The first analysis of NeoTRIP study supports the notion that pathologic complete response (pCR) may not be the most appropriate surrogate endpoint to measure the role of immune checkpoint inhibitors (ICIs) in early triple-negative breast cancer (TNBC). Atezolizumab with neoadjuvant carboplatin/nab-paclitaxel was feasible in patients with high-risk early TNBC without limiting immune-related side effects, but it led to modest, statistically non-significant increase of pCR rate, which was higher for PD-L1-positive than for PD-L1-negative tumours. Addition of ICI to neoadjuvant chemotherapy significantly improved pCR rate in KEYNOTE-522 and IMpassion031. However, KEYNOTE-522 and GeparNUEVO showed that event-free survival (EFS) was independent of pCR. The primary endpoint of NeoTRIP is EFS, and lack of pCR improvement may be misleading as to the impact of atezolizumab on long-term efficacy in high risk TNBC, according to Dr. Luca Gianni of the Fondazione Michelangelo, Milano, Italy and colleagues who published the findings from the first NeoTRIP analysis on 16 February 2022 in the Annals of Oncology.
TNBC of high proliferation or grade is a subgroup characterised by very poor prognosis, rapid progression to metastatic disease and rapid onset of resistance to chemotherapy after initial response. Early high-risk and locally advanced TNBC, including cases of inflammatory breast cancer, represent a specific area of medical need for new therapeutic approaches.
Emerging evidence shows that many breast cancers with triple negative and basal like features have infiltration by mononuclear cells and lymphocytes. Retrospective analysis also shows that the highest level of infiltration is associated with higher probability of PD-L1 expression, and with likelihood of tumour eradication in neoadjuvant treatment programmes with chemotherapy. These data suggest that a subset of patients have an ongoing immune response within the tumour micro-environment, and that PD-L1 expression is an adaptive method of tumour resistance to tumour infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Blockade of immune checkpoints may synergise with chemotherapy and improve patient outcome.
The study team enrolled 280 patients with TNBC in the NeoTRIP multicentre study and randomised to neoadjuvant carboplatin AUC2 and nab-paclitaxel without (142 patients) or with atezolizumab (138 patients). Both regimens were given every 3 weeks for 8 cycles before surgery and 4 cycles of an adjuvant anthracycline regimen. The primary aim of the study is to compare EFS. An important secondary aim was the rate of pCR, defined as absence of invasive cells in breast and lymph nodes. The primary population for all efficacy endpoints is the intention-to-treat (ITT) population.
The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab (44.4%; odds ratio [OR] 1.18; 95% confidence interval 0.74-1.89; p = 0.48).
Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminases abnormalities with atezolizumab.
In multivariate analysis the presence of PD-L1 expression was the most significant factor influencing pCR rate (OR 2.08).
Continuing follow-up for the EFS is ongoing, and molecular studies are underway.
The authors concluded that in NeoTRIP, the addition of atezolizumab to neoadjuvant chemotherapy with carboplatin and nab-paclitaxel for 8 cycles led to a numerical, non-statistically significant increase of 4.2% in the pCR rate in women with high-risk early TNBC, and to an increase of 7.6% in the subgroup with PD-L1 positive tumours. The administration of atezolizumab correlated with immune side effects as expected from previous experience with the ICI.
The authors commented that their report from the neoTRIP first analysis is a contribution to the ongoing understanding of the ICI use in TNBC. It underscores the need for dependable predictors of activity and efficacy of ICI. The follow-up of the study and the analysis and molecular characterisation of the vast collection of tumour and blood specimens in neoTRIP is ongoing and will provide an additional contribution.
The study sponsor is Fondazione Michelangelo, a non-profit organisation that collaborated in the study design. The study was supported by an unrestricted grant and free study drugs from Hoffman-La Roche, Celgene, Bristol Myers Squibb. This work has also been supported in part by a Breast Cancer Research Foundation grant to Dr. Gianni.
Reference
Gianni L, Huang CS, Egle D, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIP Michelangelo randomized study. Annals of Oncology; Published online 16 February 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.004