CDK4/6 Inhibitors Alter HR+ Breast Cancer Paradigm

Melissa K. Accordino, MD, MS

The emergence of CDK4/6 inhibitors has affected treatment decisions for patients with hormone receptor (HR)—positive, HER2-negative breast cancer, allowing for more options and leading to more investigational efforts, explained Melissa K. Accordino, MD, MS.

“Even in the last 5 years, we have more treatment options for patients who have HR-positive, HER2-negative metastatic breast cancer,” said Accordino. “In the past, we were often having to reach for chemotherapy much earlier. Now, we have many targeted agents that help us delay our time toward chemotherapy and probably improve quality of life for our patients, which is always our goal.”

For example, in the phase III MONALEESA-7 trial, the addition of ribociclib (Kisqali) plus endocrine therapy was evaluated in peri- or premenopausal women with advanced HR-positive, HER2-negative breast cancer.¹ Results showed that the median overall survival (OS) was not reached for those on ribociclib compared with 40.9 months for patients on placebo (HR, 0.71; 95% CI, 0.54-0.95; P = .00973).

In the PALOMA-2 trial, palbociclib (Ibrance) plus letrozole was compared with letrozole alone in the first-line setting in postmenopausal patients with HR-positive/HER2-negative metastatic breast cancer. In a real-world database analysis of the trial, results showed that the median OS was not yet reached in the palbociclib arm versus 38.1 months in the letrozole-alone arm (HR, 0.52; 95% CI, 0.40-0.68; P <.0001).²

The MONARCH 3 trial examined a nonsteroidal aromatase inhibitor plus abemaciclib (Verzenio) or placebo in treatment-naïve postmenopausal patients with HR-positive, HER2-negative metastatic breast cancer. Final progression-free survival (PFS) data showed that the median PFS was 28.18 months in the abemaciclib arm versus 14.76 months in the placebo arm (HR, 0.540; 95% CI, 0.418-0.698; P&thinsp;=&thinsp;.000002).³

In addition to the investigations with the CDK4/6 inhibitors, researchers continue to examine the use of PI3K inhibitors in breast cancer treatment.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Breast Cancer, Accordino, an assistant professor of medicine in the Division of Hematology/Oncology of the Herbert Irving Comprehensive Cancer Center at Columbia University, discussed the treatment options for patients with HR-positive, HER2-negative breast cancer.

OncLive: What agents are available to treat patients with HR-positive, HER2-negative metastatic breast cancer? How do you choose which agent to administer?

Accordino: The CDK4/6 inhibitors are widely used for patients in the first-line setting or for patients who [have received prior treatment]. Regarding efficacy, the trends for hazard ratio for PFS are very similar across the PALOMA-2, MONARCH 3, and MONALEESA-7 studies. The largest differentiating factors are the different safety profiles of the different medications, specifically palbociclib and ribociclib versus abemaciclib.

Abemaciclib is also unique because some data suggest it has penetration to the central nervous system. For patients who have brain metastases, it might be a different option to think about. The other differentiating [quality of] abemaciclib is that it can be given as a single agent, without endocrine therapy, which is [significant] to consider for patients who might not be able to tolerate endocrine therapy.

Can these CDK4/6 inhibitors be used sequentially?

That is an area of ongoing research. We have a clinical trial, of which Kevin Kalinsky, MD, MS, is the primary investigator, at the Herbert Irving Comprehensive Cancer Center at Columbia University. Hopefully, that trial will answer the question of whether it makes sense to continue with a CDK4/6 inhibitor after progression on a CDK4/6 inhibitor. As of now, there are no convincing data either way.

Does a CDK4/6 inhibitor have an optimal combination partner?

In the first-line setting without previous endocrine therapy in metastatic disease, all of the CDK4/6 inhibitors have been tried with an aromatase inhibitor as the backbone. It seems convincing that it's probably the best agent to start with. In patients who have been treated in the metastatic advanced setting or who relapsed on an aromatase inhibitor, fulvestrant (Faslodex) seems to be the better option based on the data available.

PI3K inhibitors have emerged in the relapsed/refractory setting. What research led to these agents?

The SOLAR-1 trial was published in 2009 in the New England Journal of Medicine; this study looked at patients who progressed on endocrine therapy, specifically patients with a PIK3CA mutation. In that study population, the PI3K inhibitor alpelisib (Piqray) showed meaningful PFS benefit.

[Following alpelisib's] approval, more patients are having PIK3CA mutation evaluations through next-generation sequencing (NGS). We're now able to offer this targeted therapy to patients who harbor these mutations.

Are liquid biopsies being used in breast cancer? How?

They are definitely being used. The reliability of liquid biopsy compared with tissue biopsy is still an ongoing area of debate. Liquid biopsies are obviously more convenient. Therefore, if we can't get tissue, it is a good place to start. We can always send archive tissue for NGS as another option.

What compelling data were presented at the 2019 San Antonio Breast Cancer Symposium?

The PEARL trial was comparing palbociclib, which is a CDK4/6 inhibitor, with either exemestane or fulvestrant versus capecitabine (Xeloda), in patients with metastatic disease who received endocrine therapy. That study showed no difference in efficacy for PFS, but the safety profiles were a little bit different. Among those patients who have already progressed on endocrine therapy, a CDK4/6 inhibitor and endocrine therapy might be a better option over chemotherapy. We don't always have to rush to chemotherapy. The time to response was also similar in both of those arms, which is reassuring.

With these data, is chemotherapy being removed from the paradigm?

Chemotherapy is definitely an option for our patients. As our patients are living longer, we're now able to give more treatment. These data suggest that we should try to exhaust all other options before reaching for chemotherapy, if it makes sense for a patient.

References

1. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765.
2. DeMichele A, Cristofanilli M, Brufsky A, et al. Overall survival for first-line palbociclib plus letrozole vs letrozole alone for HR+/HER2— metastatic breast cancer patients in US real-world clinical practice. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P1-19-02.
3. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi: 10.1038/s41523-018-0097.