Novel Targeted Therapies Emerging for NSCLC

Tetsuya Mitsudomi, MD

Several receptor tyrosine kinase (RTK) inhibitors are rapidly moving through development for non—small cell lung cancer (NSCLC), particularly for RET, NTRK, and EGFR exon 20. Agents targeting these alterations are well positioned to join the already established standard-of-care therapies forEGFR,ALK,ROS1, andBRAF.

Further down the line, several novel agents are beginning to show promise for new targets, especiallyNRG1andLKB1. As these agents are developed, the number of patients applicable for targeted therapy continues to increase, with the potential that one day all oncogenetic drivers will be uncovered, according to Tetsuya Mitsudomi, MD, PhD, at the 19th Annual International Lung Cancer Congress.

"Inhibition of mutated versions ofEGFR, ALK, ROS,andBRAFV600E is standard of care," said Mitsudomi, professor, Thoracic Surgery, Kindai University, Osaka, Japan. "These days, many new drivers are being discovered. Most of the targetable alterations in lung cancer are fusions or alterations in receptor tyrosine kinases."

Focusing on the success with RTKs, Mitsudomi highlighted other potential targets that are in early phase development, includingFGFR, DDR2, NRG1, RIT1,andKRAS. "KRASis the oldest driver, yet, targeted therapy toKRAShas been difficult," he said.

One of the more promising targets has beenNRG1. In a single-patient case study,¹an 86-year-old treated with the anti-ERBB3 monoclonal antibody GSK2849330 at 30 mg/kg had a confirmed partial response, which was ongoing at 19 months. This patient, who had anNRG1rearrangement, had progressed on several prior therapies, including nivolumab. This response was accompanied by resolution of dyspnea.

Others included in this phase I study without theNRG1fusion did not have a response to GSK2849330. The unique activity of this drug inNRG1-rearranged tumors was further verified in preclinical findings. In these studies, ERBB3/ERBB2 inhibition resulted in decreased cell growth in cell lines with aberrantNRG1expression.

LKB1, which is altered in NSCLC, is another promising target in development, with several trials ongoing. This target is unique for its role in glucose homeostasis in the liver. Given this connection with glucose, metformin, which is used for type 2 diabetes and works throughLKB1-dependent activation of adenosine monophosphate-activated protein kinase (AMPK), has been the topic of clinical trials.

In preclinical studies, metformin has shown activity in NSCLC cell lines, with targeted inhibition of proliferation along with cell cycle arrest. Phase II studies are currently exploring the impact of metformin in various settings for NSCLC, either as a single agent or in combinations. In prior phase II findings, activity with metformin plus chemotherapy was seen in a broad population, although none hadLKB1alteration. The objective response rate was 23%.²

"Many trials forLKB1are in progress," Mitsudomi noted. "There are no results yet but it shows there are ways to cope withLKB1mutations."

Mitsudomi said that the p53 pathway also represents a potential target, along with STK11, oxidative stress pathways, nucleosome remodeling genes, and histone modifiers. There are several agents in development that potentially impact mutant p53, through a variety of mechanisms. The search for an effective agent for p53 spans across numerous cancers, as this target is involved in several malignancies.

"p53 has been known as an important tumor suppressor for 30 years," said Mitsodomi. "Many strategies have been tried but none have been very successful."

With so many targets emerging, there is a potential role for synthetic lethal relationships, wherein treatment with one agent causes a deficiency that makes it more susceptible to another agent. Research into this type of strategy has gained popularity using PARP inhibition and platinum-based chemotherapy.

The oxidative stress pathway often causes resistance to chemotherapy, making it a unique target for synthetic lethality combinations. In early studies, the agent brusatol was found to enhance the efficacy of chemotherapy, by inhibiting the Nrf2-mediated cellular defense mechanism. These findings suggest that brusatol may prevent chemoresistance. However, research into this approach has been slow, as these initial findings were released in 2011.³

Other synthetic lethal approaches are currently in development, Mitsudomi noted. Recently, it was found that EZH2 inhibition sensitizesBRG1andEGFR-mutant lung cancer to TopoII inhibitors, like etoposide,⁴suggesting a potentially new approach.

Other synthetic lethal approaches are also intriguing, including the combination of SMARCA4 and EZH2 inhibition and ARID1A with PI3K/AKT or PARP inhibition. Trials looking at the latter combinations are currently ongoing, while SMARCA4/EZH2 trials are still being planned.

References:

1. Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers.Cancer Discov. 2018;8(6):686-695.
2. Parikh AB, Kozuch P, Rohs N, et al. Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial.Invest New Drugs. 2017;35(6):813-819.
3. Ren D1, Villeneuve NF, Jiang T, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.Proc Natl Acad Sci U S A. 2011;108(4):1433-1438.
4. Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.Nature. 2018;520:239-242.