Beyond CDK4/6 Inhibitors: What Subsequent Treatment Is Best?

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Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have changed the natural history of hormone receptor–positive metastatic breast cancer. While median progression-free survival on these drugs is approximately 27 months, the disease eventually progresses and clinicians must choose a subsequent therapy.

Adam M. ­Brufsky, MD, PhD

Adam M. ­Brufsky, MD, PhD

At the 2020 Miami Breast Cancer Conference, Adam M. ­Brufsky, MD, PhD, Professor of Medicine and Co-Director of the Comprehensive Breast Cancer Center at the University of Pittsburgh Medical Center Hillman Cancer Center, offered his thoughts on treatment after disease progression.1

The primary options are to continue the CDK4/6 inhibitor and switch the endocrine agent; keep the endocrine agent and switch to a different CDK4/6 inhibitor; or continue both the endocrine agent and the CDK4/6 inhibitor and target a collateral pathway with another agent. “They are just three of the many options available out there,” Dr. Brufsky said.

The results of several phase I and II trials of these strategies are pending. In the meantime, oncologists can learn from analyses of “real-world” experience, he said.

Switching CDK4/6 Inhibitors

Several recent studies are informative, including one retrospective analysis of 58 patients who had disease progression on palbociclib, then received abemaciclib.2 One-third of patients received the drugs sequentially, and two-thirds received abemaciclib after at least one intervening treatment. Abemaciclib was given alone or with endocrine therapy.

“You can get a response [with abemaciclib], but one-third had early disease progression, suggesting cross-resistance.”
— Adam M. Brufsky, MD, PhD

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“Continued benefit from treatment with abemaciclib after a previous CDK4/6 inhibitor was observed in about one-third of patients [who remained on treatment for about 6 months]. If you give abemaciclib, you can get a response. But one-third had early disease progression, suggesting cross-resistance between CDK4/6 inhibitors,” said Dr. Brufsky, who was a co-investigator of this study.

Endocrine Agents and Exemestane

“Another option is to give exemestane plus the mTOR inhibitor everolimus after patients have had disease progression on the CDK4/6 inhibitor,” he said. This strategy is supported by numerous studies (though not all have included patients with disease progression after CDK4/6 inhibitors).

One such study was a retrospective analysis of 33 patients with hormone receptor–positive metastatic breast cancer who switched to a different type of drug after disease progression on a nonsteroidal aromatase inhibitor; 17 had also received a CDK4/6 inhibitor.3 Patients with and without prior anti-CDK4/6 therapy had similar progression-free survival (5.7 vs 4.7 months, respectively) and overall survival (17.8 vs 11.4 months; P = .1777), though survival was numerically longer after prior anti-CDK4/6 treatment.

In another study, Mayo Clinic researchers evaluated the efficacy of first-line and second-line CDK4/6 inhibitors in 136 patients with advanced hormone receptor–positive disease.4 The median time to treatment failure was 19.7 months in the first-line setting and 8.3 months in the second line. Among various single agents or combinations used for subsequent therapy, everolimus plus exemestane seemed to convey the greatest benefit: median time to treatment failure was 13.2 months.

Mayo Clinic researchers also treated 309 patients with advanced hormone receptor–positive/HER2-negative breast cancer, after disease progression, with (1) everolimus as a single agent, (2) everolimus in combination with exemestane, or (3) single-agent capecitabine.5 Median progression-free survival ranged from 6.8 months with single-agent everolimus to 9.6 months with capecitabine but did not differ significantly among the groups. In another trial of 131 patients with aromatase inhibitor resistance, adding everolimus to fulvestrant doubled the progression-free survival time.6

“We have many options in this pathway…. Clearly, mTOR is a central player…. In my practice, this is something I tend to use in patients who have [had disease progression] through a CDK4/6 inhibitor and an aromatase inhibitor,” said Dr. Brufsky, who acknowledged that mucositis is a frequent side effect. “If you give a steroid mouthwash (which is free to the patient), for a month or two, mucositis is substantially reduced,” he said.

“Everolimus plus exemestane is one of my go-to regimens, or at least it was, until PI3K inhibitors became available,” he commented. “This is clearly something where you can get benefit.”

“Everolimus plus exemestane is one of my go-to regimens, or at least it was, until PI3K inhibitors became available.”
— Adam M. Brufsky, MD, PhD

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PI3K Pathway

The PI3K pathway helps transmit cell signals from the surface to the nucleus and plays a role in tumor growth, proliferation, and survival. PI3K inhibitors, particularly those targeting the PI3K-α isoform, which are associated with less toxicity, have shown promise in a clinical trial.7 The study evaluated fulvestrant with or without the PI3K-α inhibitor alpelisib in patients with advanced hormone receptor–positive breast cancer and validated this approach in patients with the PIK3CA mutation, Dr. Brufsky said.

