Clinical trials are starting to focus more on the tumor's genetic makeup than the tumor's location.
Precision medicine continues to take hold of the lung cancer space, meaning that many patients are starting to receive more individualized treatments for their specific cancer. However, while researchers have figured out how to target genetic mutations such as EGFR, ALK, ROS1 and BRAF, others — such as KRAS – still need further investigation, according to Vassiliki A. Papadimitrakopoulou, M.D.
Papadimitrakopoulou, who is the Jay and Lori Eisenberg Distinguished Professor of Medicine and chief of the Thoracic Medial Oncology Section in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, spoke with OncLive, a sister publication of CURE, about the changing treatment landscape for non-small cell lung cancer (NSCLC).
“We have a long way to go because about 50 percent of our patients do not have alterations that we recognize as drivers,” she said. “Even within the other 50 percent of patients who have aberrations, there are some, including KRAS mutations, that are not targetable.”
A genetic aberration is a genetic mutation that occurs when part of a cell’s DNA is lost or deleted during DNA replication. Tumors with EGFR mutations are the “poster child” of targeted therapies, according to Papadimitrakopoulou, who noted that the use of Tagrisso (osimertinib) in this group has emerged as “the bigger and better inhibitor that is better tolerated by patients and targets central nervous system disease quite effectively.”
Similarly, treatment has expanded for those with ROS1 or ALK fusions or BRAF mutations in recent years, too.
But there is still more work that needs to be done.
“We still have alteration, such as KRAS; it is in about 25 percent of patients with adenocarcinoma and that we haven’t been successful in targeting,” Papadimitrakopoulou said. “We will continue to target this alteration in clinical trials, to try and find mechanisms that make this tumor so invulnerable to our therapies.”
In continuing to research KRAS and other lung cancer groups, Papadimitrakopoulou said that it is likely that researchers will turn to basket trials. Basket trials — also commonly referred to as “umbrella trials” – match patients with a type of treatment based on the genetic makeup of their tumor, rather than the tumor location.
“The bottom line is that we need to find therapies that match the patients’ tumor,” Papadimitrakopoulou said.
An example of a basket trial is the NCI-MATCH (National Cancer Institute — Molecular Analysis for Therapy Choice), where patients are selected based on the fact that they have not benefitted from a variety of targeted therapies.
Cancer types that are accepted in this trial include advanced solid tumors, lymphoma or myeloma, as long as they have progressed on standard therapy.
Three arms of the trial were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in June. The first (arm I) showed that taselisib, a PI3K inhibitor, did not induce any objective responses in patients with PI3CA mutations. But, 27 percent of patients experienced progression-free survival (PFS) of six months or longer.
Arm Q showed that treatment with T-DM1 and Kadcyla (ado-trastuzumab emtansine) was well-tolerated in patients with HER2-amplified tumors, excluding those with breast and gastric/gastroesophageal adenocarcinoma. Three out of the 37 patients demonstrated a partial response to therapy.
The findings from arm W showed that AZD45487, a FGFR1/2/3 inhibitor, had some activity across a diverse patient population with FGFR abberations. The drug also had an acceptable safety profile and induced a partial response in 10 percent of patients.
Papadimitrakopoulou, who also discussed master protocols in clinical trial designs in a talk that she gave at the 2018 International Lung Cancer Congress, noted these types of trials are the most cost-effective.
“By no means am I a statistician, so the designs of the clinical trials in this lecture were from the clinician’s point of view, and how we can benefit more patients at the same time by designing umbrella, or basket, clinical trials,” she said. “This is the most cost-effective way to screen many patients and offer therapies to almost everyone.”