Repotrectinib Elicits an Intracranial Response in ROS1+ Advanced NSCLC

CASE SUMMARY

• A 59-year-old woman presented to her primary care physician with complaints of persistent, nonproductive cough, chest pain, and intermittent low-back pain for 6 weeks.
• Patient was a lifelong nonsmoker​ with no history of cardiovascular disease, peripheral vascular disease, or diabetes mellitus.
• There was no family history of malignancy​.
• Hypertension well controlled on with 160 mg of an angiotensin II receptor blockers taken orally once a day​.
• Blood pressure, 114/76 mmHg; pulse, 78 bpm and regular​
• ECOG performance status: 0​
• Pulmonology report: diminished breath sounds on auscultation over posterior, right midline​
• Chest radiograph: opaque mass visualized in right, central lung field​
• Patient referred to a thoracic oncologist for further consultation and evaluation ​
• ​Chest CT: visualized solid, 7 cm, centralized, right mid-lobe mass; no evidence of air bronchogram, cavitation, or calcification; positive ipsilateral, 20 mm, mediastinal lymph node
• ​Fludeoxyglucose F18 PET/CT: avid uptake detected from L3-L5; bilateral iliac crests and ischial spine
• Brain MRI: negative for suspicious lesions​
• The patient underwent endobronchial ultrasound-guided transbronchial needle aspiration without complication​.
• ​Immunohistochemistry of formalin-fixed paraffin-embedded tissue specimen was positive for elevated ROS1 protein level with finely granular cytoplasm (H-score >150); TTF-1 positive; PD-L1: (<1%)​.
• ​Histopathology: adenocarcinoma marked by aggregates of malignant glandular cells; enlarged, pleomorphic nuclei; vesicular nuclear chromatin; and high nuclear-to-cytoplasmic ratio​
• Molecular Profiling: positive for ROS1 (with a CD74 gene partner); negative for other actionable mutations​
• Stage of disease: T3N2M1b​

First-Line Therapy

• Pre-Treatment Liver Function Test: serum alanine transaminase, asparate transaminase, and bilirubin concentrations within normal limits​.
• ​Patient commences a course of repotrectinib (Augtyro) at 160 mg given orally once a day for 14 days, then an increase of the dose to 160 mg orally twice a day until disease progression or unacceptable toxicity​.
• The patient has intermittent episodes of transient, low-grade, self-limiting dizziness that did not require dose interruption nor delay.
• They were recommended to increase to a total daily dose of 320 mg on day 14 of repotrectinib.

Follow-Up Plan: ​

• Return to office every 3 months
• Monitor therapeutic response for sustained efficacy and tolerability​
• Repeat diagnostic testing, including imaging studies as needed​

Targeted Oncology: How many patients in the phase 1/2 TRIDENT-1 trial (NCT03093116) had a central nervous system (CNS) metastasis?

CHRISTINE BESTVINA, MD: Thirty-six percent of patients at diagnosis [had a CNS metastasis], but at the time of diagnosis about half [of the patients] had CNS progression, if they’ve been on crizotinib.¹ So, most patients will encounter brain metastases at some point in their disease trajectory. [In this study], 36 months is about as far out as we’re going for median intracranial progression, which is about the median [PFS] too.¹

What were the response rates for patients with ROS1+ NSCLC who either had a CNS metastasis at baseline or later?

The objective response rate [ORR] in that population was about 90%. In patients without CNS metastasis, it’s also impressive [at 75% (95% CI, 62%-86%)] for those patients who were TKI naive....² For the patients who had 2 prior TKIs, the response rates were not impressive [with an ORR of 40% (95% CI, 12%-74%) and no complete responses (CRs)]. Further, if they had brain metastasis but 2 prior ROS1 TKIs, then it was about a 12% response rate…and that arm of the trial was actually closed early.² In general, I would say regardless of presence of brain metastases at diagnosis or not, it’s still very impressive responsive response rates [for TKI-naive patients and just 1 prior ROS1 TKI].

What safety concerns should be noted with this therapy?

The big safety point to [highlight] about this drug is dizziness.¹ Dizziness of any grade occurs in about 60% of patients, and it can be grade 3 or higher in about 3% of patients. Outside of that, patients will...have paresthesia, [with 34% of any-grade paresthesia events occurring],¹ and these can be very strange with [repotrectinib]. I had a patient who felt like his skin was on fire, and that was just how he continued to describe it. Dyspnea of a kind of unknown origin does occur with this drug, too. You’ll do a big workup, and it will all be negative, and it’s thought to just be dyspnea related to the drug.

You’ve got a few options [to help manage the dizziness]. There’s 2 weeks prior to dose escalation with this drug, a 2-week dose lead-in, and if the dizziness occurs in that time frame, you can decide [whether] you should increase the dose…. [If you do not increase the dose], then you would just leave the dose as is. If the dizziness does continue to be a problem later and the patient is on the full dose, then you have the option to dose reduce, and one-third of the patients in this trial were either dose reduced or dose interrupted due to toxicity.¹

REFERENCES:

1. Drilon A, Camidge DR, Lin JJ, et al; TRIDENT-1 Investigators. Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer. N Engl J Med. 2024;390(2):118-131. doi:10.1056/NEJMoa2302299

2. Lin JJ, Drilon A, Cho BCC, et al. Intracranial and systemic efficacy of repotrectinib in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC) and central nervous system metastases (CNS mets) in the phase 1/2 TRIDENT-1. J Clin Oncol. 2023;41(16):9017. doi:10.1200/JCO.2023.41.16_suppl.9017