In the PIK3CA mutation cohort, treatment with alpelisib/fulvestrant resulted in almost doubling progression-free survival vs fulvestrant alone (median = 11.0 vs 5.7 months; P < .001) and a 13% improvement in 12-month progression-free survival (46.3% vs 32.9%). Response rates in the mutation cohort with measurable disease were also doubled (35.7% vs 16.2%; P = .0002).

More recently, alpelisib was paired with fulvestrant or letrozole in the 160-patient nonrandomized phase II BYLieve study in patients who have CDK4/6 inhibitor–resistant PIK3CA mutations.8 In an early analysis, response rates were somewhat higher with letrozole (28%) than fulvestrant (14%), but more patients had stable disease with fulvestrant (59% vs 34%).

Alpelisib is approved in combination with fulvestrant for ­PIK3CA-mutated hormone receptor–positive/HER2-negative advanced or metastatic breast cancer after disease progression on endocrine therapy. The drug is contraindicated for patients with uncontrolled hyperglycemia, since the incidence of hyperglycemia in the SOLAR-1 trial was 64%. “In my practice, we do a weekly fasting glucose on all patients, and if it goes above 140 to 150 mg/dL, the patient gets metformin. We also give [loratadine] as a prophylaxis for rash [which occurred in 36% of patients]. These measures work very well to ameliorate a lot of the side effects with alpelisib,” he said.

“Alpelisib is a new standard of care for PIK3CA-mutant hormone receptor–positive metastatic breast cancer post–CDK4/6 inhibitor therapy,” Dr. Brufsky said.

AKT Inhibitors

AKT, a component of the PI3K signaling pathway, is also a key regulator of normal cellular processes involved in cancer progression. Inhibitors of AKT, therefore, may have a role in treatment after disease progression.

The FAKTION trial evaluated the AKT inhibitor capivasertib plus fulvestrant vs fulvestrant alone in 140 patients with hormone receptor–positive metastatic breast cancer resistant to an aromatase inhibitor.9 The combination resulted in a doubling in progression-free survival (10.3 vs 4.8 months; P = .0035) and a trend for improved overall survival (26.0 vs 20.0 months; P = .071).

“Large phase III trials of capivasertib and fulvestrant vs fulvestrant alone are currently ongoing,” he said. “In fact, there is a trial in estrogen receptor–negative patients as well, in the first-line setting, evaluating capivasertib and paclitaxel.”

Studies are also underway or planned for evaluating other AKT inhibitors, antibody-drug conjugates, and oral formulations of paclitaxel in this setting, Dr. Brufsky said. 

DISCLOSURE: Dr. Brufsky has served in a consulting or advisory role for Agendia, Bayer, Bioarray Therapeutics, Biotheranostics, Celgene, Eisai, Genentech, Genomic Health, Lilly, Merck, Myriad Pharmaceuticals, NanoString Technologies, Novartis, Pfizer, and Puma Biotechnology.


1. Brufsky AM: Beyond CDK inhibitors: Targeting PIK3CA. Invited lecture. 2020 Miami Breast Cancer Conference. Presented March 7, 2020.

2. Wander SA, Zangardi M, Niemierko A, et al: A multicenter analysis of abemaciclib after progression on palbociclib in patients with hormone receptor-positive/HER2- metastatic breast cancer. 2019 ASCO Annual Meeting. Abstract 1057. Presented June 2, 2019.

3. Cook M, Al Rabadi L, Mitri ZI, et al: Everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer patients previously treated with CDK4/6 inhibitor-based therapies. 2019 ASCO Annual Meeting. Abstract 1058. Presented June 2, 2019.

4. Giridhar KV, Choong GM, Leon-Ferre RA, et al: Clinical management of metastatic breast cancer after CDK4/6 inhibitors: A retrospective single-institution study. 2018 San Antonio Breast Cancer Symposium. Abstract P6-18-09. Presented December 8, 2018.

5. Jerusalem G, de Boer RH, Hurvitz S, et al: Everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, HER2-negative advanced breast cancer: The BOLERO-6 randomized clinical trial. JAMA Oncol 4:1367-1374, 2018.

6. Kornblum N, Zhao F, Manola J, et al: Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: Results of PrE0102. J Clin Oncol 36:1556-1563, 2018.

7. André F, Ciruelos E, Rubovszky, et al: Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.

8. Rugo HS, Bianchi GV, Chia SKL, et al: BYLieve: A phase II study of alpelisib with fulvestrant or letrozole for treatment of PIK3CA mutant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer progressing on/after cyclin-dependent kinase 4/6 inhibitor therapy. 2018 ASCO Annual Meeting. Abstract TPS1107. Presented June 2, 2018.

9. Jones RH, Carucci M, Casbard AC, et al: Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION). 2019 ASCO Annual Meeting. Abstract 1005. Presented June 4, 2019.