Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in
the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program
revealed genetic alterations in a substantial proportion of patients including (i)
alterations that lead to aberrant activation of BRAF, ERBB2, ALK, and the PI3K-AKT and MAPK
pathways and (ii) changes that predict sensitivity to immune checkpoint inhibition, such as
high tumor mutational burden and specific alterations of the PD-L1 locus.
Within this seven-arm basket phase II clinical trial, we aim to investigate the efficacy of
targeted-therapy plus immune checkpoint inhibition in patients with advanced tumors
exhibiting one of the following genetic alterations detected within the NCT/DKTK MASTER
study: (i) BRAF V600E/K, (ii)ERBB2 amplification and/or overexpression or activating ERBB2
mutation, (iii) ALK rearrangement or activating ALK mutation, (iv) activating PIK3CA or AKT
mutations or other aberration predicting increased PI3K-AKT pathway activity, (v) abberations
predicting increased RAF-MEK-ERK pathway activity; (vi) patients with high tumor mutational
burden and/or specific alteration predicting sensitivity to PD-1/PD-L1 inhibition are
eligible within this study for immune checkpoint inhibition. Recruitment of adequate patient
numbers into these well-defined molecular subgroup is achieved in a multicenter approach
including NCT Heidelberg and NCT Dresden as well as DKTK partner sites. Eligible patients
will be identified by in-depth molecular characterization of tumors within the NCT/DKTK
MASTER program. All study arms are based on similar biometrical assumptions, and sample size
as well as power calculations are based on Simon's optimal two-stage design for each study
arm separately. The overall aim is to reduce the cumulative hazard of progression-free
survival observed within the study (PFS2) compared to the cumulative hazard of the
progression-free time before inclusion into the study (PFS1) using a paired log-rank test.
The sample size of the entire trial varies according to the performance of the individual
study arms, ranging between 98 and 175 patients.