UK Partnership Targets Lung Cancer

Cancer Research UK (CRUK) has joined with two major pharmaceutical companies in a large multiarm clinical trial that will test the effectiveness of promising experimental therapies in treating patients with rare forms of advanced lung cancer.

Dubbed the National Lung Matrix trial, and scheduled to begin at the end of July, the investigation will eventually include up to 14 drugs under development for late-stage non–small cell lung cancer (NSCLC) by pharmaceutical partners AstraZeneca and Pfizer. Initially, eight drugs will be tested in 21 single-arm cohorts, each made up of about 30 patients who will be selected based on how likely they are to benefit from therapies targeting specific mutations in their tumors.

“The breadth and depth of this trial is what makes it really unique,” says Gary Middleton, MD, professor of medical oncology and the trial's chief investigator, based at CRUK's Clinical Trials Unit at the University of Birmingham in England.

The multiarm, adaptive design, which allows drugs to be dropped or added quickly based on how well patients respond to therapies, is similar in structure to other innovative trials, such as the Master Protocol Trial, which is testing five drugs as second-line therapy for NSCLC (Cancer Discov 2014;4:266). Like the Master Protocol, the Lung Matrix trial uses next-generation sequencing technology to screen large groups of patients for mutations, says Middleton.

“As exciting new drugs come along, the scientific and clinical rationale will be reviewed in real time by an international peer-review committee, and if approved can then be put forward as an amendment to the main protocol,” he says. “We want to be flexible and nimble.”

Six of the eight initial drugs will be tested in multiple cohorts with different abnormalities along common pathways, Middleton says. For example, an AKT inhibitor will target separate cohorts of patients with PIK3CA mutations, PIK3CA amplifications, PTEN loss, PTEN mutations, and AKT mutations, as it is likely that response and resistance will be different according to the exact deregulatory mechanism. Two drugs will be tested in single cohorts: a T790M inhibitor targeting tumors resistant to an EGFR inhibitor and a PD-L1 antibody for patients with no actionable mutation.

The eight initial drugs are:

• AKT inhibitor (AZD5363; AstraZeneca): PIK3CA mutations, PIK3CA amplifications, PTEN mutations, PTEN loss, AKT mutations (separate cohorts)

• FGFR inhibitor (AZD4547; AstraZeneca): FGFR2/FGFR3 mutations

• MTORC1/MTORC2 (AZD2014; AstraZeneca): LKB1 mutation, TSC1/TSC2 mutations

• CDK4/6 inhibitor (palbociclib; Pfizer): KRAS mutation, CDK4, p16, and cyclin D1 alterations

• ALK inhibitor (crizotinib [Xalkori]; Pfizer): ROS fusions and MET amplifications

• MEK inhibitor (selumetinib; AstraZeneca) combined with docetaxel: NRAS and NF1 mutations

• EGFR inhibitor (AZD9291; AstraZeneca): EGFR T790M point mutation in patients resistant to EGFR inhibitor

• PD-L1 antibody (MEDI4736; AstraZeneca): patients with no actionable mutation.

The drugs will be assessed based on response rate (with the exception of the CDK4 inhibitor arm, which will be assessed on progression-free survival). Those that achieve at least a 30% to 50% response rate will be considered for further phase II studies. Drugs that fall below the 30% threshold will be dropped, says Middleton.

The trial is likely to expand beyond 21 arms as other pharmaceutical companies join the study, he says. Currently, investigators are in advanced negotiations with five more companies interested in participating.

“This is the first trial of its type in lung cancer in the UK,” says Middleton. “It's a real opportunity for the UK to be part of the global story of personalized lung cancer medicine.”

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