Episode 14: NeoTRIP and IMpassion030: are ICI effective in early TNBC?

Presented by Dr Kevin Punie (GZA Hospitals) and Prof Evandro De Azambuja (Institut Jules Bordet)

Professor Evandro de Azambuja from Institut Jules Bordet and Dr Kevin Punie from GZA Hospitals will discuss two important trials concerning immune checkpoint inhibitors in TNBC patients: the NeoTRIP trial and the Impassion030 trial. Both trials add to the expanding body of evidence on immune checkpoint inhibitors for early TNBC treatment.

The NeoTRIP trial, a relatively small phase 3 study, investigates the addition of atezolizumab to neoadjuvant carboplatin and nab-paclitaxel chemotherapy compared to a placebo. Post-surgery, patients underwent four cycles of anthracycline treatment. Initial data, published in the Annals of Oncology in 2022, showed no significant improvement in the pCR rate for the treatment group. Recently, at ESMO2023, the primary outcome data, the 5-year EFS revealed that the addition of atezolizumab did not improve the 5-year EFS; numerically, the EFS was slightly better in the comparator arm than in the experimental arm.

Despite the negative outcome, notable aspects emerged. Firstly, the trial population was smaller compared to similar trials like KEYNOTE-522. Additionally, the study included an enriched population with node-positive disease, excluding T2N0 patients. Interestingly, the translational analysis indicated that a higher baseline density of CD8+/TCF1+ activated immune cells was strongly associated with the pCR benefit of atezolizumab. The exploratory analysis presented at ESMO2023 confirms the positive association with the EFS benefit in patients enriched in this immune cell subset, suggesting the potential of a predictive biomarker, though it requires validation in independent datasets.

Experts attribute the negative primary endpoint outcome to differences in trial design, the use of an anti-PD-L1 versus an anti-PD1 checkpoint inhibitor, variations in the chemotherapy backbone, and the duration of the neoadjuvant treatment. The main factor, however, is probably the small sample size decreasing the probability of detecting a small effect.

Considering the results, it is unlikely that atezolizumab will be approved in the neoadjuvant setting, but the biomarker may play a crucial role in selecting eligible patients.

Transitioning to the adjuvant setting, the ALEXANDRA/Impassion030 trial also yielded negative results. Stage II-III TNBC patients underwent surgery and were randomized into adjuvant atezolizumab plus standard anthracycline/taxane adjuvant chemotherapy versus chemotherapy alone. Futility criteria were met, with invasive DFS analysis curves overlapping and an HR >1, subgroup analysis showing no benefit and as expected OS curves overlapped fully.

The trial setting differs significantly, suggesting that what we know from other disease areas, and in breast cancer we only have indirect evidence, that the presence of the tumour is crucial for inducing anti-tumour immunity with checkpoint inhibitors.

The mixed results in the early setting lead to an indirect conclusion: patients with high-risk, positive stage II-III disease could benefit from immune checkpoint inhibitors in the neoadjuvant setting when the tumour is contained.

The standard of care remains unchanged in Belgium, where patients with early-stage or locally advanced TNBC at high risk of recurrence receive pembrolizumab in both the neoadjuvant and adjuvant settings, with reimbursement for stage II-III.

References:

Gianni L et al, 2023, Event-free survival (EFS) analysis of neoadjuvant taxane/carboplatin with or without atezolizumab followed by an adjuvant anthracycline regimen in high-risk triple negative breast cancer (TNBC): NeoTRIP Michelangelo randomized study. Annals of Oncology 34, S2, S1258-S1259.

Ignatiadis M et al, Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/Impassion030 phase 3 trial. SABCS2023 #GS01-03