Immunotherapy with checkpoint inhibitors, established as a treatment of many solid tumors, may be finding a role in the treatment of breast cancer. The current state of the art regarding immunotherapy for triple-negative breast cancer was the focus of a talk by Heather L. McArthur, MD, MPH, Medical Director of Breast Oncology and Associate Professor of Medicine at Cedars-Sinai Medical Center, Los Angeles, at the virtual edition of the 2020 Chemotherapy Foundation Symposium.1
The data supporting immunotherapy in the metastatic triple-negative breast cancer setting are not concordant, although there have been some positive phase III trials. In addition, phase II and III (neo)adjuvant trials are supportive of this strategy in triple-negative breast cancer. More data are needed, and, with many studies underway, a clearer role for this type of treatment should emerge.
Heather L. McArthur, MD, MPH
IMpassion130 Trial Update
One of the first inroads in treating triple-negative breast cancer with immunotherapy was the global randomized phase III IMpassion130 trial. This study showed improved progression-free and overall survival with the combination of atezolizumab plus nab-paclitaxel vs placebo plus nab-paclitaxel in treatment-naive locally advanced or metastatic triple-negative breast cancer.2,3
This trial enrolled 902 patients with previously untreated or inoperable locally advanced triple-negative breast cancer. Patients were stratified for PD-L1 status on immunohistochemistry. A total of 41% of patients in each arm were PD-L1–positive. Approximately two-thirds of patients in each arm received prior (neo)adjuvant treatment.
At a median follow-up of 12.9 months, atezolizumab plus nab-paclitaxel prolonged progression-free survival in both the intent-to-treat analysis and the PD-L1–positive subgroup. An updated informal analysis found that in PD-L1–positive patients, median overall survival was 25 months with combination therapy vs 18 months with placebo plus nab-paclitaxel, whereas in PD-L1–negative patients, median overall survival was identical in each arm (19.1 months).3
“Interim analysis showed 7-month improvement in overall survival, which is clinically significant for a patient population where median overall survival is typically 12 to 18 months,” Dr. McArthur commented.
The survival improvement led to accelerated approval in March 2019 of atezolizumab plus nab-paclitaxel, the first immunotherapy combination for triple-negative breast cancer indicated for unresectable or locally advanced unresectable triple-negative breast cancer.
“Most of the toxicity in the experimental arm came from the chemotherapy backbone,” Dr. McArthur stated. “Grade 3 and 4 adverse events were extremely rare, so the data are reassuring,” she added.
IMpassion131 and KEYNOTE-355
The next trial was IMpassion131, which compared atezolizumab plus paclitaxel vs placebo plus paclitaxel in an intent-to-treat analysis and in PD-L1–positive patients with metastatic triple-negative breast cancer.4 About 50% of patients received prior anthracycline, and about 30% in both arms had de novo metastatic breast cancer.
The primary analysis showed that median progression-free survival did not significantly differ in PD-L1–positive patients: 6.0 months with placebo plus paclitaxel and 5.7 months with the immunotherapy combination. These results were somewhat of a surprise and disappointing, Dr. McArthur noted.
Next up, the phase III, randomized, placebo-controlled KEYNOTE-355 trial compared pembrolizumab plus chemotherapy vs placebo plus chemotherapy in previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer.5 Chemotherapy consisted of paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin.
Patients were randomly assigned 2:1 to the experimental arm vs the control arm. Stratification factors included chemotherapy type, PD-L1 expression according to a Combined Positive Score (CPS) > 1 vs < 1, and prior treatment with the same chemotherapy in the adjuvant setting (yes or no). About 30% had de novo metastatic disease.
An intent-to-treat analysis of progression-free survival showed a median of 7.5 months for the experimental arm vs 5.6 months for the control arm—an 18% reduction in the risk of disease progression for the immunotherapy combination. In the PD-L1–positive population (CPS > 10), the difference between regimens was magnified: median progression-free survival was 9.7 months with immunotherapy plus chemotherapy vs 5.6 months with placebo plus chemotherapy (P = .0014).
Discordant Data
“IMpassion131 did not meet its primary endpoint. How do we reconcile the data from IMpassion131 with the data from the other two trials?” asked Dr. McArthur.
“IMpassion131 did not meet its primary endpoint. How do we reconcile the data from IMpassion131 with the data from the other two trials?”— Heather L. McArthur, MD, MPH
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Some possible explanations are differences in baseline characteristics, chemotherapy exposure differences, type of chemotherapy backbone, steroid administration, or use of paclitaxel vs nab-paclitaxel (two positive studies for paclitaxel and two negative studies and one positive study for nab-paclitaxel). Also, there are no data on subsequent treatments. In KEYNOTE-355, the treatment-free interval was 6 months, whereas it was 12 months in the prior studies.
