Chul Kim, MD, MPH, discusses the impact of optimizing rare targets in lung cancer, highlighting the FDA approval of repotrectinib in ROS1-positive disease.

Dr Kim on the Importance of the FDA Approval of Repotrectinib for ROS1+ NSCLC

Chul Kim, MD, MPH, thoracic oncologist, associate professor, medical oncology, Georgetown University Lombardi Comprehensive Cancer Center, MedStar Health, discusses the impact of optimizing rare targets in non–small cell lung cancer (NSCLC), such as ROS1 and ALK, highlighting the FDA approval of repotrectinib (Augtyro) in 

Previously, the NSCLC treatment armamentarium included 2 ROS1 TKIs: crizotinib (Xalkori) and entrectinib (Rozlytrek), Kim begins. On November 15, 2023, 

 for patients with locally advanced or metastatic 

-positive NSCLC, heralding the advent of a new generation of ROS1 TKIs, he emphasizes. In the first-line phase 1/2 TRIDENT-1 trial (NCT03093116), repotrectinib elicited a response rate of 79% (95% CI, 68%-88%) coupled with a median duration of response (DOR) of 34.1 months. Conversely, in patients pretreated with ROS1 TKIs, the response rate was 38% (95% CI, 25%-52%), with a median DOR of 14.8 months, he explains. Repotrectinib showcased activity in a substantial subset of patients who experienced disease progression on prior ROS1 TKI therapy, even overcoming resistance mechanisms such as G2032R, Kim states.

Notably, repotrectinib targets ROS1 and the TRK pathway. Consequently, it becomes imperative to monitor adverse events (AEs) related to TRK inhibition, he expands. Neurological AEs, including dizziness, altered taste, neuropathy, and ataxia, are occasionally observed in association with TRK inhibition. Additionally, vigilant monitoring for other AEs, such as weight gain and withdrawal pain, is warranted, Kim says.

Antibody-drug conjugates (ADCs) represent a burgeoning field in thoracic oncology and oncology at large, he continues. Among these, fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed ADC, has garnered approval for patients with 

-positive NSCLC, Kim explains, adding that numerous ADCs are in development for various indications, targeting diverse entities such as TROP2, MET, and others.

Kim emphasizes that telisotuzumab vedotin (Teliso-V), a MET-directed ADC, exhibited an objective response rate of 36.5% (95% CI, 23.6%-51.0%) in patients with c-Met–high NSCLC in the phase 2 LUMINOSITY trial (NCT03539536). Currently, the randomized phase 3 TeliMET NSCLC-01 trial (NCT04928846) is underway to compare telisotuzumab vedotin with docetaxel, and the trial's final outcomes are eagerly awaited, he concludes.

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Chul Kim, MD, MPH, an attending physician at MedStar Health and an assistant professor of medicine at Georgetown University, discusses overcoming mechanisms of resistance to TKIs in non—small cell lung cancer (NSCLC).

Investigators are exploring several strategies to overcome resistance mechanisms to TKIs in the lung cancer space. Specifically, in 

-mutant NSCLC, combination strategies have shown success, says Kim. For example, data from the phase III NEJ009 trial demonstrated a significant improvement in overall survival with the combination of gefitinib (Iressa), carboplatin, and pemetrexed versus gefitinib alone in patients with 

-activating mutations. Osimertinib (Tagrisso), a third-generation EGFR TKI, may show similar promise when used in combination with pemetrexed and osimertinib, but those studies are ongoing, adds Kim.

The second strategy under exploration involves isolating the mechanism of resistance in each patient and intervening with the appropriate targeted agent. For example, in a presentation from the 19th World Conference on Lung Cancer, investigators identified 

 fusions in patients who had been treated with second-line osimertinib. These patients were treated with osimertinib and a RET inhibitor. The combination achieved partial responses, which were ongoing at 4 months, says Kim.

Chul Kim, MD, MPH, an attending physician at MedStar Health and an assistant professor of medicine at Georgetown University, discusses overcoming mechanisms of resistance to TKIs in non–small cell lung cancer (NSCLC).

Chul Kim, MD, MPH

Articles

Dr Kim on the Importance of the FDA Approval of Repotrectinib for ROS1+ NSCLC

Dr. Kim on Overcoming Resistance to TKIs in NSCLC