New Trial Designs Hope to Enhance Biomarker Discovery

Primo N. Lara Jr, MD

Clinical trial designs are undergoing a dramatic transformation geared toward the discovery and validation of new predictive biomarkers for patients with non—small cell lung cancer (NSCLC) and other types of solid tumors, according to a presentation by Primo N. Lara Jr, MD, at the 2015 International Lung Cancer Congress.

"If you look at it on the basis of tumor types for which there is an established biomarker in the clinic for us to use to select patients, in non—squamous non–small cell lung cancer, there's EGFR and ALK," said Lara, associate director for Translational Research at the UC Davis Comprehensive Cancer Center. "You can see in the other solid tumors, as well as in GIST, there are predictive biomarkers, but there's not enough, even though they've been hyped up over the past decade."

Biomarkers, which Lara defined as any molecular feature that is indicative of a clinically relevant phenomenon, have proven difficult to uncover, due to small populations of patients, a limited number of drugs, and intra/inter-tumoral genetic complexity. Adding to the dilemma are the antiquated methods used for biomarker testing, which can easily lead to misinterpretation, Lara explained.

"IHC and light microscopy date back to the 16 and 17 hundreds. We need to move beyond just IHC and light microscopy," he said. "There are several ways we can order next-gen sequencing or molecular phenotyping tests. There are 7 commercial labs that do this."

Umbrella Trials

Once next-generation sequencing and other molecular profiling is conducted, clinical trials that randomize patients based on their genetics become more plausible. To this end, in the past 5 years, basket and umbrella protocols have been formed and the NCI has enhanced the study of exceptional responders. These steps are essential to accelerating biomarker development, Lara added.In an umbrella trial, upfront next-generation sequencing is conducted and patients are randomized based on the results to smaller individualized arms or substudies. Each smaller group explores a targeted therapy matched to the patient’s biology. This type of trial generally explores various markers within a single histology and can grow to be very large, with 20 or more arms.

"There are difficulties and costs associated with opening this type of trial, and unfortunately a bunch of those arms will not succeed," Lara pointed out.

Basket Trials

The umbrella trial strategy is a hallmark of the Lung-MAP trial, which is a multi-drug, multi-arm, biomarker-driven clinical trial for patients with advanced squamous cell NSCLC. This trial uses genomic profiling to match patients to one of several therapies targeted against PIK3CA, CCND1/2/3, CDK4, FGFR, and other markers. Immunotherapy will be administered for those without an apparent molecular driver and chemotherapy will be used as a comparator (NCT02154490).In a basket trial, patients with various types of cancer are enrolled based on the presence of a biomarker, such as a genetic alteration or a distinct molecular signature. This style of trial takes the emphasis off histology and focuses it on the underlying genetics of each tumor. Typically, these protocols explore a single therapy across various types of cancer.

"The disadvantage here is that biology is not always histology agnostic. An example would be BRAF in colorectal cancer, which didn't quite pan out," Lara noted.

In the recently launched NCI-MATCH basket trial, 1000 adult patients with progressive advanced solid tumors or lymphomas will be assigned to 1 of 10 groups based on their molecular profiles and regardless of histology. While 6 of the agents being explored in this trial have gained approvals for other indications, the remaining 4 are still investigational. The NCI anticipates the need to screen 3000 patients in order to enroll the required number of participants.

Other Considerations

"NCI-MATCH is a classic basket study. I encourage everyone to open this trial at your center," Lara noted. "The NCI tells us that it will take 10 to 14 days for the genetic report, which they have ensured us is feasible even in the context of an NCI trial."A number of basket and umbrella trials are open to enrollment, outside of the NCI-MATCH and Lung-MAP investigations. While these study designs are not new, they have begun to gain greater attention in recent years. However, in past trials that used these designs, the results were not always positive and all of the intended arms frequently had trouble enrolling, Lara cautioned.

"Not all basket and umbrella strategies work out, sometimes it is a lot of resources and it doesn't pan out," he said. "This is not new, this is an accepted drug development pathway."

In 2014 the NIH/NCI launched a study focused on exceptional responders to cancer therapy. Under this paradigm, the genetics of those who demonstrate an unusually robust response will be examined using deep sequencing to uncover potential molecular drivers. The findings from these investigations could be used to help tailor therapy for other individuals who also display these characteristics.

"This takes advantage of a real world experience with that agent in that patient population. It also takes advantage of luck," Lara noted.

Training and stakeholder agreement from all those involved is required in order to put molecular testing into practice at a community center, especially regarding reimbursement, Lara noted. Additionally, he encouraged the establishment of a set decision-making strategy, once results were returned. Once molecular screen is in place, referrals could easily be made to the appropriate trials, Lara advised.