Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400

Abstract

The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.

Figure 1

Umbrella and Basket Trials. The trials listed are currently on-going or soon to be activated trials with Umbrella or Basket designs with partial funding from US or United Kingdom governments. Details of these studies are presented in Table 1. Abbreviations: BATTLE=Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; I-SPY 2=Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2; Lung-MAP=Lung Master Protocol; MATCH=Molecular Analysis for Therapy Choice; MPACT=Molecular Profiling-based Assignment of Cancer Therapy.

Figure 2

Lung-MAP Study Schema. Fresh tumor biopsy or archival FFPE tumor from eligible patients with Stage IIIB or IV lung SCCA whose disease has progressed on first-line therapy is evaluated using NGS (FoundationOne) and, in some cases molecular assays (e.g., IHC-based), carried out in a CLIA-certified laboratory for the presence of drug-specific biomarkers relevant to lung SCCA that may serve as targets for drugs currently under study in Lung-MAP. Results are returned within 10–14 days of tissue submission. Patients are then assigned to substudies based on their biomarkers or to a non-match therapy substudy; within the substudies the patients are randomized to biomarker-driven targeted or SOC therapy. Patients with more than one relevant biomarker are assigned to substudies based on an algorithm designed to best balance accrual among the substudies. Accrual and treatment in phase 2 continues within each substudy until a sufficient number of progression events has been observed to estimate whether or not a drug will likely be successful in the phase 3 component. Drugs meeting PFS criteria will continue on in phase 3 until a sufficient number of progression events has occurred to determine whether or not the targeted drug regimen shows statistically and clinically significant improvement in PFS over SOC. Patients will be followed for up to three years to determine effects on OS.

Figure 3

Schema for Lung-MAP Substudies, June 2014. *Archival formalin-fixed, paraffin-embedded (FFPE) tumor, fresh core needle biopsy (CNB) if needed. NGS=Next Generation DNA Sequencing; OS=overall survival; PFS=progression free survival; TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), TKI=tyrosine kinase inhibitor (erlotinib). See Table 2 for description of initial substudies in Lung-MAP.

Figure 4

Prevalence of Genomic Alterations in Lung SCCA. This chart shows the prevalence and pattern of mutations, amplifications and rearrangements seen in 108 consecutive FFPE lung SCCA tumor samples sequenced using the FMI FoundationOne platform to an average unique median depth (the number of times a given region has been sequenced by independent reads) of >500x. This plot highlights the diversity of alterations in lung SCCA and the importance of a comprehensive genomic assessment with respect to both the number of genes assessed and alteration types.