Clinical Challenges: What’s Next for CDK4/6 Therapy?

Randomized clinical trial programs for CDK4/6 inhibitors have demonstrated that combining palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio) with first- and second-line endocrine therapies can significantly delay the time to progression in advanced and metastatic hormone receptor-positive (HR+) breast cancer.

Yet while these agents have raised the bar on treatment for this largely fatal disease, “many questions remain about integrating CDK4/6 inhibitors into clinical practice,” said Vered Stearns, MD, of Johns Hopkins School of Medicine in Baltimore, and colleagues in an online review in Oncology.

“These include whether there are biomarkers that may predict response to a CDK4/6 inhibitor, how to determine if a CDK4/6 inhibitor should be continued or switched after progression, whether CDK4/6 inhibitors may be combined with therapies other than endocrine therapies, and whether the use of these agents can be expanded to HR+/HER2− [human epidermal growth factor receptor 2-negative] early-stage breast cancer and HR+/HER2-positive [HER2+] disease,” Stearns and co-authors said.

In patients progressing on first-line treatment with endocrine therapy in combination with a CDK4/6 inhibitor, “little is known regarding the optimal treatment strategy,” Rupert Bartsch, MD, of the Medical University of Vienna, Austria, told MedPage Today. “Trials evaluating the optimal treatment sequence are urgently required.”

Post-progression therapy usually consists of endocrine therapy plus everolimus (Afinitor), single-agent endocrine therapy, or chemotherapy, Bartsch pointed out. “This could be challenged by strategies such as continuing the same CDK4/6 inhibitor beyond progression while switching the endocrine combination partner or by a switch of endocrine therapy and the CDK4/6 inhibitor from palbociclib/ribociclib to abemaciclib,” he said.

Whether a CDK4/6 inhibitor should be continued after disease progression in ER+/HER2− disease is being tackled by at least two ongoing studies. In the first, the study population is made up of 100 women and men with estrogen or progesterone receptor-positive, HER2-negative metastatic breast cancer who developed disease progression while receiving palbociclib and an aromatase inhibitor (AI). During the study, which is being conducted at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, all participants will continue on palbociclib but switched to fulvestrant (Faslodex).

“We are looking at whether changing the AI will maintain the benefit,” said Stearns, who is co-director of the breast cancer program at Sidney Kimmel.

The study will also determine the prevalence rate, in the study population, of estrogen receptor α (ESR1) and phosphatidylinositol-3-kinase (PI3K) mutations, and evaluate the progression-free survival (PFS) in participants with and without these mutations, among other things.

Clinicians with patients who have experienced tumor progression following CDK4/6 inhibition “may want to consider clinical trials in which the CDK4/6 inhibitor is continued with a different hormonal agent, or in which a different CDK4/6 inhibitor is studied,” Stearns told MedPage Today.

“These and other studies will help clinicians gain an understanding of the likelihood that the continuation or a change in CDK4/6 will be effective, and whether there are patient or tumor characteristics that can help guide therapy in the future,” she said. “Patients may consider other combinations of hormonal and targeted agents, or chemotherapy.”

The second study is called MAINTAIN and is being conducted at New York University Langone Health Perlmutter Cancer Center in New York City. This randomized, open-label trial is looking at the efficacy of ribociclib with fulvestrant versus fulvestrant alone following progression on either front-line palbociclib or ribociclib. Investigators will determine whether there is continued benefit for remaining on a CDK4/6 inhibitor at the time of switching anti-estrogen therapy.

“Outside a clinical trial, the standard of care is to discontinue these drugs at the time of progression,” Francisco J. Esteva, MD, director of the breast medical oncology program at NYU Langone, told MedPage Today.

Meanwhile, the hunt for new gene- and protein-based predictive biomarkers continues in a number of ongoing studies.

“Approximately 20% of patients will not respond to CDK4/6 inhibitors initially, and all patients will ultimately develop resistance,” noted Stearns and colleagues in their review. ” A better understanding of biomarkers of intrinsic and acquired resistance may help guide therapy.”

The PYTHIA trial is investigating potentially innovative biomarkers for the selection of patients to palbociclib/fulvestrant treatment. The study is part of the Breast International Group’s AURORA program to collect and characterize biological samples, including metastatic tissue, from patients with advanced breast cancer.

Other studies looking for new biomarkers predictive of treatment response include an open-label, multicenter study in 100 patients with metastatic breast cancer who are candidates for first-line treatment with palbociclib or ribociclib plus endocrine therapy. Investigators are using diagnostic biopsies of metastatic lesions to identify CDK4/6 inhibitor response predictors and create a post-treatment multi-omic signature.

