CDK4/6 Inhibitors, Alpelisib Continue to Show Benefit in HR+/HER2- Breast Cancer


Kevin Kalinsky, MD, MS, highlights the recent data with alpelisib and CDK4/6 inhibitors, the toxicity differences between the 3 available CDK4/6 agents, and the next steps for both classes of agents.

Kevin Kalinsky, MD

Kevin Kalinsky, MD

Kevin Kalinsky, MD

Updated data with CDK4/6 and PI3K inhibitors showing progression-free and overall survival (OS) benefits are transforming the hormone receptor (HR)—positive, HER2-negative breast cancer arena, according to Kevin Kalinsky, MD, MS.

“HR-positive, HER2-negative breast cancer is the most common type of breast cancer that we see, and we have a landscape in which we are adding in targeted drugs, CDK4/6 inhibitors, and an mTOR inhibitor,” said Kalinsky, an assistant professor of medicine, Department of Medicine, at Herbert Irving Comprehensive Cancer Center, NewYork-Presbyterian Hospital/Columbia University Medical Center.

The 3 FDA-approved CDK4/6 inhibitors—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—have continued to demonstrate efficacy and improvements in progression-free survival (PFS) in select patients with HR-positive, HER2-negative disease. Most recently, results from the PALOMA-3 trial showed that the combination of palbociclib plus fulvestrant (Faslodex) led to a clinically meaningful benefit in OS in some patients with advanced breast cancer who had progressed or relapsed on prior endocrine therapy.1 The regimen showed a 10.0-month OS improvement in patients who were sensitive to previous endocrine therapy.

Moreover, for patients who harbor PIK3CA mutations, the investigational PI3K inhibitor alpelisib (BYL719) improved PFS when combined with fulvestrant versus fulvestrant alone in these patients with advanced breast cancer, regardless of line of therapy or prior CDK4/6 inhibitor treatment, according to results of the phase III SOLAR-1 trial.2 Additionally, the median OS had not been reached with alpelisib in an interim analysis of the study.

In the PIK3CA-mutant cohort of SOLAR-1, the median PFS was 22.1 months with alpelisib/fulvestrant versus 19.1 months with fulvestrant in the first-line setting in endocrine-sensitive patients (HR, 0.87; 95% CI 0.35-2.17) and 9.0 months versus 4.7 months, respectively, in endocrine-resistant patients (HR 0.69; 95% CI, 0.46-1.05). In the second-line setting, median PFS was 10.9 months in the alpelisib/fulvestrant arm and 3.7 months in the fulvestrant arm (HR, 0.61; 95% CI, 0.42-0.89).

OncLive: What have been the key advances in HR-positive, HER2-negative breast cancer?

What pivotal data do we have with these agents?

How do the toxicity profiles differ between the CDK4/6 inhibitors?

What are your take-home messages about the CDK4/6 inhibitor advances?

There were intriguing data with PI3K inhibition. Could you discuss that?

Following these findings, what is the tone of the community regarding PI3K inhibition?

What are the next steps for this agent?

What is your overall hope with this targeted therapy?

In an interview during the OncLive® State of the Science SummitTM on Advanced Breast Cancer, Kalinsky highlighted the recent data with alpelisib and CDK4/6 inhibitors, the toxicity differences between the 3 available CDK4/6 agents, and the next steps for both classes of agents.Kalinsky: [In my presentation], we discussed the landscape in HR-positive, HER2-negative breast cancer, and we focused on the CDK4/6 inhibitors and how important those drugs are for treating patients with this disease. We talked about the responses that we are seeing in patients who get them in the first- and second-line settings. There are 3 CDK4/6 inhibitors, and we talked about the differences between their toxicity profiles and how they are delivered. Palbociclib and ribociclib are both given in a 3-weeks-on/1-week-off schedule, and abemaciclib is given continuously twice a day.The updated results from PALOMA-3 were published in the New England Journal of Medicine. That was a study that looked at fulvestrant with or without palbociclib, and we awaited the results of the OS data. Those data are quite interesting and compelling, in the sense that patients deemed to be endocrine sensitive had a longer OS of 10 months compared with those who did not get palbociclib. Therefore, endocrine sensitivity was defined as being on hormonal therapy in the operable setting for 2 years, or for having stability or response in the metastatic setting for 6 months or greater. It really defined a population that seemed to live longer if they received that combination.Of the 3 agents, when we look at ribociclib or palbociclib, the main toxicity that we see is neutropenia. The rates of febrile neutropenia are quite low at less than 2%. We also see some other side effects, such as fatigue, increased rates of alopecia, and gastrointestinal (GI) issues. However, when we think about GI issues we think about abemaciclib, which can have higher rates of diarrhea. Although, the rates of neutropenia are less with abemaciclib compared with the other 2 CDK4/6 inhibitors.These agents are really important for patients with metastatic breast cancer. They significantly improve how long patients are on hormonal therapy; they delay how long it takes to initiate chemotherapy. The real question is, “What is the role going to be in the operable setting?” We are awaiting the results of large randomized studies to see if they help benefit in terms of decreasing the likelihood of recurrence if given to patients with early-stage breast cancer.We talked about the results of the SOLAR-1 trial, which was presented at the 2018 ESMO Congress and then updated at the 2018 San Antonio Breast Cancer Symposium. This is a study for patients with PIK3CA mutations, which is seen in one-third to 40% of patients with HR-positive, HER2-negative metastatic breast cancer. It showed that patients who progressed on prior hormonal therapy—an aromatase inhibitor—that if they received fulvestrant with or without alpelisib, which is a PI3K alpha-specific inhibitor, we saw an improvement in PFS if they received the combination compared with fulvestrant plus placebo.There have been prior PI3K inhibitors that have been evaluated throughout the years, including taselisib, which was reported in the SANDPIPER trial at the 2018 ASCO Annual Meeting. Unfortunately, due to toxicities, they were not well tolerated. Therefore, it is nice that we have a specific target with a specific inhibitor that we can treat these patients with. The main side effects we see with alpelisib are hyperglycemia, some GI issues, and rash. That is something we should keep a close eye on, but it’s nice to have an inhibitor that specifically targets a gene that is commonly seen in breast cancer.What we are trying to learn about PI3K inhibitors is exactly what the best setting is to evaluate them in. This particular study was in patients who had endocrine-resistant disease. Also, this study did not primarily have patients who previously received a CDK4/6 inhibitor. There is a very small population, about 20 patients or so, with prior CDK4/6 inhibitor therapy who seem to benefit if they received the combination compared with a single agent. However, we really are waiting to see, in a larger series, what the response could be with these drugs following CDK4/6 inhibition.We will have on the market, hopefully soon in 2019, a PI3K inhibitor. Other drugs are being evaluated in this space. The hope is that we can continue on hormonal therapy plus a targeted therapy for a long time before we need to initiate chemotherapy. It is important to keep in mind that you can see good responses when you give a CDK4/6 inhibitor along with hormonal therapy. You potentially don’t need to start out with chemotherapy, because you can get a really nice, robust response with the combination.


  1. Turner NC, Slamon DJ, Ro, I, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. doi: 10.1056/NEJMoa1810527.
  2. Juric D, Ciruelos EM, Rubovszky G et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 5-8, 2018; San Antonio, TX. Abstract GS3-08.
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