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Ref Type Journal Article
PMID (32669708)
Authors Middleton G, Fletcher P, Popat S, Savage J, Summers Y, Greystoke A, Gilligan D, Cave J, O'Rourke N, Brewster A, Toy E, Spicer J, Jain P, Dangoor A, Mackean M, Forster M, Farley A, Wherton D, Mehmi M, Sharpe R, Mills TC, Cerone MA, Yap TA, Watkins TBK, Lim E, Swanton C, Billingham L
Title The National Lung Matrix Trial of personalized therapy in lung cancer.
Journal Nature
Vol
Issue
Date 2020 Jul 15
URL
Abstract Text The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA mutant lung adenocarcinoma no benefit Capivasertib Case Reports/Case Series Actionable In a Phase II trial (NLMT), Capivasertib (AZD5363) treatment did not result in a conformed response (0/8) or durable clinical benefit (0/8) in patients with lung adenocarcinoma harboring mutations in PIK3CA, PTEN, or AKT, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708
PIK3CA mutant lung squamous cell carcinoma no benefit Capivasertib Case Reports/Case Series Actionable In a Phase II trial (NLMT), Capivasertib (AZD5363) treatment did not result in a conformed response (0/4) or durable clinical benefit (0/4) in patients with squamous cell lung cancer harboring PIK3CA mutations, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708
FGFR3 P573S lung non-small cell carcinoma no benefit AZD4547 Case Reports/Case Series Actionable In a Phase II trial (NLMT), AZD4547 treatment did not result in a confirmed response or durable clinical benefit in a patient with non-small cell lung cancer harboring FGFR3 P575S (corresponds to P573S in the canonical isoform (PMID: 32669708, NCT02664935). 32669708
AKT1 mutant lung adenocarcinoma no benefit Capivasertib Case Reports/Case Series Actionable In a Phase II trial (NLMT), Capivasertib (AZD5363) treatment did not result in a conformed response (0/8) or durable clinical benefit (0/8) in patients with lung adenocarcinoma harboring mutations in PIK3CA, PTEN, or AKT, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708
FGFR3 S756P lung non-small cell carcinoma no benefit AZD4547 Case Reports/Case Series Actionable In a Phase II trial (NLMT), AZD4547 treatment did not result in a confirmed response or durable clinical benefit in a patient with non-small cell lung cancer harboring FGFR3 S758P (corresponds to S756P in the canonical isoform (PMID: 32669708, NCT02664935). 32669708
ROS1 fusion lung non-small cell carcinoma sensitive Crizotinib Clinical Study - Cohort Actionable In a Phase II trial (NLMT), Xalkori (crizotinib) treatment resulted in an observed objective response rate (ORR) of 71% (5/7), durable clinical benefit rate (DCBR) of 75% (6/8), and medial progression-free survival (PFS) of 44.6 months in patients with non-small cell lung cancer harboring ROS1 fusions, with Bayesian estimated OR and DCBR of 68% and 71%, respectively, and Bayesian posterior probability for OR and DCBR of 0.99 and >0.99, respectively (PMID: 32669708, NCT02664935). 32669708
STK11 loss lung non-small cell carcinoma no benefit Vistusertib Clinical Study - Cohort Actionable In a Phase II trial (NLMT), Vistusertib (AZD2014) treatment resulted in an observed objective response rate (ORR) of 0% (0/17), durable clinical benefit rate (DCBR) of 12% (2/17), and medial progression-free survival (PFS) of 2.3 months in patients with non-small cell lung cancer harboring STK11 loss, with Bayesian posterior probability for OR and DCBR of <0.01 and 0.06, respectively, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708
FGFR2 V514L lung non-small cell carcinoma no benefit AZD4547 Case Reports/Case Series Actionable In a Phase II trial (NLMT), AZD4547 treatment did not result in a confirmed response or durable clinical benefit in a patient with non-small cell lung cancer harboring FGFR2 V515L (corresponds to V514L in the canonical isoform (PMID: 32669708, NCT02664935). 32669708
CDKN2A loss lung adenocarcinoma predicted - sensitive Palbociclib Clinical Study - Cohort Actionable In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 4% (1/27), durable clinical benefit rate (DCBR) of 27.5% (8/29), and medial progression-free survival (PFS) of 3.3 months in patients with lung adenocarcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 6% and 29%, respectively, and Bayesian posterior probability for PFS of 0.69 (PMID: 32669708, NCT02664935). 32669708
CDKN2A loss lung squamous cell carcinoma predicted - sensitive Palbociclib Clinical Study - Cohort Actionable In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 0% (0/19), durable clinical benefit rate (DCBR) of 22% (4/18), and medial progression-free survival (PFS) of 4.2 months in patients with lung squamous cell carcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 3% and 24%, respectively, and Bayesian predictive probability of success for PFS >0.99 (PMID: 32669708, NCT02664935). 32669708
FGFR2 - MBIP lung non-small cell carcinoma predicted - sensitive AZD4547 Case Reports/Case Series Actionable In a Phase II trial (NLMT), AZD4547 treatment resulted in a confirmed response for over 20 months in a patient with non-small cell lung cancer harboring FGFR2-MBIP fusion (PMID: 32669708, NCT02664935). 32669708
PIK3CA amp lung squamous cell carcinoma no benefit Capivasertib Case Reports/Case Series Actionable In a Phase II trial (NLMT), Capivasertib (AZD5363) treatment resulted in no conformed response (0/12) and durable clinical benefit in 9% (1/11) of patients with squamous cell lung cancer harboring PIK3CA amplification, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). 32669708