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MADRID -- The CDK4/6 inhibitor abemaciclib made a case for a role as initial therapy for postmenopausal women with advanced hormone receptor (HR)-positive, HER2-negative breast cancer, significantly increasing progression-free survival (PFS) when added to endocrine therapy.

The combination of abemaciclib and a nonsteroidal aromatase inhibitor resulted in a 45% reduction in the hazard for progression or death as compared with endocrine therapy alone. The primary analysis showed a median PFS of 14.7 months with endocrine therapy alone, whereas the median had yet to be reached in the abemaciclib arm.

The PFS benefit with combination therapy held up in analyses of all prespecified subgroups. However, an exploratory analysis suggested patients with poor-prognosis features (such as liver metastases) derived greater benefit from adding the CDK4/6 inhibitor to endocrine therapy. Conversely, patients with favorable-risk features (such as bone metastases only or an extended treatment-free interval, TFI) might do fine with endocrine therapy alone, as reported here at the congress.

"The treatment effect of abemaciclib was consistently observed across subgroups, based on hazard ratios," said Angelo Di Leo, MD, of the Istituto Toscano Tumori in Prato, Italy. "Abemaciclib, which is dosed on a continuous schedule, was generally well tolerated."

Although the prespecified subgroup analysis showed a "consistent treatment effect," he added.

The exploratory analyses showed that women with a TFI <36 months had a statistically significant 52% reduction in the PFS hazard, whereas those with a TFI >36 months had a nonsignificant 17% hazard reduction. Patients with metastases in bone only had a nonsignificant 42% reduction in the hazard as compared with statistically significant reductions of 49% and 53% for patients with multiple metastatic sites or liver metastases, respectively.

During a discussion of the MONARCH3 findings, Nicholas Turner, MD, of the Royal Marsden Hospital in London, said more mature data will likely result in an 11- or 12-month PFS advantage in favor of abemaciclib.

"This is practice-changing data," said Turner. "We see substantial efficacy with abemaciclib, with a safety profile compatible with long-term dosing. We're now seeing consistent benefit across studies, suggesting a class effect for CDK4/6 inhibitors."

The positive results from the phase III trial, known as MONARCH3, positioned abemaciclib for a bid as front-line combination therapy for advanced/metastatic HR+/HER2- breast cancer. However, the FDA already approved that indication for two competitors -- palbociclib (Ibrance) and ribociclib (Kisqali).

Assuming FDA approval of abemaciclib, how clinicians and patients distinguish among the three drugs in the class might come down to nuanced perspectives on side effects and tolerability.

"We have three drugs that are quite similar in terms of efficacy, and all three showed important benefits in progression-free survival," said Evandro de Azambuja, MD, a breast cancer specialist at the Jules Bordet Institute in Brussels. "I don't think that we have a preferred agent at the moment."

Di Leo and de Azambuja both noted that abemaciclib is associated with substantially less neutropenia than the other two CDK4/6 inhibitors, owing to its greater potency against CDK4, but causes more diarrhea, which often is an ongoing rather than intermittent issue. On the other hand patients on palbociclib require biweekly laboratory monitoring of blood-cell counts during the first 2 months of treatment, de Azambuja noted.

The differing toxicity profiles also raise the question about potential sequential use of the agents as a means of dealing with toxicity.

"I think it will depend on the type of patient and the degree of diarrhea," de Azambuja told 名媛直播. "Normally, the diarrhea is manageable with abemaciclib, for example. I think switch [to a different CDK4/6 inhibitor] is a possibility, but we do not have the data to make empirical changes."

Investigators in MONARCH3 enrolled 493 postmenopausal patients with metastatic or locally recurrent HR+/HER2- breast cancer and no prior treatment for advanced disease. The patients were randomized 2:1 to abemaciclib and investigator's choice of anastrozole (Arimidex) or letrozole (Femara) or to endocrine therapy alone.

The trial had a primary endpoint of investigator-assessed PFS. The trial ended early when an interim data analysis at 18 months of follow-up showed a significant advantage in favor of the abemaciclib arm (P=0.000021).

The objective response rate in all patients was 48.2% with combination therapy and 34.5% with aromatase inhibitor monotherapy (P=0.002). The clinical benefit rate was 78% with abemaciclib and 71.5% without the CDK4/6 inhibitor (P=0.101). The data remained immature for an overall survival analysis (49 of 315 required clinical events).

The combination was associated with a higher incidence of adverse events. Median achieved dose intensity was higher with monotherapy (98.1% versus 85.7%), although the median number of cycles of therapy was similar (16 with abemaciclib, 15 without).

About 20% of patients in the abemaciclib arm discontinued treatment because of adverse events as compared with 2.5% of patients on endocrine therapy alone. Dose reduction rates were 43.4% with abemaciclib and 6.2% without. Serious adverse events occurred in 27.5% of the abemaciclib arm and 14.9% of patients treated with endocrine monotherapy.

The most common grade 3/4 adverse events in the abemaciclib group were neutropenia (21.1%), diarrhea (9.5%), and anemia (5.8%). Grade 3/4 laboratory adverse events were topped by decreased neutrophil count (22.1%) and decreased white cell count (12.8%).

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