Precision Medicine Approaches Evolving With CDK4/6, PI3K Inhibitors in HR+ Breast Cancer

Sara M. Tolaney, MD, MPH

The addition of CDK4/6 inhibitors to endocrine therapy in hormone receptor (HR)—positive, HER2-negative breast cancer has significantly improved outcomes for patients, and now the key challenge is determining what sequence to use these agents in, according to Sara Tolaney, MD, MPH.

“It’s important to understand that CDK4/6 inhibitors not only double progression-free survival (PFS) but have also shown an improvement in overall survival (OS),” said Tolaney, associate director, Susan F. Smith Center for Women’s Cancers, director, Clinical Trials, Breast Oncology, and senior physician, Dana-Farber Cancer Institute. “This substantial survival benefit makes it important for us to consider using a CDK4/6 inhibitor with endocrine therapy as a first-line treatment for patients with metastatic HR-positive disease.”

In the prospective, phase II Young-PEARL trial, investigators sought to determine whether a CDK4/6 inhibitor plus endocrine therapy would be superior to chemotherapy in improving outcomes in premenopausal patients with HR-positive metastatic disease. In the trial, patients were randomized to receive either chemotherapy with capecitabine (Xeloda; n = 92) or the CDK4/6 inhibitor palbociclib (Ibrance) in combination with endocrine therapy (n = 92).

After a median follow-up of 14 months, the median investigator-assessed PFS was found to be superior in the palbociclib/endocrine therapy arm compared with the capecitabine arm (20.1 vs 14.4 months; HR, 0.659; 95% CI, 0.437-0.994; P = .0469). Other studies, such as the PEARL trial, are continuing to compare the use of a CDK4/6 inhibitor plus endocrine therapy with that of chemotherapy.

Another remaining question is determining what to do when a patient progresses after CDK4/6 inhibition plus endocrine therapy. “In patients who have a PIK3CA mutation, which is about 40% of those with HR-positive breast cancer, using alpelisib (Piqray) in combination with endocrine therapy after progression on CDK4/6 inhibition should be considered,” advised Tolaney.

For those who do not harbor PIK3CA mutations, investigators are exploring many avenues, including continuing treatment with CDK4/6 inhibitors and either switching the endocrine backbone or using a different CDK4/6 inhibitor. “This idea of continuing CDK4/6 inhibition is certainly a very open one at this point in time,” said Tolaney.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Breast Cancer, Tolaney, who is also an assistant professor of medicine at Harvard Medical School, reflected on the encouraging findings observed with CDK4/6 inhibitors in combination with endocrine therapy in the treatment of patients with HR-positive, HER2-negative breast cancer.

OncLive: What recent data in HR-positive, HER2-negative breast cancer are you excited about?

Tolaney: Treatment for patients with metastatic HR-positive, HER2-negative breast cancer has evolved significantly over the past few years. We have seen the introduction of CDK4/6 inhibitors, and we know that when these agents are added to endocrine therapy, it extends not only PFS but now, with more recent data, we know there is also an OS benefit. Given these data, CDK4/6 inhibition has been established as the standard of care [for these patients] in the first-line setting.

We have also seen data with alpelisib, an alpha-specific PI3K inhibitor. When added to endocrine therapy, [this agent] improved objective response rates and PFS. Using alpelisib in combination with endocrine therapy after progression on CDK4/6 inhibition should be considered in those with a PIK3CA mutation. That underscores the need for us to test patients for a PIK3CA mutation in order to decide what the appropriate therapy would be for them in the second-line setting.

Although endocrine therapy has evolved a lot [over the years], it has left us with many questions regarding how to appropriately sequence therapy and how we should be using treatment—specifically after CDK4/6 progression. Will there be a role for the continuation of CDK4/6 inhibition beyond disease progression?

We also know that certain resistance mechanisms to CDK4/6 inhibitors have been found. I believe that potentially targeting specific mutations in that setting may provide benefit, but more work will need to be done in that area [to confirm that].

