Current Targeted Therapy Options in ROS1-Positive NSCLC

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ROS proto-oncogene 1 (ROS1) is encoded by the ROS1 gene located at chromosome 6q22 and belongs to a subfamily of tyrosine kinase insulin receptors.¹ The physiological role of ROS1 is not fully understood, but it has shown expression mainly in the lung tissue, followed by the cervix and the colon. ROS1 gene fusions result in oncogenic drivers that signal ROS1 kinase activity, leading to increased cell proliferation and survival.¹

ROS1 rearrangements occur in approximately 1% to 2% of patients with non–small cell lung cancer (NSCLC).² These patients may develop brain metastases, resulting in a poor prognosis. According to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), the NSCLC Panel recommends ROS1 testing in patients with metastatic nonsquamous NSCLC or NSCLC not otherwise specified.² ROS1 testing may also be considered in patients with metastatic squamous cell NSCLC, although ROS1 identification may be seen at a lower rate than nonsquamous NSCLC.² Patients with a ROS1 rearrangement are less likely to benefit from immune checkpoint inhibitor therapy due to low expression of PD-L1 and tumor mutational burden.² Therefore, treatment with oral ROS1-targeted therapies is recommended given the higher response rate. The Table reviews the current FDA-approved ROS1-targeted therapies.

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system; CPK, creatine kinase; QTc, corrected QT interval.

NCCN Guidelines recommend entrectinib (Rozlytrek; Genentech, Inc), crizotinib (Xalkori; Pfizer Inc), or repotrectinib (Augtyro; Bristol Myers Squibb) as preferred first-line monotherapy for ROS1 rearrangement discovered prior to first-line systemic therapy.² Ceritinib (Zykadia; Novartis Pharmaceuticals Corporation) is outlined as an additional treatment option. If ROS1 rearrangement is discovered during first-line systemic therapy, it is recommended to either complete the planned therapy or interrupt the planned therapy, followed by entrectinib (preferred), crizotinib (preferred), repotrectinib (preferred), or ceritinib.² Entrectinib or repotrectinib may be better options for patients with brain metastases.²

Upon progression on entrectinib, crizotinib, repotrectinib, or ceritinib, subsequent therapy is based on symptomatic involvement. Lorlatinib (Lorbrena; Pfizer Inc) is recommended as a subsequent therapy option for patients with ROS1-positive metastatic NSCLC and disease progression.² Entrectinib, repotrectinib, or lorlatinib would be recommended as subsequent therapy options for patients with symptomatic brain lesions after progression on crizotinib or ceritinib.²

Crizotinib

Crizotinib is a first-generation oral tyrosine kinase inhibitor (TKI) that inhibits ROS1, ALK, and MET.³ Crizotinib is approved for the treatment of adults with ROS1-positive and ALK-positive metastatic NSCLC.3 Crizotinib has shown efficacy for patients with ROS1 rearrangements, with response rates of approximately 70% to 80%, including complete responses.³

In the phase 1 PROFILE 1001 clinical trial (NCT00585195), patients with ROS1-positive advanced NSCLC were treated with crizotinib at a starting dose of 250 mg orally twice daily. The objective response rate was 72% with crizotinib, and median overall survival (OS) was 51.4 months. The most commonly reported treatment-related adverse events (AEs; > 30%) were vision disorder (87%), nausea (51%), edema (47%), diarrhea (45%), vomiting (38%), elevated transaminases (36%), and constipation (34%).⁴

Entrectinib

Entrectinib is an oral TKI that inhibits several kinases including ROS1, ALK, and TRK. Entrectinib is approved for the treatment of adults with ROS1-positive metastatic NSCLC. Compared with crizotinib, entrectinib has better central nervous system (CNS) penetration but has a higher toxicity profile.⁵

Entrectinib has been studied in several phase 1 and 2 trials for patients with ROS1-positive metastatic NSCLC who received entrectinib at a dose of at least 600 mg orally once daily. An integrated analysis of the ALKA-372-001/STARTRK-1 trial (NCT02097810) and STARTRK-2 (NCT02568267) showed a median duration of response (DOR) of 24.6 months and overall response rate (ORR) of 77%. In patients with CNS disease, intracranial ORR was 55%. In the safety population, 34% of patients had grade 3 or 4 treatment-related AEs, with the most common being weight increase and neutropenia. Serious treatment-related AEs occurred in 11% of patients, with the most common being nervous system disorders and cardiac disorders.⁶

