PublishedOctober 1, 2026
JournalClinical Cancer Research
TrialA-BRAVE (phase III, NCT02926196)

High Baseline TILs Flag Adjuvant Avelumab Benefit in High-Risk Triple-Negative Breast Cancer, but the A-BRAVE Trial Missed Its Co-Primary Endpoints and the Finding Is Hypothesis Generating

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Article Summary
  • A-BRAVE randomized 466 patients with high-risk early triple-negative breast cancer (TNBC) to 52 weeks of adjuvant avelumab or observation. The co-primary endpoints were not met (ITT DFS: HR 0.81; 95% CI 0.61–1.09; P = 0.172). This report is a prespecified analysis of the prognostic and predictive role of stromal tumor-infiltrating lymphocytes (TILs) and residual cancer burden (RCB).
  • In stratum B (neoadjuvant chemotherapy without documented pathologic complete response), 3-year distant DFS was 92% with avelumab versus 58.7% with control among patients with baseline TILs (BSL-TILs) ≥30%, and 70.4% versus 70.1% among those with BSL-TILs <30% (interaction adjusted P = 0.019).
  • The authors state that the findings are not sufficient to alter clinical practice and are hypothesis generating: the trial was not powered for subgroup analyses and missed its co-primary endpoints. Validation in independent cohorts is needed.

Why This Study Matters

For early TNBC with cT ≥2 and/or cN1–N2 disease, neoadjuvant chemotherapy plus pembrolizumab followed by adjuvant pembrolizumab is the current standard, based on KEYNOTE-522. The authors note that no biomarker is currently available to guide immunotherapy in early TNBC, and that PD-L1 expression is not predictive of pembrolizumab benefit. TILs are an established prognostic biomarker, but their role as a predictor of immunotherapy benefit remained underexplored.

1
A-BRAVE randomized 466 patients with high-risk early TNBC to 52 weeks of adjuvant avelumab or observation; the co-primary endpoints were not met (ITT DFS: HR 0.81; 95% CI 0.61–1.09; P = 0.172).
2
Among patients with BSL-TILs ≥30% in stratum B, 3-year distant DFS was 92% with avelumab versus 58.7% with control; in BSL-TILs <30% it was 70.4% versus 70.1% (interaction adjusted P = 0.019).
3
In stratum B, residual-disease TILs (RD-TILs) ≥10% versus <10% gave 3-year DDFS of 80.6% versus 57.8% (log-rank P < 0.001; adjusted HR 0.53; 95% CI 0.33–0.88).

Study Design

A-BRAVE (NCT02926196) was an investigator-initiated, randomized, multicentric trial conducted in Italy and the United Kingdom. It randomized 466 patients with early TNBC at high risk of relapse to adjuvant avelumab for 52 weeks or observation, after completion of curative-intent surgery and chemotherapy. This report is a prespecified analysis of the prognostic and predictive role of TILs and residual cancer burden (RCB). Stromal TILs were centrally assessed on H&E slides. Because analyses used patients with available biomarker data, no formal sample size calculation was performed. The number of sites and the randomization ratio are not specified in the source. Sponsor and support: University of Padova; financial support and avelumab supply from Merck KGaA; AIRC grants.

Patient Population

Stratum A (n = 83) comprised patients with primary surgery followed by adjuvant chemotherapy at high risk by pathological stage. Stratum B comprised patients treated with neoadjuvant chemotherapy and surgery without documented pathologic complete response. BSL-TILs were available for 387 patients (83% of the ITT population; 67 in stratum A and 320 in stratum B). RD-TILs were available for 330 stratum B patients, 290 of whom also had BSL-TILs. Median BSL-TIL level was 10% (Q1 5%; Q3 25%). High BSL-TILs (≥30%) were more prevalent in stratum A than B (34.3% vs 21.6%; P = 0.026). Median follow-up in the ITT population was 52.1 months.

Primary Endpoint Results (Parent Trial)

As summarized in this paper, the co-primary endpoints were not met. At a median follow-up of 52.1 months, avelumab did not significantly improve DFS in the ITT population (HR 0.81; 95% CI 0.61–1.09; P = 0.172; 3-year DFS 68.3% vs 63.2%) or in stratum B (HR 0.80; 95% CI 0.58–1.10; P = 0.170; 3-year DFS 66.9% vs 60.7%). A descriptive analysis of overall survival favored avelumab (HR 0.66; 95% CI 0.45–0.97; 3-year OS 84.8% vs 76.3%), supported by exploratory DDFS (HR 0.70; 95% CI 0.50–0.96; 3-year DDFS 75.4% vs 67.9%).

Subgroup Analyses: TILs as Prognostic and Predictive Markers

Each 5% increase in BSL-TILs was associated with a lower risk of DFS events (HR 0.93; 95% CI 0.88–0.98; P = 0.007) and DDFS events (HR 0.93; 95% CI 0.88–0.98; P = 0.012). In stratum B, RD-TILs outperformed BSL-TILs as a prognostic marker, and RCB III (vs I–II) was independently prognostic (DFS HR 2.78; 95% CI 1.76–4.39; P < 0.001).

Group (3-year DDFS)AvelumabControlStatistic reported
Both strata, BSL-TILs ≥30%93.5%69.8%Unadjusted HR 0.31 (95% CI 0.11–0.87)
Both strata, BSL-TILs <30%71.5%70.9%Unadjusted HR 0.89 (95% CI 0.60–1.33); interaction adjusted P = 0.065
Stratum B, BSL-TILs ≥30%92%58.7%HR 0.20 (per abstract); interaction adjusted P = 0.019
Stratum B, BSL-TILs <30%70.4%70.1%HR 0.92 (per abstract)

Among stratum B patients with low BSL-TILs, the RD-TIL × treatment interaction for DDFS was significant (adjusted P = 0.048): avelumab was numerically worse than control with RD-TILs ≥10% and numerically better with RD-TILs <10%. RCB was not predictive of avelumab benefit, and RD-TILs alone were not predictive across stratum B.

TILs may predict benefit from adjuvant immunotherapy in early TNBC.
— Dieci et al., Clinical Cancer Research

Safety Profile

Adverse-event data by arm are not reported in this biomarker analysis (not specified in source).

Interpretation and Broader Context

The authors state that the findings are not sufficient to alter clinical practice and should be considered hypothesis generating. They call for validation in independent cohorts and for TIL assessment in ongoing immunotherapy trials in early TNBC.

Limitations

The trial was not powered for subgroup analyses and missed its co-primary endpoints, so the TIL-stratified results are exploratory. The authors note imbalances such as nonstandardized adjuvant capecitabine use, and that A-BRAVE gave immunotherapy sequentially after all standard therapy, which limits direct comparison with KEYNOTE-522 and NSABP-B59/GBG-96-GeparDouze. Biomarker data were available for 387 of 466 randomized patients (83%), and no formal sample size calculation was performed for these analyses. The combined-strata interaction did not reach significance (P = 0.065), and the continuous-TIL interaction was not significant for any endpoint.

Trial registration

Primary source: DOI 10.1158/1078-0432.CCR-26-0975 · PubMed 42467210 · PMC13628102

References

  1. Dieci MV, Gasparini E, Nicolé L, et al. Tumor-infiltrating lymphocytes as a predictor of adjuvant avelumab efficacy in patients with high-risk triple-negative breast cancer. Clinical Cancer Research. 2026;32:4282–91. DOI: 10.1158/1078-0432.CCR-26-0975. PMID: 42467210.
  2. ClinicalTrials.gov: NCT02926196 (A-BRAVE).