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ESMO 2021 Report — Breast Cancer
At this year's European Society of Medical Oncology (ESMO) Congress — held virtually September 16 to 21 in Paris, France — investigators reported the latest findings in cancer research. Here, NEJM Journal Watch Oncology and Hematology Editor-in-Chief William J. Gradishar reviews key presentations of new breast cancer therapies. All abstracts can be accessed via ESMO 2021 Oncology Meeting Resources.
Trastuzumab Deruxtecan Versus Trastuzumab Emtansine in HER2-Positive MBC
One of the most awaited presentations was DESTINY-Breast03, an industry-sponsored randomized phase 3 trial of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) as second-line therapy for HER2-positive metastatic breast cancer (MBC; abstract LBA1). The current sequencing of agents for most patients with HER2-positive MBC is first-line taxane, trastuzumab, pertuzumab, and at disease progression, T-DM1. Recent approvals of T-DXd and tucatnib have provided options for many patients with disease progression following T-DM1.
The trial enrolled 524 patients with HER2-positive MBC who had previously been treated with trastuzumab and a taxane. Approximately 99% had received prior trastuzumab and 60% had received pertuzumab. The primary endpoint, progression-free survival (PFS), was strikingly superior in the T-DXd arm compared with the T-DM1 arm (median, 25.1 vs. 7.2 months). Data on overall survival (OS) were immature at the time of the presentation but trended in favor of T-DXd. In addition, the objective response rate favored T-DXd (79% vs. 34%).
A concern since the approval of T-DXd has been the low but real risk of interstitial lung disease (ILD) including death. In DESTINY-Breast03 there was no grade 4 or 5 ILD. Based on these results, T-DXd will likely become a preferred second-line option for patients with HER2-positive MBC.
Trastuzumab Duocarmazine Versus Physician's Choice of Treatment for Pretreated HER2-Positive MBC
Another anticipated presentation in the HER2 space was the TULIP trial, an industry-sponsored randomized phase 3 trial comparing the antibody–drug conjugate trastuzumab duocarmazine (SYD985) to treatment of physician's choice in patients with pretreated HER2-positive MBC (abstract LBA15). The active payload of SYD985 is duocarmazine, a DNA alkylator, which is internalized and released intracellularly. Additionally, the active agent has a “bystander effect” that allows it to diffuse to adjacent cells.
In a 2:1 randomization, patients who received ≥2 prior therapies for MBC or previous treatment with T-DM1 were eligible. Options for physician's choice included trastuzumab with eribulin, vinorelbine, or capecitabine; lapatinib with capecitabine was an option. Of 457 patients, approximately 90% had received prior trastuzumab and T-DM1 and 60% received pertuzumab. The primary endpoint of the study — PFS as assessed by central review — favored SYD985 (7.0 vs. 4.9 months; HR, 0.64).
The most common adverse events (AEs) with SYD985 were conjunctivitis, keratitis, and fatigue. AEs of special interest with SYD985 included ILD (grade ≥3 in 2.4%), which resulted in discontinuation of treatment in 5% of patients, and eye toxicity (grade ≥3 in 21%), which resulted in discontinuation in 21% of patients.
The results of this trial may lead to yet another drug approval for patients with previously treated HER2-positive MBC. The challenge to clinicians going forward will be the optimal sequencing of these many new agents.
Follow-Up Survival Data from KEYNOTE-355
Two other presentations provided reassuring long-term survival data from trials in two different populations. The previously reported KEYNOTE-355 trial comparing chemotherapy with pembrolizumab to chemotherapy alone in 847 patients with triple-negative MBC showed a statistically significant and clinically meaningful improvement in PFS. Now, with a median follow-up of 44 months in both treatment arms, researchers reported final survival data (abstract LBA16).
Patients with a programmed cell death-ligand 1 combined positive score (PD-L1 CPS) ≥10 had a significant OS benefit with the addition of pembrolizumab (median, 23.0 months, vs. 16.1 months with placebo). The previously reported improvements in response rate, disease control rate, and duration of response with pembrolizumab were sustained with longer follow-up. No new adverse events were reported.
Follow-Up Survival Data from MONALEESA-2
The randomized phase 3 MONALEESA-2 trial compared ribociclib plus letrozole to placebo plus letrozole in 668 postmenopausal patients with ER-positive/HER2-negative MBC who received no prior therapy for advanced disease (abstract LBA17_PR). Previous reports showed a statistically significant and clinically relevant improvement in PFS, but data for OS were immature.
Now, with a median follow-up of 80 months, an OS improvement of 12.5 months was observed for those receiving ribociclib compared with placebo (median, 63.9 vs. 51.4 months). The OS benefit was observed in all subsets of patients, including those in the placebo arm who subsequently received a cyclin-dependent kinase (CDK) 4/6 inhibitor at disease progression. Furthermore, patients receiving ribociclib had roughly a 1-year longer time until first chemotherapy. No new safety signals were observed with longer follow-up.
These results support the use of a CDK4/6 inhibitor in the first-line treatment of ER-positive/HER2-negative MBC.
Empfohlen von
William J. Gradishar, MD