ROS1 Targeted Therapies: Current Status

Christine M. Azelby 1 & Mandy R. Sakamoto 1 & Daniel W. Bowles 2,3 Accepted: 30 April 2021

# This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021

Abstract

Purpose of Review
Molecular drivers are increasingly identified as therapeutic targets for non-small cell lung cancer (NSCLC). This review focuses on the role of ROS1 inhibitors in treating relapsed/metastatic ROS-1 altered (ROS1+) NSCLC.

Recent Findings
Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib. Each drug yields an overall response rates exceeding 60% with ciritinib, lorlatinib, and entrectinib possessing intracranial activity. The drugs have manageable toxicity profiles.

Summary
ROS1 alterations are rare molecular drivers of NSCLC that can be effectively treated with a variety of ROS1-targetd drugs. New agents are being identified that may treat resistance mutations.

Keywords ROS1 . Non-small cell lung cancer . Targeted therapy . Molecular drivers

 

Introduction

Non-small cell lung cancer (NSCLC) accounts for approxi- mately 80% of lung cancers, with ROS1-fusion positive (ROS1+) NSCLC accounting for 1–2%. Patients with ROS1+NSCLC tend to be younger, female, without a signif- icant smoking history, and display adenocarcinoma as the predominant histological subtype. As a gene fusion driven cancer, small molecule inhibitors have been explored to treat this unique disease. Given its genetic and clinical similarities with anaplastic lymphoma kinase (ALK+) NSCLC, several
ALK-targets agents have been repurposed as ROS1 inhibitors. In 2016, the FDA-approved crizotinib as first line therapy for ROS1+ NSCLC based upon the PROFILE 1001 trial. This review will summarize the basics of the ROS1 signaling path- way and touch upon the patterns of metastatic spread, paying particular attention to the prevalence of brain metastasis. Most importantly, this review will provide a summary of first line tyrosine kinase inhibitors (TKIs) used to treat ROS1+ NSCLC patients and new agents under investigation.

 

This article is part of the Topical Collection on Evolving Therapies

* Daniel W. Bowles [email protected]

ROS1 Signaling Pathway and Genetic Rearrangement

The ROS1 gene is located at 6q22 on the long arm of chro- mosome 6 and encodes a receptor tyrosine kinase in the sub-

1

2
Department of Medicine, University of Colorado Anschutz Medical Campus, Colorado, AU, USA
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, 1665 Aurora Court, Colorado, AU, USA
class of the insulin receptor family. Genetic rearrangements in ROS1 result in constitutive activation of the tyrosine kinase, serving as an oncogenic driver for tumor cell proliferation [1]. The ROS-1 oncogene was first identified in 1987 in a glio- blastoma cell line [2]. It was later discovered that the 3′ region

3 Rocky Mountain Regional VA Medical Center, Aurora, CO, USA of ROS1 was found fused to the 5′ region of the fused in
glioblastoma gene (FIG) via the deletion of 240 kb on chro- mosome 6q22, resulting in a fusion protein with a constitu- tively active kinase [3]. Interestingly, the function of the wild- type ROS1 gene in human cellular physiology remains un- clear and its ligand undefined [4].
ROS1 chromosomal rearrangements were subsequently described in non-small cell lung cancer in 2007, and were similarly found to contain fusion genes, identified as SLC34A2-ROS, CD74-ROS [5]. Since then, multiple partner genes have been implicated including TMP3, SDC4, EZR, LRIG3, KDELR2, and CCDC6, all of which appear to fuse with the ROS-1 3’ fragment containing the intact tyrosine kinase domain [6]. The expression of these ROS1 fusion genes results in auto-phosphorylation of the ROS-1 tyrosine kinase initiating a signaling cascade via the MAPK pathway and phosphorylation of RAS. This constitutively activated tyrosine kinase likely drives malignant cell proliferation [7]. ROS-1 gene rearrangements have been identified in various other cancers including colorectal carcinoma, sarcoma, ovar- ian carcinoma, and cholangiocarcinoma. ROS1 rearrange- ments are found in approximately 1–2% of patients with NSCLC [8].
The most common ROS-1 fusion gene product in NSCLC is CD74-ROS [9]. CD74-ROS1 gene fusion proteins expressed in fibroblast models result in activation of common- ly recognized signaling pathways involving SHP-2, MEK, ERK, STAT3, and AKT. Interestingly, the tyrosine kinase domain of ROS-1 is structurally similar to anaplastic lympho- ma kinase (ALK), another molecular driver of NSCLC. Given the structural similarities, crizotinib, an ALK inhibitor, was successfully repurposed as a ROS1 inhibitor, leading to its approval to treat ROS1+ NSCLC [10]. ROS1 TKIs will be detailed below.
Despite several TKIs’ success in treating ROS1+ NSCLC, emerging resistance poses a significant threat to their clinical utility. There are seven ROS1 mutations conferring resistance to TKIs that have been documented in the literature. Most notable is the G2032R mutation, which occurs in the solvent-front region of the ATP-binding site of ROS1 and is analogous to an ALK resistance mutation, G1202R, seen after development of crizotinib, ceritinib, and alectinib resistance [11, 12]. The G2032R mutation in ROS1+ NSCLC is believed to result in steric hindrance in the presence of crizotinib [11]. Additional ROS1 mutations that have been identified include D2033N and S1986F. The D2033N mutation results in a loss of electrostatic potential at the ATP binding site on the recep- tor inhibiting binding with crizotinib [13]. ROS1 S1986F is suspected to confer resistance by causing a conformational change in the ROS1 kinase domain, the target of crizotinib [14]. In a study analyzing biopsy specimens of patients with metastatic ROS1+ NSCLC who progressed on crizotinib, ROS1 resistance mutations were identified in 9/17 (53%) bi- opsy specimens. All patients underwent tissue sampling

