What is the optimal therapeutic option for patients diagnosed with hormone receptor-positive, HER2-negative breast cancer in visceral crisis?—insights from the RIGHT CHOICE trial

The treatment of patients with newly diagnosed (first-line) hormone receptor-positive (HR-positive) and human epidermal growth factor receptor 2-negative (HER2-negative) metastatic breast cancer has been transformed by cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as ribociclib, palbociclib and abemaciclib. In combination with endocrine therapy (ET), these inhibitors significantly prolong progression-free survival (PFS) and, for some, overall survival (OS) in both premenopausal and postmenopausal patients (1).

However, one clinical situation that has not been adequately evaluated in these trials is that of patients experiencing a visceral crisis, which is considered an “aggressive” manifestation of the disease and occurs in around 10–15% of first-line metastatic breast cancer (2). The definition of a visceral crisis has evolved from metastatic involvement of a visceral organ to severe organ dysfunction requiring rapid therapeutic intervention to preserve vital organ function. Visceral crises pose an immediate threat to the short-term prognosis of affected patients, making fast and effective therapeutic decisions essential. In the absence of evidence supporting the use of CDK4/6 inhibitors in this setting, chemotherapy remains the most established option (3,4).

The RIGHT CHOICE trial was an open-label, multicenter, randomized phase II study conducted in premenopausal and perimenopausal women with aggressive HR⁺/HER2⁻ metastatic breast cancer (MBC). The trial compared the efficacy of ribociclib combined with an ET (letrozole or anastrozole, and goserelin) versus a combination chemotherapy (CT) regimen, including docetaxel with capecitabine, paclitaxel with gemcitabine, or capecitabine with vinorelbine.

Patients were considered to have aggressive disease and, therefore, eligible if a combined scan was clinically indicated, as judged by the investigator, i.e., symptomatic visceral metastases, rapid disease progression or imminent visceral involvement, or symptomatic non-visceral disease.

Of the 222 patients enrolled between 2019 and 2021 (112 in the ribociclib group and 110 in the chemotherapy group), 106 (47.7%) were considered by investigators to be in visceral crisis, 150 (67.6%) had symptomatic visceral metastases, and 41 (18.5%) had rapid disease progression as assessed by investigators. The primary endpoint was the median of PFS, with 21.8 months in the ribociclib plus ET group (95% CI: 17.4–26.7) compared to 12.8 months in the CT arm [95% CI: 10.1–18.4; hazard ratio (HR) = 0.61; 95% CI: 0.43–0.87; P=0.003]. The median OS was not reached (NR) in either the ribociclib group (95% CI: 38.6–NR) or the CT group (95% CI: 30.8–NR), with no significant difference between them (HR =0.92; 95% CI: 0.56–1.52). The objective response rate (ORR) was similar between the two groups, at 66.1% for the ribociclib arm and 61.8% for the CT arm, while the clinical benefit rate (CBR) was 81.3% in the ribociclib arm and 74.5% in the CT arm. The median time to response (TTR) was 4.9 months with ribociclib plus ET versus 3.2 months with combination CT (HR =0.76; 95% CI: 0.55–1.06). All patients experienced at least one adverse event (AE), with grade 3 or 4 toxicities occurring in 79.5% of patients in the ribociclib arm and 73.0% in the CT arm. Hematologic AEs like neutropenia and leukopenia were more common in the ribociclib arm, while nonhematologic AEs such as nausea and fatigue were more frequent in the CT arm. Treatment-related severe AEs were higher in the CT arm, leading to a greater rate of treatment discontinuation (27.0% vs. 6.3%). While no on-treatment deaths occurred in the CT arm, five deaths were reported in the ribociclib arm, all attributed to breast cancer progression (5).

The first challenge was to enroll the target population successfully. However, investigators have revealed that less than half of the patients included in the study were in a visceral crisis. Severe hepatic dysfunction was an exclusion criterion; less than 3% of patients had brain metastases. A visceral crisis requires urgent treatment, limiting the time available to enroll patients in a clinical trial. In addition, the investigator’s judgment criterion was not a strict and precise definition (6). Some intermediate situations may have been, and they were classified as aggressive in allowing patients to receive treatment with CDK4/6 inhibitors in countries where reimbursement was not systematic or widespread. Although there was no precise definition, visceral crisis typically includes extensive hepatic involvement with abnormal liver enzyme levels, pulmonary involvement with dyspnea, cerebral involvement with neurologic deficits, and hematologic involvement requiring transfusion support. Moreover, patients with hormone-resistant cancers, which are far from rare and often involve particularly aggressive tumors with poor prognoses, were excluded from the study.

The second challenge is to determine the optimal treatment sequence for patients with visceral crises. Should we start with chemotherapy or a CDK4/6 inhibitor, or is it possible to begin with either treatment?

