Adjuvant avelumab versus control does not significantly improve DFS but does improve OS in high-risk TNBC patients
Prof Pier Conte - University of Padova, Padova, Italy
This is an academic-driven trial conducted in early high-risk triple negative breast cancer patients. The high risk definition included two groups of patients, one was a group of patients who underwent surgery up front and they had pathological stage 2 or 3 disease and received adjuvant chemotherapy. The second was a group of patients who received neoadjuvant chemotherapy and still had invasive residual disease at the time of surgery. In fact, in the study 82% of the patients were in this second group, the post-neoadjuvant group.
These patients are both at high risk of relapse in spite of adjuvant chemotherapy and were randomised 1:1 to observation or one year of avelumab, an anti-PD-L1 antibody. The main finding of the study was disease free survival, secondary endpoints were overall survival and safety, there were also several ongoing translational studies on biological materials from these patients.
The primary endpoint was not met because we did observe a reduction in the risk of relapse with a hazard ratio of 0.8 with an absolute difference between avelumab and observation of 5.1% which is not statistically significant. On the contrary, the difference in overall survival was statistically significant, a hazard ratio of 0.66, so a reduction of 34% in the risk of death which is statistically significant.
Trying to understand why we did observe a larger benefit in terms of overall survival than in terms of disease free survival, we have also made a post hoc exploratory analysis on distant disease free survival. In that case we do observe a significant advantage for avelumab with a hazard ratio of 0.7 which means a 30% reduction in the risk of developing distant metastases which is statistically significant.
The last point is that the tolerability was very good, very, very few grade 3 or more toxicities. Most of the patients were able to complete one year of avelumab without discontinuation. The major reason for treatment discontinuation was in fact relapse of disease.
This is a very good question because, of course, we know that nowadays in many countries, certainly in the US and in Europe, in most European countries, now we have pembrolizumab approved for high risk triple negative breast cancer patients. Pembrolizumab is given in the neoadjuvant setting in combination with chemotherapy and also is given after surgery, both to patients who achieve a pathological complete response and to those who do not achieve a pathological complete response. Of course, the benefit of pembrolizumab is quite clear in terms of disease free survival. We also know from a recent press release that there is also an overall survival advantage.
So the question is now which might be the position of avelumab based on our own results. There are still patients who do not receive neoadjuvant pembrolizumab. Many patients with smaller tumour size or clinically negative axillary lymph nodes or patients who for some comorbidities or not completely fit, the physician is uncertain on the potential toxicities of combining pembrolizumab to chemotherapy. So there are patients who receive chemotherapy only in the neoadjuvant setting. If these patients do not achieve a pathologic complete response there now is a new option, avelumab, which is effective in reducing risk, especially risk of death.
Of course, the efficacy is important to outline that this is an academic trial. Of course we have the drugs supplied and also budget by the company, Merck, but it’s important that 60 Italian hospitals and 60 UK hospitals participated to this trial.
