THE PHASE III IMpassion130 trial, first reported at the European Society for Medical Oncology (ESMO) 2018 Congress1 and published in The New England Journal of Medicine,2 found that the combination of front-line atezolizumab plus nab-paclitaxel significantly improved disease-free and overall survival in women with metastatic triple-negative breast cancer vs placebo plus nab-paclitaxel in an intent-to-treat analysis of all patients. These results were even more impressive in the programmed cell death ligand 1 (PD-L1)-positive cohort.
Digging deeper into the data, an exploratory analysis of IMpassion130 found no benefit from the immunotherapy combination vs nab-paclitaxel in patients with PD-L1–negative disease. This analysis was presented at the 2018 San Antonio Breast Cancer Symposium.3
Significance of New Findings
THESE RESULTS are important and perhaps somewhat surprising, because studies in other types of cancer have shown a benefit for checkpoint inhibitor therapy in patients with very low levels of PD-L1 expression and PD-L1–negative expression. The results of the exploratory analysis of IMpassion130 support the use of atezolizumab plus nab-paclitaxel exclusively in PD-L1–positive triple-negative breast cancer.
Leisha A. Emens, MD, PhD
“IMpassion is the first phase III study to demonstrate a benefit with immunotherapy in triple-negative breast cancer. No targeted agent has been able to show a survival benefit in this population. In the IMpassion130 study, clinically meaningful progression-free survival and overall survival were improved in PD-L1–positive patients, with a nice separation of the survival curves. Further analysis of results of IMpassion130 demonstrates that PD-L1 expression in immune cells is a highly reliable predictor of response. However, in PD-L1–negative patients, there is no treatment effect of atezolizumab/nab-paclitaxel,” stated presenting author Leisha A. Emens, MD, PhD, of UPMC Hillman Cancer Center, Pittsburgh.
In the PD-L1–negative patients, median progression-free survival was identical with atezolizumab/nab-paclitaxel vs placebo/nab-paclitaxel: 5.6 months. By contrast, a 10-month improvement in disease-free survival was found in PD-L1–positive patients treated with the immunotherapy combination vs placebo plus nab-paclitaxel.
The new data show there is no significant effect of atezolizumab/nab-paclitaxel on overall survival in PD-L1–negative patients. Median overall survival was 18.9 months for immunotherapy vs 18.4 months for chemotherapy.
“These results support routine testing for PD-L1–positive status in newly diagnosed patients with metastatic and unresectable locally advanced triple-negative breast cancer to determine if they could benefit from atezolizumab plus nab-paclitaxel.”— Leisha A. Emens, MD, PhD
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“A continued benefit of the immunotherapy combination was observed across all PD-L1–positive subgroups. These results support routine testing for PD-L1–positive status in newly diagnosed patients with metastatic and unresectable locally advanced triple-negative breast cancer to determine if they could benefit from atezolizumab plus nab-paclitaxel,” Dr. Emens told listeners.
Original IMpassion130 Details
IMPASSION130 ENROLLED 902 patients with previously untreated metastatic triple-negative breast cancer and randomly assigned them to receive atezolizumab/nab-paclitaxel or placebo plus nab-paclitaxel. At a median follow-up of 12.9 months, disease-free survival was improved by 20% with the checkpoint inhibitor combination in all patients and by 38% in the PD-L1– positive patients compared with placebo/nab-paclitaxel recipients. Median progression-free survival was 7.2 months for the immunotherapy combination vs 5.5 months for placebo/nab-paclitaxel.
Median overall survival for all patients was 21.3 months with the immunotherapy combination vs 17.6 months for placebo/ nab-paclitaxel. In the PD-L1–positive group, median overall survival was 25.5 months for the immunotherapy combination vs 15.5 months for placebo/nab-paclitaxel—a 10-month difference.