First, the choice of a CT regimen as the comparator in this trial differed from standard practice in Europe, where monotherapy with taxanes or anthracyclines was preferred. This preference is based on the lack of evidence of a significant difference in response rates between combination and monotherapy, as well as the need to minimize toxicity in these vulnerable patients (7). In addition, a combination of chemotherapy with bevacizumab may be a more appropriate comparator for patients who require a rapid therapeutic response due to a visceral crisis. Although bevacizumab has never demonstrated a survival benefit in first-line therapy in meta-analyses, the ORRs vary between 30–60%, and the odds ratio (OR) of response associated with the addition of bevacizumab to chemotherapy was OR =1.81 (95% CI: 1.53–2.14) (8).

Second, the selection of the primary endpoint in this setting is challenging. While PFS allows for the evaluation of the duration of response, the primary goal in a visceral crisis is the magnitude of response and the time required to achieve it to alleviate symptomatic or life-threatening conditions. Therefore, ORR and TTR are more appropriate endpoints. However, no significant differences were observed between the ribociclib and chemotherapy groups for these two endpoints.

Finally, the subgroup analysis did not show significant differences in PFS between poor prognostic factors or endocrine refractory groups, the patient populations most similar to those in visceral crisis. For patients with visceral crisis status, a disease-free interval of less than two years, the presence of liver metastases, recurrent disease, and estrogen receptor levels below 50%, the HRs were not significantly different: HR =0.95 (95% CI: 0.57–1.58); HR =0.85 (95% CI: 0.33–2.23); HR =0.68 (95% CI: 0.42–1.11); HR =1.02 (95% CI: 0.56–1.84); and HR =1.46 (95% CI: 0.12–17.08), respectively.

Finally, the RIGHT CHOICE trial suggests that neither ribociclib nor chemotherapy is superior in a selected population of patients with visceral crisis, and the choice of the first-line treatment ultimately has little impact on OS. This is essential information! The lack of difference in OS supports the hypothesis that starting with either chemotherapy or a CDK4/6 inhibitor does not affect the response to subsequent treatments, suggesting no wrong choice between these two options.

These findings are firstly consistent with real-world data from the French ESME cohort, where no significant difference was observed after propensity score adjustment (HR =0.94; 95% CI: 0.86–1.03, P=0.19) in the overall population of HR⁺ MBC patients receiving ET alone or chemotherapy ± maintenance ET (9). Second, they are consistent with subgroup analyses from the Young PEARL trial, which compared palbociclib plus ET to CT as first-line treatment in pre/peri-menopausal patients without visceral crises, showing improved PFS without affecting OS (10).

Our goal, however, is to do better for these patients struggling with an aggressive form of the disease. Recently, the INAVO trial evaluated the addition of inavolisib to palbociclib and fulvestrant in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer. This population was relatively severe, with 50% of patients having ≥3 sites of metastases and 80% having visceral metastases. The experimental arm significantly improved PFS, increasing from 7.3 to 15.0 months (HR =0.43; P<0.0001), and in ORR, from 25% to 58.4%. An OS trend was also observed, with a hazard ratio of 0.64 at the first interim analysis. The patients receiving inavolisib experienced better pain control, functional status, and quality of life, with minimal additional treatment burden (11). Soon, the role of this treatment in the therapeutic sequence will be clarified.

Moreover, two ongoing phase II trials are evaluating CDK4/6 inhibitors (abemaciclib and dalpiciclib) in the first-line treatment of visceral crisis in HR⁺/HER2⁻ breast cancer (NCT04681768, NCT05431504).

Trastuzumab deruxtecan, a HER2-targeting antibody-drug conjugate (ADC), has recently demonstrated benefits in HER2-low and ultra-low patients, showing promising response rates (12). Meanwhile, sacituzumab govitecan, a Trop2-targeting ADC, has also proven effective in metastatic triple-negative and luminal breast cancer (13). However, to date, no trials specifically include patients with HR⁺HER2⁻ breast cancer in visceral crisis.

In a population of premenopausal patients with newly diagnosed metastatic HR-positive breast cancer and aggressive disease but without hepatic impairment or endocrine resistance, ribociclib in combination with ET is significantly superior in terms of PFS, but not in terms of ORR or TTR. This study allows us to offer both treatment options to patients with symptomatic disease and no evidence of subsequent resistance. However, this study highlights an unmet medical need for these patients. It underscores the need to conduct trials specifically designed for this population, particularly with ADCs and PIK3CA inhibitors, which appear promising.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-156/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-156/coif). T.G. reports grants from AMGEN, Fundation Philippe, payments or honoraria from Cancérologie pratique, support for attending meetings and/or travel from AstraZeneca, Gilead, Pfizer; and is on the Data Safety Monitoring Board or Advisory Board of Aztrazeneca. The other author has no conflicts of interest to declare.

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