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Current status and challenges of ROS1-TKIs treatment
Organize | Blue sky, Xiao Qi
On May 11, repretinib was approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).
Figure 1 Screenshot of the approved application
The approval builds on the TRIDENT-1 pivotal study, which evaluated the efficacy of repretinib in treatment-naïve patients with tyrosine kinase inhibitors (TKIs) and patients with ROS1-positive NSCLC who have received TKIs.
Results showed that 79% (95% CI: 68-88) of treatment-naïve patients responded to treatment, 6% achieved complete response (CR), and 73% achieved partial response (PR). The median duration of response (mDOR) was 34.1 months. Among patients previously treated with a TKI (n=56), the ORR was 38% (95% CI: 25-52), with CR in 5% and PR in 32%, with an MOR of 14.8 months. Of the patients with measurable brain metastases at baseline, an intracranial response was observed in 7 of 8 treatment-naïve patients; Of the 12 patients who had received TKIs, an intracranial response was observed in 5.
The FDA-approved dose of repretinib is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or intolerable toxicity.
ROS1-TKIs: Classical drugs are still the "mainstay", and new drugs can be expected in the future
In addition to the recently approved repretinib drugs, the medical community has compiled the current status and research data of other ROS1 target drugs[1] to take you to understand ROS1-positive NSCLC and diagnosis and treatment options in one article.
At present, the classic targeted drugs of ROS1 are crizotinib, ceritinib and entrectinib; At the same time, a new generation of drugs also plays an indispensable role, such as lorlatinib, repretinib, tarelitinib, TQ-B3139, cabozantinib and brigatinib.
1 crizotinib
Crizotinib is the first FDA-approved drug for advanced ROS1 fusion-positive NSCLC based on the Phase I PROFILE 1001 study. The results showed that a total of 50 patients with advanced NSCLC who were treated with standard-dose crizotinib had an objective response rate (ORR) of 72%, a median duration of response (DOR) of 17.6 months, and a mean progression-free survival (PFS) of 19.2 months. At the same time, the latest follow-up data showed that the DOR increased by 24.7 months and the PFS increased by 19.3 months after patients receiving crizotinib, with adverse effects including visual impairment, edema, vomiting and diarrhea.
Follow-up phase II single-arm trials (NCT01945021), EUROS1 and EUCROSS trials have also demonstrated efficacy in patients with NSCLC of different ethnicities. However, the majority of patients with advanced NSCLC treated with crizotinib will eventually develop disease progression due to ROS1 resistance or central nervous system (CNS) metastases.
2 ceritinib
Seritinib is currently approved by the NMPA for the first-line treatment of ALK-positive locally advanced or metastatic NSCLC, but multiple studies have also demonstrated the efficacy of ceritinib in ROS1-positive NSCLC.
A phase II trial (NCT01964157) showed that patients treated with standard doses of ceritinib (750 mg once daily) had an ORR of 62%, a DOR of 21 months, and a mean PFS of 9.3 months, with common adverse events (AEs) being gastrointestinal symptoms (78% diarrhea, 59% nausea, and 56% anorexia).
3 Entrectinib
Entrectinib is the second targeted drug approved by the FDA for the treatment of patients with advanced ROS1-positive NSCLC, based on Phase I/II clinical trials (ALKA-372-001, STARTRK-1 and STARTRK-2).
The results showed an ORR of 67.1% and a DOR and PFS of 15.7 months. At the same time, due to the weak interaction between entrectinib and P-glycoprotein, it can cross the blood-brain barrier, and is also effective for NSCLC patients with CNS metastases. The results showed that the subgroup with CNS metastases had an ORR of 79.2%, a DOR of 12.9 months, and a PFS of 12.0 months, and the main adverse reactions were weight gain and neutropenia.
4 lorlatinib
In the single-arm Phase I-II trial (NCT01970865), lorlatinib demonstrated an ORR of 62% and a PFS of 21.0 months for TKI-naïve patients and an ORR of 35% and a PFS of 8.5 months for crizotinib-treated patients. Common adverse effects included hypertriglyceridemia (19%) and hypercholesterolemia (14%).
5. Repretinib
Recently, repretinib was approved by the NMPA for the treatment of adult patients with ROS1-positive locally advanced or metastatic NSCLC.
6 taretinib
Phase I studies in the United States (NCT02279433) and Japan (NCT02675491) showed an ORR of 66.7% and a mean PFS of 29.1 months for treatment-naïve ROS1-positive NSCLC, compared with an ORR of 33.3% and a PFS of 14.2 months for patients treated with TKIs, with adverse effects including abnormal liver function (72.7%) and gastrointestinal symptoms (50%).
7 Miscellaneous
The clinical efficacy of TQ-B3139 has been preliminarily validated, with a Phase I trial (NCT03099330) showing an ORR of 66.7% and a PFS of 20.2 months (PR) or 27.0 months (CR) in patients treated with TQ-B3139. Cabozantinib (ORR, 25%; PFS: 4.9-13.8 months) and brigatinib (ORR, 29%) also showed potent antitumor activity.
Notably, next-generation TKIs also performed well in NSCLC patients who were resistant to TKIs, such as repretinib for G2032R/D2033N mutations, lorlatinib and tarelitinib for G2032R mutations, and cabozantinib and brigatinib for CD74 mutations.
At present, ROS1-TKIs face three major challenges
1. Adverse reactions: The use of most ROS1-TKIs in clinical practice is limited because there are many adverse reactions related to their mechanism of action and may be life-threatening, such as edema, visual impairment, gastrointestinal symptoms, and in severe cases, abnormal liver function, neutropenia, etc.
2. Drug resistance: The long-term use of ROS1-TKIs usually produces drug resistance. The mechanisms of drug resistance include mutations in the kinase domain (G2032R, D2033N, etc.) and activation of bypass signals, and there are also some unknown mechanisms of drug resistance. The main solution is to use the new generation of ROS1-TKIs or in combination with other ROS1-TKIs.
3. CNS metastasis: CNS metastasis occurs in about 36% of patients with stage IV ROS1-positive NSCLC. Patients with CD74 ROS1-positive NSCLC have a higher probability of CNS metastases than non-CD74 ROS1-positive patients. Fortunately, the new generation of ROS1-TKIs shows potential.
As a proto-oncogene, ROS1 is mainly expressed in malignant tumors such as NSCLC. At present, only a few ROS1-TKIs have been approved for NSCLC, and the efficacy of other ROS1-TKIs in NSCLC and other malignancies has not been determined and is still being explored in clinical trials. Due to the high affinity of the new generation of ROS1-TKIs, it may be able to solve the problem of drug resistance and delay the transfer of CNS to a certain extent, but at the same time, it may bring a higher incidence of adverse reactions.
Overall, the new generation of ROS1-TKIs is worth looking forward to. At present, there are relevant studies to further explore the new generation of ROS1-TKIs, including the localization of ROS1 and its fusion partners, the binding site of targeted drugs, and the combination regimen with other drugs. In addition, the relevance of TKIs to chemotherapy or immunotherapy in clinical practice needs to be further studied.
参考文献：[1] Li S, Zhang H, Chen T, Zhang X, Shang G. Current treatment and novel insights regarding ROS1-targeted therapy in malignant tumors. Cancer Med.2024; 13(8):e7201.doi:10.1002/cam4.7201
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