within 7 days of crizotinib discontinuation, and persistence of the original ROS1 rearrangement was identified in 9/9 (100%) of the specimens. The resistance mutations identified included G2032R (41%), D2033N (6%), and S1986F (6%) [12]. Thus, identification and classification of ROS1 muta- tions, along with the development of new therapies to target these mutations, is essential.
Clinicopathologic Features of ROS-1 rearranged NSCLC

A meta-analysis of 18 studies comprising 9898 patients with NSCLC found that ROS1+ NSCLC tends to develop in pa- tients who are never smokers, are of an average younger age compared with other types of lung cancers, and are most com- monly found to have adenocarcinoma on histology. There was also a higher prevalence of the ROS1 fusion gene in Caucasian female patients compared with Caucasian male pa- tients (OR =1.54, 95% CI: 1.02-2.34, P=0.042) [15]. This mirrors the clinical characteristics found in patients with ALK+ NSCLC. Interestingly, ROS1 mutations rarely occur with simultaneous mutations in ALK, EGFR, and KRAS [16]. Despite its homology to the ALK rearrangement and similar clinical characteristics, dual positive ROS1/ALK fusion genes rarely co-exist [17]. In another study of 103 patients with ROS1-positive NSCLC, only 4.8% had EGFR mutations coexisting with their ROS1 rearrangements. The clinical sig- nificance remains unclear [18•].
Given the similar molecular and clinical characteristics of ALK+ and ROS1+ NSCLC, several studies have compared crizotinib response rates patients with ALK and ROS1 gene mutations. A retrospective study of f 30 ROS1+ and 175 ALK1 NSCLC treated with crizotinib found that ROS1+ dis- ease had a significantly longer median progression free sur- vival (PFS) with crizotinib compared to those with ALK+ disease (11.0 v 7.9 months; P = .007). When these findings were adjusted for patients receiving crizotinib as a second-line therapy, patients with ROS1+ NSCLC also exhibited a longer median PFS (11.5 v 8.8 months), yet this did not reach statis- tical significance (P = .086). However, there was no difference in median overall survival between patients with ALK+ and ROS1+ NSCLC [12].
Studies have investigated the metastatic pattern of spread in ROS1+ NSCLC [19]. One study evaluated 39 and 196 pa- tients with metastatic ROS1+ and ALK+ NSCLC, respective- ly, finding a similar incidence of metastatic involvement for the majority of disease sites; however, ROS1+ patients had a significantly lower rate of brain metastases at initial metastatic diagnosis compared to ALK+ patients (ROS1, 19.4%; ALK, 39.1%; P = .033). Additionally, patients with ROS1+ disease had significantly lower rates of total extra thoracic metastases (ROS1, 59.0%; ALK, 83.2%; P = .002) [12]. These results
conflict with a subsequent retrospective review of 33 patients with ROS1+ and 115 patients with ALK+ stage IV NSCLC taking crizotinib. These patients did not reveal a statistically significant difference in the incidence of brain metastases be- tween ROS1+ (12/33; 36%) and ALK+ NSCLC (39/115; 34%) [20]. However, the brain remains a common site of distant metastases in NSCLC regardless of the type of onco- genic driver, and effective targeted therapies with optimal rates of CNS penetration are needed.
There has also been interest in analyzing the differing met- astatic patterns and responses to TKIs among different ROS1 fusion partner genes. This was inspired by the difference in responses to treatment between various EGFR and ALK mu- tations in NSCLC [21, 22]. One study looked at 36 ROS1+ tumor specimens from patients with NSCLC treated with cri- zotinib. Nineteen of these specimens were found to harbor the CD74-ROS1 mutation, the most common fusion partner. When compared to non-CD74-ROS1+ NSLC, this study found that patients with CD74ROS+ positive NSCLC were more likely to have brain metastases prior to therapy (six versus 0; p = 0.020). Furthermore, there was a possible trend towards longer PFS and OS in the non-CD74-ROS1+ positive cohort, but this did not achieve statistical significance on the multivariate analysis [23]. These findings do propose the pos- sibility that classification of the ROS1 fusion partner mutation may be relevant to treatment choice as our understanding of these mutations expands.
ROS1 Targeted Therapies in NSCLC

