Early-Phase Drug Development in Rare Cancers: A Decade of Progress and Future Directions

Rare cancers represent a substantial health burden, comprising 25% of cancer mortality. Early-phase oncology trials are essential for rare cancers, where limited patient numbers, biological heterogeneity, and the absence of established standards of care necessitate innovative approaches to drug development. Advances in trial design—including basket, umbrella, and adaptive platforms—have enabled efficient evaluation of molecularly defined subgroups and accelerated identification of clinically meaningful activity across rare tumor types. Early-phase studies have demonstrated the therapeutic potential of antibody-drug conjugates, immunotherapy, targeted agents, and cellular therapies, particularly when guided by predictive biomarkers and tumor-agnostic strategies. These approaches have expanded treatment options for patients with historically limited therapeutic opportunities. Persistent challenges remain, including restricted trial access, difficulties with patient accrual, variability in biomarker assessment, and uncertainty regarding generalizability of outcomes. Additional challenges persist after early-phase trial completion, as continued access to therapies demonstrating clinical benefit may remain limited when regulatory approval or broader clinical availability has not yet been established. Evolving regulatory and collaborative frameworks have partially mitigated these barriers by supporting multi-institutional enrollment and pathway-flexible approvals. Over the past decade, biomarker-driven strategies have been increasingly incorporated into modern clinical trial design, shifting the field away from traditional histology-based approaches. Continued innovation in trial design, biomarker integration, and collaborative infrastructure will be essential to sustaining progress and expanding durable clinical benefit for patients with rare cancers.