BARCELONA—More pre-menopausal women who have ER-positive advanced breast cancer could be spared chemotherapy—according to latest findings from the MONALEESA-7 double-blind, randomized, phase III trial in which either placebo or the cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib were added to tamoxifen or a non-steroidal aromatase inhibitor with all patients also having ovarian suppression by goserelin therapy (Abstract 1LBA).
At the 2018 European Breast Cancer Conference, Nadia Harbeck, MD, PhD, Professor of Gynecology and Head of the Breast Center at the University of Munich in Germany, said the study showed that practice should change for young pre-menopausal patients who presented for the first time with ER-positive and HER2-negative advanced breast cancer.
“Don't think about chemotherapy,” she said. “Think about ribociclib plus ovarian suppression and either tamoxifen or an aromatase inhibitor. This will give you rapid response—a long-lasting response. And the patients will have good quality of life during their treatment.”
MONALEESA-7 studied 672 patients who had no previous endocrine therapy and not more than one line of chemotherapy. They were treated with goserelin and randomized to ribociclib or placebo in combination with either tamoxifen, letrozole, or anastrozole. The primary endpoint was progression-free survival (PFS). Among the secondary endpoints were health-related quality of life and duration of response (DoR).
The rationale was that CDK 4/6 inhibition was already known to improve response to endocrine therapy in post-menopausal women. So Harbeck said they wanted to evaluate potential benefits of adding it to first-line therapy in pre-menopausal patients.
PFS was significantly longer with ribociclib (HR-0.553). Median PFS was 23.8 months compared with 13.0 months with placebo. And the benefits were consistent in different subgroups. Fifty-one percent of patients who had measurable disease at baseline treated with ribociclib had a complete or partial response compared with 36 percent of those who received placebo. And the probability of a response by 6 months was greater with ribociclib—35 percent compared with 25 percent in patients who had placebo.
The median DoR was 21.3 months with ribociclib and 17.5 months with placebo. Mean pain reduction was assessed as 20 percent with ribociclib and 14 percent among patients in the placebo arm.
“We had a better response rate [and] a shorter time to response, which is important because most of these patients are treated by chemotherapy today and we can see now that, with ribociclib-based endocrine therapy, we can already have a response after 8 weeks. And the majority of patients—over 80 percent—will have clinical benefit. And about 50 percent will have an objective response with this therapy,” she said.
Harbeck reported that the therapy was well-tolerated—as already shown with post-menopausal women—with major adverse events found to be hematological. “There's a high rate of neutropenia grade 3 and also some grade 4, but this is not clinically meaningful because once you stop the drug the neutrophils go back to normal. And before you start your next cycle you measure them again and if they're over a thousand you can restart the drug. If patients have prolonged or severe neutropenia you can dose-reduce. So, the rate of febrile neutropenia is very low.”
The study found the efficacy of the drug “mirrored” quality-of-life data. “We already see a reduction in pain after 8 weeks, which is greater in the ribociclib arm. And we saw a clinically meaningful reduction of pain in the ribociclib arm, [but] not in the placebo arm,” she noted.
The researchers concluded that in pre- or peri-menopausal women having ovarian suppression by means of goserelin who had ER-positive, HER2-negative advanced breast cancer, ribociclib combined with tamoxifen, letrozole, or anastrozole significantly prolonged PFS and was associated with a higher objective tumor response rate when compared with the same endocrine therapy with placebo. The superiority of the ribociclib-based combination included early and durable tumor response and a reduction in pain at week 8.
Harbeck's conclusions were quite clear: “This is the new first-line standard [for] patients with hormone-receptor positive HER2-negative advanced breast cancer if they are pre-menopausal—unless they need a very rapid response. If they are in a visceral crisis, they need chemotherapy. But all other patients can go with CDK 4/6 inhibitor-based endocrine therapy,” she noted.
Emiel J.T. Rutgers, MD, PhD, FRCS, from the Netherlands Cancer Institute, and Professor of Surgical Oncology at the University of Amsterdam, who was not involved with the study, said the results were very interesting. “We now have another possibility added to our armamentarium. My opinion is that, in pre-menopausal women who recur with hormone-sensitive estrogen-dependent breast cancer with visceral or bony metastasis, a re-challenge with anti-hormonal treatment including ribociclib—or a comparable [agent]—is now the first option. And the side effect profile is rather mild, so that's another positive thing about it.”
Peter M. Goodwin is a contributing writer.