Which Patients Should Get CDK4/6 Inhibitors?

In Clinical Studies News by Barbara Jacoby

Some, however, are asking instead: who should not get them?

By: Kristin Jenkins

From: medpagetoday.com

The approval of three cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors for the treatment of patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer has completely changed the way in which oncologists view and manage up to 75% of invasive breast cancers, say experts.

Randomized clinical trials have demonstrated that progression-free survival (PFS) is doubled when palbociclib (Ibrance) or ribociclib (Kisqali) are added to endocrine therapy in first- or second-line therapy, or when abemaciclib (Verzenio), which has been approved for use as a single agent, is used as monotherapy in patients with more extensive previous treatment.

Results from a recent meta-analysis of seven randomized controlled trials in 3,854 patients showed that the addition of CDK 4/6 inhibitors to endocrine therapy was consistently associated with a 50% reduction in the rate of disease progression both in first and subsequent lines of treatment (HR 0.54, P<0.001).

This “dramatic” reduction in PFS appeared to be independent of age, site of metastasis, or the disease-free interval, Alessandra Gennari, MD, PhD, of the University of Eastern Piedmont in Novara, Italy, and colleagues wrote in their study online in the Journal of Clinical Oncology.

Four of the trials included first-line therapy, and in three studies, patients had undergone prior treatment for metastatic breast cancer. Although overall survival (OS) data were available in only two studies, “this translates into a clinically meaningful survival advantage,” the study authors wrote.

The jury may still be out on the impact on OS of CDK4/6 inhibitors in the first-line setting, but evidence has emerged that at least one of these agents confers a survival benefit in the second-line setting.

Findings from the PALOMA-3 trial showed that the addition of palbociclib to fulvestrant (Faslodex) prolonged median OS by almost 1 year in women who had disease progression or relapse during prior endocrine therapy. Of 410 patients, those treated with palbociclib and fulvestrant had a median OS 10 months longer than in women treated with fulvestrant alone (39.7 vs 29.7 months; HR 0.72).

Combined palbociclib-fulvestrant also resulted in a longer time to chemotherapy: 17.6 months vs 8.8 months in the placebo-fulvestrant group (HR 0.58, P<0.001).

“The clinical results with all three CDK4/6 inhibitors have been so impressive that the question is not who should be getting a CDK4/6 inhibitor but who should not be getting one,” said Shom Goel, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, in an interview.

With the exception of patients who are in true visceral crisis and those who are extremely frail, most patients are good candidates for CDK4/6 inhibitor therapy, he told MedPage Today. “The combination of hormonal therapy plus CDK4/6 inhibitor therapy can produce a durable response, and it should probably be used more often than not.”

Rupert Bartsch, MD, of the Medical University of Vienna in Austria, agreed: “Given the relevant clinical activity and the favorable toxicity profile, CDK4/6 inhibitors are a safe and efficacious therapy option,” he told MedPage Today. Bartsch emphasized that CDK4/6 inhibitor therapy “may be considered as the new standard of care for the majority of hormone receptor-positive HER2-negative metastatic breast cancer patients in the first-line setting.”

The addition of palbociclib, ribociclib, and abemaciclib to endocrine therapy “has resulted in the longest improvement in PFS seen to date in advanced ER-positive breast cancer,” confirmed Francisco J. Esteva, MD, director of the breast medical oncology program at the Laura and Isaac Perlmutter Cancer of New York University Langone Health in New York City.

“The endocrine therapy backbone was similar in all the randomized phase III trials with all three agents superior to endocrine therapy alone,” he told MedPage Today.

For the patient who is leading an active life, perhaps raising a family or working, or both, the addition of a CDK4/6 inhibitor to an aromatase inhibitor as a first-line therapy significantly extends time to progression. It also preserves quality of life by delaying the need for chemotherapy, noted Goel, adding that despite this, a significant proportion of patients treated in community settings continue to receive first-line chemotherapy.

Goel pointed to results from the PALOMA-2 trial showing that in women with previously untreated breast cancer, median PFS was significantly increased when palbociclib was combined with letrozole (Femara) as compared with therapy with placebo and letrozole: 24.8 months vs 14.5 months (P<0.001).

In their own review and summary of the literature on CDK4/6 inhibition in breast cancer, Goel and colleagues noted that 60% of patients had visceral disease at baseline and about 40% had metastatic de novo breast cancer. “Remarkably, these trials demonstrate ORRs [overall response rates] of over 50%, similar to that achieved with first-line chemotherapy,” the team wrote online in Therapeutic Advances in Medical Oncology.

“It is my opinion that most women with hormone receptor-positive, HER2-negative advanced breast cancer who are without symptoms related to the cancer are candidates for hormone therapy,” said Vered Stearns, MD, co-director of the breast cancer program at Johns Hopkins Medicine, in Baltimore. “I reserve first-line chemotherapy for women who need a rapid response to therapy or those with tumors that are not likely to respond to hormone therapy.”

Women older than 80 are also candidates for first-line CDK4/6 therapy in combination with endocrine therapy, said Goel. “The decision to use anti-cancer therapy cannot be made on the basis of age,” he emphasized.

“Data presented to date suggest that women of all age groups benefit from this treatment,” said Stearns, who pointed to results from a retrospective pooled subgroup analysis conducted by a research group from the U.S. Federal Drug Administration (FDA).

The FDA researchers looked at 329 women ages 70 and older enrolled in registration trials of CDK4/6 inhibitor therapy, and found that CDK 4/6 inhibitors used as part of endocrine therapy were just as efficacious in older women as in younger women.

The median PFS was 23.75 months in women ages <70 treated with a CDK4/6 inhibitor in combination with an aromatase inhibitor. At the time of reporting, median PFS had not been reached in women ≥70 who received the same treatment. In women treated with an aromatase inhibitor alone, the median PFS was 13.8 months in those ages <70 and 18 months in those ≥70.

“In my own practice, I have had women in their 80s on treatment,” said Stearns. “The dose and schedule can be adjusted in the first 1-3 months to ensure tolerability.”

A lingering reluctance to treat older patients with anti-cancer therapy may be reflected in results from a recent analysis of 2000-2012 Surveillance, Epidemiology, and End Results data in 486,118 women diagnosed with stages I to IV breast cancer. The analysis showed that when compared with their younger counterparts, women ages 75 and older had worse breast cancer outcomes, including a consistently higher risk of death from breast cancer, regardless of the disease subtype and stage.

The only exception to this increased age-based risk was seen in women with stage IV triple‐negative disease, Rachel A. Freedman MD, MPH, of the Dana-Farber Cancer Institute, in Boston, and colleagues reported online in Cancer.

“With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority,” the study authors wrote.