Key Data Inform Treatment Decisions in Early HER2+ Breast Cancer

The growing number of treatments within the HER2-positive breast cancer armamentarium signals a need to redefine and tailor neoadjuvant and adjuvant strategies to individual patients, said Sarah M. Tolaney, MD, MPH, in a presentation during the 19th Annual International Congress of the Future of Breast Cancer® East meeting.

“We’ve learned that we can change long-term outcomes for our patients with HER2-positive disease by adapting adjuvant therapy based on response to preoperative therapy,” said Tolaney, associate director of the Susan F. Smith Center for Women’s Cancers and director of Clinical Trials and Breast Oncology at Dana-Farber Cancer Institute. “This is really a paradigm shift. This adaptive treatment approach puts an end to future adjuvant trials that are focused on stage II/III patients.”

At the meeting, Tolaney discussed key data to inform treatment de-escalation and escalation, the push toward less chemotherapy-intensive regimens and more precision medicine-based approaches, and where future research efforts should be focused in the HER2-postive breast cancer paradigm.

Era of Targeted Therapy Signals Treatment De-Escalation

Substitution of traditional chemotherapy regimens with less toxic chemotherapies or targeted therapies has been an area of significant interest in the HER2-positive breast cancer space.

Final results of the randomized phase 3 BCIRG-006 trial1 confirmed that adjuvant trastuzumab (Herceptin)-containing regimens elicited significant disease-free survival (DFS) benefit in patients with operable node-positive or high-risk node-negative HER2-positive breast cancer.

At 10 years, investigators showed an insignificant difference in efficacy with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCH).

At a median follow-up of 10.3 years, DFS was 67.9% with doxorubicin plus cyclophosphamide followed by docetaxel (AC-T; HR, 1), 74.6% with AC-TH (HR, 0.72; 95% CI, 0.61%-0.85%; P <.0001), and 73% with TCH (HR, 0.77; 95% CI, 0.65%-0.90%; P = .0011).¹ An overall survival (OS) benefit was also observed in the trastuzumab-containing arms.

Regarding safety, patients who received TCH had less cardiac toxicity and a lower incidence of secondary leukemia.

These findings demonstrate that even in high-risk patients with HER2-positive breast cancer, anthracycline-based therapies do not provide a DFS advantage, explained Tolaney.

Moreover, the randomized phase 3 TRAIN-2 trial evaluated whether taxanes could replace anthracyclines as the chemotherapy backbone in combination with dual HER2 blockade in the neoadjuvant setting in patients with HER2-positive breast cancer.^2,3

In the study, patients with previously untreated, histologically confirmed stage II/III disease were randomized to receive 5-fluorouracil, epirubicin, and cyclophosphamide, followed by paclitaxel and carboplatin, or paclitaxel and carboplatin alone. Patients received concurrent trastuzumab and pertuzumab (Perjeta) with all chemotherapy cycles.

Results showed that the pathologic complete response (pCR) rates were comparable in both arms. However, the rates of grade 3/4 febrile neutropenia were significantly higher in the anthracycline arm versus the paclitaxel/carboplatin-alone arm, at 10% versus 1%, respectively.

Additionally, 97% of patients completed a full year of trastuzumab in the paclitaxel/carboplatin alone arm compared with 89% in the anthracycline arm.

These findings suggest that omitting anthracyclines may be a preferred neoadjuvant strategy for patients with early-stage HER2-positive breast cancer receiving concurrent dual HER2 blockade. Although longer-term follow-up is needed, Tolaney said that it is difficult to justify using anthracyclines in the era of HER2-directed therapies.

Whether ado-trastuzumab emtansine (T-DM1; Kadcyla) could serve as a substitute for taxanes remained another question in this space.

At the 2020 ASCO Virtual Scientific Program, findings from the phase 3 KAITLIN study⁴ demonstrated that anthracycline-based chemotherapy followed by T-DM1 plus pertuzumab (AC-KP) did not induce a clinically meaningful improvement in invasive DFS (iDFS) compared with taxane-based chemotherapy plus concurrent trastuzumab and pertuzumab (AC-THP) in the node-positive and intent-to-treat (ITT) populations, missing the coprimary end points of the trial.

In the ITT population, 86 iDFS events were observed in the AC-KP arm versus 88 in the AC-THP arm(stratified HR, 0.98; 95% CI, 0.72-1.32). The 3-year iDFS rates were 93.1% versus 94.2%, respectively.

