In November, the Food and Drug Administration (FDA) granted an accelerated approval for the combination of Keytruda (pembrolizumab) and chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) with a PD-L1 expression. This accelerated approval allows for the combination treatment to be given to a wider population of patients with metastatic TNBC, according to Dr. Hope S. Rugo.
Rugo, director of breast oncology and clinical trials education at the University of California, San Francisco Comprehensive Cancer Center, was the principal investigator of the Keynote 355 study that led to this accelerated approval, and recently presented updated findings of the study at the 2020 San Antonio Breast Cancer Symposium.
Rugo sat down with CURE® to discuss the implications of the FDA approval as well as what the updated findings of Keynote 355 mean for patients with metastatic TNBC.
CURE®: Can you provide a brief overview of what led to the approval of Keytruda and chemotherapy for this patient population?
Rugo: The further analysis suggested that, if you looked at the intent to treat population, then almost all samples would be positive with a combined positive score (CPS; the number given to determine the expression of PD-L1 protein in a patient) of one or greater compared to only just over 40% by SP142 (an assay used to measure PD-L1 in the tumor itself). Suggesting, as has other data, that SP142 identifies a smaller percentage of patients whose tumors are positive for PDL one and the definition with SP142 are immune cells, not using a scoring system. So based on the combined data, their primary endpoint was changed in Keynote 355 to evaluate efficacy in patients whose CPS was 10 or more, compared to the intent to treat population, and then an additional analysis was made about patients whose CPS were one or more, and both of those groups had alpha assigned for this statistical analysis.
What’s the biggest highlight of this approval and study that patients should understand?
Patients were enrolled whose cancer had returned six months or more after their last treatment of curative intent, and also patients who had de novo untreated metastatic triple negative breast cancer could enroll. So, it’s a little bit of a broader population.
We looked at the efficacy based on the different chemotherapy agents and there appear to be efficacy for adding Keytruda regardless of the chemotherapy agent chosen, although there’s a trend towards what appears to be better PFS if you received paclitaxel or NAB Paclitaxel (Abraxene), compared to gemcitabine or carboplatin.
We also looked at the overall response rate and the clinical benefit rate, and these were all improved. And this is particularly looking at the CPS of 10 or greater population. We also looked at another endpoint of interest, duration of response, and in the group of patients whose tumors had a CPS of 10 or more, the duration of response went from seven to about 19 months in patients receiving placebo versus Keytruda. So, it was really a dramatically longer duration of disease control in patients whose tumors had a CPS of 10 or more and who received Keytruda along with their chemotherapy.
Where does this treatment fit in the overall landscape of TNBC?
Well, I think that there’s several implications. One is, it markedly broadens the options we have for treating patients in the first line metastatic setting. If the cancer recurs within the first year after treatment, in the early stage setting, we tend to think of these cancers as being more chemotherapy-resistant. So, having gemcitabine and carboplatin as an option is really important, and being able to treat patients with immunotherapy who relapse a little, whose cancers recur a little bit earlier, it’s also important.
Overall, I think the biggest implication of all of these trials is that we have an additional treatment option that has improved efficacy for patients with triple negative breast cancer, that it benefits a limited number of patients in the metastatic setting. Our current research is focusing on how to further expand the number of patients who can benefit from immunotherapy in the metastatic setting.
Of course, I think we are anxiously awaiting both regulatory review and additional long-term endpoints from the use of checkpoint inhibitors in the early stage setting.