Neoadjuvant Pembro Plus Chemo Shows EFS Benefit at 5-Years in TNBC

Peter Schmid, FRCP, MD, PhD

The addition of neoadjuvant pembrolizumab (Keytruda) to chemotherapy, followed by adjuvant pembrolizumab reduced the risk for recurrence, progression, complications, or death vs neoadjuvant chemotherapy alone in the KEYNOTE-522 study (NCT03036488) evaluating the combination in high-risk triple-negative breast cancer (TNBC).¹

According to updated findings presented at the European Society for Medical Oncology (ESMO) 2023 Annual Congress, 5-year results from the KEYNOTE-522 trial—, a first prospective, randomized, placebo-controlled phase 3 study, revealed that among patients treated with chemotherapy plus pembrolizumab, the event-free survival (EFS) rate was 81.3% vs 72.3% in the placebo arm. This resulted in a reduction in risk for recurrence, progression, complications, or death by 37% (HR, 0.63; 95% CI, 0.49-0.81).

Additionally, the benefit in EFS was consistent across subgroups stratified by PD-L1 status, nodal status, tumor size, carboplatin schedule, age, and ECOG performance status, and the median EFS was not achieved in either group. Of note, the reduction in EFS events were seen regardless of pathologic complete response outcomes.

“[I]n my opinion, unless there are specific contraindications, all patients with stage II or stage III triple-negative breast cancer should be considered for preoperative chemotherapy in combination with pembrolizumab for 6 months, followed by surgery, and then followed by adjuvant treatment,” explained Peter Schmid, FRCP, MD, PhD, in an interview with Targeted Oncology^TM.

In the interview, Schmid, professor, cancer medicine, centre lead at the, Centre of Experimental Cancer Medicine, and director of the, Barts Breast Cancer Centre, discussed the implication of findings from the KEYNOTE-522 trial of the addition of pembrolizumab to neoadjuvant chemotherapy in patients with high-risk TNBC.

Breast Cancer Image: © Giovanni Cancemi- stock.adobe.com

Targeted Oncology: Can you discuss the KEYNOTE-522 trial in breast cancer?.

Schmid: The KEYNOTE-522 trial was the first phase 3 trial of immunotherapy in combination with chemotherapy as a neoadjuvant, preoperative treatment, in triple-negative breast cancer. It was a large phase 3 trial where patients with stage II or stage III triple-negative breast cancer were randomized to either pembrolizumab or placebo in combination with chemotherapy for 6 months, then they had surgery, and then they carried on with pembrolizumab or placebo for another 6 months. The trial had 2 end points. The short-term end point was pathological CR, which is the disappearance of all invasive cancer, and then a long-term end point was event-free survival, so the number of recurrences.

We had previously demonstrated the short-term benefits. We had shown that the addition of pembrolizumab to chemotherapy significantly increased the pathological [complete response (CR)] rates from around 51% to nearly 65%, so 13.6% difference and increase in those pathological CR rates. We also had previously shown that the addition of pembrolizumab led to an improvement in event-free survival, so a reduction of recurrences by about 37%. That was at a time with 39 months follow-up.

What updated findings were presented at ESMO 2023?

We presented updated data with just over 5 years [of] follow-up, 63 months to be precise, and that's important because in triple-negative breast cancer, a lot of the recurrences happen relatively early. We know that about 2 thirds2/3rds to 70% of recurrences happen in the first 2 to 3 years. About 85% to 90% of recurrences happen in the first 5 years. So providing 5-year follow-up data is critically important because it gives us the final confidence that these are definitive data that improved the patient's outcomes.

What were some of those efficacy data that you can share?

With 5 years of follow-up, we could confirm that the addition of pembrolizumab to neoadjuvant chemotherapy significantly reduces recurrences, and the event-free survival was improved. The hazard ratio is .63. If you look at the 5-year recurrence rates or event-free survival rates, they're 81% with pembrolizumab and chemotherapy compared with 72% with chemotherapy and placebo, so it's about a 9% better event-free survival rate with the addition of pembrolizumab. We looked at all the different subgroups and if there were any subgroups that benefited more or less with the addition of immunotherapy. Again, all subgroups may be by PD-L1 status, by stage, by lymph node involvement, and they seemed to have the same relative benefit from immunotherapy.

We couldn't show overall survival data, because this is what we call an event-driven analysis, so unfortunately, we have to wait for a certain number of events—in this instance, deaths occurring. The outcome of patients so far has been so good that these events haven't occurred. But therefore, we weren't able to present overall survival data. What we did show were distant recurrence-free survival data, so this means metastatic recurrence-free survival data, and in 85% of all events, we saw metastatic events. As we all know, unfortunately, we can't cure patients with metastatic disease, and the median survival of patients with metastatic triple-negative breast cancer is around 2 years. So knowing that, we also did see a benefit in distant event-free survival with a hazard ratio of .64 and an 8% difference in the 5-year rates. This makes it clear that over time, this will lead to an improvement in survival.

The final analysis we did was interesting. Iit has long been known that if you have a pathological complete response to preoperative chemotherapy, that this is linked with a substantially better outcome, whereas patients with residual disease have, unfortunately, a relatively high risk of recurrence. Preplanned analysis in this trial was to look at patients with a pathological CR and patients with residual disease and then see if there was a difference between patients who received immunotherapy or not. Interestingly, we saw in patients with a pathological CR that those who have a pathological CR with the help of immunotherapy and chemotherapy have a better outlook. The 5-year event-free survival rates in this group are 92.2% compared with 88.2%, with patients who only received chemotherapy, so a 4% better outcome which is quite remarkable considering how good the outcome is anyway in this group. That's the first time we could show that you have different outcomes despite having a complete pathological response. That suggests to me that the quality of the pathological response is also determined by the treatment we give.

The second reading from this analysis was in patients who have residual disease where we know that these patients have a higher risk of disease recurrence. We saw again that there's more than 10% better event-free survival after 5 years if that residual disease was after chemotherapy and immunotherapy. Overall, the data of KEYNOTE-522 confirm that the addition of immunotherapy significantly improves outcomes. We now have, with mature 5-year follow-up data, demonstrated that we significantly reduced the risk of recurrence by about 63%. We've also demonstrated that the benefit is seen regardless of whether patients have a pathological CR or residual disease. They will do better if they receive pembrolizumab in combination with chemotherapy.

What are the future implications of these findings? Where else is research headed?

We obviously don't have a new standard-of-care. We have been having this for a couple of years now in stage II and stage III triple-negative breast cancer with the addition of pembrolizumab to preoperative chemotherapy. There's a number of interesting research ideas going on. First of all, in stage I, we are [asking], can we de-escalate some of the treatment strategies and can we possibly bring in immunotherapy? That may allow us to de-escalate some of the chemotherapy. Can we bring in some of the new antibody-drug conjugates? There's a number of studies ongoing to look into this.

In stage II and stage III triple-negative breast cancer, which is obviously where the KEYNOTE-522 trial was focused on, there's still a lot of work for us to do in those patients who don't achieve a pathological complete response. Despite the improved outcome, the recurrence risk is still about 38% over 5 years, and that is too high in patients with residual disease. At the moment, there's a number of promising trials ongoing looking at a new class of drugs called antibody-drug conjugates. These antibody-drug conjugates are given alone or, or even better, in my opinion, with immunotherapy. I think those combinations are powerful and have a great chance of improving the outcomes in patients with residual disease.

In patients who have a complete response, there are ongoing studies to see how much benefit is from the postoperative immunotherapy, again, an important question for us to assess. We are also trying to set up a trial where we try to bring it to use escalation and deescalation, because some patients respond quickly to this KEYNOTE-522 regimen, and we will explore whether there may be an option of giving less than 6 months chemotherapy. On the other hand, some patients respond slower. We will also explore whether we can possibly incorporate some of those new antibody-drug conjugates before patients have surgery and whether we can improve outcomes. We've pushed the threshold up, we have a much better outcome now, but of course, there's still work to do because not every patient needs all that treatment at the same time not every patient is cured. We will continue to try to improve patient outcomes.

For a community oncologist, what are the key takeaways from this research?

The key takeaways from the KEYNOTE-522 trial is that with 5-year follow-up, we have confirmed that the addition of immunotherapy to chemotherapy significantly improves outcomes and reduces the risk of recurrences by about 37%. That's important. We have also seen that this benefit is seen regardless of PD-L1 status, so the same benefit was seen in PD-L1-positive or -negative patients, and regardless of the nodal status. We saw the same benefit in stage II and stage III disease. Therefore, in my opinion, unless there are specific contraindications, all patients with stage II or stage III triple-negative breast cancer should be considered for preoperative chemotherapy in combination with pembrolizumab for 6 months, followed by surgery, and then followed by adjuvant treatment.

REFERENCE

Schmid P, Cortés J, Dent RA, et al. Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Onc. 2023;34(S2):S1256-S1257. doi:10.1016/j.annonc.2023.10.008.