Two Studies Confirm OS Benefit of CDK4/6 Inhibitors in Breast Cancer

Two studies reported at the ESMO Congress 2019 have shown that use of a CDK4/6 inhibitor plus fulvestrant can significantly improve the survival of women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer.

Data from the phase 3 MONARCH-2 study showed that abemaciclib plus fulvestrant provided a significant 9.4-month overall survival improvement in pre- or perimenopausal women and postmenopausal women with HR-positive, HER2- advanced breast cancer who had failed on endocrine therapy.

Data from the phase 3 MONALEESA-3 trial showed that ribociclib plus fulvestrant – as first-line or second-line treatment -- demonstrated a statistically significant improvement in overall survival among postmenopausal women with HR-positive, HER2- advanced breast cancer.

“Both of these randomized trials showed an improvement in overall survival, which implies that patients receiving these drugs live longer than patients taking endocrine therapy alone,” Lajos Pusztai, MD, DPhil, director of breast cancer translational research at Yale Cancer Center, told Cancer Network.

“After the announcement of these trial results, we now have four trials that have each showed improved survival in metastatic estrogen receptor positive breast cancer for patients who take a CDK4/6 inhibitor along with endocrine therapy (in 3 of the 4 trials the endocrine therapy was fulvestrant),” Pusztai said. “Three of these trials have reached statistical significance (MONALEESA-7, MONALEESA-3, MONARCH-2) and one (PALOMA-2) showed a very strong trend that has just barely missed a stringent predefined threshold of statistical significance. The results, including the magnitude of benefit, are remarkably consistent across these trials.”

MONALEESA-3

These final data from the MONALEESA-3 study showed that first-line, as well as second-line, treatment with the CDK4/6 inhibitor ribociclib plus fulvestrant significantly improved overall survival in this patient group.

“This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib upfront at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease,” study author Dennis Slamon, MD, University of California Los Angeles, said in a press release.

In the study, 726 postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomly assigned 2:1 to ribociclib plus fulvestrant or placebo plus fulvestrant in first-line and second-line settings. Overall survival was evaluated after 275 deaths.

With a median follow-up of 39.4 months, the median overall survival for ribociclib plus fulvestrant had not yet been reached compared with 40 months for fulvestrant plus placebo (HR=0.74; 95% CI, 0.568-0.924; P=.00455), according to the data.

The overall survival benefit was consistent across all studied subgroups, including those undergoing first-line treatment (not reached vs. 45.1 months; HR=0.70; 95% CI, 0.479-1.021) and second-line treatment (40.2 months vs. 32.5 months; HR=0.730; 95% CI, 0.530-1.004).

Patients receiving first-line therapy also had a significant progression-free survival benefit compared with the placebo arm (33.6 vs. 19.2 months; HR=0.546; 95% CI, 0.415-0.718).

According to the study abstract, “these data combined with results form MONALEESA-7, confirm ribociclib’s benefit with multiple combination partners in pre- and postmenopausal patients and support ribociclib as a recommended CDK4/6 inhibitors in first-line and second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer.”

Pusztai also noted that this trial included a substantial number of patients who just developed metastatic cancer, and based on these results, it is appropriate to include a CDK4/6 inhibitor in the very beginning of therapy.

MONARCH-2

MONARCH-2 results also showed promise, with longer OS times.

“Results from Monarch 2 study presented two years ago showed significant improvement in progression free survival for patients treated with the combination of abemaciclib plus fulvestrant compared to fulvestrant alone. Now, with further follow-up we have overall survival data showing a statistically significant and clinically meaningful improvement in overall survival with the combination,” study first author George Sledge, MD, Stanford University School of Medicine, said in a press release.

The study randomly assigned 669 patients 2:1 to abemaciclib plus fulvestrant or placebo plus fulvestrant. Previously reported, progression-free survival was the primary endpoint; overall survival was a gated secondary endpoint.

At a prespecified interim analysis, 338 deaths had occurred in the intent-to-treat population. The median overall survival was 46.7 months for the abemaciclib plus fulvestrant arm compared with 37.3 months for placebo plus fulvestrant (HR=0.757; 95% CI, 0.606-0.945; P=.0137).

More pronounced survival effects were seen in certain subgroups including those with visceral disease (HR=0.675) and primary resistance to prior endocrine therapy (HR=0.686).

“The MONARCH-2 results also point out that abemaciclib and fulvestrant was highly effective in patients with liver metastasis, adding to growing evidence debunking a medical myth from the 1980s that patients with extensive organ involvement should start with chemotherapy rather than endocrine therapy,” Pusztai said.

Together, these results should reassure current practice in the United States, Pusztai said, which has already adopted these therapies in these clinical settings based on the earlier results from these same trials that have demonstrated delayed progression of cancer treated with CDK4/6 inhibition.

“For clinical investigators and regulators, like the FDA, these findings are also important because they reaffirm that progression free survival, is a valid early read out from large trials and substantial  improvements in progression-free survival do eventually translate into improved overall survival if the study includes enough patients who are followed long enough to have sufficient statistical power,” Pusztai said.