Recent Advances in Treatment of NSCLC with NTRK Fusions

Benjamin Levy, MD: Let’s move on to the last module, which is on gene fusions. Clearly, we’ve got a lot of crowded space, potentially some rare fusions that we have some drugs for, and then the more common ones that we see. We’ll talk about NTRK, ALK, and ROS. We’ll put RET on the table for now and not talk about it. But we’ll end up with some ADCs [antibody-drug conjugates] as well. That’ll be added on. Misako, do you want to talk to us a little about NTRK fusions and some of the data we’ve got with targeting NTRK?

Misako Nagasaka MD, PhD: Sure. NTRK [neurotrophic tyrosine receptor kinase] gene fusions encode TRK [tropomyosin receptor kinase] fusion proteins, which are oncogenic drivers in various tumor types. Larotrectinib was the first-in-class, highly selective, CNS-active TRK inhibitor approved to treat adult and pediatric patients with TRK fusion–positive cancer.

At ASCO [American Society of Clinical Oncology Annual Meeting] 2021, Dr [David] Hong and colleagues provided an updated efficacy and safety analysis with longer follow-up from the initial data of larotrectinib in an expanded data set that included 3 clinical trials. As of data cut-off, 218 patients were treated with larotrectinib, of which 206 were evaluable for efficacy. There were 21 different tumor types. The common ones included soft tissue sarcoma, thyroid, salivary gland, lung, and colorectal cancer. The objective response rate was 75%, with a median follow-up of 22.3 months. The median duration of response was 49.3 months. The median PFS [progression-free survival] was 35.4 months. The median OS [overall survival] wasn’t reached. The 36-month OS was 77%. The objective response rate for patients with brain metastases was 73%. Treatment-related adverse events [TRAEs] were mainly grade 1 and 2, with 18% having grade 3 or 4 TRAEs. Only 2% of patients discontinued due to TRAEs.

The lung data presented by Dr Lin and colleagues at ASCO 2021 were consistent with this as well. Among 15 evaluable patients, the confirmed objective response rate was 73%. In those with CNS [central nervous system] metastasis, the objective response rate was 63%. The median overall survival was 40.7 months at a median follow-up of 16.2 months.

The other drug in this space is entrectinib. Data on entrectinib was updated by Dr [Christian] Rolfo at ASCO 2020 through an integrated analysis of 3 phase 1/2 studies. There were 74 evaluable patients with advanced or metastatic NTRK fusion–positive solid tumors. The objective response rate was 63.5%. The median duration of response was 12.9 months. The median PFS was 11.2 months. The median OS was 23.9 months. In patients with no CNS disease at baseline, the objective response rate was 65.5%. In patients with baseline CNS disease, objective response rate was 57.9%. Safety was in line with what was previously reported. The most common grade 3 or higher treatment-related adverse events were weight gain, anemia, and fatigue.

Transcript edited for clarity.