The pathway alteration load is a pan-cancer determinant of outcome of targeted therapies: results from the Drug Rediscovery Protocol (DRUP).

Background: Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP).

Base editing screens define the genetic landscape of cancer drug resistance mechanisms.

Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes.

Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the Drug Rediscovery Protocol.

Purpose: To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.

Patients And Methods: In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity.

The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol.

Purpose: The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches.

Patients And Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks).

Maximizing Treatment Opportunities: Assessing Protocol Waivers' Impact on Safety and Outcome in the Drug Rediscovery Protocol.

Purpose: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain.

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer.

Background: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.

PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe.

Background: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful.

Patients And Methods: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon.

The evolution of precision oncology: The ongoing impact of the Drug Rediscovery Protocol (DRUP).

Background And Purpose: The Drug Rediscovery Protocol (DRUP) is a Dutch, pan-cancer, nonrandomized clinical trial that aims to investigate the efficacy and safety of targeted and immunotherapies outside their registered indication in patients with advanced or metastatic cancer.

Patients: Patients with advanced or metastatic cancer are eligible when there are no standard of care treatment options left and the tumor possesses a molecular genomic variant for which commercially available anticancer treatment is accessible off-label in DRUP. Clinical benefit is the study's primary endpoint, characterized by a confirmed objective response or stable disease after at least 16 weeks of treatment.

Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma.

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.

Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy.

In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS.

Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol.

Purpose: To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing-based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).

Patients And Methods: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML >290. Patients received pembrolizumab 200 mg every 3 weeks.

Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target.

Generating and using real-world data: A worthwhile uphill battle.

The precision oncology paradigm challenges the feasibility and data generalizability of traditional clinical trials. Consequently, an unmet need exists for practical approaches to test many subgroups, evaluate real-world drug value, and gather comprehensive, accessible datasets to validate novel biomarkers. Real-world data (RWD) are increasingly recognized to have the potential to fill this gap in research methodology.

Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer.

Purpose: The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease.

Experimental Design: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing.

Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial.

Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer.

Efficacy and Safety of Panitumumab in Patients With RAF/RAS-Wild-Type Glioblastoma: Results From the Drug Rediscovery Protocol.

Background: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP).

Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics.

Purpose: Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals.

Precision cancer medicine: Concepts, current practice, and future developments.

Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue- and liquid-based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount.