Debu Tripathy, MD
Debu Tripathy, MD, Professor of Medicine and Chair of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, said that the study points the way to further exploration of the benefit of adding immunotherapy to treatment after patients develop resistance to CDK4/6 inhibitors for several reasons.
“These findings are not exactly as expected, because hormone receptor–positive breast cancer is generally not as immune-active as other cancers, where immunotherapy has been very effective. Then we have to ask: is there something unique about this combination? Also, when patients have disease progression on prior CDK4/6 inhibitors, adaptive mechanisms develop that might make the cancer more receptive to immunotherapy. There is laboratory evidence for both of these theories,” Dr. Tripathy explained.
Underlying Mechanisms
“In preclinical models, the combination of a CDK4/6 inhibitor plus immunotherapy shows activity in cell lines and animal models, but the mechanism is not clear. One potential reason why these patients appeared to do better with avelumab added is the context of prior resistance to CDK4/6 inhibition,” he said.
“It is also possible, as we have shown in lab models, the induction of resistance to palbociclib changes cell ‘wiring’ in several ways. One is the activation of PD-L1 and immune pathways, suggesting increased sensitivity to immunotherapy. The other possibility is that once the cancer becomes resistant to CDK4/6 inhibition, it may be more vulnerable to DNA inhibitors. In our lab experiments, we saw upregulation of other signal pathways…. “Other data suggest that it might make sense to combine immunotherapy with CDK4/6 inhibitors in patients who have become resistant to CDK4/6 inhibitors. This study tested both strategies,” Dr. Tripathy said.
Further Research Needed
However, he noted this is a small study, and although the triplet arm looked better, the confidence intervals for time to disease progression overlap. “This is not a definitive study. The results do suggest the triplet strategy is valid and needs to be tested in a larger clinical trial,” Dr. Tripathy said.
“We need to drill down further to understand the biology better. Data from tissue samples may shed light on the molecular changes, and both animal studies and tissue studies will be helpful. Blocking two pathways is more effective,” he stated.
DISCLOSURE: Dr. Tripathy has received institutional research support from Novartis, Pfizer, and Polyphor; and has consulted for Gilead Sciences, Puma Biotechnology, GlaxoSmithKline, AstraZeneca, Novartis, OncoPep, Pfizer, Personalis, and Sermonix.
