Editor's Note: At the 2024 ESMO Congress, Dr. Peter Schmid from Barts Cancer Institute, Queen Mary University of London shared the overall survival data from the KEYNOTE-522 study with a follow-up of 75.1 months. The long-term follow-up results of the study showed that the combination of immunotherapy and chemotherapy significantly extended the event-free survival and overall survival of patients with triple-negative breast cancer, reducing the risk of recurrence and death. This breakthrough not only reaffirms the therapeutic position of immunotherapy in early triple-negative breast cancer but also points the way for further optimizing treatment plans in the future, bringing longer survival hopes for patients. Oncology Frontier specially invited Dr. Peter Schmid to share the relevant data.

Oncology Frontier：You presented the KEYNOTE-522 data in“Presidential Symposium II: Practice-changing trials”. How have you updated the KEYNOTE-522 data at the ESMO Congress?

Dr. Peter Schmid：The KEYNOTE-522 trial was the first phase Ⅲ trial of chemotherapy and immune therapy first in the neo-adjuvant setting but then with continuation of immune therapy in the adjuvant setting. The trial was for stage 2 and stage 3 patients with early triple negative breast cancer. The chemotherapy regimen was a 6-month chemotherapy regimen which I would consider an optimal regimen with 12 weeks of weekly paclitaxel carboplatin followed by 4 cycles of AC or EC either all the way through with pembrolizumab or placebo followed by surgery and then followed by 6 months of pembrolizumab or 6 months of placebo. The trial has two co-primary endpoints, a short-term endpoint which is called pCR the complete disappearance of all invasive cancer and that hit positive, was positive in 2019 here in Barcelona as well as the Presidential Lecture at that time where we showed that the addition of immune therapy to chemotherapy increased pCR rates about 13.6% to just under 65%.

The second co-primary endpoint is event-free survival and again we showed this first time after 3 years of follow-up where we saw that the addition of pembrolizumab leads to a 37% reduction in the risk of recurrences hazard ratio 0.63. Now with triple negative breast cancer it’s really interesting we see most of the recurrences relatively early after 2 to 3 years about 70% or even more events occur that early about 90-95% of events occur in the first 5 years and so that’s what we’ve seen in KEYNOTE-522 as well we presented 5-year data a year ago where we saw that the EFS curves the event-free survival curves are starting to flatten out with very few additional events between year 3 and year 5, and the hazard ratio has remained absolutely stable.

Now here at ESMO 2024 we have key new data we have now a follow-up of 75.1 months, so over 6 years which is long for triple negative breast cancer in terms of event-free survival the data have remained absolutely stable hazard ratio 0.65, 5 years event-free survival rates about 81.2% with chemotherapy and immune therapy and about 72.2% with chemotherapy alone, that’s highly significant. But most importantly and long awaited are the overall survival data with 75.1months of follow-up we see a significant improvement in overall survival, the hazard ratio is 0.66 that means it’s a 34% reduction in the risk of death and that’s attributed to the addition of Pembrolizumab to preoperative and postoperative chemotherapy.

Looking at the benefits in subgroups it seems that this benefit is consistent across all relevant clinical subgroups whether it’s PD-1 positive or PD-1 negative, stage 2 or stage 3 node positive or node negative. So in other words we can’t really identify a clinical group of patients with stage 2 or stage 3 disease who shouldn’t be considered for the combination of Pembrolizumab and chemotherapy and for event-free survival presented before even for the smallest cancer T2 and 0, we see a hazard ratio of nearly 0.5 with a substantial delta, so even in the smallest tumours there seems to be that benefit.

Oncology Frontier：From a clinical practice perspective, how do the results of the KEYNOTE-522 study change our understanding of immunotherapy for early-stage TNBC? How will these results guide future clinical practice?

Dr. Peter Schmid：An interesting pre-planned analysis was looking at patients who have an optimal benefit and who haven’t gotten the optimal benefit in terms of patients who have residual disease at the time of surgery and we had shown for EFS that patients who have a pCR with chemotherapy and immune therapy seem to do better than patients who have a pCR only after chemotherapy but more importantly in patients who have residual disease after chemotherapy and immune therapy there was a lower risk of recurrence if this was after immune therapy compared to after chemotherapy alone. And the same is the case for survival. Really exciting, really important from a patient perspective. If you are one third of patients who have residual disease at the time of surgery but this was after chemotherapy and immune therapy there is a 6% better chance of being alive at 5 years compared to patients who had only chemotherapy. I think that’s really important, really meaningful.

In terms of safety, long-term follow-up data didn’t show any new safety signals pretty much what we have reported before in keeping with previous analysis and with what we know about chemotherapy and immune therapy. So in summary, this is a practice-changing trial. It’s already been in all the guidelines. It’s already approved in many, many countries and will continue to be. That’s based on the positivity for the two co-primary endpoints improving pCR rates significantly and reducing recurrences significantly but most importantly as we can now demonstrate also reducing the risk of death by 34%.

Oncology Frontier：Combined with the data of KEYNOTE-522 study, would you please share with us, which patients with early-stage TNBC are the preferred population for neoadjuvant immunotherapy?

Dr. Peter Schmid：I think what is clear is we have a new standard of care. That’s widely accepted. That’s chemotherapy and immune therapy in stage 2 and stage 3 disease. So there’s a little bit of work for us to do. Unfortunately, there’s still a third of patients who have disease recurrence even with that excellent therapy and there’s a lot of focus going on how can we improve their outcome. I have a lot of hope in antibody drug conjugates in that setting. We will see whether patients who are optimal responders for pCR need the whole year of treatment or whether we can shorten the treatment. We are looking into fine-tuning studies where possibly in smaller tumors excellent response, maybe we can shorten chemotherapy a little bit but also in patients who don’t respond optimally maybe we can bring antibody drug conjugates in to boost the pCR rates. For stage 1 disease, we haven’t really done very much in that setting. We’re currently looking at ADCs alone and in combination with immune therapy to see whether we can spare patients from chemotherapy. So although KEYNOTE-522 is an important study and has clearly improved the outcome of patients clearly reduced the risk of dying of breast cancer there’s still work to do. The exciting trial is ongoing and hopefully they will help us to further improve the outcome of patients of early stage triple negative breast cancer.

Oncology Frontier：Based on the results of the KEYNOTE-522 study, what are your future prospects for immunotherapy in TNBC? What other research directions are worthy of further exploration?

Dr. Peter Schmid：So the data for event-free survival and actually now for overall survival show very clearly that based on clinical parameters there’s no subgroup that does not benefit and even in patients with small tumors with lower risk of recurrence there’s a substantial benefit, absolute benefit from adding pembrolizumab to chemotherapy. So we are unable and that’s great news we are unable to define a subgroup of patients who shouldn’t be treated with pembrolizumab. There’s a lot of biomarker work ongoing which we will share in the next few months and maybe that can contribute to this but as it stands based on clinical parameters it should be considered for all patients who meet the eligibility criteria.

So we’ve already talked about where the development is going to and I think immunotherapy is there to stay, it will stay in early triple negative breast cancer as standard of care, it’s standard of care in metastatic triple negative breast cancer and PD-1 positive tumors. We will obviously fine-tune the KEYNOTE-522 regimen possibly as we go forward as outlined for patients who respond extremely well maybe we can shorten some of the chemotherapy for patients who don’t respond as well as we hope maybe we can increase the response and possibly improve the long-term outcome by adding in antibody drug conjugates. There’s a clear signal from some of the metastatic studies that we have synergistic activity between ADCs and immunotherapy so I hope that ADCs will help us to optimally unlock the potential of immunotherapy in this early disease setting.