Expert Covers CDK4/6 Combos, Use Beyond Progression in Breast Cancer

Komal L. Jhaveri, MD, associate professor of oncology and urology at Johns Hopkins Medicine

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.

OncLive: How have CDK4/6 inhibitors impacted the treatment of patients with breast cancer?

What are your thoughts on combination strategies with CDK4/6 inhibitors?

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.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. 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.

What is the rationale for CDK4/6 inhibitors in combination with immunotherapy?

How do you determine which CDK inhibitor to administer?

The other combination is with immunotherapy. There is certainly a lot of preclinical data justifying synergistic combinations. I can think of at least 2 trials; one is with abemaciclib and pembrolizumab (Keytruda) as a combination. The other ongoing trial is the PACE trial, led by Dr Erica L. Mayer, which is looking at palbociclib and avelumab (Bavencio) with fulvestrant (Faslodex). There is a lot of exciting stuff, a lot of unmet need in terms of this clinical conundrum that we are facing post CDK4/6 inhibition that is being addressed in trials. The neoantigen presentation can be increased, and CDK4/6 inhibition did that with the antigen presentation. When we combined them, we saw a better synergistic profile. It's predominantly that it can impact immunity based on antigen presentation. That's the largest preclinical evidence that is being utilized. Once we have an answer to whether we can continue CDK4/6 beyond CDK4/6 progression, we can better answer this question. Abemaciclib is the exemestane of CDK4/6 inhibitors in some ways, given its inhibition of other CDK kinases beyond CDK4/6. If there were data to justify this, could we use, say, first-line ribociclib or palbociclib and, upon progression, switch over the endocrine therapy partner and the CDK4/6 partner and use abemaciclib that way?

How have you seen CDK4/6 inhibitors impact QOL?

We have data for MONARCH-1 with single-agent abemaciclib in the later-line setting. The caveat there is that it’s not in patients who have already progressed on CDK4/6 inhibition. Right now, we have to think about whether we can use all of them. All of them have the same hazard ratios, so with more data and more experience, physicians will start having preferences the way they have preferences with aromatase inhibitors. The QOL has been very impressive, in terms of how quickly symptomatic patients become asymptomatic patients. I have sometimes gone beyond the true eligibility that was used in clinical trials and phase III trials. For example, the definition of visceral crisis that we use for chemotherapy can be vague and has been defined very differently in different trials.

A patient came in with a 10-cm lung metastasis and had significant shortness of breath, couldn't walk her dog, and was on 2 daily cough medications. One would be tempted to start chemotherapy in such a patient. She was in the first-line setting with de novo metastatic disease. I worked with her very closely and explained to her that, if we did not see a benefit quickly, we might have to switch over to chemotherapy. I would normally see a patient in the first-line setting every 4 weeks, or every 2 weeks initially. I saw this patient weekly. By the second week, she did not use any cough medications, and by the fourth week, she was walking her dog again. She had a significant partial response in tumor shrinkage on her first scan.

Sometimes, you have to make a decision on an individualized basis depending on how compliant that patient is and how good that patient is going to be in terms of reporting symptoms and showing up to clinic more often than not.

How are CDK4/6 inhibitors being used outside of breast cancer?

It's not for everybody. Some patients will require chemotherapy upfront. These agents have an impressive activity that I've seen, whether patients have visceral metastases or not. If you look at the preliminary data and the secondary endpoints, you will see that the response rates have been impressive. These agents have been utilized as monotherapy in liposarcomas. There is a lot of excitement there. There is a lot of preclinical rationale to look at senescence. They have a role beyond breast cancer. Clearly, the most impressive results and the furthest development is in breast cancer, but this class of agents has some activity beyond breast cancer. Is there anything else you would like to emphasize? The MONALEESA-7 trial has been exciting in that now we have a dedicated trial. Most of us were already doing [what is being explored in that trial] in clinic, in which we had a premenopausal woman who we would give ovarian suppression and letrozole with a CDK4/6 inhibitor, too. However, it's always nice to see a dedicated trial for premenopausal women and replicate the data we have seen in postmenopausal women. That should be considered.

Sometimes, the thought is these women have aggressive cancers that should be treated with chemotherapy and not endocrine therapy. These data justify that we should use this combination, even in that population.