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Medicine Matters oncology

So as you know, KEYNOTE-355 is a randomized, placebo-controlled phase-3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients with non-treated, locally recurrent, or metastatic triple-negative breast cancer. So the data with checkpoint inhibitors in triple-negative breast cancer are interesting. There are some important data with pembrolizumab single-agent showing that there is some efficacy. However, preliminary data showed that chemotherapy plus pembrolizumab seems to improve outcomes. This is why this randomized study was designed.



And chemotherapy included different, usually, drugs in the clinic-- paclitaxel, or nab-paclitaxel, or carbo-Gem plus pembrolizumab, a PD-1 inhibitor, or same chemotherapy plus placebo. Again, they ran a randomized phase-3 study. It was a pivotal study.



The primary endpoints included progression-free survival and overall survival in patients with PD-L1-positive tumors. And PD-L1-positive tumors were considered in two ways-- one of them with a PD-L1 CPS score-- it's a way of measuring PD-L1 status-- it doesn't matter-- of 10 or more or one or more-- and the same for survival.



So the primary endpoint was clearly met. The hazard ratio was 0.65. Median PFS-- median progression-free survival moved from 5.6 months to 9.7 months in favor of patients who received chemotherapy and pembrolizumab for all patients with PD-L1 CPS more or equal to 10. It was a clear signal, also, for patients with CPS more equal to 1, but these did not reach statistical significance. That's why pembrolizumab improves progression-free survival significantly from a clinical and mathematical perspective in PD-L1 10 or more triple-negative breast-cancer patients in the first-line setting.



Toxicity was as expected-- no more toxicity in chemo plus pembro compared to chemo. And, of course, it's normal to highlight that there were significantly higher number of patients with some immune-related toxicity-- basically, hypo- or hyperthyroidism. So the trial met the primary endpoint, and pembrolizumab could be considered a new standard of care or a good option for this group of patients.



What is the optimal PD-L1 cut-off for use of pembrolizumab plus chemotherapy?

Remember that there was another important study, which is the IMpassion130. IMpassion130 was a very similar trial design-- first line, triple-negative breast cancer. One of the chemotherapeutic agents, nab-paclitaxel, with or without placebo or atezolizumab, which is have PD-L1 inhibitor by Roche.



In this study, the PD-L1 was measured by another assay. It was VENTANA. And the antibody was SP142-- another assay, another antibody. In about 40% of patients, they have positivity for PD-L1 status-- one or more. And the trial was positive, clearly, for this group of patients.



In our study, in KEYNOTE-355, another assay, Dako, and another antibody, 22C3, was used. In this case, the clinical study was clearly positive for patients with PD-L1 CPS 10 or more, which is, more or less, to 38%/ 40% of all patients. So going back to your question, I think that we have-- or we need-- a CPS score of 10 or more for this drug to be used, in my opinion.



What is the big picture for immunotherapy in triple-negative breast cancer?

Remember that there is another important study. In the neoadjuvant study-- in the neoadjuvant setting-- sorry-- presented by Peter Schmid last year at ESMO-- it was a very similar idea-- chemo-pembro or chemo alone in the neoadjuvant setting, also with very positive data.



So I think that we have now two randomized phase-3 studies showing that pembrolizumab adds activity to chemotherapy in the neoadjuvant setting, at ESMO last year, and in metastatic-disease first-line ASCO this year.