Long-Term Outcomes Bolstered by Atezolizumab in Early-Stage Triple-Negative Breast Cancer

The addition of atezolizumab (Tecentriq) to neoadjuvant chemotherapy continues to demonstrate favorable long-term outcomes in patients with stage II/III triple-negative breast cancer (TNBC), according to the prespecified final analysis of the randomized phase 3 IMpassion031 trial (NCT03197935).¹

The updated data, with approximately 3 years of follow-up, reinforce earlier findings of improved pathologic complete response (pCR) rates and provide crucial insights into event-free survival (EFS), disease-free survival (DFS), and overall survival (OS). Furthermore, exploratory analyses of circulating tumor DNA (ctDNA) dynamics offer promising prognostic value beyond pCR.

Previously, the IMpassion031 trial met its primary end point, showing a significantly improved pCR rate with the addition of atezolizumab to neoadjuvant chemotherapy. In the intention-to-treat (ITT) population, pCR rates were 58% in the atezolizumab-chemotherapy arm vs 41% in the placebo-chemotherapy arm, representing a 17% improvement. This benefit was observed irrespective of programmed death-ligand 1 (PD-L1) status. The long-term follow-up now provides a more comprehensive picture of the survival benefits associated with this regimen.

Survival Outcomes Favor Atezolizumab Arm

The latest analysis reveals that long-term outcomes consistently favored the atezolizumab group across all survival endpoints. While the trial was not powered for formal statistical comparison of these secondary end points, the hazard ratio (HR) point estimates suggest a positive trend:

• EFS: HR, 0.76 (95% CI, 0.47–1.21)
• DFS: HR, 0.76 (95% CI, 0.44–1.30)
• OS: HR, 0.56 (95% CI, 0.30–1.04)

These consistent directional improvements across EFS, DFS, and OS align with observations from other trials evaluating neoadjuvant immunotherapy in early-stage TNBC, such as the KEYNOTE-522 trial (NCT03036488) which evaluated pembrolizumab (Keytruda).² The long-term safety profile of atezolizumab was also consistent with previous reports, with no new safety signals or treatment-related deaths. Patient-reported outcomes indicated no additional treatment burden with atezolizumab.¹

The Prognostic Power of ctDNA

A significant advancement from this study lies in its exploratory analyses of ctDNA, which provide valuable insights into its prognostic role in early-stage TNBC. This trial uniquely performed ctDNA analyses in all patients, offering a more comprehensive understanding compared to studies focused solely on residual disease.

Key findings from the ctDNA analysis included:

• Baseline ctDNA-Negative Status: A small subset of patients (6%) presented with ctDNA-negative status at baseline. These individuals demonstrated excellent long-term outcomes, regardless of whether they achieved a pCR. This suggests that the absence of ctDNA at baseline could be a strong indicator of favorable prognosis and may inform future de-escalation strategies.
• ctDNA Clearance During Treatment: Most patients (87%) who were ctDNA-positive at baseline experienced ctDNA clearance by the time of surgery. This clearance was associated with improved DFS and OS. Early ctDNA clearance at week 7 (halfway through nab-paclitaxel therapy) was also observed in 72% of patients and was linked to more favorable outcomes.
• Persistent ctDNA as a Marker of Poor Prognosis: Conversely, patients with persistent ctDNA-positive status at surgery (3% of the cohort) showed a particularly poor prognosis, even within the non-pCR group. All 10 samples collected at the time of disease recurrence were ctDNA-positive. This highlights ctDNA as a powerful biomarker for identifying patients at highest risk of relapse.

These findings suggest that dynamic ctDNA monitoring throughout neoadjuvant therapy could serve as an early surrogate for long-term outcomes and potentially guide personalized treatment strategies. The ability to identify patients with very low or very high risk based on ctDNA status could lead to adaptive approaches, tailoring therapy intensity according to individual patient response and risk stratification.

Trial Design and Future Implications

The IMpassion031 trial utilized a dose-dense chemotherapy backbone and uniquely allowed for additional systemic adjuvant therapy at the investigator's discretion for patients not achieving a pCR. This aspect reflects standard-of-care practices and distinguishes it from some other trials. The imbalance in adjuvant capecitabine use between the 2 arms (33% in placebo vs 20% in atezolizumab for non-pCR patients) and the exploratory nature of the post hoc analyses on patients without a pCR warrant careful interpretation. However, the overall consistency of the results with other immunotherapy trials in early-stage TNBC underscores the growing importance of immune checkpoint inhibitors in this setting.

While the trial's smaller sample size for a pCR primary end point meant it was not powered to detect statistically significant differences in EFS, DFS, and OS, the consistent HR point estimates favoring atezolizumab provide compelling evidence. Further research is needed to determine whether the observed long-term benefits are primarily due to the neoadjuvant administration of atezolizumab, its continuation in the adjuvant setting, or a combination of both.

The insights gained from the IMpassion031 trial, particularly regarding ctDNA dynamics, offer a promising avenue for improving risk stratification and guiding treatment decisions in early-stage TNBC. Defining and implementing adaptive treatment strategies driven by both tumor response and dynamic ctDNA monitoring represents a critical challenge for future clinical practice and research.

REFERENCES:

1. Mittendorf EA, Assaf ZJ, Harbeck N, et al. Peri-operative atezolizumab in early-stage triple-negative breast cancer: final results and ctDNA analyses from the randomized phase 3 IMpassion031 trial. Nat Med. 2025 Jun 4;31(7):2397–2404. doi: 10.1038/s41591-025-03725-4.

2. Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022 Jul 21;387(3):217-226. doi: 10.1056/NEJMoa2202809.