At the 2019 ASCO Annual Meeting, two pivotal breast cancer trials reported final or additional analyses: one confirmed the negative results seen in earlier reports,1 and the other supported a new survival benchmark.2
KRISTINE: Neoadjuvant T-DM1/Pertuzumab
“The similar risk of an invasive disease–free survival event with T-DM1 plus pertuzumab and TCH-P suggests that systemic chemotherapy may be unnecessary for some patients.”— Sara A. Hurvitz, MD
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Sara A. Hurvitz, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, reported 3-year outcomes for patients in the phase III KRISTINE trial, which evaluated neoadjuvant trastuzumab emtansine (T-DM1) plus pertuzumab vs docetaxel/carboplatin/trastuzumab plus pertuzumab (TCH-P) in stage II/III HER2-positive breast cancer.1 Treatment with T-DM1/pertuzumab was associated with an increased risk of event-free survival events before surgery and a similar risk of invasive disease–free survival after surgery compared with TCH-P.
In addition, T-DM1/pertuzumab was associated with more grade ≥ 3 adverse events and adverse events leading to treatment discontinuation during adjuvant therapy, which may have been at least in part due to the use of standard adjuvant chemotherapy in 50 patients. However, in the neoadjuvant portion of the study, this was not the case.
Although the study did not meet its primary endpoint, the message is not all negative, according to Dr. Hurvitz. “With neoadjuvant/adjuvant dual HER2 blockade, patients attaining a pathologic complete response had about a 97% rate of 3-year invasive disease–free survival. The similar risk of an invasive disease–free survival event with T-DM1 plus pertuzumab and TCH-P suggests that systemic chemotherapy may be unnecessary for some patients,” she said.
Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Medical Oncology and Director of the Stanford Breast Oncology Program, agreed with Dr. Hurvitz. “T-DM1–based neoadjuvant regimens appear to be clinically active and well tolerated in HER2-positive early breast cancer. Early adopters may consider neoadjuvant T-DM1 in patients who are not candidates for chemotherapy or who refuse chemotherapy. We all have some of these patients,” he commented.
KRISTINE Trial Details
In the trial, 444 patients were randomly assigned to neoadjuvant T-DM1 plus pertuzumab or TCH-P for 6 cycles. Patients who received T-DM1/pertuzumab continued adjuvant T-DM1/ pertuzumab, and patients who received TCH-P received adjuvant trastuzumab/pertuzumab. Patients in the T-DM1/pertuzumab arm who did not achieve a pathologic complete response were encouraged to receive standard adjuvant chemotherapy.
With 3 years of follow-up, the risk of an event was higher with T-DM1/pertuzumab (hazard ratio [HR] = 2.61, 95% confidence interval [CI] = 1.36–4.98), reflecting more locoregional disease progression before surgery and noninvasive recurrences after surgery. The event-free survival rate at 3 years was 85.3% with T-DM1/pertuzumab vs 94.2% with TCH-P. This higher rate was driven mainly by more locoregional disease progression during neoadjuvant therapy, which was associated with lower HER2 expression and higher HER2 heterogeneity, Dr. Hurvitz indicated.
The risk of an invasive disease–free survival event was similar in the two groups, with 3-year invasive disease–free survival rates of 93% with T-DM1 and 92% with TCH-P. Pathologic complete response was associated with a greatly reduced risk of an invasive disease–free survival event, irrespective of the treatment received (HR = 0.24, 95% CI = 0.09–0.60).
Overall, grade ≥ 3 adverse events were less common with T-DM1 plus pertuzumab (31.8% vs 67.7%) but increased in this arm (24.5% vs 9.9%) during adjuvant treatment. Similarly, the experimental arm experienced more adverse events leading to treatment discontinuation (18.4% vs 3.8%). Patient-reported outcomes favored T-DM1 plus pertuzumab during neoadjuvant treatment, but no clinically meaningful differences were seen between the arms during adjuvant treatment.