What are some of the remaining questions with CDK4/6 inhibitors?

Specifically, with CDK4/6 inhibitors, one major question that has come up is, “Are there differences in outcomes between patients receiving chemotherapy compared with endocrine therapy plus CDK4/6 inhibition?”

We have seen some hints of data [offering insight into] this question at the 2019 ASCO Annual Meeting, when the Young-PEARL trial was presented. This phase II trial [enrolled] premenopausal patients who progressed on prior tamoxifen. These patients were randomized to receive either aromatase inhibition and palbociclib or capecitabine. Results demonstrated superiority with endocrine therapy and CDK4/6 inhibition over chemotherapy. The study confirmed what many of us felt, given the data that we have to date: CDK4/6 inhibition does seem to be highly effective for these patients and is likely superior to chemotherapy.

We are all eagerly awaiting data from the PEARL trial; this study had 2 cohorts in which investigators compared capecitabine or exemestane and palbociclib. The second cohort compared capecitabine with fulvestrant (Faslodex) and palbociclib. The study did not meet its primary end point, which was to demonstrate superiority of the endocrine therapy and CDK4/6 inhibition over chemotherapy; the results looked very similar [between the arms].

Investigators also analyzed ESR1 wild-type patients across both cohorts and found very similar results. Again, the endocrine therapy and CDK4/6 inhibition combination was not found to be superior to chemotherapy. It is important to keep in mind that this was a population of patients who had progressed on prior aromatase inhibition. However, I do not believe that [these results] address the question of [what to do with] a patient who is either endocrine-naïve or who had a significant interval of time after adjuvant endocrine therapy before they recurred. Showing similar outcomes was, at the very least, reassuring. Given these data, I feel comfortable using endocrine therapy and CDK4/6 inhibitors up front in all of my patients.

What are some sequencing challenges faced in the clinic?

Some sequencing questions are, "If we start someone on endocrine therapy and a CDK4/6 inhibitor, what do we do when they progress? Should we continue the CDK4/6 inhibitor and swap the endocrine backbone? Would there still be a benefit in continuing CDK4/6 inhibition beyond progression?" Truthfully, we do not know the answer to those questions but a couple of ongoing trials are trying to address them.

The PACE trial is enrolling patients who have progressed on up-front CDK4/6 inhibition and is randomizing them to receive either fulvestrant alone, fulvestrant with palbociclib, or fulvestrant with palbociclib and avelumab (Bavencio). Investigators are looking for synergistic activity with immunotherapy.

There is also the question of, “Would it make a difference if you swap the CDK4/6 inhibitor, too?” For example, if a patient was treated with palbociclib or ribociclib (Kisqali) up front and then they were switched over to abemaciclib (Verzenio) in the second-line setting. The question is, “Would that agent have more benefit than continuing the same CDK4/6 inhibitor?” Again, some small trials are hoping to address that question.

One trial is specifically looking at patients who were treated with, for example, an aromatase inhibitor and palbociclib, but then continued the same endocrine agent and then swapped the CDK4/6 inhibitor with abemaciclib at the time of disease progression. I believe that would help us understand if switching a CDK4/6 inhibitor will benefit patients.

What is your take-home message to your colleagues?

One important message is to ensure that we test all patients for PIK3CA mutational status to know if, at time of progression on the CDK4/6 inhibitor, alpelisib should be used in combination with endocrine therapy in the second-line setting.

Many other agents are currently being explored, such as kinase inhibitors and EGFR inhibitors. There are also many exciting targeted agents that we will hopefully see more of in the future.

For now, using CDK4/6 inhibitors up front and then alpelisib in patients with mutations at progression should be considered.

Park YH, Kim TY, Kim GM, et al. A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746). J Clin Oncol. 2019;37(suppl 15; abstr 1007). doi: 10.1200/JCO.2019.37.15_suppl.1007.