Therapeutic Breakthroughs on the Horizon
Naiyer A. Rizvi, MD, has become a household name in the field of lung cancer and immunotherapy drug development. Dr. Rizvi, who serves as Director of Thoracic Oncology and Co-Director of Cancer Immunotherapy at NewYork-Presbyterian/Columbia University Irving Medical Center, played a significant role in the FDA approval path of immune checkpoint inhibitors for melanoma and lung cancer, and his pioneering research continues with a focus on tumor mutation burden and the role of neoadjuvant immunotherapy for non-small cell lung cancer.
The Benefit of Tumor Mutation Burden
In 2015, Dr. Rizvi published the first data on lung cancer and tumor mutation burden (TMB) in Science showing a correlation with benefit. It became one of the most cited papers in immunotherapy, with over 3,000 citations. “As more mutations accumulate, the tumor ends up subverting the immune system and turning off the immune recognition. Immunotherapies turn the immune system back on and eradicate these mutations,” says Dr. Rizvi. In a subsequent large phase 3 clinical trial, Dr. Rizvi and his colleagues were able to determine the tumor mutation burden from the plasma of patients. “This was important for two reasons. We could actually determine the tumor mutation burden from a 2mL plasma sample, and we now knew that we could use this to select high TMB patients who may benefit from combination immunotherapy.”
Next Generation Cancer Vaccines
“Beyond tumor mutation burden, we now know that there are very unique mutations that are immunologically important, and when immune checkpoint inhibitors such as nivolumab and pembrolizumab are given to patients, there are very specific T cells that expand against very specific mutations,” says Dr. Rizvi. “There are likely only to be very few of these mutations, called neoantigens, within a tumor and we are now able to predict these mutations with great accuracy, work we published in Nature Biotechnology in 2018. The next step is to see if we could ‛target’ these neoantigens with cancer vaccines.” However, the challenge is that neoantigens are typically patient specific so a vaccine needs to be created for each patient as a personalized immunotherapy approach. This approach has now entered the clinic with personalized vaccine treatments being conducted at NewYork-Presbyterian/Columbia.
A New Take on Neoadjuvant Therapy
Dr. Rizvi is also leading a global phase 3 clinical trial with an estimated 400 patients comparing combination immunotherapy versus chemotherapy plus neoadjuvant immunotherapy in patients who have locally advanced lung cancer that is resectable. “We recently finished a phase 2 trial of 30 patients who were given neoadjuvant chemotherapy in conjunction with the immune checkpoint inhibitor atezolizumab,” says Dr. Rizvi. “About 30 percent of the patients had a complete pathologic response. If the global trial also shows positive outcomes, it too will offer a landscape-changing therapy for FDA approval.”
Catherine A. Shu, MD, Clinical Director of the Thoracic Medical Oncology Service, is Principal Investigator of the phase 2 trial. “Our work directly led to a pharmaceutical company adapting our study for the global phase 3 trial,” says Dr. Shu. “This trial has truly been a Columbia team effort. As a matter of fact, our thoracic pathologist, Dr. Anjali Saqi, is now serving as the phase 3 trial study pathologist given her experience with the phase 2 effort.”
“Neoadjuvant chemotherapy is an accepted treatment approach for resectable non-small cell lung cancer,” says Dr. Shu. “However, the cancer recurs in 30 to 70 percent of patients, who then ultimately succumb to the disease. Our goal is to improve upon this. Using a combination of chemotherapy and immunotherapy in this preoperative setting is novel, and we are extremely encouraged by results from our phase 2 trial.”