City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the United States with its National Medical Center ranked among the nation's top cancer centers by U.S. News \& World Report, has opened an innovative Phase 2 clinical trial designed to map how tumors change as they begin to resist immunotherapy, treatment that improves the immune system's ability to fight disease. The research will focus on advanced non-small cell lung cancer (NSCLC), the most common type of lung cancer, accounting for 87% of cases.

Aiming to enroll 535 patients newly diagnosed with NSCLC, the six-year IMMUNO-BIOMAP trial will use sophisticated predictive models to tailor treatments to the evolving biology of patients' tumors. An up to $23.7 million award from the Advanced Research Projects Agency for Health (ARPA-H) to City of Hope's Ravi Salgia, Jyoti Malhotra and Aritro Nath funds the research.

Our goal is to create clear guidelines for selecting the best next treatment when a patient's cancer doesn't respond to initial therapy. City of Hope is determined to find a reliable way to predict who will benefit from immunotherapy and who might experience better results with other treatment options."

Ravi Salgia, M.D., Ph.D., lead principal investigator, professor and chair of City of Hope's Department of Medical Oncology \& Therapeutics Research and the Arthur and Rosalie Kaplan Chair in Medical Oncology

For patients with advanced NSCLC, doctors often rely on powerful drugs called immune checkpoint inhibitors that target a protein called PD-L1 on cancer cells. Fewer than 40% of patients see positive results, however, and many develop resistance to the drugs.

Researchers from Beckman Research Institute of City of Hope aim to revolutionize how oncologists treat NSCLC using PD-L1 immunotherapy. They are diving deep into the world of biomarkers - biological clues that can help physicians match patients' cancers to the most effective treatments. The team also will explore circulating tumor DNA to develop new strategies that could keep patients responding positively to these life-prolonging drugs longer.

In the trial's second phase, researchers will roll out new therapies guided by these biomarkers in real time, aiming to halt disease progression and boost treatment success rates. The team will focus on how second-line immunotherapy drugs tackle the challenges of resistance, particularly in patients with tumors containing specific genetic mutations known to drive the growth and spread of cancer.

"Our ultimate goal is to identify groups of patients who respond well to personalized treatments and biomarker-guided therapies, allowing them to live longer without relapse," Dr. Salgia said. "With the support of ARPA-H, these findings could mark a new era in the fight against lung cancer."

City of Hope is the only institution in the nation to receive ARPA-H funding for lung cancer research in the ADAPT study.

Under ARPA-H's Advanced Analysis for Precision Cancer Therapy (ADAPT) program, the ambitious $142 million initiative aims to integrate the latest technologies with top experts in tumor biology to provide personalized cancer care that evolves with the patient's disease.

The study will explore the best way to use immunotherapy and evaluate whether combining it with other treatments is more effective than traditional chemotherapy alone.

"Late-stage non-small cell lung cancer is unique in that a patient's response to initial therapy often influences the success of later treatment. Patients who demonstrate a positive response in the first two years tend to have a better chance of achieving lasting improvement. Unraveling this mystery is one of our key objectives," said principal investigator Aritro Nath, Ph.D., assistant professor with the Division of Molecular Pharmacology, Department of Medical Oncology \& Therapeutics Research.

While immunotherapy has improved survival rates for some patients, those receiving chemotherapy after immunotherapy often don't do as well. Many cancers shed malignant cells or release circulating tumor DNA into the bloodstream before visible changes appear on patient scans. This phenomenon emphasizes the need for more precise and timely monitoring of patients' responses to treatment.

"Measuring tumor DNA levels in the blood over time will help us pinpoint which patients face a greater risk for drug resistance and relapse after immunotherapy. Understanding how checkpoint drugs interact with tumor cells will allow us to tailor treatment plans based on each patient's unique cancer DNA signature, enhancing the likelihood of a successful outcome," said principal investigator Jyoti Malhotra, M.D., City of Hope associate professor, Department of Medical Oncology \& Therapeutics Research, and director of Thoracic Medical Oncology at City of Hope Orange County.

The clinical trial will draw on City of Hope's network of nearly 40 clinical sites with a diverse cross-section of lung cancer patients across the nation.

"We believe that the insights gained from this trial will transform how doctors manage care for non-small cell lung cancer patients," Dr. Salgia said. "We are excited to work with all of our colleagues across City of Hope to improve care for our patients with lung cancer. Our findings offer hope for greater treatment success and longer lives for the 200,000 people diagnosed each year in the United States."