Explosion in Next-Generation Agents on Horizon in NSCLC

Tony Mok, MD

Highly effective next-generation therapies are currently in development for patients with oncogene-driven non—small cell lung cancer (NSCLC), specifically those with alterations in EGFR, ALK, ROS1, NTRK, or a variety of other genes, according to a keynote address by Tony Mok, MD, at the 2015 International Lung Cancer Congress.

"At this moment, we have a good number of driver mutations that we already know, and there are a lot of exciting developments," explained Mok, a professor in the Department of Clinical Oncology at the Chinese University of Hong Kong.

For patients with EGFR-driven NSCLC, many of the next-generation therapies are aimed at overcoming acquired resistance to frontline EGFR inhibition. Chief among these therapies are AZD9291 and rociletinib (CO-1686). Both therapies have shown encouraging efficacy in early phase trials, with breakthrough therapy designations from the FDA.

In early August, Clovis Oncology completed submitting a new drug application to the FDA for rociletinib for patients with EGFR T790M-positive metastatic NSCLC, based on phase I/II TIGER-X trial. For AZD9291, the pivotal AURA2 study completed enrollment with results expected in early September 2015, according to Mok. In a financial statement, AstraZeneca expressed plans to submit data for AZD9291 in the third quarter of 2015 for T790M-positive NSCLC.

"Even with all of these, there are still a lot of questions that will drive our next studies, such as sequences," Mok said. "There has been so much discussion on immunotherapy, studies will need to look at combining EGFR TKIs with immunotherapy."

For patients with ALK-rearranged NSCLC, there are a number of next-generation options that are building on the success seen with crizotinib, Mok noted. In April 2014, ceritinib (Zykadia) gained approval for patients with ALK-positive NSCLC following crizotinib. Additionally, alectinib and brigatinib have each received breakthrough therapy designations.

"The study that will change the frontline treatment will be the ALEX trial. This is a head-to-head study of alectinib 600 mg BID, which is a continuous dose, and crizotinib in the first-line," Mok said. "This study is accruing really, really well. Hopefully, within a year or so we will begin to get an answer."

The NCI's ALK Master Protocol is currently exploring various ALK inhibitors in the first- and second-line setting. In the study, patients will be randomized to receive one of four ALK inhibitors in the first-line setting followed by a second agent upon disease progression. This study could provide hints at an optimal sequence for these therapies.

In addition to the more established ALK and EGFR-driven subtypes, there are a number of therapies currently in development for patients with rare alterations in ROS1 or NTRK. In this space, crizotinib has received a breakthrough therapy designation from the FDA for patients with ROS1-positive NSCLC. Additionally, for those with NTRK alterations, the Trk family TKI entrectinib has demonstrated promise in early phase clinical trials.

In February 2015, entrectinib received an orphan drug designation from the FDA as a treatment for patients with TrkA, TrkB, TrkC, ROS1, and ALK-positive NSCLC. In joint findings from the phase I STARTRK-1 and ALKA-372-001 studies, which were presented at the 2015 ASCO Annual Meeting, treatment with entrectinib demonstrated promising activity in this same molecularly defined subset of patients.

In 11 patients across both phase I studies who had not received a prior ALK and/or ROS1 inhibitor and who harbored an NTRK1/2/3, ROS1, or ALK alteration, treatment with entrectinib at 400 mg/m² demonstrated an objective response rate of 91%. This dose and patient population has been selected for future study in a phase II trial.

In the 11 patients who met these criteria, all those with ROS1 alterations had NSCLC (n = 6), and those with ALK alterations had NSCLC (n = 1) and another solid tumor (n = 1). Patients with NTRK1/2/3 fusions had NSCLC (n = 1), colorectal cancer (n = 1; CRC), and acinic cell cancer (n = 1). No drug-related serious adverse events were seen with entrectinib in the study.

The phase II STARTRK-2 trial, which is a so-called basket study, is enrolling patients with NSCLC, CRC, and other solid tumors based on molecular profiles (alterations in ALK, ROS1, and NTRK1/2/3). Tumors will be analyzed using a potential companion diagnostics that has been developed by the drug's developer, Ignyta (NCT02097810).

"This is actually a registrational study. This is the first time the FDA will allow a basket study as a registration study," explained Mok. "This is very exciting, in a way we're transitioning from the tissue-based to the molecular-based for treatment selection."

Other targets for patients with NSCLC include BRAF, MET, RET, and a host of other targets, Mok explained. Early data for each of these alterations were presented at the 2015 ASCO Annual Meeting. Based on a phase II study, the FDA granted a breakthrough therapy designation to dabrafenib and trametinib in combination for patients with BRAFV600E-mutant NSCLC.

However, for rare targets like RET, patient enrollment becomes a concern. For these small subtypes, there are many questions regarding the best way to conduct clinical trials, including the primary endpoints and minimum samples sizes. For these small subtypes, it will take some thinking outside of the box, Mok concluded.