the rates of long-term toxicities were lower in the T-DM1 arm vs the trastuzumab arm. Grade 3 or higher nonhematologic toxicities occurred in 10% and 11% of patients in the T-DM1 and trastuzumab arms, respectively, and grade 2 or higher neurotoxicity occurred in 11% and 23% of patients, respectively.

Tripathy noted that larger trials are attempting to validate the ATEMPT findings and may change the SOC and de-escalate therapy for patients with stage I disease.¹

Trastuzumab Partners With Pertuzumab in High-Risk Disease

“The advent of another HER2 antibody that targets the dimerization domain of HER2 has been shown to be not really active as a single agent, but active when you combine with trastuzumab,” Tripathy said regarding pertuzumab.

Based on this principle, the phase 2 NeoSphere trial (NCT00545688) evaluated the addition of pertuzumab to trastuzumab-based regimens in patients with HER2-positive breast cancer. The pathologic complete response (pCR) rate in patients who received trastuzumab plus docetaxel and pertuzumab (group B) was 45.8%, compared with 29.0%, 16.8%, and 24.0% with trastuzumab plus docetaxel (group A), trastuzumab plus pertuzumab (group C), and pertuzumab plus docetaxel (group D), respectively.5 Based on these findings, the combination of trastuzumab, docetaxel, and pertuzumab was granted accelerated FDA approval in 2012 for use in the neoadjuvant and adjuvant setting for patients with stage II or higher breast cancer, as well as for patients with metastatic disease.⁶

To finalize this FDA approval, the phase 3 APHINITY trial (NCT01358877) compared standard adjuvant chemotherapy plus trastuzumab alone (n = 2402) or with pertuzumab (n = 2400) in patients with HER2-positive early-stage breast cancer.7 At a median follow-up of 45.4 months, the 4-year invasive DFS (iDFS) rates were 92.3% and 90.6% in the pertuzumab and placebo arms, respectively (HR, 0.81; 95% CI, 0.66-1.00; P = .045). Supported by these findings, chemotherapy plus trastuzumab and pertuzumab has become the adjuvant SOC for patients with stage II or higher HER2-positive breast cancer, Tripathy emphasized.¹

KATHERINE Compares Trastuzumab With T-DM1

Notably, Tripathy explained that patients with HER2-positive breast cancer who achieve pCR after HER2-directed neoadjuvant therapy often achieve better DFS outcomes compared with those who do not achieve pCR.

“Patients who have residual disease after neoadjuvant therapy are the ones [in whom] we might need to do [treatment] escalation, and it might allow us to select our treatments better,” Tripathy added.

The phase 3 KATHERINE trial (NCT01772472) was designed to investigate T-DM1 vs trastuzumab in patients with HER2-positive early-stage breast cancer who did not achieve a pCR with prior neoadjuvant therapy.8 In KATHERINE, the 3-year iDFS rate was significantly longer in patients who received T-DM1 vs those who received trastuzumab, at 88.3% vs 77.0%, respectively (unstratified HR, 0.50; 95% CI, 0.39-0.64; P < .0001). Tripathy noted that T-DM1 is now the SOC for patients with HER2-positive disease who do not achieve pCR with neoadjuvant trastuzumab-based therapy.¹

Extended follow-up data from KATHERINE showed that at a median follow-up of 8.4 years, T-DM1 continued to elicit robust iDFS outcomes, with a 7-year iDFS rate of 80.8% vs 67.1% in the trastuzumab arm (unstratified HR, 0.54; 95% CI, 0.44-0.66; P < .0001). Furthermore, findings from the second overall survival (OS) interim analysis demonstrated 7-year OS rates of 89.1% with T-DM1 vs 84.4% with trastuzumab (unstratified HR, 0.66; 95% CI, 0.51-0.87; P = .0027).

Further Research Aims to Combat Residual Disease

Ongoing phase 3 trials, such as compassHER2 RD (NCT04457596) and DESTINY-Breast05 (NCT04622319), are evaluating ways to improve upon the outcomes observed in KATHERINE, particularly for patients who will still experience disease recurrence and die of their disease after receiving T-DM1, Tripathy explained.

“These trials…will hopefully point us in the right direction to better improve the outcomes of this higher-risk group,” Tripathy said.

He also contextualized findings from the phase 3 ExteNET trial (NCT00878709), which evaluated neratinib (Nerlynx) vs placebo in 2840 patients with HER2-positive breast cancer who had completed prior adjuvant trastuzumab and chemotherapy.9 At a median follow-up of 8 years, the iDFS rates were 90.8% (95% CI, 88.1%-93.0%) with neratinib vs 85.7% (95% CI, 82.6%-88.3%) with placebo (HR, 0.58; 95% CI, 0.41-0.82; 2-sided P = .002). Tripathy emphasized that patients with hormone receptor (HR)–positive disease benefitted the most from neratinib therapy in this trial.

“[Neratinib] is a treatment that can be used in higher-risk disease, and we use it [for patients with] HR-positive [disease],” Tripathy noted.¹

He explained that patients with node-negative, HER2-positive breast cancer or tumors that are smaller than 2 cm can receive de-escalated therapy, and those with node-positive disease or tumors that are greater than 2 cm should receive neoadjuvant therapy. In the latter patient population, pCR status after neoadjuvant therapy can guide subsequent treatment decisions, such as T-DM1 in patients with no pCR and neratinib for patients with HR-positive disease.

In the future, HER2DX gene profiling score may serve as a more accurate way to predict patient responses to therapy, and PET scans may identify patients whose disease resolves with de-escalated therapy on the basis of pCR, Tripathy emphasized. Meanwhile, in the surgical setting, neoadjuvant therapy can improve breast conservation rates, he noted.

“This tells us that we can de-escalate surgery with the use of these therapies,” Tripathy concluded.

References

1. Tripathy D. Management of HER2+ Breast Cancer. Presented at: 41st Annual Miami Breast Cancer Conference. March 7-10, 2024; Miami, Florida.
2. Early Breast Cancer Trialists’ Collaborative Group. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139-1150. doi:10.1016/S1470-2045(21)00288-6
3. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2019;37(22):1868-1875. doi:10.1200/JCO.19.00066
4. Tolaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emtansine versus paclitaxel in combination with trastuzumab for tage I HER2-positive breast cancer (ATEMPT): a randomized clinical trial. J Clin Oncol. 2021;39(21):2375-2385. doi:10.1200/JCO.20.03398
5. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32. doi:10.1016/S1470-2045(11)70336-9
6. Center for Drug Evaluation and Research. Approval package for: application number: 125409Orig1s000. FDA. 2012. Accessed March 9, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000Approv.pdf
7. Loibl S, Jassem J, Sonnenblick A, et al. Adjuvant pertuzumab and trastuzumab in patients with early HER-2 positive breast cancer in APHINITY: 8.4 years’ follow-up. Ann Oncol. 2022;33(9):986-987. doi:10.1016/j.annonc.2022.06.009
8. Loibl S, Mano MS, Untch M, et al. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. Presented at: 2023 San Antonio Breast Cancer Symposium. December 5-9, 2023; San Antonio, Texas. GS03-12.
9. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7. doi:10.1016/j.clbc.2020.09.014