The addition of the checkpoint inhibitor atezolizumab to chemotherapy with carboplatin and nab-paclitaxel failed to significantly improve pathologic complete response rates compared with chemotherapy alone in patients with early high-risk, locally advanced triple-negative breast cancer. According to a multivariate analysis, programmed cell death ligand 1 (PD-L1) expression correlated with response to atezolizumab.

These preliminary results of the NeoTRIP trial were somewhat surprising and differed from those of the KEYNOTE-522 trial, which showed a significant benefit on pathologic complete response for the checkpoint inhibitor pembrolizumab, regardless of PD-L1 expression, in a similar patient population. Both studies were presented at the 2019 San Antonio Breast Cancer Symposium.^1,2

“As neoadjuvant therapy, atezolizumab added to carboplatin/nab-paclitaxel did not significantly increase the rate of pathologic complete response in women with triple-negative breast cancer. In a multivariate analysis, PD-L1 expression was the most significant factor influencing the rate of pathologic complete response,” said lead author Luca Gianni, MD, President of the Fondazione Michelangelo, Milan, Italy.

“In a multivariate analysis, PD-L1 expression was the most significant factor influencing the rate of pathologic complete response.”

— Luca Gianni, MD

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“Triple-negative breast cancers have a poor prognosis, rapidly progressing to distant metastases and rapidly developing resistance to chemotherapy. Immune filtration of triple-negative breast cancer is linked to prognosis and probability of response to chemotherapy,” Dr. Gianni noted.

“We have known for many years that blockade of PD-L1 or programmed cell death protein 1 (PD-1) may favor durable responses in triple-negative breast cancer by immune mechanisms themselves and in combination with classical chemotherapy,” he continued. “The IMpassion130 study found that the addition of atezolizumab to nab-paclitaxel significantly improved progression-free survival and overall survival in PD-L1–positive metastatic triple-negative breast cancer.”

Study Details

NeoTRIP was designed to study the primary endpoint of event-free survival at 5 years following randomization of the last patient. Dr. Gianni presented preliminary results of the trial based on pathologic complete response rates—that is, disappearance of all cancer following neoadjuvant chemotherapy, which is known to correlate with overall survival.

NeoTRIP randomly assigned 280 women with early high-risk or locally advanced, unilateral triple-negative breast cancer 1:1 to receive neoadjuvant therapy with either atezolizumab plus carboplatin/nab-paclitaxel or placebo plus the same chemotherapy. Both regimens were given every 3 weeks for eight cycles. All patients underwent surgery and then received four further cycles of anthracycline-based chemotherapy as per investigator’s choice.

The median age was 50 years (range = 24–79 years). Among all patients, 49% had locally advanced triple-negative breast cancer, and 56% had PD-L1–positive disease. Only 13% had node-negative disease.

Major Outcomes

Pathologic complete response rates were not significantly different between the two study arms: 43.5% with atezolizumab vs 40.8% with chemotherapy alone. A multivariate analysis showed that the only variable associated with pathologic complete response rate was PD-L1–positive status according to immunohistochemistry (P < .0001). A trend was observed favoring treatment with atezolizumab in the overall study population, but the difference was not statistically significant.

The rates of clinical overall response did not differ significantly between the two arms: 76.1% for atezolizumab vs 68.3% for controls. Complete responses were observed in 29% of atezolizumab-treated patients vs 26.1% for controls; partial response rates were 47.1% vs 42.3%, respectively. Progressive disease occurred in 5.8% vs 8.4%, respectively.

Regarding treatment-related adverse events, the main difference between the two treatment arms was more frequent abnormal liver transaminase levels with atezolizumab, “but that didn’t limit the ability to administer the drug,” Dr. Gianni said. Most treatment-related adverse events were infusion-related reactions (8% with atezolizumab and 5.7% for controls), and other events were mild or rare.

Dr. Gianni noted that the investigators plan to analyze tumor-infiltrating lymphocytes at diagnosis, after the first cycle of neoadjuvant chemotherapy, and after surgery. They also plan to assess PD-L1 expression, he said.

