Purpose

To evaluate the cost-effectiveness of adding ribociclib to endocrine therapy for pre/perimenopausal women with hormone receptor-positive (HR+), human epidermal receptor 2-negative (HER2-) advanced breast cancer from the US payer perspective.

Methods

A partitioned survival analysis model with three health states (progression-free, progressed disease, and death) was developed to compare the cost and effectiveness of ribociclib in combination with endocrine therapy versus endocrine therapy alone based on clinical data from the MONALEESA-7 phase 3 randomized clinical trials. Life years (LYs), quality-adjusted life-years (QALYs), and total costs were estimated and used to calculate incremental cost-effectiveness ratio (ICER) over a lifetime. Deterministic and probabilistic sensitivity analyses were conducted to test the uncertainties of model inputs. Additional scenario analyses were performed.

Results

In the base-case, ribociclib plus endocrine therapy was more effective than endocrine therapy with an additional 1.39 QALYs but also more costly with an ICER of $282,996/QALY. One-way deterministic sensitivity analysis showed that overall survival associated with the treatments and the cost of ribociclib had the greatest impact on the ICER. The probabilistic sensitivity analysis showed that only beyond a willingness-to-pay (WTP) threshold of $272,867, ribociclib plus endocrine therapy would surpass endocrine therapy alone as a cost-effective option.

Conclusions

From the US payer perspective, ribociclib plus endocrine therapy for pre/perimenopausal patients with HR+/HER2- advanced breast cancer is not cost-effective at a WTP threshold of $100,000 or $150,000 per QALY in comparison of endocrine therapy alone.

Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAF^V600E tumours, we found mechanisms of intrinsic resistance to BRAF^V600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAF^V600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.

BRAF^V600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAF^V600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E₂ loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAF^V600E CRC.