Tolaney Spotlights Tailoring Therapy by Risk in HER2+ Breast Cancer

By adapting adjuvant therapy based on responses to preoperative therapy, investigators may be able to change long term outcomes for patients with HER2-positive breast cancer, creating a paradigm shift in the space, Sara M. Tolaney, MD, MPH, said in a presentation during the The 20th Annual International Congress on the Future of Breast Cancer® East.¹

The time for designing only adjuvant trials for the development of novel strategies to improve outcomes has ended, and future research is paving the way for more tailored approaches to treatment, according to Tolaney, the associate director of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School. For example, for all patients with HER2-positive tumors greater than 2 cm or who are clinically node-positive, should receive preoperative trastuzumab (Herceptin)- and pertuzumab (Perjeta)-based chemotherapy. Additionally, all those who fail to achieve a pathologic complete response (pCR) should receive adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla).

Assigning patients to extended adjuvant therapy with 1 year of treatment with neratinib (Nerlynx) can also lead to positive outcomes, particularly in those with hormone-receptor (HR)–positive disease who are at a high risk for recurrence, Tolaney said. She added that there is currently no data on this approach for patients who have received prior treatment with pertuzumab or T-DM1, but those with stage I HER2-postive breast cancer can receive adjuvant treatment with paclitaxel (Abraxane) and trastuzumab or T-DM1.

“What we have learned over the last several years is that treatment with HER2-directed therapy has really revolutionized outcomes for our early stage HER2-positive patients,” Tolaney said. “The challenge, however, is that there are still patients who we know will recur, despite the use of trastuzumab, and several other HER2-directed therapies. This has left us with the challenge of how to best personalize treatment decisions for our early-stage patients.”

As such, strategies must be developed to both de-escalate treatment for those with lower-risk disease and escalate treatment for those with higher-risk disease.

De-escalating Treatment May Be Appropriate for Some Patients

Physicians looking to de-escalate treatment in the HER2-positive space have been shifting away from anthracycline-based chemotherapy and moving to a taxane-based approach, Tolaney noted. The earliest data on this approach came from the phase 3 BCIRG 006 trial (NCT00021255), which randomized patients to either doxorubicin plus cyclophosphamide followed by docetaxel (AC-T), doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC-TH), or docetaxel, carboplatin and trastuzumab (TCH). Outcomes were similar in patients who received AC-TH and TCH in terms of disease-free survival (DFS; 74.6% vs 73.0%), and overall survival (OS; 85.9% vs 83.3%).²

“Importantly, when looking at DFS in this trial, even in those patients who had multimode positive disease, you still see similar outcomes with taxane therapy compared to anthracycline therapy,” Tolaney said.

More recently, investigators in the phase 3 TRAIN-2 trial (NCT01996267) examined this approach and found that pCR and event-free survival (EFS) rates were consistent across bother anthracycline- and taxane-based groups (67% vs 68% and 11% vs 10%). However, patients in the anthracycline-free arm reported less cardiac toxicity, as well as fewer cases of leukemia. Additionally, there were no differences between the 2 study arms based on nodal status.³

“Given these data, I have really shifted my practice away from using anthracyclines, and towards using taxane-based therapy for my early-stage patients,” Tolaney said.

Taking it a step further, efforts have also been made to substitute the use of taxane-based therapy with something even less toxic, such as T-DM1, she explained. This approach has been evaluated in several studies, including the phase 3 KRISTINE trial (NCT02131064) which randomized patients to received either TCH plus pertuzumab or T-DM1 plus pertuzumab for 6 cycles prior to surgery, followed by trastuzumab plus pertuzumab or T-DM1 plus pertuzumab for 12 cycles after therapy. Results from the study showed that patients receiving TCH plus pertuzumab had higher rates of pCR, though T-DM1 plus pertuzumab was associated with less toxicity.⁴

“If we look at outcomes from the time of surgery moving forward, we can see that there was no difference in invasive DFS [iDFS], though this does not account for local occurrences that occurred in the T-DM1 plus pertuzumab arm,” Tolaney said. “This makes me curious to see if we could select out those patients who do not do as well with T-DM1, and then substitute with T-DM1 instead of taxane-based therapy. One question is here is whether we should be getting rid of those patients who have either lower HER2 expression or those who have HER2 heterogeneity, who may be those patients who are not going to do as well with the substitution of T-DM1.”

As such, further research is needed to assess whether a de-escalation strategy with T-DM1 alone in patients with strong HER2 expression would beneficial.

Efforts to de-escalate treatment by decreasing the amount of chemotherapy given have been focused on patients who are at a lower risk of recurrences. For example, the phase 2 APT trial (NCT00542451), which assigned patients whose tumors were less than 3 cm to paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab alone.

