Dr Lajos Pusztai Speaks on the KEYNOTE-522 Trial

Dr Lajos Pusztai Speaks on the KEYNOTE-522 Trial


In this video, Dr Pusztai speaks on the Phase III Keynote-522 trial.



So thank you for the opportunity to discuss the KEYNOTE-522 results with you. I'm Lajos Pusztai, I'm a Professor of Medicine, a breast medical oncologist at Yale University, and one of the co-investigators of the KEYNOTE-522 Trial.

KEYNOTE-522 probably represents one of the most important advances in the management of early stage triple-negative breast cancer in the past 20 years, since the introduction of taxanes. KEYNOTE-522 was a neo-adjuvant trial that aimed to improve pathological CR rates, and had a joint co-primary endpoint with event-free survival. The trial accrued stage two and stage three triple-negative disease, and 1,174 patients were participating in the study.

At the first pre-planned interim analysis to assess the differences in pathological CR rates, we demonstrated a significant improvement in pathological CR, complete response rate, from 55 to 65%, which met its primary endpoint. The study continued and followed patients for event-free survival, and earlier last year, we presented the event-free survival results, which were also positive. At a three-year follow-up, at the fourth pre-planned interim analysis, the study met its primary endpoint and showed a significant improvement in event-free survival. The event-free survival in the control arm was 76.8%, approximately 77%, compared to 85% in the Pembrolizumab arm. Most importantly, there was a significant reduction in distant metastatic recurrences as well. The recurrence rate, the distant recurrence rate, was almost halved by Pembrolizumab. There were about 13% of patients who experienced distant recurrence in the control arm, and 7.7% in the experimental arm, and there were also fewer death, however, the overall survival results are not major to make any conclusions, but there were fewer death in the Pembrolizumab arm.

I also would like to point out the adverse events that occurred during the trial. As expected, there were more immune-related adverse events in the Pembrolizumab arm so, somewhat surprisingly, even the control arm had an 11% immune-related adverse event rate but in the Pembrolizumab arm, this was 33%, including both grade one, grade two, and grade three events. If we focus on the grade three immune-related adverse events, this was 13% of the patients who experienced some form of severe immune-related event. The most common finding, however, was thyroid function abnormalities, hypothyroidism, or hypothyroidism.

To perhaps reiterate also the regimens, the treatment that was used in KEYNOTE-522 between the experimental arms, Pembrolizumab, 20 milligram given every three weeks, concurrent with weekly Taxol and Carboplatin. The Carboplatin could be given either weekly with an AUC of 1.5, or every three weeks with an AUC of five and after completion of this Carboplatin Taxol phase, patients continued with neoadjuvant AC, Adriamycin and Cyclophosphamide, or EC, Epirubicin and Cyclophosphamide, concurrent with Pembrolizumab and after completion of surgery, patient also had a maintenance phase of single agent Pembrolizumab. In this trial, Capecitabine was not allowed for the group that had residual disease.

So, I think this is a really important advance in terms of improving the outcome of early stage, high risk triple-negative disease, defined as stage two or stage three disease. So additional follow-ups, will be forthcoming on the trial when the overall survival data …..this will be reported as a secondary outcome, and also, during the upcoming 2022 ASCO meeting, I will present additional results on event-free survival by pathological response categories. The trial, as we earlier reported, increased the pathological CR rate at the first interim analysis. This difference in the pathological CR rates decreased, when the CR was compared on the full study population, that is the entire 1,174 patients, and we will also show outcome by residual cancer burden categories.

What existing data or circumstances lead you, and applicable co-investigators, to evaluate this?

In the past 10, 15 years, it's become clear that a subset of triple-negative breast cancers contains a lot of infiltrating immune cells, and these patients tend to do well. There is another substantial minority, probably 40, 50% of the patients, who have some immune cells and the study tested the hypothesis whether we could bend the curve of this immune relatively low patients…the immune rich patients, and maybe improve the outcome, even among the immune rich patients, by stimulating the local anti-tumor immune response.

So, this hypothesis that the immune system controls breast cancer has been around for a long time, and the association with immune cells and prognosis has been noted by many people, but it's really the advent of effective PD ligand one and PD one target therapies that allowed us to test this question prospectively, that there is a real cause and effect relationship, or it's just simply an association and the KEYNOTE-522 trial suggests that this is a cause and effect relationship, that it's the immune cells that actually improve the survival of these patients, and we can improve the anti-tumor immune response by using a PD ligand one targeting, or a PD one targeting, agent.

How do you personally encourage patients to enroll in clinical trials?

KEYNOTE-522 is really an example that participating in a clinical trial, you give a chance for your patients to receive tomorrow's therapies today. The KEYNOTE-522 results really led to the approval of Pembrolizumab as a neo-adjuvant treatment for triple-negative disease, and that's the new standard of care. So patients who participated in this study, three, four years ago, received what has become the future standard of care, and this has become the future of standard of care because it improved survival and saved people's lives so, I think participating in clinical trial is really a good idea because it gives an opportunity to really be among the first ones to benefit from a new drug. The downside, of course, is that it's not guaranteed that a new therapy will eventually work.

What are some immediate action-items that oncologists and other oncology health care professionals can employ to better meet the needs of these patients?

I think it's important to consider offering Pembrolizumab as together with neo-adjuvant chemotherapy for stage two and three triple-negative patients… and that is an ongoing active autoimmune disease. I also probably should add that, unlike in the metastatic setting, the PD ligand one inhibitors in the early stage, neoadjuvant setting did not show any relationship with, in terms of their efficacy, and PD ligand one or PD one expression, or even immune cell presence so the benefit from Pembrolizumab was seen, both in the immune rich and immune poor, and the PD ligand one positive and the PD ligand one negative tumors, so it's very different from how we use immunotherapy in the metastatic triple-negative setting, where only PD ligand one positive patients have a chance to benefit from Pembrolizumab.

I think this is really among the initial trials that really opened up a new set of vista, a new therapeutic frontier exploiting the immune system. Obviously, this is not the end because, even in the Pembrolizumab arm, we still see recurrences and still see death from metastatic disease, so I think there will be chapter two and chapter three to the immunotherapy studies in breast cancer.