With several pivotal trials providing evidence for the escalation and de-escalation of anti-HER2 therapy in certain early breast cancer scenarios, personalized treatment is possible. How can clinicians optimize treatment by applying the studies’ findings? Debu Tripathy, MD, Professor and Chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, shared his thoughts on this topic at PER’s 2021 Miami Breast Cancer Conference.1
“Dual HER2 targeting is a way to escalate treatment in a poor-risk patient, and the results of neoadjuvant therapy are actionable.”— Debu Tripathy, MD
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After its approval 25 years ago in the metastatic setting, the first HER2-targeted agent, trastuzumab, rapidly moved to the adjuvant setting. There, numerous trials clearly showed its impact on disease-free and overall survival. A Cochrane meta-analysis concluded that trastuzumab reduced the risk of recurrence by approximately one-third and mortality by one-fourth.2
Trastuzumab remains a powerful tool in the treatment of early breast cancer but has been joined by a number of other agents: the monoclonal antibody pertuzumab, the tyrosine kinase inhibitors lapatinib and neratinib, and the immunoconjugate ado-trastuzumab emtansine (T-DM1). Dr. Tripathy described how he uses these drugs in the neoadjuvant and/or adjuvant setting to personalize therapy.
“Personalization of therapy has some basic requirements,” began Dr. Tripathy. “We have to know the natural history of the disease, so we can understand the impact of our therapies. We have to characterize the toxicities and long-term effects and understand which patients may be more vulnerable to them. We have to know who benefits most from specific therapies. We need to develop risk-adapted and biomarker-adapted techniques that we can use in the clinic. For this, we need clinical trials, which can let us know who may need escalation of therapy and who may be able to de-escalate treatment.”
De-escalation of Therapy
In low-risk patients, the impact of anti-HER2 therapy is small. Although this is difficult to show in randomized trials (very large populations are needed), information has nevertheless come from clinical observations and single-arm studies.
“We know that for patients with T1a and T1b tumors, outcomes are very good, regardless of treatment or not,” Dr. Tripathy said. This was most notably shown in the single-arm APT trial by Tolaney et al, in which patients with HER2-positive tumors between 1 and 3 cm and no positive nodes received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year total.3 Outcomes were excellent: 3-year disease-free survival was 98.5% (95% confidence interval [CI] = 97.2%–99.7%), remaining high, 93.3% (95% CI = 90.4%–96.2%), at 7 years. This was especially true for patients with hormone receptor–positive disease, as those with hormone receptor–negative disease had a slight drop-off in benefit at 7 years (90.7%; 95% CI = 84.6%–97.2%).
The APT trial was followed by the recent ATEMPT trial, which has been recently published.4 This trial was designed and powered to compare toxicity, rather than disease-free survival, in a population similar to the APT trial, randomly assigned to weekly paclitaxel or T-DM1.
Although not a formal comparison, the study did show greater 3-year disease-free survival with T-DM1 (97.7% vs 92.8%). The main finding, however, was that although the rates of toxicity were similar (46% per arm), side-effect profiles differed. In particular, there was more grade ≥ 2 neurotoxicity with chemotherapy (23% vs 11%) but more toxicity leading to treatment discontinuation with T-DM1 (17% vs 6%).
Escalation of Therapy in the Neoadjuvant Setting
Patients at higher risk, however, may need escalated treatment. To this end, in the neoadjuvant setting, dual HER2 targeting (plus taxane) led to higher rates of pathologic complete response, as demonstrated in the four-arm NeoSphere trial evaluating the addition of pertuzumab to trastuzumab.5
With longer follow-up, patients receiving both anti-HER2 agents plus docetaxel, and who thus were the most likely to achieve a pathologic complete response (45.8%), had high disease-free survival with dual targeting vs trastuzumab alone and docetaxel (84% vs 81%). Dual HER2 targeting, therefore, is a way to escalate treatment in a poor-risk patient, and the results of neoadjuvant therapy are actionable, according to Dr. Tripathy.
