Changing Lung Cancer Clinical Trial Design in the Era of Precision Medicine and Immunotherapy

Changing Lung Cancer Clinical Trial Design in the Era of Precision Medicine and Immunotherapy


Dr. Steven Finkelstein

Dr. Roy Herbst

Dr. Gregory Masters

Dr. Hope Rugo

Dr. Dhaval Shah

Dhaval Shah, MD; Gregory Masters, MD, FACP, FASCO; Hope Rugo, MD; Steven Finkelstein, MD, FACRO; and Roy Herbst, MD, PhD

Article Highlights

  • The standard treatment for patients with advanced non–small cell lung cancer has been chemotherapy, but more recently our understanding of the molecular basis of this disease has led to groundbreaking progress.
  • Given the rapid evolution of treatment options for unique groups, several clinical trials now incorporate molecular testing and targeted therapy in their design.
  • Clinical trials must be more nimble and adaptable, with inclusion of broader groups of patients under one consent and protocol.

Lung cancer is the most common cause of cancer-related death worldwide. The standard treatment for patients with advanced non–small cell lung cancer (NSCLC) has been chemotherapy, but more recently our understanding of the molecular basis of this disease has led to groundbreaking progress. Identification of driver gene alterations has allowed a more targeted approach in many patients, and the development of immune checkpoint inhibitors has permitted us to release the power of the immune system to fight lung cancer.

But this progress also has complicated clinical trial design. No longer can large studies with broad categories of “non–small cell lung cancer” compare minor alterations in cytotoxic chemotherapy. New trial design mandates partitioning patients into more select, precise populations, and identification of these unique groups requires clinical trials to evolve quickly to provide clinically relevant outcomes.

Randomized clinical trials (RCTs) have classically been required to change the standard of care in oncology. These trials are venerated as the gold standard for the evaluation of a new therapy, with overall survival and disease-specific survival as primary endpoints; however, some large studies may be positive only because they are statistically significant, not necessarily clinically impactful. Alternatively, a study may miss a targeted endpoint because the accrued patients’ tumors do not have the requisite molecular profile for a positive response. Given the expanded number of molecularly directed therapies that require increasing technical stratifications, appropriate clinical trials may be impractical and too costly.

Similarly, surrogate endpoints must be identified that reduce reliance on patient survival as the only endpoint. Biomarkers have been used previously as alternatives to standard RCTs for the approval of some new targeted agents, and studies with more immediate endpoints may help to optimize patient accrual. Overcoming some of the barriers of randomized trials in an age of mounting molecular stratification may decrease the number of patients needed to show an effective response. Indeed, this may also minimize adverse events associated with lengthier and larger RCTs. The potential for improved clinical trial endpoints to reduce patient suffering, achieve more rapid advancement of new treatments, and outperform randomized studies at identification of efficacious treatments has strong patient support.

The 2018 update from the College of American Pathologists (CAP) and the International Association for the Study of Lung Cancer (IASLC) recommends upfront testing for EGFR, ALK, and ROS-1 mutations in all patients with advanced non-squamous NSCLC.1 Routine testing for BRAF, RET, HER2, KRAS, and MET genes is not recommended as a standalone test, but is considered as part of a broader testing panel or if EGFR, ALK, and ROS-1 testing are negative. CAP/IASLC and ASCO guidelines both recommend use of multiplex gene panels (where available) for identifying mutations beyond EGFR, ALK, ROS-1, and BRAF.

Immune checkpoint inhibitors are revolutionizing treatment of multiple cancers, including advanced NSCLC. There are several immune checkpoint inhibitors approved for second-line treatment in advanced NSCLC, and pembrolizumab has been approved as a frontline treatment in patients with advanced NSCLC whose tumors have 50% PD-L1 expression or greater and do not have EGFR or ALK mutations. Therefore, testing for PD-L1 expression at diagnosis has become routine for patients with advanced NSCLC. High mutational burden has also been associated with improved response to immune checkpoint inhibitors.2

Given the rapid evolution of treatment options for unique groups, several clinical trials now incorporate molecular testing and targeted therapy in their design. The ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) trial is looking at use of EGFR or ALK inhibitors or nivolumab in the adjuvant setting for patients with resected early-stage NSCLC.3 In this trial, patients with EGFR or ALK mutations are randomly assigned to targeted therapy or observation. Patients without these mutations are randomly assigned to receive nivolumab or observation following resection and any adjuvant chemotherapy.

A number of “basket” trials are looking at targeted therapy in various solid tumors. Such basket trials have various designs, one of which is to test a single targeted drug across multiple tumor types. One of the earliest phase II trials that used this design incorporated vemurafenib in multiple non-melanoma cancers with BRAF mutations.4,5 This trial showed activity of vemurafenib in NSCLC and Langerhans cell histiocytosis. A subsequent phase II trial confirmed activity of BRAF inhibitors in BRAF-
mutated NSCLC, leading to their approval in the treatment of advanced NSCLC in 2017.6

Another design of basket trials uses multiple drugs tested across multiple tumor types in a single trial. Two large trials using this design are the NCI-MATCH (Molecular Analysis for Therapy Choice) study and ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study.

More recently, the LUNG-MAP (SWOG S1400) study is using a multidrug, targeted screening approach to match patients in one of multiple trial substudies, each testing a different drug. This study, which is designed for patients with squamous cell lung cancer, is a forward-thinking public-private collaboration between the National Cancer Institute, academic institutions, and private industry.7

Despite these rapid advancements in testing and attempts to adapt clinical trials to the current biological research, most patients are not able to benefit from these studies.8 Therefore, future trials will have to keep up with the rapid pace of change in testing and drug availability. Peripheral blood testing for molecular markers is also showing rapid advancement and will likely be more widely applied in the future. Clinical trials must be more nimble and adaptable, with inclusion of broader groups of patients under one consent and protocol.9 Additionally, as more targeted agents are evaluated in early-stage lung cancer, trials in these patients will need to adopt a more personalized approach.

The majority of patients receive their treatments in the community setting; therefore, it is critical to provide resources for continued involvement of community oncologists in the implementation of these more complicated trials.   

About the Authors: Dr. Shah is an attending physician with the Helen F. Graham Cancer Center. Dr. Masters is an attending physician with the Helen F. Graham Cancer Center and serves as an associate professor with the Thomas Jefferson University Medical School. Dr. Rugo is the director of the Breast Oncology Clinical Trials Program with the University of California, San Francisco. Dr. Finkelstein is the Cancer Center director with the Bay Regional Cancer Center. Dr. Herbst is chief of Medical Oncology with the Yale Cancer Center and Smilow Cancer Hospital.