There are several TKIs that inhibit both ROS1 and ALK and are approved to treat either form of NSCLC. These include crizotinib, ceritinib, and lorlatinib. Other agents, including entrectinib, inhibit ROS1 and NTRK. The approved and ex- perimental ROS1 inhibitors are summarized in Table 1 with key toxicities described in Table 2.
Crizotinib

Crizotinib (Xalkori®) was the first TKI to receive FDA ap- proval to treat advanced ROS1-rearranged NSCLC [24]. Approval was based on the expansion cohort of PROFILE 1001, a multicenter, single-arm, phase I clinical trial of 50 patients with metastatic ROS1-positive NSCLC [25]. All pa- tients received crizotinib 250 mg twice daily. Initial results demonstrated an overall response rate (ORR) of 72% (95% CI, 58–84%) with median duration of response (DOR) of 17.6 months (95% CI, 14.5-not reached), disease control rate (DCR) of 90%, and median progression free survival (PFS) of 19.2 months (95% CI, 14.4-not reached). Updated analysis revealed a median overall survival (OS) of 51.4 months (95%

CI, 29.3-not reached) as well as an increase in median DOR to 24.7 months after a median follow up of 62.6 months [26••]. There was no correlation between the type of ROS1 rearrange- ment and survival or treatment response to crizotinib. Of note, the proportion of patients with baseline CNS disease was not reported. Side effect from crizotinib includes visual impair- ment, edema, and various gastrointestinal toxicities (Table 2).
Several phase II clinical trials evaluating crizotinib’s efficacy in ROS1-positive NSCLC have since been performed. In an open-label, single-arm trial of 127 East Asian patients with ROS1-rearranged NSCLC, the ORR was 71.7% (95% CI, 63.0–79.3%) regardless of baseline brain metastases or prior lines of therapy [27]. The median PFS was 10.2 months (95% CI, 5.6–13.1) in patients with baseline CNS disease, compared to 18.8 months (95% CI, 20.1–23.0) in patients without CNS disease. Patients with baseline brain metastases accounted for 18% of the study population and were included if asymptomatic or neurologically stable for at least two weeks if treated. A recent multicenter, single-arm, phase II trial of 34 European patients with advanced ROS1-positive NSCLC showed a sim- ilar ORR of 70% (95% CI, 51–85%) and median PFS of 20.0 months (95% CI, 10.1-not reached) [28]. TP53 co-mutant pa- tients were found to have a shorter median PFS of 7.0 months (95% CI, 1.7–20.0) compared to 24.1 months (95% CI, 10.1– not reached) in wild-type patients. Patients with baseline brain metastases accounted for 21% of the study population and were included if asymptomatic and not receiving increasing doses of steroids. Intracranial ORR was not reported in either study.
Despite high initial response rates, the majority of patients treated with crizotinib eventually experience disease progres- sion due to inadequate drug CNS penetration and/or the de- velopment of ROS1 resistance mutations [29, 30].
Ceritinib