Patient-reported outcomes (PROs) demonstrated a lower risk of patient deterioration with AC-KP versus AC-THP from the start of HER2-targeted therapy (stratified HR, 0.71; 95% CI, 0.62-0.80).

The phase 3 KRISTINE trial demonstrated similar iDFS findings when patients with HER2-positive breast cancer were randomized to receive TCH plus pertuzumab (TCHP) or TDM-1 plus pertuzumab in the neoadjuvant setting followed by trastuzumab/pertuzumab or T-DM1/pertuzumab in the adjuvant setting.⁵

The pCR rate was 11.3 percentage points lower with T-DM1/pertuzumab compared with TCHP. At 3 years, iDFS was 92% with TCHP versus 93% with T-DM1/pertuzumab (stratified HR, 1.11; 95% CI, 0.52-2.40).

According to Tolaney, these results do not establish a clear role for pertuzumab in combination with T-DM1; however, T-DM1/pertuzumab was associated with less toxicity than TCHP.

The Move Toward Chemotherapy-Free Regimens

Attempts to de-escalate or eliminate patients’ exposure to chemotherapy has been an ongoing challenge.

Longer-term follow-up from the phase 2 APT study continued to show favorable outcomes with 12 weeks of paclitaxel and trastuzumab followed by 9 months of trastuzumab in patients with HER2-positive breast cancer whose tumors were 3 cm or smaller and were node negative.⁶

The 7-year DFS rate 93.3% (95% CI, 90.4%-96.2%), and the recurrence-free interval (RFI) was 97.5% (95% CI, 95.9%-99.1%).

These findings support the use of the combination in the adjuvant setting for patients with stage I disease and shed light on the potential to maintain positive outcomes with de-escalated treatment.

In the same population, the phase 2 ATEMPT trial demonstrated high rates of disease control and minimal recurrence rates with adjuvant T-DM1 compared with the combination of paclitaxel and trastuzumab.⁷

At 3 years, the DFS rate was 97.7% (95% CI, 96.2%-99.3%; P <.0001), and the RFI rate was 99.1% with postoperative T-DM1 (95% CI, 98.1%-100%).

Regarding toxicity, T-DM1 was associated with lower rates of grade 2 or higher neurotoxicity compared with paclitaxel/trastuzumab. However, a greater percentage of patients required early treatment discontinuation due to any toxicity with T-DM1 (17%) versus paclitaxel/trastuzumab (6%).

PROs revealed that patients who received T-DM1 reported better quality of life (QOL) versus patients who received paclitaxel/trastuzumab. Moreover, T-DM1 led to significantly improved rates of alopecia compared with chemotherapy.

Given the low incidence of events reported with T-DM1, the regimen may provide a potentially less toxic alternative to chemotherapy, said Tolaney.

Planned studies, such as the phase 2 ATEMPT 2.0 trial will further evaluate alternative options to standard chemotherapy in this setting.

Finally, multiple studies have sought to determine whether shorter treatment duration leads to a difference in outcomes in patients with HER2-positive breast cancer.

Although 1 year of trastuzumab remains a standard of care in this patient population, trials such as SOLD, Short-HER, PHARE, Hellenic Oncology, and Persephone appear to unanimously indicate that stopping treatment with trastuzumab plus chemotherapy early due to toxicity in patients with lower-risk disease will likely not have a significant impact on patient outcomes. Additionally, some of these studies reported less cardiac toxicity with the shorter duration of trastuzumab.

Escalation Strategies for Higher-Risk Patients

Escalating therapy for patients with higher-risk disease has also been of great clinical interest, said Tolaney.

The phase 3 APHINITY trial randomized patients with HER2-positive early disease to receive chemotherapy plus trastuzumab and pertuzumab versus chemotherapy plus trastuzumab and placebo in the adjuvant setting.⁸

The updated 6-year analysis showed an iDFS rate of 90.6% with the addition of pertuzumab versus 87.8% with placebo (HR, 0.76). Clinically meaningful benefit was observed among patients with hormone receptor (HR)–positive, hormone receptor–negative, and node-positive disease. iDFS benefit was not observed in patients with node-negative disease.

The addition of pertuzumab led to a 0.9% reduction in the risk of death compared with placebo which was not found to be statistically significant as per a predetermined P value of .0012 (HR, 0.85; 95% CI, 0.67-1.07; P = .170).