The 7-year DFS rate was 93.3% (95% CI, 90.4%-96.2%) with a 7-year recurrence-free interval (RFI) rate of 97.5% (95% CI, 95.9%-99.1%).⁵

“It is important when we look at trials, particularly de-escalation trials in lower risk populations, that we think about what the right endpoint is,” Tolaney noted. “In a lower-risk population, we are likely to have events that might dilute the endpoint and may not be related to the treatment that we are actually studying.”

Additionally, based on the results of the phase 2 ATEMPT trial (NCT01853748), treatment with T-DM1 for 1 year was associated with few recurrences, Tolaney said. As such, the agent could be an alternative to paclitaxel plus trastuzumab. However, T-DM1 did not reduce rates of toxicity that resulted in dose delay or early discontinuation.⁶

Escalating Treatment with Targeted Agents and More Effective Agents

Initially, efforts to escalate treatment for higher-risk patients with HER2-positive disease focused on the addition of pertuzumab to the combination of trastuzumab and chemotherapy, which led to the FDA approval of 3 regimens. For example, in the phase 3 APHINITY trial (NCT01358877), adding pertuzumab to that combination resulted in a significant improvement in iDFS, with an absolute difference of 2.8%.⁷

Additionally, pertuzumab conferred an iDFS benefit to patients with HR-positive disease, as well as those with HR-negative and node-positive disease.

“My preference is to use pertuzumab in any patient I am giving preoperative therapy to,” Tolaney said. “We know that it is improving DFS in our node-positive patients, but it does mean we may be overtreating some patients with this approach, because there may be some node-negative patients you are treating preoperative with pertuzumab. The challenge is, we are not always able to know when a patient has node-positive or node-negative disease up front.”

In the phase 3 ExteNET trial (NCT00878709), investigators examined the addition of neratinib after trastuzumab-based adjuvant treatment. Neratinib led to an improvement in iDFS, though there was no improvement seen in OS. Moreover, the improvement in iDFS was restricted to those patients with ER-positive disease.

Patients with HR-positive disease who had failed to achieve a pCR to preoperative therapy derived the most significant benefit with this approach. Results from an exploratory analysis showed a 7.4% absolute difference in iDFS for this population, as well as a small improvement in OS.⁸

“Interestingly, there was also numerically fewer CNS events in those patients receiving neratinib compared with placebo,” Tolaney said. “This is really the first time that we have seen an agent that can prevent CNS recurrence.”

In the phase 3 KATHERINE trial (NCT01772472), patients with residual disease after HER2-directed therapy were randomized 1:1 to receive either trastuzumab or T-DM1. Results from the trial showed significant benefit associated with T-DM1, with a 50% reduction in iDFS events, Tolaney noted. However, investigators did not observe a reduction in terms of CNS recurrence.⁹

“The benefit was seen across all subgroups, regardless of HR status, regardless of whether the patient received dual HER2-directed therapy, and regardless of the amount of tumor that was left at the time of surgery,” Tolaney said. “The question remains whether we can do better than KATHERINE. I still think there are patients who have high-risk disease where we need to think about improving outcomes.”

As such, future studies should focus on further treatment escalation. Approaches under investigation include add on strategies with tucatinib (Tukysa) to T-DM1, substitution strategies with fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201), and extended adjuvant therapy with abemaciclib (Verzenio) plus endocrine therapy.

References

1. Tolaney, S. Tailoring HER2-directed neo/adjuvant therapies by risk. Presented at The 20th Annual International Congress on the Future of Breast Cancer® East. July 16, 2021, Virtual. Accessed July 16, 2021.
2. Slamon DJ, Eiermann W, Robert NJ, et al: Ten-year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2-positive early breast cancer patients. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.
3. Ramshorst M, van der Voort A, Werkhoven E, 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. 2018;19(12):1630-1640. doi: 10.1016/S1470-2045(18)30570-9
4. Hurvitz S, Martin M, Symmans F, 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. 2018;19(1):115-126. doi:10.1016/S1470-2045(17)30716-7
5. Tolaney S, 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(supp 22):1868-1875. doi: 10.1200/JCO.19.00066
6. Tolaney S, Tayob N, Dang C, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J Clin Oncol. 2021;39(supp 21): 2375-2385. doi:10.1200/JCO.20.03398
7. Piccart M, Procter M, Fumagalli D, et al: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized, multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab vs chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 11, 2019.
8. Martin M, Holmes F, 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. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9
9. Von Minckwitz, Huang C, Mano M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019;380:617-628. doi: 10.1056/NEJMoa1814017