Dataset Information

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2- Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7.

ABSTRACT:

Purpose

The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7.

Experimental design

Tumor samples from MONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for clinical prognostic factors.

Results

Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28).

Conclusions

The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2- ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes.

SUBMITTER: Prat A

PROVIDER: S-EPMC10870119 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2- Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7.

Prat Aleix A Solovieff Nadia N André Fabrice F O'Shaughnessy Joyce J Cameron David A DA Janni Wolfgang W Sonke Gabe S GS Yap Yoon-Sim YS Yardley Denise A DA Partridge Ann H AH Thuerigen Astrid A Zarate Juan Pablo JP Lteif Agnes A Su Fei F Carey Lisa A LA

Clinical cancer research : an official journal of the American Association for Cancer Research 20240201 4

<h4>Purpose</h4>The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with ...[more]

PMID: 37939142

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Project description:BackgroundThe phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.MethodsPostmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).ResultsAt data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.ConclusionsThis analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.

Project description:PurposeThe prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials.MethodsA retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease.ResultsOverall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P < .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P < .0001), LumB (HR, 0.52; P < .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77).ConclusionIn this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like.

Project description:In normal cell cycle progression, transition of G0/G1 phase to synthesis (S) phase for breast and other cells is regulated by association of cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6) that leads to phosphorylation of retinoblastoma (Rb) protein. Imbalance of this cyclin D-CDK4/6-inhibitors of CDK4/6-Rb phosphorylation pathway is associated with tumorigenesis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancers. Despite effective first-line endocrine therapy, HR+/HER2- metastatic breast cancers remain still incurable. Currently, advances in understanding of cell cycle checkpoints are evolving as promising strategy to target in treatment of various types of cancers including breast cancer. Therapies that target this cell cycle machinery in HR+/HER2- breast cancers are getting approval by the US Food and Drug administration (FDA) including ribociclib (LEE011). Ribociclib got the first FDA approval in March 13, 2017, as an initial therapy for HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor. This review, therefore, addresses the role of selective CDK4/6 inhibitors in advanced or metastatic breast cancer with a specific focus on ribociclib. Some findings of clinical trials involving ribociclib found pivotal benefits of ribociclib in HR+/HER2- metastatic breast cancer in terms of prolonging progression-free survival and objective response rates. Daily dosage range of the drug for such benefits is 50-900 mg with common daily doses of 400 or 600 mg and 600 mg in early and advanced breast cancer therapies, respectively. Along with its therapeutic benefits, however, more incident but manageable dose-limiting grade 3 or 4 toxicities, primarily hematologic adverse events, are common in patients treated with ribociclib. Generally, there are several active clinical trials undergoing to investigate the clinical efficacy and toxicity profile of the drug in various cancerous conditions other than breast cancer and will likely benefit patients with other cancer types.

Project description:BackgroundIdentification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.MethodsA research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.ResultsA total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).ConclusionsCombining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

Project description:PurposeThe aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS).Patients and methodsDisease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations).ResultsThis cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness.ConclusionFrom the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.

Project description:IntroductionThe MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system.MethodsWe calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs.ResultsRibociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case.ConclusionRibociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system.

Dataset Information

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2- Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7.

Purpose

Experimental design

Results

Conclusions

Publications

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2- Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7.

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