Abstract
A massive 5 year–plus effort to find molecularly targeted therapies for patients with recurrent, advanced-stage squamous cell carcinoma of the lungs has demonstrated the feasibility of rapidly screening tumors for rare genomic alterations and assigning drug treatments accordingly. Yet, the Lung Cancer Master Protocol study has yet to identify a broadly effective targeted agent for patients with biomarker-defined subtypes of the disease.
A 5 year–plus effort to find molecularly targeted therapies for patients with recurrent, advanced-stage squamous cell carcinoma of the lungs has demonstrated the feasibility of rapidly screening tumors for rare genomic alterations and assigning drug treatments accordingly. However, the Lung Cancer Master Protocol (Lung-MAP) study has yet to identify a broadly effective targeted agent for patients with biomarker-defined subtypes of the disease, which accounts for about 30% of non–small cell lung cancers (NSCLC).
In a recent report, Lung-MAP researchers describe enrolling hundreds of patients with previously treated, advanced squamous NSCLC; in a series of substudies, patients with potentially druggable molecular alterations, as revealed by genetic testing, received targeted agents, whereas those without actionable mutations received immune checkpoint inhibitors.
Unique among master protocol trials, Lung-MAP—a $90 million public-private partnership convened by the Foundation for the National Institutes of Health (FNIH)—was designed with FDA input so that any successful substudy could inform regulatory decision-making. Across all the protocols, however, none met that benchmark.
Only 10 of 143 patients (7%) responded to a targeted therapy; 53 of 315 patients (17%) responded to anti–PD-1 or anti–PD-L1 therapy. Median overall survival was about 6 months for the targeted therapy groups, 11 months for those who received immunotherapy, and 8 months for patients in control arms, who received docetaxel chemotherapy. Median progression-free survival was comparable across the three groups, ranging from 2.5 months to 3 months.
Notably, the targeted agents tested—including the PIK3CA inhibitor taselisib (Roche), the FGFR inhibitor AZD4547 (AstraZeneca), and the PARP inhibitor talazoparib (Talzenna; Pfizer)—are directed at proteins already blocked by drugs approved for other cancers. Yet, in squamous NSCLC, “those drugs just don't work,” says co–principal investigator David Gandara, MD, of the University of California, Davis.
To Gary Middleton, MD, of the University of Birmingham, UK, the findings underscore that “context dependency is just so important.” Middleton led the National Lung Matrix Trial, a British umbrella trial that, like Lung-MAP, didn't identify any response-generating genotype-matched targeted therapies for patients with squamous NSCLC.
Because of tobacco exposure, malignant lung squamous cells tend to harbor concomitant genomic aberrations that offer escape routes for tumors, Middleton notes. Plus, “you've got ongoing genomic instability, so it's a perfect storm for rapidly developing acquired resistance, even if you've got a decent [targetable] oncogene.”
On the upside, the trial helped save industry partners from pursuing indications that proved to be dead ends, notes Stacey Adam, PhD, director of cancer research partnerships at FNIH. “The trial has tested 12 therapies over 5 years—performance that is faster and cheaper compared to what companies could have achieved with these rare-patient cohorts in single-drug studies,” she says.
Despite the initial disappointing results, Lung-MAP hasn't ended. As Gandara explains, “The entire project was designed to be adaptable and flexible so that we could meet the changing landscape of a rapidly evolving field.”
During the first phase of the trial, that meant modifying all the substudies after the FDA approved the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) for the treatment of refractory squamous NSCLC in 2015. For example, targeted therapy substudies dropped docetaxel control arms and became single-arm, signal-finding trials, and a substudy to evaluate the addition of the CTLA4 inhibitor ipilimumab (Yervoy; Bristol Myers Squibb) to standard-of-care nivolumab began.
Last year, the trial also expanded to include patients with other subtypes of NSCLC refractory to treatment to evaluate targeted therapies for rare alterations in nonsquamous tumors and to find effective treatments for patients who relapse after immunotherapy. –Elie Dolgin