NeoTRIP vs KEYNOTE-522

NeoTRIP and KEYNOTE-522 were both discussed at a press conference during the San Antonio meeting. Press conference moderator C. Kent Osborne, MD, FASCO, Director of the Dan L. Duncan Comprehensive Cancer Center, Professor of Medicine, and the Dudley and Tina Sharp Chair for Cancer Research at Baylor College of Medicine, Houston, pointed to several possible explanations for the different findings of these studies—both of which were conducted with a checkpoint inhibitor plus chemotherapy as neoadjuvant therapy in a similar population of patients with early triple-negative breast cancer.

“The [immunotherapy] drugs were different, and the chemotherapy regimens were different. Both pembrolizumab and atezolizumab interfere with PD-1, and we may assume that they would have the same effect, but subtle differences may exist. Both trials were designed to evaluate pathologic complete response, which is a known powerful predictor of event-free survival. But when you move to immunotherapy, this may change. We have little knowledge of the subtle differences in immunomodulation, and we didn’t know if we would see an increase in pathologic complete response [in NeoTRIP],” Dr. Osborne said. The assays used to evaluate PD-L1 expression were different in KEYNOTE-522 and NeoTRIP, he added.

“Based on these results, I don’t think we can give up on atezolizumab. It is too early to tell if it will work.”

— C. Kent Osborne, MD, FASCO

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“Based on these results, I don’t think we can give up on atezolizumab. It is too early to tell if it will work. Perhaps a different chemotherapy backbone would work, like doxorubicin,” Dr. Osborne said.

Dr. Gianni commented: “These trials are different. The type of chemotherapy backbone and the overall type and duration of treatment were different. Atezolizumab may affect pathologic complete response, but our study was not designed with this as an endpoint. We had a relatively smaller study [than KEYNOTE-522] and only a trend toward improved pathologic complete response at the preliminary analysis. It is way too early to conclude that atezolizumab doesn’t work [in this setting]. It may be a long-term effect.”

Lead author of the KEYNOTE-522 trial, Peter Schmid, MD, PhD, Professor of Cancer Medicine and Lead of the Centre of Experimental Cancer Medicine at Barts Cancer Institute, London, also weighed in on this discussion at the press conference. “There is a difference between metastatic and early breast cancers. Tumors don’t change with chemotherapy, and the immune system is less active in early disease,” he said. “This is why PD-L1 is less relevant in early disease. When PD-L1 expression increases, the ability to mount an immune response increases. In early disease, activated immune cells can still get into the cancer.”

Peter Schmid, MD, PhD

Dr. Schmid continued: “So far, there are two positive trials with checkpoint inhibitors in triple-negative breast cancer: atezolizumab in metastatic disease [IMpassion130] and pembrolizumab in early disease [KEYNOTE-522]. Based on these results, we can’t speculate which checkpoint inhibitor is better. It could be the chemotherapy used in the trial, it could be that the NeoTRIP study is a smaller study. I would not say atezolziumab is better than pembrolizumab or vice versa. We need more trials. I am confident that at the end of the day, we will establish immunotherapy as a standard of care—not just in metastatic breast cancer, but in early breast cancer.”

DISCLOSURE: NeoTRIP was supported by an unrestricted grant from Hoffmann-LaRoche and Celgene. Dr. Gianni has served on advisory boards for ADC Therapeutics, AstraZeneca, Celgene, Eli Lilly, GI Therapeutics, Genentech, Genomic Health, MSD, Oncolytics Biotech, Odonate Therapeutics, Onkaido Therapeutics, Roche, Pfizer, Taiho Pharmaceuticals, Sandoz, Seattle Genetics, Synthon, and Zymeworks; has been a consultant for Forty Seven, Genenta Science, Metis Precision Medicine, Novartis, Odonate Therapeutics, Revolution Medicines, Synaffix, and Zymeworks; has received research support from Zymeworks, Daiichi Sankyo, and Revolution Medicine; and is a co-inventor and patent holder for intellectual property related to PD-L1 expression in anti-HER2 therapy. Dr. Osborne has served on advisory boards for Genentech and AstraZeneca; has been a consultant for Tolmar Pharma; and holds stock in GeneTex. Dr. Schmid has received research support from AstraZeneca, Genentech, Roche, OncoGenex Pharmaceuticals, Novartis, Astellas, and Medivation and has received honoraria or consultation fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma.

REFERENCES

1. Gianni L, Huang C, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.

2. Schmid P, Park YH, Ferreira M, et al: KEYNOTE-522 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer: Pathologic complete response in key subgroups. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 12, 2019.