Two recent trials evaluating neoadjuvant immunotherapy in early triple-negative breast cancer (TNBC) have yielded conflicting results, adding to the ongoing debate about the role of immunotherapy in this setting. While one trial showed an improvement in pathologic complete response (pCR), neither demonstrated a significant benefit in survival outcomes.
NSABP B-59 Trial: Atezolizumab Fails to Improve EFS
The NSABP B-59 trial, a multinational study, investigated the addition of perioperative atezolizumab (Tecentriq) to neoadjuvant chemotherapy in patients with stage II-III TNBC. The trial randomized 1,550 patients, with 1,248 evaluable for analysis. While the pCR rate was significantly higher in the atezolizumab arm (63.3%) compared to the placebo arm (57.0%, P = 0.0091), the primary endpoint of event-free survival (EFS) was not significantly improved (4-year EFS: 85.2% vs 81.9%, HR 0.80, 95% CI 0.62-1.03, P = 0.08).
According to Charles E. Geyer Jr., MD, of the UPMC Hillman Cancer Center in Pittsburgh, these results highlight the need for translational studies to identify biomarkers that can predict which patients are most likely to benefit from checkpoint inhibitors in the neoadjuvant or adjuvant setting for TNBC. The study population had a median age of 49, with approximately 60% having node-negative disease and tumors ≤3 cm, and 36% with PD-L1-positive tumors. About 80% had grade 1 tumors, and approximately 53% had BRCA wild-type cancers.
CamRelief Trial: Camrelizumab Improves pCR but Not Survival
In contrast, the CamRelief trial, conducted in China, evaluated the PD-1 inhibitor camrelizumab in combination with neoadjuvant chemotherapy in 441 patients with stage II-III TNBC. The study, led by Zhi-Ming Shao, MD, of Fudan University and Shanghai Cancer Center, showed a significant improvement in pCR with camrelizumab (56.8%) compared to placebo (44.7%, P = 0.0038). All patients received nab-paclitaxel plus carboplatin followed by epirubicin-cyclophosphamide chemotherapy and were randomized to camrelizumab or placebo. Following surgery, patients continued treatment with adjuvant camrelizumab or placebo.
However, similar to the NSABP B-59 trial, the CamRelief trial failed to demonstrate a significant improvement in secondary endpoints such as EFS, disease-free survival (DFS), and distant disease-free survival (DDFS), despite hazard ratios suggesting a potential benefit with camrelizumab (HR 0.62-0.80). The patient population in CamRelief also had a median age of 49, but differed from NSABP B-59 in that 57-58% of patients had a PD-L1 combined positive score (CPS) ≥10, and only 13-14% had a PD-L1 CPS <1. Three-fourths of the tumors were T2, and about 30% of patients were node negative.
Interpreting the Mixed Signals
The mixed results from these trials underscore the complexity of treating TNBC and the challenges of using pCR as a surrogate endpoint for long-term survival. Giampaolo Bianchini, MD, PhD, of San Raffaele University in Milan, an invited discussant at the San Antonio Breast Cancer Symposium (SABCS), emphasized that there is no definitive evidence that pCR is a reliable surrogate for long-term benefit at the trial level. He also cautioned against interpreting the failure to reject the null hypothesis as proof of no effect, noting that observed differences could still be due to chance.
Differences in patient and tumor characteristics, trial design, and the specific drugs used may contribute to the variability in outcomes observed across different trials of neoadjuvant immunotherapy for TNBC. Further research is needed to identify predictive biomarkers and optimize treatment strategies for this aggressive form of breast cancer.
