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HER2+ EBC: Evolution

CE / CME

The Evolving Therapeutic Landscape for HER2-Positive Early-Stage Breast Cancer

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: August 10, 2020

Expiration: August 09, 2021

Lee Schwartzberg
Lee Schwartzberg, MD
CME/CE Information

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Elevated Risk of Recurrence in Patients With HER2+ T1a,bN0M0 Breast Cancer

When considering adjuvant therapy, let’s first address lower-risk patients with EBC based on anatomic features. The main questions for patients with the smallest tumors (stage 1: T1a or T1b primary tumor ≤ 1 cm, node-negative disease) include the following: What is the patient’s risk of relapse? Do these patients need adjuvant therapy at all? Is adjuvant trastuzumab beneficial?

A retrospective analysis of outcomes by HER2 status in patients with T1a,bN0M0 breast cancer was conducted on a large dataset from M.D. Anderson Cancer Center right before trastuzumab was introduced as a new standard of care.13 As shown here, patients who were HER2 positive with these small tumors did have a higher risk of relapsing, compared with patients who were HER2 negative. The DFS was 93.7% in HER2-negative patients vs 77.1% in patients who were HER2 positive (P < .0001). Similarly, distant relapse-free survival was 97.2% vs 86.4%, respectively (P < .0001). In short, in the absence of effective adjuvant treatment, patients with EBC and very small HER2-positive tumors do not have a good outcome.

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APT Trial: Adjuvant Paclitaxel Plus Trastuzumab for Small (Less Than 3 cm), Node-Negative HER2-Positive EBC

Originally, the benefit of HER2-targeted agents in breast cancer was shown in large trials of combination chemotherapy regimens. The question then became whether such aggressive chemotherapy is needed for patients with very small tumors, particularly when combined with trastuzumab. This was addressed by the APT trial, a single-arm, open-label phase II trial of adjuvant paclitaxel and trastuzumab in more than 400 patients with small, node-negative, HER2-positive EBC.14 All the patients in this trial had a tumor smaller than 3 cm and were either node negative, or they had only a single, completely dissected micrometastasis. Participants received 12 cycles of paclitaxel 80 mg/m2 plus trastuzumab 2 mg/kg weekly, with additional trastuzumab to complete 1 year of HER2-targeted therapy.

As shown in this table, the majority of patients had stage I cancers, with nearly one half having tumors larger than 1 cm, including 9% with tumors bigger than 2 cm. The other one half of patients had small tumors, T1a and T1b. Most patients enrolled in this trial were also hormone receptor positive (67%). For these patients, adjuvant endocrine therapy was also recommended after paclitaxel was completed.

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APT Trial: Adjuvant Paclitaxel Plus Trastuzumab for Small (Less Than 3 cm), Node-Negative HER2-Positive EBC: 7-Year Report

The outcome of this trial was very favorable. At 7 years of follow-up, the DFS was excellent at 93.3%. Notably, the hormone receptor–positive group seemed to do better, particularly in later years, where there were fewer relapses. The 7-Year DFS rate was 94.6% for hormone receptor–positive patients vs 90.7% for the hormone receptor–negative subgroup (HR: 0.61).

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T-DM1 Plus Trastuzumab: Background

Based on the APT trial, the combination of paclitaxel and trastuzumab became a new standard of care for patients with small, EBC. Additional trials explored the substitution of standard chemotherapy with the HER2-targeted antibody–drug conjugate (ADC) T-DM1, which is approved for HER2-positive, previously treated metastatic breast cancer as well as more recently being approved in the adjuvant setting for patients with HER2-positive EBC and residual disease after neoadjuvant therapy.15

T-DM1 includes a backbone of trastuzumab covalently linked with a cytotoxic payload called emtansine.16 In effect, T-DM1 functions as a smart bomb. The trastuzumab antibody binds to cells with increased expression of HER2 on the surface. These cells will then internalize the ADC, after which the cytotoxic payload is released intracellularly. This intracellular release of emtansine spares patients the full toxicity of chemotherapy because the cytotoxic agent is not broadly released into the blood but only into the targeted tumor cells.

