Based on some unexpected negative results, oncologists using atezolizumab for metastatic triple-negative breast cancer should pair it with nab-paclitaxel, not paclitaxel. In contrast to the overall survival benefit shown for atezolizumab plus nab-paclitaxel in the previous IMpassion130 trial—further validated in an update—atezolizumab plus paclitaxel failed to improve outcomes in IMpassion131, which was reported at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1
David Miles, MB, BSc, lead clinician for breast cancer at Mount Vernon Cancer Centre, Northwood, United Kingdom, presented the results of IMpassion131, and Leisha Emens, MD, PhD, Professor of Medicine and Co-Leader of the Hillman Cancer Immunology and Immunotherapy Program, University of Pittsburgh, reported the mature overall survival analysis of IMpassion130.2 Both trials were in the first-line setting.
Leisha Emens, MD, PhD
“We have to be totally honest. In terms of the primary objective—progression-free survival in the PD-L1–positive group—this is a negative trial,” said Dr. Miles. “This was a study that was really pragmatic, asking whether we can use paclitaxel with atezolizumab because nab-paclitaxel is not universally available. As things currently stand, outside of the context of a clinical trial, the answer is no. You don’t use it with paclitaxel.”
IMpassion130 established the anti–PD-L1 antibody atezolizumab as a new standard of care in PD-L1–positive metastatic triple-negative breast cancer.3 In combination with nab-paclitaxel, atezolizumab significantly improved progression-free survival (hazard ratio [HR] = 0.62; P < .001) and overall survival (HR = 0.62; 95% confidence interval [CI] = 0.45–0.86). The first-line phase III IMpassion131 trial evaluated atezolizumab in combination with a different backbone, paclitaxel.
The double-blind, placebo-controlled phase III trial enrolled 651 patients with metastatic or unresectable locally advanced triple-negative breast cancer and no prior chemotherapy or targeted therapy for advanced disease. PD-L1 positivity (≥ 1%) was documented in 291 patients.
“In terms of the primary objective—progression-free survival in the PD-L1–positive group—this is a negative trial.”— David Miles, MB, BSc
Tweet this quote
Patients were randomly assigned 2:1 to atezolizumab at 840 mg on days 1 and 15 plus paclitaxel at 90 mg/m2 on days 1, 8, and 15 or to placebo and paclitaxel. Patients received 8 to 10 mg of dexamethasone or its equivalent for at least the first two infusions.
The statistical design followed hierarchic testing where the primary endpoint, investigator-assessed progression-free survival, was tested first in the PD-L1–positive population. A statistically significant result (based on a HR of 0.62 and median progression-free survival increasing from 5 to 8 months) would lead to testing in the intent-to-treat population. Secondary endpoints, including overall survival, would be formally tested only if previous tests were significant.
IMpassion131: No Improvement in PD-L1–Positive Disease
Progression-free survival was not significantly improved by atezolizumab plus paclitaxel vs paclitaxel alone in either the PD-L1–positive (6.0 vs 5.7 months; HR = 0.82; P = .20) or the intent-to-treat population (5.7 vs 5.6 months; HR = 0.86; significance not formally tested for hierarchy). No subgroup derived additional benefit from the checkpoint inhibitor.
The combination also did not improve overall survival in the PD-L1–positive group (22.1 vs 28.3 months; HR = 1.12) or the intent-to-treat population (19.2 vs 22.8 months; HR = 1.11). It did slightly improve response rates, which were 63.4% vs 55.4% among PD-L1–positive patients and 53.6% and 47.5%, respectively, in the overall population, Dr. Miles reported.
“We were actually concerned that there was a trend toward better survival in the placebo group,” he said, based on an initial hazard ratio of 1.55, after 27% of deaths. A more recent analysis, however, based on 47% of deaths, found a much lower hazard ratio, 1.12, with a median overall survival of 22.1 months in the atezolizumab arm and 28.3 months in the placebo arm. “This gave us some confidence that we were not seeing an adverse effect in the atezolizumab arm.”
