Oncologists now have a means of bringing personalized medicine to advanced squamous cell carcinoma, and it involves a biomarker-driven clinical trial that maximizes the chance of successful treatment and new drug approvals.
Lung-MAP (Lung Cancer Master Protocol) is a unique concept in which the government, private foundations, advocacy groups and industry are working together to match molecular profiles of tumors to novel agents, possibly enhancing the efficacy of second-line treatment and accelerating the approval of promising drugs. It is noteworthy for its collaborative nature and scope.
Partners include the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, five pharmaceutical companies—Amgen, Genentech, Pfizer, AstraZeneca PLC, and AstraZeneca’s global biologics research and development arm, MedImmune, and two diagnostic companies—Foundation Medicine and Clarient, Inc. Other companies have supported the development portion of the protocol.
Benefits of More-Precise Diagnostics
“Lung-MAP advances personalized medicine, and it is a faster way to get drugs to patients,” said one of the study’s leaders Roy S. Herbst, MD, PhD, Chief of Medical Oncology at the Yale Cancer Center, New Haven, Connecticut.
He emphasized that far too few patients are undergoing molecular profiling. Even in the case of non–small cell lung cancer (NSCLC) patients with non-squamous histology, who may have actionable mutations in ALK or EGFR, perhaps only 50% to 60% of tumors are tested. “It’s clearly not 100%. Either the test is not available, or clinicians don’t want to wait for the results. And in squamous cell disease, almost no patients are profiled since no driver mutations are known. Lung-MAP gives us an opportunity to potentially help these patients in real time and develop new agents for the future,” he said.
The trial will be conducted at more than 200 medical centers by the NCI’s newly formed National Clinical Trials Network (NCTN), said Jeffrey S. Abrams, MD, Associate Director of NCI’s Cancer Therapy Evaluation Program. “The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it can now offer an ideal platform for bringing the benefits of more-precise molecular diagnostics to cancer patients in communities large and small.”
Calling All Clinicians
Any oncologist with access to cooperative group clinical trials can enroll patients, Dr. Herbst said. The aim is to ultimately involve as many as 500 centers and to enroll as many as 1,000 patients a year for 5 years.
Physicians have good reasons to enroll their patients with squamous cell NSCLC on Lung-MAP, he said. Considering that these tumors lack the known actionable mutations for which drugs are currently available in NSCLC, enrollment “will provide access to drugs they otherwise could not obtain,” he pointed out.
Enrollment is also made attractive by the fact that capitation per patient is “double the usual” for a cooperative group trial, that molecular profiling is provided free of charge, with no reimbursement issues, he added.
“It’s a multiple win for patients and oncologists,” he said.
In spite of these features, Dr. Herbst emphasizes the need to closely monitor the study—along with Ellen V. Sigal, PhD, of Friends of Cancer Research, he cochairs the Oversight Committee—to ensure that Lung-MAP will meet its accrual target. Squamous cell disease represents only 20% to 30% of all NSCLC cases, and while this still amounts to 60,000 patients a year, “we need patients who have suitable performance status and are motivated for the study,” he indicated. “It will take a full cooperative effort to make this work.”
More information on patient eligibility and enrollment is available online at www.lung-map.org.
Study Design
Patients will be screened by Foundation Medicine for more than 200 cancer-related genes. Based on their molecular characteristics—with test results returned within 2 weeks—they will be assigned to one of five groups testing a relevant novel agent. Within that group, patients will be randomly assigned to standard second-line chemotherapy or chemotherapy plus the experimental drug. Drugs showing promise can rapidly move into phase III testing, ineffective drugs can be eliminated, and new compounds can be added to the protocol as they emerge.
For the initial round of testing, the drugs include the following: GDC-0032, a PI3K inhibitor provided by Genentech; palbociclib, an oral cyclin-dependent kinase (CDK) inhibitor believed to selectively inhibit CDK-4 and CDK-6, from Pfizer; AZD4547, an oral fibroblast growth factor receptor (FGFR) inhibitor from AstaZeneca; rilotumumab, an antibody to human hepatocyte growth factor (HGF) from Amgen that will be given along with erlotinib (Tarceva); and MED14736, a monoclonal antibody binding to the programmed death receptor ligand (PD-L1) by MedImmune.
“These drugs were selected because they gave us hints of efficacy in this setting,” Dr. Herbst said.
The phase II endpoint is an improvement of at least 2 to 2.5 months in median progression-free survival, to be determined after 56 events. At that point, the drug will either move to phase III or be discontinued. The final analysis will be based on 290 progression-free survival events and 256 deaths. The trial is being led by SWOG.
Dr. Herbst predicted that the “next-generation arms” of Lung-MAP (they are modular) will include more combinations, as this first set of agents prove their worth. “We envision that we will want to target multiple pathways,” he said.
Model for Future Clinical Testing
“Lung-MAP represents the first of several planned large, genomically driven treatment trials that will be conducted by the NCTN,” Dr. Abrams reported in a session on clinical trials at the ASCO Annual Meeting.
ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial), which will be conducted by the Alliance and the Eastern Cooperative Oncology Group (ECOG), is set to launch this summer in non–squamous cell NSCLC. It will test the efficacy of drugs targeting ALK rearrangements (crizotinib [Xalkori]) and EGFR mutations (erlotinib) in the adjuvant setting.
ALCHEMIST also has a research component that will examine such aspects of the tumor as circulating DNA and white cells. “We also hope to be able to follow the natural genomic history of this tumor through serial biopsies. We want to develop a rich public resource with genomic characterization that is tied to detailed clinical outcomes, with long-term follow-up,” he indicated.
Up to 8,000 patients will need to be screened to identify 400 with an ALK or EGFR abnormality. The primary endpoints for the separate trials testing ALK or EGFR abnormalities will be a hazard ratio of 0.67 for overall survival.
NCI Match Study
The third NCTN biomarker-driven multiarm phase II trial is the NCI Match study. This trial will identify mutations, amplifications, and gene fusions in advanced-disease patients with solid tumors or lymphomas (25% will have uncommon malignancies without a standard treatment). Based on their actionable mutations, patients will be assigned an agent using a “rules-based approach.”
Upon disease progression, they will be retested for subsequent mutations and assigned another study agent accordingly or discontinued if no additional mutations are found. Sequential tumor biopsies will help to illuminate mechanisms of resistance. The trial may also include whole-exome sequencing in selected patients to further study mechanisms of resistance.
“NCI Match is a discovery trial that is a partnership between the NCTN and a large number of pharmaceutical companies. We will use a national network of academic sequencing centers, and we will make the information available to researchers around the world,” Dr. Abrams said.
“I am pretty fired up about this trial. I think it could change the landscape significantly and bring a personalized medicine approach to community centers around the country,” he added. “These new trials are good examples of how researchers are partnering, and not working in separate silos.”
Plans for similar study approaches in colon cancer and pediatric solid tumors are being considered. ■
Disclosure: Drs. Herbst and Abrams reported no potential conflicts of interest.
