Biomarker-driven Immunotherapy in Patients with Advanced Solid Tumors
Authors:   , Geurts Birgit Sanne 
Published: July 2024

Precision oncology has introduced a new era in the treatment of cancer and is characterized by gene-directed, tumor-agnostic approaches that are personalized for each patient based on biomarkers. This new era is reflected by the emergence of innovative protocol designs to accelerate clinical drug development, improve trial efficiency, and enable early access to potentially effective anticancer drugs. Examples of precision oncology protocols are the Drug Rediscovery Protocol (DRUP; NCT02925234) and the DRUG Access Protocol (DAP). The DRUP is an ongoing multicenter, multidrug, prospective, non-randomized, pan-cancer platform trial in which patients with advanced or metastatic solid tumors, who have exhausted all standard-of-care treatment options, are treated based on their tumor molecular profile with approved targeted- or immunotherapies outside the registered indication to identify signals of clinical activity of these drugs. The DAP provides timely access to anticancer drugs that are either under review by the United States Food and Drug Administration or European Medicines Agency, or awaiting reimbursement in the Netherlands. Meanwhile, prospective real-world data on efficacy and safety of these drugs are systematically collected.

In the past decades, several types of immunotherapies have been introduced, including programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) blockade, which have now been widely approved for use in the treatment of diverse solid tumors. Although this approach has emerged as an effective and promising treatment option, still a considerable proportion of patients with advanced solid tumors does not benefit from current immunotherapies, highlighting a clear and unmet clinical need to further refine patient selection. In this thesis, we aimed to address this need by selecting patients with advanced solid tumors for ICB treatment based on genomic biomarkers, including tumor mutational load, mismatch-repair deficiency, and microsatellite instability. In this thesis, we showed that anti-PD(L)1 therapy provided durable clinical benefit in a subset of patients with advanced solid tumors selected based on these genomic biomarkers. However, a considerable proportion of patients still did not benefit. Hence, we explored potential predictors of response or resistance to ICB therapy at baseline, providing some suggestions for future research. First, our explorations provide a rationale for investigation beyond the adaptive immunity. A focus on the innate immunity may also aid in further refinement of patient selection and development of novel treatment approaches. Second, our findings indicate that the biomarker landscape predictive for ICB efficacy likely depends on tumor type, supporting the generation of tumor context-specific biomarker profiles. Third, our explorations highlight the need for more fundamental research to gain deeper insights into the immune cell types involved in antitumor immune responses.

Furthermore, in this thesis we illustrated that the DRUP and DAP create ongoing opportunities for patients with cancer by providing a framework that provides timely access to potentially effective anticancer drugs, while simultaneously collecting valuable data. These data can accelerate the clinical translation of novel insights into the use of current anticancer drugs and can facilitate reimbursement evaluations. Moreover, these protocols create an extensive database for future (translational) research to advance precision oncology.