Treatment Guided by Comprehensive Genome and Transcriptome Analysis Versus Standard of Care in Advanced Rare Cancers

Rare cancers, defined by an incidence of fewer than 6 cases per 100,000 persons per year, constitute nearly 25% of adult malignancies. They are associated with poor patient outcomes due to incomplete biological understanding and inadequate representation in clinical trials. To address this gap, the DKFZ/NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program, developed by NCT and DKFZ, integrates whole-genome/exome sequencing (WGS/WES), RNA sequencing (RNA-seq), and genome-wide DNA methylation profiling to inform clinical decision-making in patients with advanced rare cancers. This approach has demonstrated significant improvements in overall response rates (ORR) in 24% and disease control rates (DCR) in 55% of cases, with a progression-free survival (PFS) ratio greater than 1.3 in 36% of patients. The randomized, multi-basket, phase II, Italian multicenter ROME study conducted among pretreated patients with metastatic cancer, demonstrated that targeted therapy guided by comprehensive genomic profiling and molecular tumor board (MTB) recommendations significantly improved overall response rate and progression-free survival. Additionally, the study revealed a substantial long-term PFS benefit extending to 12 months and beyond. Although the toxicity profiles differed between the targeted therapy and standard-of-care groups, the incidence of adverse events was comparable. These findings, reported at the ESMO Congress 2024, emphasize the pivotal role of MTBs in advancing precision oncology through a tumor agnostic, molecularly guided therapeutic approach. The objective of the randomized, multicentric, diagnostic RATIONALE trial is to evaluate the efficacy of molecularly guided treatment versus standard treatment in patients with rare cancers by comparing progression-free survival (PFS) between the two arms: an immediate molecular profile-informed treatment arm (MPI arm) and a standard treatment arm with molecular profile-informed treatment upon progression or intolerable toxicity after standard therapy (MPP arm). Patients with rare epithelial and mesenchymal neoplasms are evenly randomized in a 1:1 ratio to either the MPl arm or MPP arm. Comprehensive molecular profiling includes WGS and RNA-seq for both arms. A multidisciplinary MTB evaluates these molecular profiles and provides clinically relevant management recommendations, including diagnostic reevaluation, genetic counseling, and molecularly informed treatment options. Recommendations may include matching patients to molecularly stratified clinical trials or - if no suitable clinical trials can be identified - coordinated applications will be provided for off-label use in routine clinical care. The primary efficacy endpoint is progression-free survival (PFS), whereas secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR) after three and six months, and patient-reported outcomes (PROs). Based on data from the MASTER cohort, it is anticipated a median PFS of three months with treatment selected by the physician's discretion. Drawing on findings from the CRAFT trial (ClinicalTrials.gov: NCT04551521), MTB-guided treatment is expected to positively impact the primary endpoint with a hazard ratio (HR) ranging from 0.4 to 0.6. Assuming 30% implementation rate of MTB recommendations, a sample size of 756 eligible patients will be required to demonstrate a significant improvement in PFS with immediate MTB guided treatment, yielding an HR of 0.5 for the MPI arm and overall study HR of 0.7862. The calculation is based on a type 1 error of 5% and a statistical power of 90%. Considering a conservative estimate that that 20% of patients will not be evaluable, the total rounded required sample size is 946 patients.