For patients not achieving a pathologic complete response, the “strongly positive” phase III KATHERINE trial indicated that treatment of residual disease and its accompanying higher risk of recurrence might be optimized with the use of T-DM1. Patients with residual disease after neoadjuvant therapy with trastuzumab/taxane were randomly assigned to receive standard adjuvant trastuzumab or T-DM1 for 14 cycles. Invasive disease–free survival at 3 years was 88.3% with T-DM1 vs 77.0% with trastuzumab (hazard ratio [HR] = 0.50; P < .0001). With the use of T-DM1, rather than trastuzumab, the number of recurrences was essentially halved, Dr. Tripathy noted.
In contrast, in the less selected population of the APHINITY trial, pertuzumab added little value.6 “At a median follow-up of 74 months, there was an infinitesimal difference with pertuzumab vs placebo—0.9% in event-free survival—showing that you may not always be able to discern who really needs or does not need treatment,” continued Dr. Tripathy. Costs, including the cost in terms of toxicity (in this case, mostly diarrhea), and financial “toxicity” are also important to consider, he added. “Of course, we do use pertuzumab, in part because of its value in the neoadjuvant setting, but its contribution to maintenance treatment is unclear.”
Additional data supporting escalation of treatment in high-risk patients comes from the ExteNET trial of neratinib, now with longer term data available. This study randomly assigned 2,840 women with residual disease after neoadjuvant/adjuvant trastuzumab plus chemotherapy to receive 1 year of neratinib or placebo.7 Neratinib reduced recurrences, primarily in the hormone receptor–positive subgroup and in higher-risk patients not achieving a pathologic complete response to neoadjuvant therapy.8 In the HER2-positive, hormone receptor–positive subgroup, for neratinib vs placebo, the following data were reported:
In patients without a pathologic complete response to neoadjuvant therapy, the absolute benefit in invasive disease–free survival favoring neratinib was 7.4% (HR = 0.60); the absolute benefit in overall survival was 9.5% (HR = 0.47).
Additionally, fewer recurrences in the central nervous system were seen with neratinib, both overall (HR = 0.72) and in the hormone receptor–positive subgroup (HR = 0.41). Neratinib, as other small molecule kinase inhibitors, crosses the blood-brain barrier.
Neratinib is now approved in the United States as adjuvant therapy and in the European Union for patients with HER2-negative and hormone receptor–positive disease within 1 year of completion of trastuzumab therapy. Treatment with neratinib needs to be personalized because it can cause significant diarrhea, noted Dr. Tripathy.
Clinical Application of Study Findings
Dr. Tripathy described how he applies the findings from these key studies. Since patients with node-negative early breast cancer usually have good outcomes, regardless, he treats with the less toxic approach of weekly paclitaxel alone with trastuzumab. For patients at somewhat increased risk, such as those with larger tumors but still node-negative, he may add carboplatin. For node-positive patients, chemotherapy should be more intensive: a taxane-based regimen plus trastuzumab and pertuzumab.
“However, except for lower-risk cases, we may want to treat in the neoadjuvant setting because it gives us a ‘real time in vivo assay’ and allows us to further stratify risk,” Dr. Tripathy explained. For patients who do not achieve a pathologic complete response, based on the KATHERINE trial results, he would prescribe T-DM1.
Finally, Dr. Tripathy said he would confine neratinib to the patient who did not achieve a pathologic complete response to neoadjuvant therapy and has hormone receptor–positive disease. This is the patient population for whom its greatest benefit was seen.
DISCLOSURE: Dr. Tripathy has served as a consultant or advisor to AstraZeneca, Exact Sciences, GlaxoSmithKline, Novartis, OncoPep, Immunomedics/Gilead, and Pfizer; has received institutional research funding from Novartis and Polyphor; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca and Novartis.
2. Moja L, Tagliabue L, Balduzzi S, et al: Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012(4):CD006243, 2012.
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 37:1868-1875, 2019.
4. Tolaney SM, Tayob N, Dang C, et al: Adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A randomized clinical trial. J Clin Oncol. Published online ahead of print, June 2, 2021.
5. Gianni L, Pienkowski T, Im YH, et al: 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17:791-800, 2016.
6. Piccart M, Procter M, Fumagalli D, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 Years’ follow-up. J Clin Oncol 39:1448-1457, 2021.
7. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367-377, 2016.
8. 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 21:80-91, 2021.