Of note, chemotherapy exposure was similar between the arms. No new safety signals were observed, and there were few serious adverse events.
IMpassion130: Survival Benefit Upheld With Atezolizumab/Nab-paclitaxel
In contrast, survival was improved in the updated prespecified overall survival analysis of the phase III IMpassion130 trial of 902 patients. Although overall survival was not formally tested due to the prespecified statistical plan, in patients with PD-L1–positive disease, it was meaningfully improved in three analyses: the first interim analysis (HR = 0.62), the second analysis (HR = 0.71), and now the mature analysis (HR = 0.67), as reported at the ESMO Virtual Congress 2020 by Dr. Emens.
In the mature analysis, 7.5 months of survival time was gained with atezolizumab and nab-paclitaxel in patients with PD-L1–positive disease (25.4 vs 17.9 months; HR = 0.67), with 3-year survival rates of 36% vs 22% with nab-paclitaxel and placebo. No such effect was observed in patients with PD-L1–negative disease, which contributed to the lack of a statistically significant benefit in the overall population (21.0 vs 18.7 months; HR = 0.87; P =.077), she said.
With additional follow-up, the combination remained safe and tolerable, and no new safety signals emerged. “These results support a positive benefit/risk profile for atezolizumab plus nab-paclitaxel as first-line therapy in patients with PD-L1–positive metastatic triple-negative breast cancer,” Dr. Emens commented.
Are Steroids to Blame?
The potential impact of steroids in blunting the effect of the checkpoint inhibitor was a topic of discussion after the presentations. Although investigators could discontinue them after two cycles, most did not. “One of the big differences between the studies was much more steroid use in IMpassion131. That certainly could have played a role,” commented Dr. Emens, who described how steroids can be immunosuppressive, especially when used early in treatment.
Dr. Miles, however, said he is “not terribly convinced” that steroids were the main factor. For one thing, he noted, their presumed use in KEYNOTE-355—which evaluated pembrolizumab with various chemotherapy regimens, including gemcitabine/carboplatin—showed no attenuation of effect.4
Although the findings are negative, IMpassion131 does offer “a positive opportunity” to learn more about the biology of this disease, Dr. Emens added. “I’m hopeful we can capitalize on that opportunity,” to understand the impact of steroids, the differences between the taxanes, and the variabilities within the patient populations, she said.
Dr. Miles agreed: “Our understanding of how to target immunotherapy is in a very immature stage…. Clearly, there are positive signals from all these studies. It just so happened that IMpassion131 failed to make a positive contribution in that respect [improving outcomes], but at least it tells us what to avoid until we do have a better understanding of what’s going on here.”
DISCLOSURE: The IMpassion trials were supported by F. Hoffmann–La Roche. Dr. Miles has received honoraria for consultancy/advisory boards from Roche/Genentech, Eisai, and Genomic Health. Dr. Emens has received honoraria and/or travel support from AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Chugai, CytomX, Gritstone, MacroGenics, MedImmune, Novartis, Peregrine, Replimune, Roche/Genentech, Shionogi, Syndax, and Vaccinex and has potential future stock in MolecuVax and royalties from Aduro Biotech.
1. Miles DW, et al: Primary results from IMpassion131, a double-blind placebo-controlled randomized phase III trial of first-line paclitaxel atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. ESMO Virtual Congress 2020. Abstract LBA15. Presented September 19, 2020.
2. Emens LA, et al: IMpassion130: Final overall survival analysis from the pivotal phase III study of atezolizumab plus nab-paclitaxel vs placebo plus nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. ESMO Virtual Congress 2020. Abstract LBA16. Presented September 19, 2020.
3. Schmid P, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
4. Cortes J, et al: KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. ASCO20 Virtual Scientific Program. Abstract 1000.
Invited study discussant Lisa A. Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research and Deputy Director of Clinical Sciences at the University of North Carolina-Chapel Hill, framed her remarks as a tale of two trials.
Dr. Carey asked these...