The addition of atezolizumab to standard neoadjuvant chemotherapy followed by adjuvant atezolizumab did not significantly improve event-free survival (EFS) in patients with stages II-III triple-negative breast cancer (TNBC), according to a phase 3 trial.
The results of NSABP B-59/GBG-96-GeparDouze were presented at the San Antonio Breast Cancer Symposium (SABCS) 2024. This international, double-blind study enrolled patients with centrally confirmed TNBC between December 2017 and May 2021. Eligible patients had T2 or T3 tumors if clinically node-negative or T1c-T3 tumors if node-positive. The study population was predominantly White (90%), with a median age of 40 years. Notably, 59% of patients had clinically node-negative disease, and 59% had tumors ≤ 3 cm.
The trial randomized 1550 patients to receive either atezolizumab or placebo combined with standard neoadjuvant chemotherapy consisting of weekly paclitaxel (80 mg/m for 12 doses) plus carboplatin (area under the curve 5 every 3 weeks for four doses), followed by four cycles of anthracycline-based therapy. After surgery, patients continued atezolizumab or placebo for up to 1 year.
In an interview, lead investigator Charles Geyer, MD, of the University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, explained that the trial allowed the use of adjuvant capecitabine or olaparib in patients with residual disease after surgery. "The chemotherapy backbone we chose came from the BrighTNess study," he said. "During the 41-month accrual period, as capecitabine became increasingly accepted as standard of care, we amended the protocol to allow its use in patients with residual disease."
Geyer added that "50% of non-pCR patients received some amount of adjuvant capecitabine," while olaparib use was limited to "just a handful of patients" with germline mutations in BRCA1 or BRCA2. "These decisions were left to investigator discretion and were not specified in the protocol," he explained.
"With a median follow-up of 46.9 months, we observed a hazard ratio of 0.8 for EFS, with a P value of 0.08, which did not meet our prespecified criteria for statistical significance," said Geyer during the presentation. The 4-year EFS rates were 81.9% in the control arm and 85.2% in the atezolizumab arm.
The pathologic complete response (pCR) rate was modestly higher with atezolizumab (63% vs 57%), but this improvement did not translate into a significant survival benefit. Overall survival was similar between the two arms, with both groups achieving approximately 90% 4-year survival.
Discussing the results, independent expert Giampaolo Bianchini, MD, noted that the pCR improvement was similar to that seen in the positive KEYNOTE-522 trial of pembrolizumab plus chemotherapy, yet the EFS outcomes differed.
"If pCR had been used as the primary endpoint, the study would have met its primary endpoint. But the EFS was quite different in the two studies," he said.
Bianchini outlined several factors that may have contributed to these differences in EFS between the KEYNOTE-522 and NSABP B-59/GBG-96-GeparDouze trials. He highlighted differences in trial design and population characteristics, noting that NSABP B-59/GBG-96-GeparDouze had "a higher proportion of patients with nodal-negative disease -- almost 60%, compared to around 52% in the KEYNOTE-522 trial." He added that the NSABP B-59/GBG-96-GeparDouze trial also mostly enrolled White patients with nearly no Asian patients, who showed particularly strong benefit from immunotherapy in the KEYNOTE-522 trial.
Bianchini added that biologic differences between anti-programmed cell death 1 and anti-programmed death ligand 1 (PD-L1) antibodies might partially explain the differences in outcomes between the NSABP B-59/GBG-96-GeparDouze study and previous trials investigating the benefit of neoadjuvant immunotherapy plus chemotherapy in patients with TNBC.
"They are similar but different molecules, and we don't have head-to-head trials comparing their efficacy," he explained.
A prespecified subgroup analysis revealed potential benefit in certain populations.
"When you look at the clinically node-negative patients, the hazard ratio is nearly 1. In the subgroups with node-positive disease, the hazard ratio is 0.6," Geyer reported.
Similar trends were observed, favoring the addition of atezolizumab to neoadjuvant chemotherapy in patients with larger tumors and higher numbers of tumor-infiltrating lymphocytes.
Although atezolizumab did not protect against brain metastasis, as demonstrated by the similar incidence of brain metastasis at first recurrence between the two arms, Geyer noted in an interview with Medscape Medical News that "brain metastases are a difficult problem for patients with TNBC, and we wanted to be able to assess the impact of the therapies on the cumulative incidence of brain metastasis." He revealed that the effects of treatment on brain metastasis-free survival will be assessed as an exploratory endpoint.
Geyer noted that the safety profile of atezolizumab in this trial was consistent with that of previous studies on immune checkpoint inhibition in TNBC. Grades 3-4 treatment-emergent adverse events were slightly higher with atezolizumab, as were serious adverse events and treatment discontinuation due to side effects. The most common immune-related adverse events were endocrinopathies, with some cases of higher-grade hypothyroidism and nephritis.
When asked about PD-L1 status, which was positive in 36% of patients, Geyer stated in the interview that he and his coauthors "did not see a difference in response patterns between PD-L1-positive and negative patients."
The findings add to a complex landscape of immunotherapy trials in early TNBC. While KEYNOTE-522 established pembrolizumab plus chemotherapy as the standard of care, results with other checkpoint inhibitors have been mixed.
Bianchini emphasized that the collective evidence suggests that neoadjuvant therapy is superior to adjuvant immunotherapy, as demonstrated by consistently better outcomes in neoadjuvant trials than in purely adjuvant studies.
Geyer noted that the study collected extensive biospecimens that may help identify patients most likely to benefit from immunotherapy.
"While we did not meet our efficacy criteria for our primary endpoint, our results do support translational studies to try to identify biomarkers to see the subsets of patients who may benefit from this class of agents in this patient population," he said.
Looking ahead, Geyer indicated in the interview that the current standard remains "pembrolizumab with chemotherapy for tumors larger than 2 cm irrespective of nodal status." He expressed hope that "translational studies from our trial will help develop predictors of benefit from immunotherapy."
The study was funded by Genentech and Roche. Geyer reported receiving grant funding from Genentech/Roche, Daiichi Sankyo, AstraZeneca, and Exact Sciences. Bianchini reported receiving consultant fees from Roche, MSD, Seagen, AstraZeneca, Daiichi Sankyo, Novartis, Gilead Sciences, Helsinn, Eli Lilly and Company, Eisai, Menarini/Stemline, and Exact Sciences; grant funding from Gilead Sciences; and honoraria from Roche, MSD, AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Eisai, Gilead Sciences, Seagen, Novartis, and Takeda.