Young women with newly diagnosed aggressive breast cancer, including life-threatening "visceral" crises in major organs, lived about twice as long with stable disease when treated with ribociclib plus a hormone-blocking drug compared to combination chemotherapy, according to results of the Phase II RIGHT Choice clinical trial presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) (Abstract GS1-10).
The findings demonstrated that ribociclib and endocrine therapy (ER) in this patient group of premenopausal and perimenopausal women with HR+/HER2- breast cancer not only increased progression-free survival (PFS), but also resulted in significantly fewer toxic side effects versus combination chemotherapy. Participating researchers and others labeled the study's conclusions as "practice-changing," perhaps representing a new standard of care for these patients.
"The results of the RIGHT Choice trial reveal that first-time ribociclib plus endocrine therapy can be an efficacious, clinically meaningful treatment option for patients with aggressive advanced breast cancer and help avoid the need for chemotherapy and its associated toxicities," said Yen-Shen Lu, MD, PhD, Division Chief of Medical Oncology with the National Taiwan University Hospital, who presented the study's results.
Virginia Kaklamani, MD, Co-Director of the symposium and Professor of Medicine in Hematology/ Oncology at UT Health San Antonio, said the SABCS abstract committee carefully reviewed this trial because the results were somewhat unbelievable.
"We were really scrutinizing to see how you [Lu and colleagues] selected the patients that have rapidly progressing disease and we couldn't find anything wrong, because we really couldn't believe the results," she said during a SABCS press briefing. "And so, really, I agree this will change some of that standard of care."
Approximately 31 percent of newly diagnosed breast cancer cases worldwide are diagnosed in pre-menopausal women (aged 50 or less), with a high risk of aggressive disease. Owing partly to its rapid rate of response, combination chemotherapy has been a preferred treatment option for many patients with aggressive HR+/HER2- advanced breast cancer-particularly for younger women who may tolerate the drug's toxic side effects better than older women. This includes patients with life-threatening visceral crises-severe organ dysfunction, whose symptoms and disease progression require rapid disease control-who generally are treated on a case-by-case basis, Lu said.
Based on recent positive findings from Phase III clinical trials, however, there now is general agreement among oncologists to treat these patients with first-line ribociclib, a novel cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6). As its name implies, CDK4/6 inhibitors work by blocking the activity of two enzymes, CDK4 and CDK6, that help control cell division. Both enzymes are commonly found at higher-than-normal levels in breast cancer cells, particularly those that overproduce hormone receptors.
Specifically, these clinical trials showed that combining CDK4/6 inhibitors with estrogen-blocking drugs could substantially lengthen the amount of time it takes for patients' tumors to become resistant to treatment.
The RIGHT Choice trial was designed to compare first-line ribociclib plus estrogen therapy (ET) against combination chemotherapy in pre- and perimenopausal women with aggressive HR+/HER2- advanced breast cancer. A total of 222 patients were enrolled in the trial with about half (112) assigned to receive 600 mg ribociclib plus ET (letrozole/anastrozole and goserelin) 3 weeks on, 1 week off; while the other half (110) were treated with physician's choice of combination chemotherapy (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine).
Baseline characteristics of age, race, and aggressive disease characteristics were well balanced between the two arms, with about 52 percent of the total cohort experiencing a visceral crisis, according to physician judgment. The primary endpoint was PFS with key secondary endpoints, including time-to-treatment failure, overall response rate (ORR), overall survival, and safety. Patients were closely monitored for disease progression during the first 3 months. After about 2 years, the study's endpoint, about 46 percent of patients in the ribociclib arm were still receiving treatment compared to 24 percent in the combination chemotherapy arm.
Patients in ribociclib plus ET arm experienced a median PFS of 24 months compared to 12.3 months for those treated with combination chemotherapy. The median time until treatment failure was also longer among patients treated with ribociclib plus ET-18.6 months versus 8.5 months among patients treated with chemotherapy. ORR for those receiving ribocliclib plus ET was slightly better than those in the combination chemotherapy arm, 65 percent versus 60 percent, respectively.
The trial also demonstrated that patients receiving combination chemotherapy experienced a higher rate of treatment-related serious adverse side effects than those in the ribociclib arm. Twenty-three percent of patients treated with combination chemotherapy discontinued at least one line of chemotherapy due to treatment-related side effects versus about 7 percent for those in the ribociclib arm.
Further, patients in the combination chemotherapy arm experienced greater levels of symptomatic adverse effects compared to those in the ribociclib arm, including nausea (27% vs. 12%, respectively), vomiting (30% vs. 7.1%, respectively), and diarrhea (26% vs. 2.7%, respectively).
"To be able to extend lives, treatment compliance is key," Lu noted. "A treatment with improved tolerability will definitely enhance compliance and thus increase the chance of longer disease control."
Limitations of this study include its relatively small sample size as a Phase II trial, as well as the exclusive applicability of these findings to first-line treatment. Though the results were limited to a Phase II trial, Lu suggested they were nevertheless practice-changing.
"Specifically, if we can provide a close monitoring plan in the first few months, this data provides very clear evidence that it is safe, it is efficacious, and it can avoid a lot of toxicities, so I believe that this is practice-changing," Lu said.
Lu hopes that forthcoming subgroup analyses will reveal clinical characteristics that may help physicians predict which patients will respond best to ribociclib plus ET versus those who may respond better to chemotherapy.
Warren Froelich is a contributing writer.