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Phase II ATEMPT: T-DM1 vs Trastuzumab vs Paclitaxel/Trastuzumab in Stage 1 HER2-Positive EBC

T-DM1 was evaluated in the phase II ATEMPT trial, which was reported by Tolaney and colleagues17 at the 2019 San Antonio Breast Cancer Symposium. This was a 3:1 randomized comparison of 1 year of T-DM1 3.6 mg/kg every 3 weeks vs paclitaxel for 12 weeks plus trastuzumab for a year (the APT trial regimen). Patients who were eligible for this study had stage 1, HER2‑positive breast cancer with node‑negative or N1 microscopic disease, which was very similar to the APT trial criteria (N = 497).

The coprimary endpoints for this trial included 3‑year DFS with T-DM1 as well as a novel endpoint of comparison of specific clinically relevant toxicities with T-DM1 vs paclitaxel plus trastuzumab. These included grade 3 nonhematologic adverse events (AEs), grade ≥ 2 neurotoxicity, grade ≥ 4 hematologic AEs, febrile neutropenia, and any AE requiring dose delay or discontinuation of protocol therapy.

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Phase II ATEMPT: Baseline Characteristics

As detailed in the study design, this study included patients with very small tumors; 43% of them had either T1a or T1b, and the other 57% had tumors that were T1c. Similar to the APT trial, the majority of patients enrolled in this study were also hormone receptor positive (75% of patients).

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Phase II ATEMPT: DFS in ITT Population

Results of the ATEMPT trial showed excellent 3-year DFS in both arms: 97.7% for T-DM1 (coprimary endpoint) and 92.8% for the paclitaxel/trastuzumab regimen, and very few recurrences occurred during this timeframe. This study was not powered to evaluate the efficacy of paclitaxel plus trastuzumab or to compare the efficacy of the 2 regimens. However, this trial numerically favored T-DM1 compared with the 3-year DFS rate with paclitaxel plus trastuzumab in ATEMPT, which was lower than the 3-year DFS rate reported from the APT trial.14

As shown in the table on this slide thumbnail, the results with T-DM1 were similar whether the tumor was larger or smaller than 1 cm.

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Phase II ATEMPT: T-DM1 and TH Clinically Relevant Toxicities

The coprimary endpoint of this study was the comparison of specific clinically relevant toxicities with T-DM1 vs paclitaxel plus trastuzumab. Of these endpoints, hematologic and nonhematologic grade 3 toxicities were quite similar between arms. One clinically relevant toxicity that was different was neurotoxicity, which is a serious concern with taxane-based chemotherapy. Rates of grade ≥ 2 neurotoxicity were 11% with T-DM1 vs 23% with trastuzumab and paclitaxel. Rates of toxicities requiring dose delays were similar at 28% with T-DM1 vs 26% for trastuzumab and paclitaxel. However, toxicities requiring early discontinuation were more common in the T-DM1 arm, at 17% vs 6% for trastuzumab and paclitaxel. Fewer than 1% of patients in each arm experienced congestive heart failure, but the asymptomatic decline in the left ventricular ejection fraction was higher in the paclitaxel plus trastuzumab arm, at 6.1% vs 1.3% with T-DM1.

The coprimary endpoint of overall reduced toxicity with T-DM1 was not met. However, with the reduction in neurotoxicity, there are specific patients with HER2-positive EBC in my practice for whom I would consider T-DM1 instead of paclitaxel plus trastuzumab. 

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Phase II ATEMPT: T-DM1 Discontinuations

In ATEMPT, a significant number of patients (n = 90; 23.5%) discontinued T-DM1 throughout the entire course of therapy, which was a higher rate than expected. The probability of discontinuing therapy in less than 6 months was 8.2%, and rose to 10.7% by 6-12 months. Most discontinuations were for toxicities such as elevated liver enzymes, elevated bilirubin, neuropathy, and thrombocytopenia. Most of the patients who discontinued T-DM1 switched over and received additional trastuzumab therapy.

Although technically this was a negative trial, T-DM1 may still be an effective agent for selected patients with HER2-positive EBC. For example, I have a patient with HER2-positive EBC who is a nurse and refused chemotherapy based on her experience with a family member. She elected to start T-DM1 based on our discussions. I explained she is not going to lose her hair, and she has a lower chance of neurotoxicity. If we have to stop T-DM1 due to toxicity, she can switch to trastuzumab. One challenge here is that T-DM1 is typically not approved by most insurers, so it may not be available for every patient.

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