23 oktober 2020: Journal of Clinical Oncology

Wetenschappers van de NCI-MATCH-studie (The National Cancer Institute Molecular Analysis for Therapy Choice ) evalueerden verschillende behandelingen in meerdere, parallelle behandelingsprotocollen als onderdeel van een zogeheten genomisch geleide therapiebenadering (DNA- en receptorenonderzoek) voor patiënten met therapeutisch bruikbare mutaties bij patiënten met progressie van hun ziekte tijdens een standaard behandeling of bij inoperabele solide tumoren.
Meer dan een derde van de bijna 6000 geëvalueerde patiënten had een bruikbare moleculaire mutatiewijziging. Meerdere bruikbare mutaties werden gezien bij 12% van de deelnemers, terwijl resistentiemutaties werden gezien bij 71%. Ongeveer 20% van de patiënten werd uiteindelijk toegewezen aan een actieve behandelgroep op basis van de gevonden mutaties. Moleculaire profilering was succesvol in 93 procent van de weefselbiopten verdeeld over verschillende vormen van kanker, inclusief Multiple Myeloma.

Deze bevindingen ondersteunen volgens de onderzoekers de haalbaarheid en efficiëntie van deze grootschalige, moleculaire benadering. De frequentie van significante gelijktijdige mutaties suggereert dat combinatiebenaderingen verder moeten worden onderzocht.

Hier een stukje uit de introductie van het studierapport met verwijzingen naar studierapporten:

Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH

The first targeted therapy successes in oncogene-driven cancers were specific to single cancer histologies (eg, BCR-ABL translocations in chronic myelogenous leukemia1;
ERBB2 gene amplification in breast cancer2;
BRAF mutations in melanoma3;
and EGFR mutations and ALK translocations in lung adenocarcinoma4,5).
BRAF-inhibitor therapy was explored across a spectrum of BRAF-mutated cancers and yielded high response rates in melanoma, non–small-cell lung cancer (NSCLC), and Langerhans cell histiocytosis but unanticipated resistance in colorectal cancer, despite ample preclinical evidence favoring efficacy.6,7
More recently, the US Food and Drug Administration (FDA) has approved the programmed death-1 inhibitor pembrolizumab for any patient with mismatch repair deficiency and high microsatellite instability. This abnormality occurs in approximately 2% of patients.8,9
Larotrectinib was approved for any patient whose tumor harbors a neurotrophic tropomyosin receptor kinase (NTRK) fusion, which, although common in several rare tumors, occurs in < 1% of most tumor histologies.10,11

Hier het abstract en klik op de titel voor het PDF studierapport: Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH)

Affiliations

PMID: 33048619
DOI: 10.1200/JCO.19.03010

Abstract

Purpose: Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.

Patients and methods: Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared.

Results: Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so.

Conclusion: We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.