First Trial of Immunotherapy in Early-Stage Triple-Negative Breast Cancer Shows Promising Results

Peter Schmid, MD, PhD

The randomized, phase III KEYNOTE-522 clinical trial evaluated the benefit of adding the immune checkpoint inhibitor pembrolizumab (Keytruda) to neoadjuvant chemotherapy treatment in patients with early triple-negative breast cancer (TNBC). Patients received with pembrolizumab or placebo in addition to the chemotherapy for 6 months prior to surgery and continued for 1 year following surgery.

The co-primary end points of this study were pathologic complete response (pCR) and event-free survival (EFS). In the pembrolizumab arm, patients achieved a pCR of 64.8% compared with 51.2% in the placebo arm, leading to an absolute difference of 13.6% (95% CI, 5.4%-21.8%; P =.00055). The difference was both significant and meaningful, suggesting pCR may be linked to positive long-term outcomes, as well as a reduced risk of recurrence.

This is the first trial to evaluate immunotherapy in patients with early TNBC. Further data are anticipated to demonstrate long-term efficacy and safety with the addition of pembrolizumab to the chemotherapy regimen in this patient population.

In an interview with Targeted Oncology, Peter Schmid, MD, PhD, lead at the Centre for Experimental Cancer Medicine, Barts Cancer Institute, discussed the findings from the interim analysis for the phase III KEYNOTE-522 study, which added pembrolizumab to neoadjuvant chemotherapy in patients with early-stage TNBC.

TARGETED ONCOLOGY: Could you provide an overview to KEYNOTE-522?

Schmid: KEYNOTE-522 is the first randomized phase III trial of immunotherapy in early TNBC. We tend to treat most patients with early TNBC with neoadjuvant preoperative chemotherapy. KEYNOTE-522 looked at patients with early-stage breast cancer and randomized them to chemotherapy plus pembrolizumab, the immune checkpoint inhibitor, or chemotherapy plus placebo, for about 6 months before surgery. After surgery, they continued with pembrolizumab or placebo for a total duration of 1 year. The chemotherapy regimen we chose for this trial is probably the most effective but most intensive chemotherapy regimen in this setting because we wanted to have a very high bar to see what we can achieve with the addition of immunotherapy. Patients received 12 weeks of combination therapy with platinum and paclitaxel followed by 12 weeks of anthracycline treatment.

The trial has 2 end points. The first primary end point is pCR, which means complete disappearance of all cancer at the time of surgery, and the second is what we call EFS, which means the rate of disease recurrence over time. At the 2019 San Antionio Breast Cancer Symposium, we presented the final definitive results for pCR, showing that patients in the control arm showed a CR of about 51% whereas patients who had the addition of pembrolizumab to chemotherapy achieved a pCR of nearly 65%, which is a significant and meaningful difference of 13.6% in pCR. As we know that a higher rate of pCR is likely to be linked with long-term outcomes with positive outcomes with a reduction in the risk of recurrences, we are very optimistic about these results.

We also analyzed patients who are at higher risk, so patients with larger tumors, stage III disease, or those with no positive disease, and in those patients, the difference or additive benefit of pembrolizumab on top of chemotherapy was between 20% and 25%, which in my opinion is a massive step forward in the treatment of these patients. At this early time point with only 15 months follow-up, we already see strong and encouraging signals in terms of reducing recurrence, although at this time point it is not significant. The HR is 0.63, which suggests if we can confirm the results going forward, we may see a reduction in recurrences possibly in about a third of patients, which would be a fantastic result and possibly make this the new standard of care for patients in this situation.

TARGETED ONCOLOGY: How can this potentially impact breast cancer treatment?

Schmid: For TNBC, there is an established pathway by the FDA and European authorities looking at changes in the differences of pCR rates of disappearance before surgery because there is a plethora of data showing that patients who have a pCR have a better outcome. If we increase the pCR rates in clinical trials, it is very likely to translate into a benefit in terms of reducing recurrences and in terms of overall survival. For that reason, the regulatory authorities have established a pathway of what we call an accelerated approval based on this end point. One can’t predict what is going to happen, but that is 1 way we hope the authorities will look at these data.

The other way is that we will hopefully we will have further data coming out in the not too distant future on the secondary end point, which is the real prevention of recurrences over time. With the strong signal we have at this point in time, I am very optimistic that the next analysis will show at least a similar signal and will hopefully be statistically significant at that time. That, in my opinion, would meet all the criteria for approval of that drug, which means if confirmed it could become the standard of care, and hopefully in as many countries as possible.

TARGETED ONCOLOGY: What markers or factors are you considering when recommending patients for this treatment?

Schmid: It is an interesting question. When we look at immunotherapy in advanced or metastatic TNBC, we learn that patients with the marker PD-L1, which seems to be the targets of these immunotherapy treatments, derive the most benefit, whereas patients with PD-L1-negative tumors do not seem to do as well. Interestingly enough, in the KEYNOTE-522 trial in early TNBC, patients who were PD-L1-negative seemed to do as well in terms of the additive benefit of the immunotherapy to chemotherapy as patients who are PD-L1-positive. That is a striking result. We are trying to understand this, and 1 theory is the tumor have higher plasticity that patients with tumors who may present as PD-1-negative change possibly into immune-reactive PD-1-positive tumors as we go along with chemotherapy. At the moment, it seems to be these subgroups of patients benefit equally from the addition of immunotherapy.

TARGETED ONCOLOGY: What are the next steps for this clinical trial?

Schmid: The first step of this trial was to demonstrate that the primary endpoint is positive for pCR. The second primary end point, and therefore the next step, is EFS. We presented data from the second interim analysis, which was the first analysis of EFS, and the next step is clearly to demonstrate data from the second interim analysis for EFS in the hope that at that point in time with more maturity, this will show statistically significant results. At the same time, we will follow our patients for side effects, although the treatment phase is practically over in all patients. We just need to ensure we do not have any late occurring side effects that occur after treatment, although if that happens it will probably only be in a very small number of patients.

The third thing we are planning to do translational biomarker work in order to better define who the patients are who will benefit and who may not benefit or need the extra treatment. These are the 3 next steps, which will keep us quite busy for the next months and years.