Ado-trastuzumab emtansine extends DFS in early-stage HER2-positive breast cancer
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SAN ANTONIO — Ado-trastuzumab emtansine extended DFS compared with paclitaxel plus trastuzumab among patients with early-stage HER2-positive breast cancer, according to results of the randomized phase 2 ATEMPT trial presented at San Antonio Breast Cancer Symposium.
However, ado-trastuzumab emtansine (Kadcyla, Genentech) was not associated with fewer clinically relevant toxicities compared with paclitaxel plus trastuzumab (Herceptin, Genentech).
“We knew that patients with early-stage HER2-positive breast cancer are at more than an insignificant risk for recurrence, with retrospective series of untreated patients suggesting rates for recurrence between 10% and 30%,” Sara M. Tolaney, MD, MPH, breast medical oncologist at Dana-Farber Cancer Institute and a HemOnc Today Next Gen Innovator, told Healio. “We previously conducted ... the APT trial, which demonstrated that paclitaxel plus trastuzumab was associated with a 7-year DFS rate of 93%, with only four distant recurrences.
“We were interested in developing a less toxic treatment regimen that would be highly effective and knew that [ado-trastuzumab emtansine] was associated with excellent efficacy in metastatic HER2-positive disease and associated with less toxicity compared with chemotherapy plus trastuzumab,” Tolaney added. “Therefore, [ado-trastuzumab emtansine] seemed like a reasonable approach.”
Researchers conducted the ATEMPT trial to examine whether ado-trastuzumab emtansine was associated with a clinically acceptable event rate compared with paclitaxel plus trastuzumab.
The trial enrolled 512 patients with early-stage HER2-positive breast cancer, and 497 began protocol therapy. The majority (73%) had hormone receptor-positive tumors (T1a, 11%; T1b, 31%; T1c, 57%).
Researchers randomly assigned patients 383 patients (median age, 56 years) to 3.6 mg/kg ado-trastuzumab emtansine via IV every 3 weeks for 17 cycles. The other 114 patients (median age, 55 years) received 80 mg/m2 IV paclitaxel plus 2 mg/kg IV trastuzumab weekly for 12 cycles, followed by 6 mg/kg trastuzumab every 3 weeks for 13 cycles.
Researchers allowed for adjuvant radiation and endocrine therapy to be initiated after completion of 12 weeks of study treatment.
DFS at 3-years in the ado-trastuzumab group, as well as a comparison of clinically relevant toxicities, served as co-primary endpoints. Median follow-up was 3.1 years.
Results showed 3-year DFS was 97.7% (95% CI, 96.2-99.3) among patients assigned ado-trastuzumab emtansine and 92.8% (95% CI, 87.8-98.1) among those assigned paclitaxel plus trastuzumab.
Researchers observed 10 DFS events in the ado-trastuzumab group. Two patients experienced local or regional recurrences, three patients developed new contralateral primary breast cancers and two patients developed distant recurrences. Three patients died of causes not associated with breast cancer.
Seven DFS events, including two distant recurrences, occurred in the paclitaxel-trastuzumab group.
The recurrence free interval — defined as invasive local or regional recurrences, distant recurrences and any breast cancer-associated death — was 99.1% with ado-trastuzumab emtansine.
Forty-six percent of patients in each treatment group developed clinically relevant toxicities. Researchers observed a higher rate of grade 2 or higher neurotoxicity in the paclitaxel-trastuzumab group (23% vs. 11%).
A comparable percentage of patients assigned ado-trastuzumab emtansine and paclitaxel-trastuzumab experienced grade 3 or higher nonhematologic toxicity (10% vs. 11%) and grade 4 or higher hematologic toxicity (1% vs. 0%)
A similar number of patients required dose delays due to any toxicity (28% vs. 26%). However, more patients assigned ado-trastuzumab emtansine discontinued treatment early due to any toxicity (17% vs. 6%).
“There were differences in the toxicity profiles between the two arms, with paclitaxel plus trastuzumab having more neuropathy [24% vs. 11%], neutropenia [13% vs. 3%] and infusion-related reactions [11% vs. 5%], and [ado-trastuzumab emtansine] having more thrombocytopenia [11% vs. 1%] and elevated liver function [9% vs. 4%],” Tolaney told Healio. “Given the low event rate observed with [ado-trastuzumab emtansine] in the study, [the agent] can be considered an alternative treatment for select patients with early-stage HER2-positive disease who are concerned about paclitaxel plus trastuzumab-associated toxicities.” – by Jennifer Southall
Reference:
Tolaney SM, et al. Abstract GS1-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Tolaney reports institutional research support from AstraZeneca, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, Eisai, Eli Lilly, Exelixis, Genentech, Immunomedics, Merck, Nektar, Novartis, Odenate, Pfizer and Sanofi; and consultant/advisory roles with AbbVie, AstraZeneca, Athenex, Bristol-Meyers Squibb, Celldex, Daiichi-Sankyo, Eisai, Eli Lilly, Genentech, Immunomedics, Merck, Nanostring Technologies, Nektar, Novartis, Paxman, Pfizer, Puma Biotechnology, Sanofi and Seattle Genetics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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A. Jo Chien, MD
The ATEMPT trial aimed to identify an even less toxic regimen from the APT trial. It is important to remember that this trial was not designed to compare the efficacy between the two treatment arms, but rather to report the 3-year DFS in the ado-trastuzumab arm and report the toxicities between these two arms. The study met its primary endpoint for DFS, with a clinically acceptable event rate of less than 5%. One year of ado-trastuzumab resulted in excellent 3-year DFS of nearly 98%. Recurrences were very low and similar to what we saw in the APT trial.
Although the 3-year DFS rate in the paclitaxel-plus-trastuzumab arm in ATEMPT was 92.8%, we have to remember that only 114 patients were enrolled in that arm and, therefore, it is not powered for efficacy or comparison. Seventy-five percent of patients enrolled in ATEMPT had hormone receptor-positive disease and, therefore, 3 years of follow-up is relatively short for this cohort. The toxicity profiles of both regimens were consistent with previous studies. Not surprisingly, there was more neuropathy in the paclitaxel-plus-trastuzumab arm, but there was a higher discontinuation rate in the ado-trastuzumab arm. This resulted in identical rates of clinically relevant toxicities, which was a co-primary endpoint in this trial. Therefore, 1 year of ado-trastuzumab is not de-escalated therapy compared with the APT regimen.
Due to the high rates of discontinuation in the ado-trastuzumab arm, it is important to remember that duration of toxicity is a contributor to overall tolerability. This often is not well-categorized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable and tolerable, but low-grade toxicities for longer duration may not be acceptable and tolerable. Also, our standard toxicity assessments are the most clinically relevant endpoints for comparing tolerability of already de-escalating therapies.
We have seen excellent outcomes in the APT and ATEMPT trials so far, but is this due to the treatment or is it just excellent upfront patient selection? We may not be able to conduct two-arm comparator studies due to the excellent prognosis for these patients, but there certainly is room for continued de-escalation.
To conclude, for early-stage disease, paclitaxel plus trastuzumab remains a standard of care and ado-trastuzumab should not be considered a standard at this time. Prognostic and predictive biomarkers are needed to better risk stratify our patients.
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