“There is a lot of discordant information in this space,” Dr. McArthur emphasized.
As for therapy earlier in the course of disease, KEYNOTE-522 evaluated neoadjuvant chemotherapy plus pembrolizumab vs neoadjuvant chemotherapy plus placebo. They also compared these two regimens as adjuvant chemotherapy in 1,174 women with newly diagnosed stage II or III triple-negative breast cancer.6 Primary endpoints were pathologic complete response and event-free survival. The study treatments were followed by anthracycline/cyclophosphamide regardless of PD-L1 status.
At an interim analysis of the first 602 patients who underwent randomization, the pathologic complete response rate was 64.8% with immunotherapy plus chemotherapy and 51.2% with placebo plus chemotherapy—an 18% difference favoring the immunotherapy arm (P < .001). Event-free survival was also higher in the immunotherapy arm.
“This was the first signal that those improvements in pathologic complete response were translating to an improved cure rate for this high-risk group,” she said.
The phase III randomized trial IMpassion031 is also evaluating neoadjuvant immunotherapy for treatment-naive triple-negative breast tumors larger than 2 cm.7 Patients were randomly assigned 1:1 to either atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel for 12 weeks, followed by atezolizumab plus doxorubicin vs placebo plus doxorubicin for 8 weeks; patients were assessed for pathologic complete response prior to surgery. After surgery, the atezolizumab group received atezolizumab for 11 doses or monitoring. Primary endpoints were pathologic complete response in the intent-to-treat and PD-L1–positive subpopulation. There was an absolute improvement of 16.5% in pathologic complete response rate for the immunotherapy arm (58% with immunotherapy vs 41% with placebo plus chemotherapy). Benefit was seen in both PD-L1–positive and PD-L1–negative patients.
“The neoadjuvant data are consistent, showing a benefit for immunotherapy combinations in triple-negative breast cancer,” Dr. McArthur told listeners.
“The neoadjuvant data are consistent, showing a benefit for immunotherapy combinations in triple-negative breast cancer.”— Heather L. McArthur, MD, MPH
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Where Are We Now?
To summarize the current state of the art in immunotherapy for triple-negative breast cancer, an informal overall survival analysis of IMpassion130 led to U.S. Food and Drug Administration approval of atezolizumab plus nab-paclitaxel for PD-L1–positive metastatic triple-negative breast cancer. “We anticipate curative-intent immunotherapy approval in 2021, based on KEYNOTE-522 and IMpassion031 neoadjuvant data,” Dr. McArthur predicted.
The best chemotherapy regimen to use with immunotherapy is not clear, and neither are the characteristics of the optimal patient population. “Should we limit immunotherapy for residual disease after neoadjuvant chemotherapy?” she asked.
Many studies are evaluating immunotherapy in combination with biologics and targeted therapies. Optimized biomarkers that predict response and toxicity are still needed.
How should patients with metastatic triple-negative breast cancer be treated after immunotherapy? “My belief is there will not be a one-size-fits-all strategy for triple-negative breast cancer. In addition to data from clinical trials, treatment decisions will have to encompass tumor features, microenvironment features, and patient characteristics,” Dr. McArthur said.
DISCLOSURE: Dr. McArthur has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Genomic Health, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, and Seattle Genetics; has received institutional research funding from Bristol Myers Squibb, Lilly, Merck, and Ziopharm Oncology; has been reimbursed for travel, accommodations, or other expenses by Amgen, AstraZeneca, Bristol Myers Squibb, Dava Pharmaceuticals, Genentech, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, and Spectrum Pharmaceuticals; and has held other relationships with Genomic Health and Lilly.
REFERENCES
1. McArthur H: Immunotherapy: Where are we and where are we going? 2020 Chemotherapy Foundation Symposium. Presented November 5, 2020.
2. Schmid P, Adams S, Rugo HS, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
3. 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.
4. Miles DW, Gligorov J, André F, et al: Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. ESMO Virtual Congress 2020. Abstract LBA15. Presented September 19, 2020.
5. Cortes J, Cescon DW, Rugo HS, 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.
6. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
7. Mittendorf EA, Zhang H, Barrios CH, et al: Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): A randomised, double-blind, phase 3 trial. Lancet 396:1090-1100, 2020.