The exploratory analysis was designed to explore the effect of immune biology (ie, CD8-positive T cells and stromal tumor-infiltrating lymphocytes) and BRCA status on benefit from the checkpoint inhibitor combination. Dr. Emens and colleagues looked at PD-L1 expression on immune cells and on tumor cells using the Ventana SP142 assay. Intratumoral CD8-positive T cells were assayed with immunohistochemistry, and stromal tumor-infiltrating lymphocytes were analyzed with hematologic and eosin staining. The investigators also looked at BRCA mutation status using the FoundationOne CDx assay.
Among the total study population, 41% were PD-L1–positive and 59% were PD-L1–negative; 27% of the PD-L1–positive group had low PD-L1 expression (1% to < 5% of immune cells).
The majority of patients who were PD-L1–positive had PD-L1 expression on immune cells; only 2% had PD-L1 expression exclusively on tumor cells. Results suggested that the threshold for benefit was PD-L1 expression of 1% or more on immune cells.
“As long as the immune cells express PD-L1 of 1% or more, patients may benefit from atezolizumab/nab-paclitaxel,” she said. “The takeaway message is that higher levels of PD-L1 are not better. All levels of PD-L1 expression at 1% or more in immune cells were associated with a benefit. PD-L1 expression on tumor cells did not provide additional information beyond PD-L1 expression on immune cells.”
The investigators looked at CD8-positive T cells and stromal tumor-infiltrating lymphocytes and found no survival benefit for atezolizumab/nab-paclitaxel vs chemotherapy if either of these markers was present in PD-L1–negative patients. However, both tumors with CD8-positive T cells and tumors with stromal tumor-infiltrating lymphocytes did benefit from the immunotherapy combination if the tumors were PD-L1–positive.
About 15% of patients had BRCA mutations. Among these patients, no associations between treatment and survival could be found in the PD-L1–negative group. By contrast, BRCA mutation–positive and PD-L1–positive status were significantly associated with progression-free survival benefit from the immunotherapy combination, and a similar trend was observed for overall survival, but there were small numbers of patients in the survival analysis, Dr. Emens noted.
“These are independent biomarkers. Patients with BRCA1 and BRCA2 mutations derive benefit [from the immunotherapy combination] only if they are PD-L1–positive,” she emphasized. ■
DISCLOSURE: IMpassion130 was sponsored by F. Hoffmann-La Roche, Ltd. Dr. Emens is a consultant/advisor for AbbVie, Amgen, Bayer, Celgene, eTheRNA, Gritstone Oncology, Macrogenics, MedImmune, MolecuVax, Novartis, Peregrine, Replimune, Syndax, and Vaccinex; has received travel, accommodations, and expenses from Bayer, Bristol-Myers Squibb, Corvus, Macrogenics, Novartis, Replimune, Roche/Genentech, and Vaccinex; has stock and ownership interest in MolecuVax; grants/research support from Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Corvus, EMD Serono, Roche/Genentech, MaxCyte, and Merck and licensing royalties with Aduro Biotech; and is a member of the FDA Advisory Committee on Cell Tissue and Gene Therapies, the Board of Directors for the Society of Immunotherapy of Cancer, the data safety and monitoring board for the TRIO 025 trial, and the steering committee for the IMpassion130 and KATE2 trials.
1. Schmid P, Adams S, Rugo HS, et al: IMpassion130: Results from a global, randomised double-blind, phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in treatment-naive, locally advanced or metastatic triple-negative breast cancer. European Society for Medical Oncology 2018 Congress. Abstract LBA1_PR. Presented October 20, 2018.
2. Schmid P, Adams S, Rugo H, et al: Atezolizumab plus nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
3. Emens LA, Loi S, Rugo HS, et al: Impassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled phase III study of atezolizumab plus nab paclitaxel in patients with treatment-naive, locally advanced or metastatic triple negative breast cancer. 2018 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 5, 2018.
Matthew P. Goetz, MD
“WHAT’S IMPORTANT for clinicians to take away from this analysis is that there is clearly zero benefit of atezolizumab/nab-paclitaxel in patients with programmed cell death ligand 1 (PD-L1)-negative disease. In PD-L1–positive patients, the combination improves...!-->!-->