The FDA has approved 26 unique cancer drugs for treating breast cancer across 42 indications from 2000 to 2023, highlighting the pharmaceutical industry's focus on addressing this significant cause of morbidity and mortality in women worldwide. A recent study published in SpringerMedizin analyzes the clinical development, efficacy, pricing, and cost-effectiveness of these novel breast cancer drugs. The study reveals critical insights into the balance between innovation, clinical benefit, and economic value in breast cancer treatment.
Clinical Development and Approval
The median development time from initial new drug application (IND) to FDA approval was 7.8 years (95% CI 6.2–10.8) for breast cancer drugs, comparable to other cancer drugs. The majority of approvals were based on standard FDA procedures rather than accelerated approvals, with over 70% receiving priority review. Interestingly, one indication received orphan drug designation: tucatinib in combination with trastuzumab and capecitabine for HER2-positive metastatic breast cancer, including patients with brain metastases.
Drug Characteristics and Mechanisms
Of the 42 breast cancer indications, 26% were first-in-indication, 48% were advance-in-indication, and 26% were addition-to-indication. Most drugs (88%) acted via a targeted mechanism, with fewer utilizing immune-regulating (7%) or cytotoxic (5%) mechanisms. Small molecules, antibodies, and antibody-drug conjugates (ADCs) showed no significant difference in novelty, although ADCs had a higher percentage of first-in-indication treatments.
Clinical Trial Design and Endpoints
Pivotal clinical trials supporting FDA approval involved a median of 585 patients (IQR: 417–752) and were primarily Phase 3 randomized controlled trials (RCTs). Progression-free survival (PFS) was the primary endpoint in 69% of trials, while overall survival (OS) was the primary endpoint in only 7%. Two-thirds of RCTs used an inactive comparator (placebo or no treatment), while one-third compared the new drug to an active anti-cancer agent.
Efficacy and Clinical Benefit
Meta-analysis of RCT data showed that new breast cancer indications significantly reduced the likelihood of death, with a hazard ratio (HR) of 0.78 (95% CI 0.74–0.82), and were associated with a median 2.8 months (IQR: 1.8–5.8) longer OS than the control. The average HR for PFS was 0.59 (95% CI 0.54–0.64), with a median PFS improvement of 4.4 months (IQR: 2.2–7.1). Approximately 60% of treatments had a high-value ESMO-MCBS score, with 14% demonstrating improvements in quality of life (QoL) and 41% in OS.
Correlation Between OS, PFS, and Tumor Response
A meta-regression of PFS hazard ratios on OS hazard ratios showed a correlation coefficient of 0.34 (95% CI 0.03 to 0.65, p = 0.031) between OS and PFS HRs. This weak correlation suggests that improvements in PFS may not always translate to better OS or QoL. Recent trial results with CDK4/6 inhibitors highlight that PFS may not be a surrogate endpoint to predict OS or even QoL outcomes.
Drug Prices and Cost-Effectiveness
In 2023, breast cancer drugs cost an average of $16,013 (95% CI 13,097 to 17,617) per month. There was no significant association between monthly drug prices and the median improvement in OS or PFS. The median value per life year gained was $62,419 (IQR 25,840–86,062) for OS and $48,053 (IQR 27,265–77,894) for PFS.
Implications for Clinical Practice and Policy
The study underscores the need for clinical trials to prioritize patient-centered endpoints like OS and QoL. Regulators should ensure that confirmatory trials are conducted with clinically relevant endpoints to validate the efficacy of new treatments, especially those receiving expedited approval. Furthermore, the misalignment between drug prices and clinical value highlights the importance of value frameworks like the ESMO-MCBS in guiding price negotiations and ensuring access to high-value treatments for breast cancer patients worldwide. Biomarker-driven drug development in breast cancer could portend better survival and treatment response outcomes.
