CHICAGO —The combination of ribociclib (Kisqali) and endocrine therapy has already been shown to yield a significant survival advantage for women with metastatic, hormone receptor–positive, HER2-negative (HR+/HER2-) breast cancer.
Now the same combination has also shown benefit in early-stage HR+/HER2- breast tumors.
The new results come from an interim analysis of the phase 3 randomized NATALEE trial, which is comparing maintenance therapy with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib plus endocrine therapy with an aromatase inhibitor to endocrine therapy alone.
At a median follow-up of 27.7 months, the 3-year invasive disease–free survival (IDFS) rate was 90.4% for patients who received the combination, compared with 87.1% for patients who received endocrine therapy alone.
This difference translates into a 25% relative reduction in risk for recurrence with the addition of ribociclib, said principal investigator Dennis J. Slamon, MD, PhD, from the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, California.
“The NATALEE results, in summary, do support this as a new treatment of choice available to physicians and patients for this broad population of patients with stage II or stage III hormone receptor–positive, HER2-negative disease in early breast cancer,” he said.
Slamon was speaking at a media briefing held prior to the American Society of Clinical Oncology (ASCO) 2023 annual meeting in Chicago, where the results will be presented (abstract LBA500).
“Early but Impressive”
“Today, Dr Slamon has shown us early but impressive data demonstrating a significant reduction in the risk of recurrence as defined by an improvement of invasive disease–free survival for patients with high-risk, node-positive and node-negative hormone receptor–positive, HER2-negative early breast cancer,” commented ASCO Expert Rita Nanda, MD, director of the breast oncology program at the University of Chicago.
“We know that a substantial proportion of patients with early-stage hormone receptor–positive breast can go on to recur,” Nanda continued. “These recurrences can be quite delayed, and for our patients with node-negative disease, to this point, we haven’t seen any improvements with the addition of a CDK4/6 inhibitor to endocrine therapy for early- stage breast cancer. Dr Slamon has also shown us that ribociclib in the context of the NATALEE trial is effective, it was well tolerated, and I do expect that these trial results will change practice.”
Approached for comment, Sylvia Adams, MD, a medical oncologist who specializes in breast cancer at the NYU Langone Perlmutter Cancer Center in New York City, told Medscape Medical News that she is comfortable with using a CDK4/6 inhibitor such as ribociclib or abemaciclib (Verzenio) in the adjuvant setting for patients with early, localized breast cancer.
She noted, however, that to date, the absolute benefit of the combination over endocrine therapy alone has been modest, at 3.3%, but that the difference may be important to many patients who feel that they need to do everything they can to prevent disease recurrence.
“I’m really looking forward to the quality-of-life data, because it’s certainly known that any of these CDK4/6 inhibitors may add a bit of fatigue, and while there were no unexpected safety signals [in NATALEE], we know that there are some GI [gastrointestinal] effects with this therapy, as well as joint pain,” she said. “Joint pain is a little tricky, because the patients are also getting aromatase inhibitors, which can cause joint pain.”
In addition, premenopausal women in the study also received goserelin, an ovarian suppressor that triggers menopause, which is also associated with arthralgias, Adams said.
Adams and Nanda both noted that the addition of ribociclib to endocrine therapy increases the treatment burden for patients because it requires a commitment of at least 3 years and more frequent monitoring, especially in the first few months of therapy, compared with endocrine therapy alone.
As previously reported by Medscape Medical News, the combination of ribociclib and standard-of-care endocrine therapy was the first to show an improvement in overall survival among women with metastatic HR+/HER2- breast cancer.
To see whether the combination could also benefit patients with early breast cancer, the investigators conducted NATALEE. They enrolled premenopausal and postmenopausal women and also men with HR+/HER2- breast cancer. Cases ranged from stage IIA (with either no nodal involvement with additional risk factors or with one to three involved axilliary lymph nodes) to stage IIB or stage III disease, based on American Joint Committee on Cancer staging (AJCC Cancer Staging Manual, 8th Edition).
Patients who had previously received neoadjuvant or adjuvant endocrine therapy were accepted into the trial if the therapy had been started within 1 year of randomization.
The patients were stratified by age, menopausal status, disease stage, prior chemotherapy status, and geographic region. They were randomly assigned to receive either ribociclib 400 mg per day for 3 weeks, then were given 1 week off each cycle for 3 years plus endocrine therapy with either letrozole 2.5 mg/day or anastrozole 1 mg/day for at least 5 years, or to endocrine therapy alone. Men and premenopausal women also received goserelin.
Slamon noted that the 400-mg dose of ribociclib is lower than the recommended starting dose of 600 mg for metastatic disease. They chose the lower dose to allow longer duration of therapy, with a goal of achieving optimal disease suppression by driving tumor cells into irreversible senenscence with less side effects.
A total of 2549 patients were randomly assigned to receive the combination; 2552 patients received endocrine therapy alone.
At the data cutoff on January 11, 2023, after the prespecified minimum number of IDFS events had occurred, 189 patients in the ribociclib arm experienced recurrence, compared with 237 patients in the endocrine therapy–only arm.
As noted, 3-year IDFS rates were 90.4% with ribociclib and 87.1% with endocrine therapy alone, which translates to a hazard ratio of 0.748 in favor of the combination (P = .0014).
The benefit of ribociclib was generally consistent across subgroups, including node-negative patients, but there were too few patients in this subgroup for the differences to reach statistical significance, Slamon said.
The most commonly reported adverse event in the endocrine therapy–alone arm were joint pain and hot flashes
The most common adverse events with ribociclib included neutropenia and joint pain. Rates of gastrointestinal adverse events and fatigue, typical of CDK4/6 inhibitors, were relatively low in this study.
Slamon compared the rates of neutropenia with ribociclib in this trial to those in pooled data from the MONALEESA series of trials, in which ribociclib was delivered at a 600-mg dose. Grade 3 or 4 neutropenia occurred in 44% of patients in NATALEE, compared with 60% of patients in the MONALEESA trials.
In the ribociclib arm, 5.2% of patients experienced prolongation of the QT interval, compared with 1.2% of patients in the endocrine therapy–alone arm. No cases of torsades des pointes or problematic rhythm disturbances were observed, Slamon said.
“As frequently happens when we have these lovely, large, phase 3 registration trials but with some restriction in eligibility, when you get out to real-world practice, we don’t know what will happen in women who are on anti-arrhythmics and if they’ll have a higher incidence of the QT elongation; they just weren’t included in the study. So it sounds like we’ll have to be paying attention to that,” commented briefing moderator Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice-president of ASCO.
The study was funded by Novartis. Slamon has a leadership position with 1200 Pharma, Biomarin, and Torl Biotherapeutics, a consulting/advisory role for Novartis, and has received honoraria, research funding, and travel expenses from Novartis and others. Multiple co-authors reported financial relationships with Novartis and others. Nanda has had consulting/advisory roles with and has received institutional research funding from several companies, not including Novartis. Adams has participated on an advisory board for Cogent Biosciences and her institution has received research funding from various companies.
American Society of Clinical Oncology (ASCO) 2023: Abstract LBA500. Presented June 2, 2023.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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