KeepHealthCare.ORG – Expert Covers CDK4/6 Combos, Use Beyond Progression in Breast Cancer
Komal L. Jhaveri, MD
The explosion in the use of CDK4/6 inhibitors is unlikely to subside in the treatment of patients with ER-positive, HER2-negative breast cancer, as combination regimens continue to be explored as a means of overcoming acquired resistance.
The 3 FDA-approved CDK4/6 agents—abemaciclib (Verzenio), ribociclib (Kisqali), and palbociclib (Ibrance)—have demonstrated improvements in progression-free survival (PFS). Moreover, preclinical evidence suggest that the benefit may be extended in combination with FGFR1 inhibitors and immunotherapy.
Though the role of CDK4/6 inhibition beyond progression has yet to determined, Komal L. Jhaveri, MD, explained that its impact on quality of life (QOL) is clear.
“I truly am a believer that these agents have a significant impact on QOL and also have a quick action, even in symptomatic patients,” said Jhaveri, a medical oncologist at Memorial Sloan Kettering Cancer Center.
In an interview during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Jhaveri, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the current and potential future uses of CDK4/6 inhibitors in breast cancer.
OncLive: How have CDK4/6 inhibitors impacted the treatment of patients with breast cancer?
Jhaveri: CDK4/6 inhibitors have certainly changed the landscape of the treatment for ER-positive, HER2-negative metastatic breast cancer. We now have 3 approved agents in this class. We have data to support their use in combination with endocrine therapy, both in the first- and second-line settings with unprecedented PFS benefits. While we don’t have overall survival (OS) data, these PFS data have been very promising. PFS data justify—at least in most patients—combination therapies, barring the toxicity issues for individual patients. This is a class of agents that has been exciting for our patients, and it certainly has been an improvement in their outcomes when it comes to PFS.
What are your thoughts on combination strategies with CDK4/6 inhibitors?
There are many questions that we still have to get answers to. We’re waiting for the OS data but having said that, these trials have not been powered for OS—they were powered for PFS. We may need a meta-analysis of these phase III trials to make any definitive conclusions about OS benefit. We know from treatment for HER2-positive breast cancer that patients who progress on anti-HER2 therapies continue to benefit from anti-HER2 therapy beyond progression. We don’t have that data thus far for CDK4/6 inhibitors, but the question of whether there is a role for CDK4/6 inhibition beyond progression is being addressed in at least 3 clinical trials.
There are exciting preclinical data, which kind of justifies the use of combination regimens to address the issue of acquired resistance. We have seen some adaptive responses with CDK4/6 inhibition, which can lead to activation of the PI3K-inhibitor pathway. That has justified the triplet combination to be evaluated in the clinic. That’s an ongoing effort.
We have some data to suggest that FGFR1 amplification could be one mechanism of resistance. There was a very early data set from the MONALEESA-2 trial, which showed that FGFR1 amplification from the baseline circulating tumor DNA may have limited PFS benefit. These were small numbers, but it goes with the preclinical data that shows FGFR1 amplification is a resistance mechanism. There are ongoing trials combining FGFR1 inhibition with CDK4/6 and endocrine therapy in a triplet.