Newer TKIs Show Better Intracranial Responses in ROS1+ 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: What stands out when considering treatment for patients with non–small cell lung cancer (NSCLC) positive for a ROS1 mutation?

CHRISTINE BESTVINA, MD​: [Patients with] ROS1 dependent NSCLC makes up [about] 1% to 2% of the patient population.¹ There are a variety of fusion partners for ROS1; largely it does not affect the efficacy of ROS1 inhibitors, but 80% of these patients are diagnosed in the metastatic setting.^1,2 Part of the big unmet need for patients who have ROS1 fusions has been a lack of intracranial efficacy [with tyrosine kinase inhibitor (TKI) therapy].

Christine Bestvina, MD​

Assistant Professor of Medicine

University of Chicago Medicine​

Chicago, IL

With the most traditional TKI we used in this space, which was crizotinib [Xalkori]...it was useful for [patients whose disease had either an] ALK or ROS1 mutation, but those patients tended to have central nervous system [CNS] progression because crizotinib does not get into the CNS space well.² So, that left a big vulnerability to those patients with CNS [metastases], and CNS is a common site of disease progression. About half of these patients will have CNS progression at some point, with about a third of patients having CNS disease at diagnosis.³

What is different between older generations of TKIs and newer ones?

Some of the limitations of earlier generation TKIs included a lack of [target] specificity, low potency, and poor penetration of the blood-brain barrier. They also can form gatekeeper mutations, which are [mutations] on the target resistance mechanisms that lead to more resistance.⁴ Several of the newer-generation TKIs that are being selectively developed include...good efficacy with gatekeeper mutations, [because] when you use them in the frontline setting, they prevent development of these gatekeeper mutations, as well as having improved CNS penetration.

What were the baseline characteristics of patients in the phase 1/2 TRIDENT-1 trial (NCT03093116) investigating repotrectinib?

For patients...who had prior ROS1 TKI therapy, the large majority [80%] had crizotinib before repotrectinib.⁵ Fifteen-percent had prior entrectinib [Rozlytrek] and 1 patient had prior ceritinib [Zykadia]. As far as the patients who had had no prior ROS1 TKI but could have had prior chemotherapy, the majority had 1 prior line [of therapy]. Patients who were TKI naive...had not received anything before [this study], and the majority [of this group] had not received any prior chemotherapy and were truly treatment naive.⁵

What were the best efficacy results with this therapy in the NSCLC population?

[The median] progression-free survival [PFS] was 35.7 months [95% CI, 27.4­­–not estimable (NE)] for these TKI-naive patients, which is essentially doubling what we've seen previously with crizotinib and entrectinib.⁵ For patients who had been pretreated with a ROS1 TKI, the PFS is still respectable at 9.0 months [95% CI, 6.8-19.6]...and patients responded regardless of the prior TKI they had, but it was certainly less impressive than when [repotrectinib is] used upfront.

How would you sequence this therapy?

The way that I've thought about [sequencing therapy with this drug] is even if you started the patient off crizotinib or entrectinib, then you use this in the second-line.⁵ However, that still doesn't get you anywhere close to that PFS of 35.7 months. For [treatment-naive] patients who had...CNS measurable disease, brain metastases, at diagnosis the median PFS [rate at 12-months was 87% (95% CI, 71%-100%)], and even for patients who had had a prior TKI it was good [at 57% (95% CI, 35%-78%)].... For patients who did not have brain metastases at diagnosis, so essentially looking at how long can you prevent brain metastases from occurring, the 12-month intracranial PFS was 91% [95% CI, 83%-100%], which meant just 10% of patients who didn't have brain metastases at diagnosis developed them in the first year.⁵

REFERENCES:

1. Li Z, Shen L, Ding D, Huang J, Zhang J, Chen Z, Lu S. Efficacy of crizotinib among different types of ROS1 fusion partners in patients with ROS1-rearranged non-small cell lung cancer. J Thorac Oncol. 2018;13(7):987-995. doi:10.1016/j.jtho.2018.04.016

2. Drilon A, Jenkins C, Iyer S, et al. ROS1-dependent cancers - biology, diagnostics and therapeutics. Nat Rev Clin Oncol. 2021;18(1):35-55. doi:10.1038/s41571-020-0408-9

3. Patil T, Smith DE, Bunn PA, et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol. 2018;13(11):1717-1726. doi:10.1016/j.jtho.2018.07.001

4. Ko B, Paucar D, Halmos B. EGFR T790M: revealing the secrets of a gatekeeper. Lung Cancer (Auckl). 2017;8:147-159. doi:10.2147/LCTT.S117944

5. 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