First CDK4/6 Inhibitor to Improve Survival in Metastatic Breast Cancer

'Striking, Wonderful' Result

Nick Mulcahy

June 01, 2019

CHICAGO — It's not often that a systemic oral therapy significantly improves overall survival (OS) in the setting of metastatic cancer.

And, in the case of CDK4/6 inhibitors for breast cancer, it was looking like one might not do so, as multiple previous trials were limited to a significant improvement in progression-free survival.

Sara Hurvitz, MD

So, understandably, there were some smiles among experts discussing the results of the MONALEESA-7 trial in premenopausal women with advanced breast cancer (abstract LBA1008) here during a press conference at the 2019 American Society of Clinical Oncology Annual Meeting.

The CDK4/6 inhibitor ribociclib (Kisqali, Novartis) plus standard-of-care endocrine therapy significantly improved OS for younger women with advanced hormone receptor-positive (HR+) breast cancer compared with endocrine therapy alone, reported lead study author Sara Hurvitz, MD, director, Breast Cancer Clinical Research, UCLA Jonsson Comprehensive Cancer Center, Los Angeles.

It is the first time that a CDK4/6 inhibitor — or any targeted therapy — has been shown in combination with endocrine therapy to significantly improve OS among women with HR+/HER2-negative metastatic disease, she told reporters.

The estimated OS rate at 42 months was 70.2% for women in the combination therapy group vs 46% for women in the endocrine therapy-only group (hazard ratio for death, 0.71; P = .009)

The new findings will be presented in an ASCO session and simultaneously published online June 4 in The New England Journal of Medicine.

The overall survival result, which was part of a planned analysis, crossed the prespecified stopping boundary for superior efficacy.

Advanced breast cancer in this younger population is a "terrible disease" due to its often aggressive nature, said Hurvitz in a meeting press statement.

Harold Burstein, MD, of Dana Farber Cancer Institute, Boston, and an ASCO expert not involved with the study told reporters that "the golden age of clinical research in oncology continues."

A theme seen in the new study and others, he added, is "that with mature and robust data, we are now seeing substantial improvements in survival with innovative drugs that are coming to market."

At a pre-meeting press event, Monica Bertagnolli, MD, chief of surgical oncology, Dana Farber Cancer Institute, and ASCO president called the results "striking and wonderful" and observed that the 42-month data amount to 3.5 years, which is "a lot" of time in advanced breast cancer.

Previously, ribociclib was approved in 2017 by the US Food and Drug Administration for use in advanced HR+ breast cancer in post-menopausal women and, in 2018, for similar use in premenopausal women on the basis of earlier progression-free survival results from this same MONALEESA-7 trial.

Charles Shapiro, MD, director of translational breast cancer research and cancer survivorship, Tisch Cancer Institute at Mount Sinai, New York City, commented on the new results: "This is going to represent a new standard of care for metastatic premenopausal women with hormone receptor-positive breast cancers."

Shapiro, who was not involved in the study, told Medscape Medical News that it is "an excellent question whether there any differences between the three CDK 4/6 inhibitors. Thus far there are no direct comparisons among them." This was a reference to palbociclib (Ibrance, Pfizer) and abemaciclib (Verzenio, Lilly) , the other members of this class of drugs.

Combination therapy in this premenopausal setting "will likely work" with other CDK 4/6 inhibitors, he added.

Agreed, said Dawn Hershman, MD, leader of the breast cancer program at Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York City, who was asked for comment.

All of the drugs in this class would probably have a similar effect "if studied using the same criteria and length of time," said Hershman, who was not involved in the study. "It's hard to believe they wouldn't," she told Medscape Medical News.

This was, in part, a reference to the fact that palbociclib was shown to improve overall survival in the PALOMA-3 trial but not significantly so. But PALOMA-3 included both post- and pre-menopausal women, who were more heavily pretreated than the women in the current trial. Indeed, in MONALEESA-7, all of the women were receiving initial endocrine therapy and only 15% had received previous chemotherapy.

However, Hurvitz defended ribociclib's newly established status in this setting during the press conference.

She said that medical oncologists have generally been "comfortable using these drugs [CDK 4/6 inhibitors] interchangeably" with these patients but, with the overall survival improvement now seen with ribociclib, other agents will have to demonstrate the same.

Study Details

MONALEESA-7 is the first trial to focus exclusively premenopausal women (< age 59 years) with advanced breast cancer who had not received prior endocrine therapy.

In the trial, investigators randomly assigned 672 women to the oral therapy ribociclib or to a placebo pill. All women also received the injectable endocrine therapy goserelin, and one of three other endocrine therapies: the aromatase inhibitors letrozole or anastrozole or the selective estrogen receptor modulator tamoxifen.

After a median follow-up of 34.6 months, 173 (26%) continued to receive treatment, but with 116 (35%) of the women still receiving ribociclib vs only 57 (17%) still receiving the placebo.

In addition, the investigators broke down the survival data by the two types of oral endocrine therapies used in the trial. They report survival rates of 71% and 70% for women who took ribociclib in combination with tamoxifen or an aromatase inhibitor, respectively, compared with a survival rate of 55% and 43%, respectively, for women who received placebo in combination with tamoxifen or aromatase inhibitors only.

No new safety signals were observed during the median of 2 years of treatment exposure in the combination therapy group, said the study authors.

The study also serves another purpose for clinicians and patients, said Dana Farber's Burstein.

"One of the myths that this study helps suppress is that younger [women] with ER+ breast cancer have a fundamentally different outcome than older women — actually their outcomes look very similar," he said, referring to earlier ribociclib research among postmenopausal women, including PALOMA-3 trial.

The study was funded by Novartis, makers of ribociclib. Study authors including Hurvitz have financial ties to the company and include Novartis employees. Shapiro, Hershman, and Burstein have disclosed no relevant financial relationships.

2019 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA1008. Presented June 4, 2019.

N Engl J Med. Published online June 4, 2019. Abstract

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