Velcheti Addresses Promising Data with Repotrectinib in ROS1+ NSCLC

CASE

• 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 eltrasound-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: Why do patients with non–small cell lung cancer (NSCLC) on repotrectinib experience dizziness with their therapy?

Vamsidhar Velcheti, MD, MBA: [After this patient starts repotrectinib], they had intermittent dizziness, which is common with repotrectinib…in the first 2 weeks of treatment. These drugs have [a lot of] cross interactivity and repotrectinib is also a TRK inhibitor, which is where some of these [toxicity] issues stem from.¹ For these patients, when they first stop these drugs, they will experience dizziness, sometimes [they could even experience] ataxia, and that's usually because of the initial TRK activity. So that's something to keep in mind.

What were the patient characteristics of those on the phase 1/2 TRIDENT-1 trial (NCT03093116)?

[In the phase 1/2 TRIDENT-1 trial], they established a phase 1 dose escalation of 160 mg [of repotrectinib] after 2 weeks then to 160 mg twice a day.² [Patients on the phase 2 dose escalation were split into cohorts based on] if they were ROS1 tyrosine kinase inhibitor- [TKI] naïve, had 1 TKI with chemotherapy, 2 TKIs with no chemotherapy, and 1 TKI with no chemotherapy.

Primary end points included the objective response rate, [with secondary end points of duration of response and time to response]. Most of the patients who were never smokers had no prior ROS1 TKI treatment, which is a higher proportion of patients. The generalization of never smokers is that they are female patients [and in this study they made up most patients in both the no prior TKI (61%) and 1 prior TKI with no chemotherapy (68%) cohorts].² I think you have to take into account that the pretest probability of [the patient] having an oncogenic mutation is also high.

What is the efficacy data behind the use of repotrectinib in the NSCLC population?

The approval [for repotrectinib] was...an accelerated approval.3 The vast majority [of the patients in this study] had a response to repotrectinib, and the progression-free survival of [patients with no prior ROS1 TKI therapy] was almost 3 years, [at a median of 35.7 months (95% CI, 27.4–not estimated [NE])].²

This is remarkable and has led to a push [at looking at phase 3 data for this patient population on repotrectinib]. Even patients who were previously treated with ROS1 TKIs...[had a nice ORR of 38% (95% CI, 25%-52%)]…. Every patient on the trial in that cohort had a tumor reduction…and these are deep responses that we see [with repotrectinib in both the TKI naïve and 1 prior TKI cohort with a median DOR of 34.1 months (95% CI, 25.6%-NE) and 14.8 months (95% CI, 7.6%-NE), respectively].²

^References:

^{1. Han SY. TRK inhibitors: tissue-agnostic anti-cancer drugs. Pharmaceuticals (Basel). 2021;14(7):632. doi:10.3390/ph14070632}

^{2. Drilon A, Camidge R, Lin J, et al. Repotrectinib in ROS1 fusion–positive non–small-cell lung cancer. N Engl J Med. 2024; 390:118-131. doi: 10.1056/NEJMoa2302299}

^{3. FDA approves repotrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. November 16, 2023. Accessed February 20, 2024. http://tinyurl.com/4hd9n7sc}