IMpassion130 Overall Survival Analysis
IMpassion130 evaluated the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab plus nab-paclitaxel as a first-line treatment of metastatic triple-negative breast cancer. The study randomly assigned a total of 902 patients (451 patients in each arm) to atezolizumab at 840 mg every 2 weeks plus nab-paclitaxel at 100 mg/m2, or nab-paclitaxel plus placebo, with treatment continued until disease progression.
In the primary analysis, after 12.9 months of follow-up and 43% of deaths having occurred, a clinically meaningful improvement in overall survival was observed in the PD-L1–positive population. At the Annual Meeting, the second interim overall analysis was presented, based on a follow-up of 18 months and 59% of deaths, by Peter Schmid, MD, PhD, of Queen Mary University of London.2
“Although not formally testable due to the prespecified statistical analysis plan, a 7-month improvement in median overall survival was observed in PD-L1–positive patients treated with atezolizumab plus nab-paclitaxel: 25 months vs 18 months (HR = 0.71, 95% CI = 0.54–0.93). “PD-L1 status predicts clinical benefit with atezolizumab plus nab-paclitaxel,” Dr. Schmid said.
“Atezolizumab plus nab-paclitaxel sets a new benchmark as the first therapy to cross the 2-year landmark overall survival benefit in the first-line treatment of PD-L1–positive metastatic triple-negative breast cancer.”— Peter Schmid, MD, PhD
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No benefit was shown for PD-L1–negative patients, whose median overall survival was approximately 20 months in each arm. The updated safety analysis showed that the immunotherapy regimen remained tolerable.
“Atezolizumab plus nab-paclitaxel sets a new benchmark as the first therapy to cross the 2-year landmark overall survival benefit in the first-line treatment of PD-L1–positive metastatic triple-negative breast cancer,” he added.
Additional Commentary
Invited discussant Cesar A. Santa-Maria, MD, MSCI, Assistant Professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, commented on the Impassion130 findings.
Cesar A. Santa-Maria, MD, MSCI
“Continued approval of atezolizumab and nab-paclitaxel may be contingent upon verification of clinical benefit in confirmatory trials,” he maintained. Although the results of IMpassion130 have “an immediate impact on clinical practice,” Dr. Santa-Maria continued, patients should be counseled that the progression-free survival benefit is “modest,” the overall survival benefit is “undefined,” and there is the potential for “severe toxicity.” ■
DISCLOSURE: The KRISTINE study was funded by F. Hoffmann–La Roche/Genentech. Dr. Hurvitz has received travel expenses from Lilly, Novartis, and OBI Pharma; and has received institutional research funding from Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Roche/Genentech, GlaxoSmithKline, Lilly, MacroGenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics. Dr. Pegram has served in a consulting/advisory role for Roche/Genentech. Dr. Schmid has served as a consultant or advisor for AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Roche/Genentech, Merck, Novartis, Pfizer, and Puma Biotechnology; and has received institutional research funding from Astellas Pharma, AstraZeneca, Genentech, Medivation, Merck, Novartis, OncoGenex, and Roche. Dr. Santa-Maria has consulted or advised for Athenex, Bristol-Myers Squibb, Genomic Health, Halozyme, and Polyphor; has received research funding from MedImmune and Pfizer; and has received institutional research funding from Tesaro.
REFERENCES
1. Hurvitz SA, Martin M, Jung KH, et al: Neoadjuvant trastuzumab, pertuzumab, and chemotherapy vs trastuzumab emtansine and pertuzumab in HER2-positive breast cancer: Final outcome results from the phase III KRISTINE study. 2019 ASCO Annual Meeting. Abstract 500. Presented June 3, 2019.
2. Schmid P, Adams S, Rugo HS, et al: IMpassion130: Updated overall survival from a global, randomized, double-blind, placebo-controlled phase III study of atezolizumab + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. 2019 ASCO Annual Meeting. Abstract 1003. Presented June 4, 2019.
