Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

Author(s): Yen-Shen Lu, MD, PhD¹; Eznal Izwadi Bin Mohd Mahidin, MD²; Hamdy Azim, MD³; Yesim Eralp, MD⁴; Yoon Sim Yap, MD, PhD⁵; Seock-Ah Im, MD, PhD⁶; Julie Rihani⁷; Erhan Gokmen, MD, PhD⁸; Ahmed El Bastawisy, MD⁹; Nuri Karadurmus, MD¹⁰; Yueh Ni Lim, MD¹¹; Chun Sen Lim, MD¹²; Le Thanh Duc, MD¹³; Wei-Pang Chung, MD¹⁴; K. Govind Babu, MD¹⁵; Konstantin Penkov, MD¹⁶; James Bowles, BMedSci¹⁷; Teresa Delgar Alfaro, PharmD, MSc¹⁷; Jiwen Wu, PhD¹⁸; Melissa Gao, MD, PhD¹⁷; Khemaies Slimane, MD¹⁷; Nagi S. El Saghir, MD¹⁹

Source: https://doi.org/10.1200/JCO.24.00144

Dr. Maen Hussein's Thoughts

Myth busted. In aggressive breast cancer, no need to start chemotherapy now, ET and CKD4/6 inhibitors are better tolerated with significant progression-free survival (PFS) benefit and same response rate.

PURPOSE

A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (ABC).

METHODS

In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2– ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator’s choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS).

RESULTS

Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator’s judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm.

CONCLUSION

First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2– ABC.

Author Affiliations

¹National Taiwan University Hospital, Taipei, Taiwan; ²Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; ³School of Medicine, Cairo University, Cairo, Egypt; ⁴Acıbadem Research Institute of Senology, Acıbadem University, Istanbul, Turkey; ⁵National Cancer Centre Singapore, Singapore; ⁶Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; ⁷Independent Patient Advocate, Amman, Jordan; ⁸Ege University Faculty of Medicine, Izmir, Turkey; ⁹National Cancer Institute, Cairo University, Giza, Egypt; ¹⁰Gülhane Education and Research Hospital, University of Health Sciences, Ankara, Turkey; ¹¹Sarawak General Hospital, Kuching, Sarawak, Malaysia; ¹²Hospital Sultan Ismail, Johor Bharu, Johor Darul Ta’zim, Malaysia; ¹³National Cancer Hospital, Hanoi, Vietnam; ¹⁴National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ¹⁵HCG Curie Centre of Oncology and Kidwai Memorial Institute of Oncology, Bangalore, India; ¹⁶Private Medical Institution Euromedservice, St Petersburg, Russian Federation; ¹⁷Novartis Pharma AG, Basel, Switzerland; ¹⁸Novartis Pharmaceuticals Corporation, East Hanover, NJ; ¹⁹American University of Beirut Medical Center, Beirut, Lebanon

First-Line Camizestrant for Emerging ESR1-Mutated Advanced Breast Cancer

Our site participated in this study, where patients were tested for ESR1 mutations via circulating tumor DNA (ctDNA). Those who tested positive were switched to camizestrant (Cami), which demonstrated improved progression-free survival.

Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly utilizes the ubiquitin–proteasome system. It was compared to fulvestrant in patients who had received one prior line of hormonal therapy with a CDK4/6 inhibitor. Among patients with ESR1 mutations, Vepdegestrant demonstrated a median progression-free survival (PFS) of 5.0 months versus 2.1 months with fulvestrant. In the overall population, the median PFS was 3.8 months for Vepdegestrant and 3.6 months for fulvestrant, indicating that the drug showed particular efficacy in tumors harboring ESR1 mutations.

Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer

Elinzanitant, a neurokinin-targeted therapy, has been shown to reduce vasomotor symptoms compared to placebo. These symptoms are one of the reasons some of my patients discontinue aromatase inhibitor (AI) therapy, so Elinzanitant presents a promising alternative to help manage these side effects. Additionally, Fezolinetant is already approved and available on the market.

Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer

The INAVO120 trial evaluated inavolisib + palbociclib–fulvestrant vs placebo + palbociclib–fulvestrant in patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer progressing on or shortly after adjuvant endocrine therapy (ET). Inavolisib significantly improved overall survival (OS) (34.0 vs 27.0 mo) and progression-free survival (PFS) (17.2 vs 7.3 mo), with a higher objective response rate (ORR) (62.7% vs 28.0%) and longer DoR (19.2 vs 11.1 mo). Toxicities were manageable but included more hyperglycemia (63.4%), stomatitis (55.3%), GI, and ocular AEs. Bottom line: this triplet sets a new bar for first-line PIK3CA-mutant HR+ MBC, but we’ll need to stay vigilant about metabolic and mucosal side effects as we bring it into practice.

Second-Line Endocrine Therapy With or Without Palbociclib Rechallenge in Patients With Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: PALMIRA Trial

Adding Palbociclib did not help, revealing that there is no need to continue with different hormonal therapy than the one used in first line. It also added more toxicity.