Biomarker-Driven Trials Set Pace in Lung Cancer

Biomarker-driven trials that include multiple substudies represent a new approach for investigating which patients with lung cancer are more likely to respond to different targeted therapies and are helping to set the pace throughout the oncology field.

Roy S. Herbst, MD, PhD

“Lung cancer is the paradigm for new drug development,” said Herbst, who is chief of medical oncology and associate director of Translational Research at the Yale Cancer Center. “It is the most common cause of cancer death worldwide [and has] ongoing clinical trials with a very strong network.”

Herbst made his remarks during a keynote address that he delivered at the 17th Annual International Lung Cancer Congress that Physicians’ Education Resource hosted August 4-6 in Huntington Beach, California.

Treatment for lung cancer has expanded from exclusively focusing on the tumor tissue to targeting the stroma and special cells within the tumor, such as cancer stem cells, immune-inflammatory cells, endothelial cells, pericytes, and cancer-associated fibroblasts.

Herbst noted that the BATTLE trial, a prospective, biomarker-based, adaptively randomized study of 255 pretreated patients with lung cancer, analyzed molecular biomarkers in tumor tissue obtained from biopsies, and represented a new paradigm for a personalized approach to clinical trials at the time.1

However, with greater focus on the tumor stroma and immune system involvement in lung cancer treatment, Herbst stated that more large-scale studies through the National Cancer Initiative are needed to investigate how manipulating the tumor microenvironment influences response to therapy.

One of these studies, the ongoing ALCHEMIST trial,2 is investigating targeted therapies following surgical resection and standard adjuvant therapy for early-stage non—small cell lung cancer (NSCLC). Patients are first enrolled in a screening trial, which includes testing tumors for molecular markers and investigational genomic analysis.

Patients with nonsquamous cell lung cancer who test positive for EGFR mutations are eligible for substudies that compare placebo with erlotinib while participants with ALK rearrangements are evaluated for a cohort that tests placebo versus crizotinib. Patients with squamous NSCLC and who do not have EGFR mutations or ALK rearrangements may be eligible for a substudy comparing nivolumab versus observation following completion of standard adjuvant therapy.

“[This trial] demonstrates ways of matching drugs and asking questions in clinical trial format,” said Herbst. He stated that these “major efforts” are essential for determining which biomarkers predict response to therapy.

Herbst also summarized the Lung-MAP S1400 trial,3 a biomarker-driven study for patients with previously treated squamous cell NSCLC. Herbst noted that the frequencies of known genetic alterations with squamous cell lung cancer are small; thus, sufficient patient recruitment and conduction of a clinical trial are difficult.

Therefore, including all of these patients within a single infrastructure, such as the Lung-MAP trial, can help streamline testing of investigational drugs and improve access to patients. The trial involves centralized biomarker processing and profiling.

When it was initially launched in 2014, Lung-MAP was designed to evaluate 4 novel targeted therapies and one immunotherapy compared with standard-of-care regimens in separate, randomized substudies.

Under a recent revision, Lung-MAP is testing 3 targeted agents in single-arm, phase II substudies for patients with matching mutations: taselisib (GDC-0032) for PIK3CA mutations; palbociclib for cell cycle gene alterations (CCGAs); and AZD4547 for FGFR mutations. Patients who are not eligible for one of these substudies and are naïve to immune checkpoint inhibitor therapy may qualify for a substudy comparing ipilimumab plus nivolumab versus nivolumab only.

Herbst stated that the research group is continuing to look at additional biomarkers and sub-studies to match more patients with therapies. Plans call for a substudy evaluating the PARP inhibitor talazoparib (BMN 673) in patients with homologous recombinant repair deficiency and another study combining the PD-L1 inhibitor durvalumab (MEDI4736) with the CTLA-4 inhibitor tremelimumab.

However, Herbst stated that although the multiple targeted therapies are more precise, tumors tend to develop resistance to targeted therapies and immunotherapies, even if those therapies are effective initially.

“I personally believe that [tumor resistance is] the most vexing question that is going to plague us,” he said. He described the Yale Lung Repeat Biopsy Program at his institution, which aims to characterize resistance mechanisms by obtaining and analyzing repeat biopsies immediately after patients begin to progress on targeted therapy or immunotherapy that they initially responded to.

Herbst noted that even patients who initially showed a strong response to immunotherapy can develop resistance that leads to tumor progression. “Once we figure out whom to give PD-1 and PD-L1 inhibitors in the neoadjuvant setting, we have to figure out what to do when they become resistant,” said Herbst. Herbst concluded that the future of targeted therapy for lung cancer is bright, and the next steps will involve figuring out how best to combine the established chemotherapy and targeted therapies with novel immunotherapy, cell therapy, and vaccines in individual patients, and to analyze the molecular mechanisms that lead to resistance for these therapies.


  1. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1):44-53.
  2. Govindan R, Mandrekar SJ, Gerber DE, et al. ALCHEMIST trials: a golden opportunity to transform outcomes in early-stage non-small cell lung cancer. Clin Cancer Res. 2015;21(24):5439-5444.
  3. Herbst RS, Gandara DR, Hirsch FR, et al. Lung master protocol (Lung-MAP)-a biomarker-driven protocol for accelerating development of therapies for squamous cell lung cancer: SWOG S1400. Clin Cancer Res. 2015;21(7):1514-1524.

Biomarker-driven trials that include multiple substudies represent a new approach for investigating which patients with lung cancer are more likely to respond to different targeted therapies and are helping to set the pace throughout the oncology field, according to Roy S. Herbst, MD, PhD.


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