Tibremciclib for Advanced Breast Cancer: Is It Worth It?

Adding the novel CDK4/6 inhibitor tibremciclib (Betta Pharmaceuticals) to second-line fulvestrant significantly extended progression-free survival (PFS) in patients with HR-positive/HER2-negative advanced breast cancer, but with the tradeoff of increased toxicity, new data suggest. 

Compared with fulvestrant alone, the combination prolonged median PFS for these patients by 11 months, according to results from the phase 3 TIFFANY trial. However, similar to existing CDK4/6 inhibitors, the tibremciclib-fulvestrant combination added to treatment side effects — including substantially higher rates of diarrhea, hematologic toxicities, and hypokalemia.

The authors of the analysis, published in JAMA Oncology, described the toxicities as “manageable,” emphasizing that few patients stopped treatment because of them. 

Study author Xichun Hu, MD, of Fudan University Shanghai Cancer Center, told Medscape Medical News that tibremciclib compares favorably with other CDK4/6 inhibitors in terms of dose reduction and discontinuation rates. However, Hu noted, that’s based on cross-trial comparisons, which have to be interpreted with caution. 

Kathy Miller, MD, who was not involved in the trial, had a similar take.

“Toxicity actually looks similar to ribociclib and palbociclib, with primarily myelosuppression and little non-heme toxicity,” Miller, of the Melvin and Bren Simon Comprehensive Cancer Center at Indiana University, told Medscape Medical News. 

Tibremciclib plus fulvestrant was recently approved in China for HR-positive/HER2-negative advanced breast cancer following results from the trial, but the combination has yet to be approved in the US.

The Benefits vs the Risks

In the trial, Hu and colleagues studied the safety and efficacy of the new agent among patients from 69 centers in China who had experienced progression while on endocrine therapy and had received no more than one line of chemotherapy.

A total of 274 patients were randomized (2:1) to receive either tibremciclib (400 mg orally, once daily) or placebo plus fulvestrant until disease progression, death, or treatment discontinuation over a median follow-up of 13 months. Eighty patients (43.5%) in the tibremciclib arm and 64 (71.1%) in the placebo arm experienced a PFS event (disease progression or death).

Tibremciclib plus fulvestrant significantly improved PFS to 16.5 months versus 5.6 months with fulvestrant alone, reducing the risk of progression by 63% (hazard ratio [HR], 0.37; P < .001).

As for safety, adverse events were higher in the treatment arm. The most common treatment-emergent adverse events were diarrhea (79.3% in the tibremciclib arm vs 13.3% in placebo arm), neutropenia (75.5% vs 15.6%), leukopenia (73.9% vs 16.7%), and anemia (69% vs 21.1%). Nausea and vomiting were also more common with tibremciclib, at 37% and 40.2%, respectively — versus 18.9% and 11.1% in the placebo group.

Most often, those adverse events were grade 1 or 2. However, 50.5% of patients in the tibremciclib group had a grade 3 or higher treatment-emergent adverse event, versus 21.1% in the placebo group. The most common were neutropenia (15.2% vs 5.6%), anemia (12.0% vs 4.4%), and hypokalemia (12% vs 0%). Hypokalemia was often due to diarrhea and was managed with electrolyte monitoring and potassium supplementation, Hu said.

One-third of patients in the tibremciclib arm developed hypertriglyceridemia (5.4% grade 3 or higher) — a rate higher than that seen with other CDK4/6 inhibitors. Cases were managed with lipid-lowering agents such as atorvastatin.

More patients on tibremciclib experienced dosing interruptions due to adverse events (54% vs 23%), and dose reductions were also more common with the combination therapy (18.5% vs 4.4%). However, only four patients (all in the tibremciclib arm) discontinued treatment due to side effects.

Overall, the adverse event profile of tibremciclib lines up with that of other CDK4/6 inhibitors and comes with better PFS, Hu said, noting that “the benefit-risk balance of tibremciclib plus fulvestrant appears highly favorable.”

In TIFFANY, the authors note d that cases of neutropenia and leukopenia were numerically lower than in trials of abemaciclib, dalpiciclib, and palbociclib plus fulvestrant. According to Hu, tibremciclib is structurally different from other drugs in its class, with a greater selectivity for CDK4 and less inhibition of CDK6 and CDK9, which may reduce the incidence of neutropenia as well as severe diarrhea.

Plus, the PFS improvement seen in TIFFANY was greater, Hu said. Pa lbociclib in PALOMA-3 showed a median PFS of 9.5 months vs 4.6 months for fulvestrant alone (HR, 0.46); abemaciclib in MONARCH led to a PFS of 11.5 months vs 5.6 months (HR, 0.38, a Chinese population); and dalpiciclib in DAWNA-1 achieved 16.6 months vs 7.2 months (HR, 0.50, also in Chinese patients).

While these are cross-trial comparisons, it’s still unclear exactly how tibremciclib stacks up against other drugs in its class (including its impact on overall survival). The authors also caution that, because the trial exclusively enrolled Chinese patients without prior CDK4/6 inhibitor exposure, the findings may not be generalizable to broader populations, particularly in regions like North America and Europe.

Miller pointed to the generalizability question as well, noting that fulvestrant monotherapy is typically not the standard of care in the US and other Western countries. 

“This [study] joins a long list of second-line endocrine studies that show drug activity but don’t compare to standard of care and don’t really tell us how to best use the drug,” Miller said. 

Funding for the study was provided by Betta Pharmaceuticals Co, Ltd, with additional support from the National Natural Science Foundation of China, the Program for Shanghai Outstanding Academic Leader, and the Shanghai Anticancer Association SOAR Project. Hu reported advisory fees from AstraZeneca, Roche, and Hengrui. No other disclosures were reported. Miller has served as a director, officer, partner, employee, advisor, consultant, or trustee for Independent Data Safety Monitoring Committees (IDMCs) for Merck, Roche and Celcuity.