In the first article of a 2-part series, Christine Bestvina, MD, discussed the role of the newer tyrosine kinase inhibitor repotrectinib for patients with non–small cell lung cancer that is positive for a ROS1 mutation.
CASE SUMMARY
First-Line Therapy
Follow-Up Plan:
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].
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
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