Until new predictive biomarkers are identified, estrogen receptor positivity is still the best biomarker to predict resistance to CDK4/6 inhibitors, said Stearns, noting that resistance is seen in about 20% of patients following initial therapy. Eventually, all patients treated with CDK4/6 inhibitors develop resistance, she noted.

Investigations into the use of CDK4/6 inhibitors with novel drugs are also underway. In the TRINITI-1 study, for instance, a ribociclib/everolimus/exemestane triplet is being used for continuous dosing in 107 men and postmenopausal women following progression on a CDK4/6 inhibitor.

Studies are also looking at the use of CDK4/6 inhibitors with novel inhibitors of the PI3K pathway. The phase 2 PACE trial will examine the use of palbociclib in a combined regimen that includes immune therapy with the anti-PD-L1 monoclonal antibody, avelumab (Bavencio). Patients with metastatic HR+/HER2- breast cancer resistant to palbociclib and endocrine therapy will be randomized to fulvestrant alone, fulvestrant and palbociclib, or fulvestrant, palbociclib, and avelumab. The FDA has granted the latter drug orphan drug status for treating metastatic Merkel cell carcinoma.

The addition of a CDK4/6 inhibitor to adjuvant treatment in patients with stage 2/3 HR+/HER2− breast cancer is also being investigated. “I would encourage women with early breast cancer that is hormone receptor-positive to consider enrolling in a clinical trial,” said Stearns.

Ongoing clinical trials are looking at the potential benefit of all three CDK4/6 inhibitors in HR+/HER2-positive advanced breast cancer.

Trials into the use of CDK4/6 inhibitors in premenopausal patients with HR+/HER-2- advanced breast cancer are continuing, supported by results from the international phase 3 MONALEESA-7 trial. With a first-line regimen that combined either ribociclib or placebo with tamoxifen or a non-steroidal aromatase inhibitor and ovarian suppression, progression-free survival was 23.8 months versus 13.0 months, respectively.

After demonstrating that the efficacy and safety of a CDK4/6 inhibitor in the premenopausal setting was comparable to published results in the postmenopausal population, the FDA extended the indications for ribociclib to include premenopausal women. It is estimated that 20% of premenopausal patients in the U.S. have metastatic HR+/HER2- breast cancer.

“It is clearly an option for this population in the first-line setting,” Debasish Tripathy, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. “By extension, it is commonly used in first- or second-line settings in combination with fulvestrant, with further supporting data from MONALEESA-3.”

Tripathy said that better understanding of the mechanisms of resistance to CDK 4/6 inhibitors, and the genomic features associated with resistance to AI therapy, such as ESR1 mutations and to fulvestrant are key research areas. His group also wants “to capitalize on other genomic targets such as PIK3CA mutations. To this end, we are testing novel SERDS — selective estrogen receptor downregulators — as well as the use of liquid biopsies to detect ESR1 and other mutations and to adapt therapy in real time.”

Ongoing trials such as the open label, randomized, multicenter, international phase II FATIMA study may shed new light on the efficacy and safety of CDK4/6 inhibitors in young women diagnosed with ER+/HER2- metastatic or locally advanced breast cancer in the Middle East, where the median age at diagnosis is less than 50 years. About 50% of these women are still menstruating.

In FATIMA, 160 premenopausal patients will be randomized to receive either palbociclib with exemestane and ovarian suppression or more conventional therapy with exemestane and ovarian suppression. The estimated trial completion date is March 2022.

The open-label, multicenter, phase 3b COMPLEEMENT-1 study is assessing the safety and efficacy of ribociclib in combination with letrozole as first-line therapy in 3258 men and pre/postmenopausal women with HR+/HER2- advanced breast cancer.

In spite of myriad avenues of inquiry, the impact of CDK4/6 inhibitors on overall survival remains the sixty-four-thousand-dollar question. And with mature OS data not yet available from first-line trials such as PALOMA-2, MONALEESA-2, and MONARCH-3, the findings from the final analysis of the PALOMA-3 trial may have to suffice for now, agreed Stearns and Bartsch. PALOMA-3 showed a longer overall survival with palbociclib-fulvestrant than with fulvestrant alone in patients who had sensitivity to previous endocrine therapy.

Median OS was 34.9 months in the fulvestrant plus palbociclib arm compared to 28 months in the control arm, Bartsch pointed out. “While this difference did not reach statistical significance, the data suggest that the progression-free survival benefit in the combination arm is maintained over time and is not reduced by impaired activity of further treatment lines.”