Repotrectinib

Repotrectinib is an oral, next-generation ROS1, ALK, and TRK TKI.⁷ Repotrectinib is approved for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC.⁷ Repotrectinib shows intracranial activity and may be a suitable option in those with resistance mutations, such as ROS1 G2032R.⁸

The TRIDENT-1 phase 1/2 trial (NCT03093116) evaluated patients with ROS1 fusion–positive NSCLC who had not previously received a ROS1 TKI and patients who had previously received crizotinib, entrectinib, or ceritinib but not chemotherapy. Patients received repotrectinib at 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 79% of patients who had not previously received a ROS1 TKI, with a median DOR of 34.1 months and median progression-free survival (PFS) of 35.7 months. Response occurred in 38% of patients who had previously received 1 ROS1 TKI and no chemotherapy, with a mediation DOR of 14.8 months and median PFS of 9 months. Of the patients with a ROS1 G2032R mutation, 59% had a response to repotrectinib.8 The most common treatment-related AEs were dizziness (58%), dysgeusia (50%), and paresthesia (30%).⁸

Ceritinib

Ceritinib is an oral TKI that has activity against ROS1 and ALK.9 Ceritinib can be considered as a treatment option for patients with ROS1-positive NSCLC, but it is not considered a preferred treatment option per NCCN Guidelines.²

A phase 2 study (NCT01964157) demonstrated potent clinical activity of ceritinib in patients with ROS1-rearranged NSCLC. Patients with ROS1-rearranged NSCLC were administered ceritinib 750 mg orally once daily. The ORR was 62%, with a DOR of 21 months. The median PFS was 9.3 months, and OS was 24 months. The most common AEs were diarrhea (78%), nausea (59%), and anorexia.¹⁰

Lorlatinib

Lorlatinib is an oral, third-generation TKI that has activity against both ROS1 and ALK.11 An open-label, single-arm, phase 1/2 trial (NCT01970865) assessed lorlatinib 100 mg orally once daily in patients with advanced ROS1-positive NSCLC with or without CNS metastases.¹² Patients included those who were TKI naive or had disease progression after at least ROS1 TKIs. An objective response was seen in 62% of treatment-naive patients and in 35% of patients previously treated with crizotinib as their only TKI.¹² Intracranial response was achieved in 64% of TKI-naive patients and 50% of previous crizotinibonly patients.12 The most common grade 3 to 4 treatment-related AEs were hypertriglyceridemia (19%) and hypercholesterolemia (14%).¹²

REFERENCES

1. D’Angelo A, Sobhani N, Chapman R, et al. Focus on ROS1-positive non-small cell lung cancer (NSCLC): crizotinib, resistance mechanisms and the newer generation of targeted therapies. Cancers (Basel). 2020;12(11):3293. doi:10.3390/cancers12113293

2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2024. Accessed July 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

3. Xalkori. Prescribing information. Pfizer Inc; 2023. Accessed July 11, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=676

4. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30(7):1121-1126. doi:10.1093/annonc/mdz131

5. Rozlytrek. Prescribing information. Genentech USA Inc; 2024. Accessed July 11, 2024. https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf

6. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):261-270. doi:10.1016/S1470-2045(19)30690-4

7. Augtyro. Prescribing information. Bristol Myers Squibb Company; 2024. Accessed July 11, 2024. https://packageinserts.bms.com/pi/pi_augtyro.pdf

8. 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

9. Zykadia. Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed July 11, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/zykadia.pdf

10. Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017;35(23):2613-2618. doi:10.1200/JCO.2016.71.3701

11. Lorbrena. Prescribing information. Pfizer Inc; 2023. Accessed July 11, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=11140

12. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20(12):1691-1701. doi:10.1016/S1470-2045(19)30655-2

The author has nothing to disclose.