Additional research is needed to flesh out which patients should receive preoperative pertuzumab up front to minimize overtreatment, explained Tolaney.

Neratinib (Nerlynx) has also been the subject of investigation in an attempt to solidify the agent’s role in the management of patients with HER2-positive disease.

In the 3 phase ExteNET study,⁹ investigators reported a modest improvement in iDFS with neratinib compared with placebo as extended adjuvant therapy following prior trastuzumab and chemotherapy.

Long-term data from the study showed that at 5 years, neratinib reduced the risk of invasive disease recurrence or death by 27% versus placebo (HR, 0.73; 95% CI, 0.57-0.92; P = .008). Rates of iDFS were 90.2% versus 87.7%, respectively.

Patients with HR–positive disease derived a significant benefit with neratinib, which translated to a 40% reduction in the risk of invasive disease recurrence or death with neratinib versus placebo (HR, 0.60; 95% CI, 0.43-0.83; P = .002).

As diarrhea is an associated toxicity with neratinib, the phase 2 CONTROL trial evaluated whether prophylactic treatment could reduce treatment-related diarrhea in patients with HER2-positive early-stage breast cancer.¹⁰

Results from the trial showed that adding budesonide or colestipol to loperamide prophylaxis reduced the incidence of diarrhea, which may lead to improved adherence rates and overall outcomes, explained Tolaney.

Updated findings from the study revealed that utilizing a dose escalation regimen of neratinib plus loperamide prophylaxis was associated with the lowest rate of treatment discontinuation due to diarrhea, as well as the lowest incidence of grade 3/4 diarrhea.

Taken collectively, Tolaney advised that although neratinib demonstrated significant benefit in patients with high-risk HR–positive HER2-positive disease, the benefit should be weighed with the toxicity. Additionally, further studies are needed to determine the utility of neratinib in patients who have previously received pertuzumab and/or T-DM1.

Finally, the influx of FDA approvals and novel agents recently opens the door to replace current standards with more effective agents.

For example, results from the phase 3 KATHERINE study showed a 50% reduction in the risk of invasive disease recurrence or death with T-DM1 compared with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P <.001) in patients with HER2-positive breast cancer who did not achieve a pCR at surgery after completing neoadjuvant chemotherapy and HER2-directed therapy.¹¹

Notably, improved iDFS rates were observed with T-DM1 versus neratinib or pertuzumab, said Tolaney.

The findings from the KATHERINE study suggest that a patient’s response to neoadjuvant chemotherapy rather than tumor size or nodal status at diagnosis informs risk in this patient population.

Although the results of KATHERINE are encouraging, Tolaney questioned whether these findings can be improved upon. Further studies evaluating additive agents such as tucatinib (Tukysa) or substitutional agents such as fam-trastuzumab deruxtecan-nxki (Enhertu) are ongoing.

The future appears bright in the neoadjuvant and adjuvant treatment of patients with HER2-positive breast cancer, concluded Tolaney.

References

1. Slamon DJ, Eiermann W, Robert NJ, et al. Abstract S5-04: ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. Cancer Res. 2016;76(4). doi:10.1158/1538-7445.SABCS15-S5-04
2. van Ramshorst MS, van der Voort A, van Wekhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640. doi:10.1016/S1470-2045(18)30570-9
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4. Harbeck N, Im SA, Barrios CH, et al. Primary analysis of KAITLIN: a phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol. 2020;38(15 suppl):500. doi:10.1200/JCO.2020.38.15_suppl.500
5. Hurvitz SA, Martin M, Jung KH, et al. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2–positive breast cancer: three-year outcomes from the phase III KRISTINE study. J Clin Oncol. 2019;37(25):2206-2216. doi:10.1200/JCO.19.00882
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7. Tolaney SM, Trippa L, Barry W, et al. Abstract GS1-05: TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Cancer Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-GS1-05
8. Piccart M, Procter M, Fumagalli D, et al. Abstract GS1-04: Interim overall survival analysis of APHINITY (BIG 4-11): a randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Cancer Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-GS1-04
9. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9
10. Hurvitz SA, Chan A, Iannotti N, et al. Abstract P3-14-01: Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Cancer Res. 2018;78(4). doi:10.1158/1538-7445.SABCS17-P3-14-01
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