Ceritinib (Zykadia®) is a second-generation TKI approved to treat of TKI-naïve and crizotinib-resistant ALK-positive NSCLC [31]. It is also a selective inhibitor of ROS1 with 20 times greater potency than crizotinib in preclinical studies [32–35]. A phase II clinical trial of 30 crizotinib-naive patients with ROS1-positive NSCLC revealed an ORR of 67% (95% CI, 48–81%) with a DOR of 21 months (95% CI, 17–25 months) and median PFS of 19.3 months (95% CI, 1–37 months) [35]. There were initially two patients who received prior crizotinib therapy; however, no responses were ob- served, and the trial was subsequently revised to include only crizotinib-naïve patients. Among eight patients with CNS dis- ease, including one crizotinib-resistant patient and seven cri- zotinib-naïve patients, the IC-ORR was 25% (95% CI, 7– 59%) and IC-DCR was 63% (95% CI, 31–86%). While this study showed that ceritinib may be a promising frontline ther- apy option in ROS1-positive NSCLC, its role in crizotinib-
Table 1 Summary of clinical

trials in ROS1+ NSCLC
Drug Study PFS ORR Incidence of brain metastases
IC-ORR
Crizotinib

PROFILE 1001* 19.2 m
(14.4-NE)

72% (58-84%;
36/50)

NR

NR

OO-1201
15.9 m
(12.9-24.- 0)
72% (63-79%;
91/127)
18% (23/127) NR

EUCROSS
9.4m
(1.7-NE) – BM
20m
(10.1-NE) – no BM
73% (54-88%;
21/30)
21% (7/34)
NR

Ceritinib
Pan-Korean study 9.3 m (0-22)
- all 19.3 m
[1–37] – CN
62% (45-77%;
20/32)—all 67% (48-81%;
20/30)—CN
25% (8/32)
25% (7–59%;
2/8)—all

Entrectinib
STARTRK 1/2
and
ALKA-372-001
19.0 m
(12.2-36.- 6) – all
13.6 m
(4.5-NE) – BM
26.3m [16–37] – No BM
77% (64-88%;
41/53)—all 74% (52-90%;
17/23)—BM 80% (61-92%;
24/30)—no BM
43% (23/53)
55% (32–77%; 11/20)

Lorlatinib
Lorlatinib Phase 2 9.9 m
(5.5-21) – all
21m
(4.2-26.7)
- CN 8.5 m
(4.4-18) – CP
36% (23-52%;
17/47)—all 62% (32-86%;
8/13)—CN 27% (13-44%;
9/34)—CP
53% (25/47)—
all
46% (5/13)—
CN
56% (19/34)—
CP
66% (22–96%; 4/6)—CN
52% (29
-76%; 10/19)—CP

Taletrectinib DS-6051b Phase 1 NR
58% (CI NR;
7/12)—all 67% (CI NR;
6/9)—CN
33% (5/15)
NR

Repotrectinib TRIDENT Phase 1 NR
80% (44-97%;
8/10)—CN 18% (4-44%;
3/17)—CP
53% (16/30)—
all
50% (5/10)—
CN
55% (11/20)—
CP
100% (29–100; 3/3)—CN
25% (1–81;
1/4)—CP
Abbreviations: PFS, progression free survival; ORR, overall response rate; IC-ORR, intracranial overall response rate; CN, crizotinib naïve; CP, crizotinib pretreated; BM, brain metastases (at baseline); NR, not reported; NE, not achieved
*Only the PROFILE 1001 has published overall survival data and therefore this was not included in summary table

 

resistant patients may be limited. These findings are consistent with preclinical data demonstrating that ceritinib is unable to overcome several crizotinib-resistant ROS1 mutations includ- ing G2032R, D2033N, L1951R, and S1986Y/F [36–39]. Compared to crizotinib, the phase II trial also identified a
higher incidence of ceritinib-related adverse effects including diarrhea (78%), nausea (59%), anorexia (56%), and vomiting (53%) when using a daily dose of 750 mg (Table 2) [25, 26, 35]. According to the ASCEND-8 study, however, a lower
Table 2 Summary of adverse

events (AEs) from ROS1 inhibitor clinical trials
Drug Overall AEs in ≥ 10% of patients Treatment-related AE (≥ grade 3)

Crizotinib
Visual impairment (82%) Diarrhea (42%) Constipation (32%) Peripheral edema (30%) Nausea (26%)
Elevated AST (18%) Dizziness (16%)
Hypophosphatemia (10%) Neutropenia (10%) Elevated ALT (4%) Vomiting (2%)

Ceritinib
Diarrhea (78%) Nausea (59%) Anorexia (56%) Vomiting (53%) Cough (47%)
Elevation of creatinine (41%) ALT/AST increase (31%)
Fatigue (16%)
AST increase (9%) Hyperglycemia (9%) Anemia (6%)
Nausea (3%)

Lorlatinib
Hypercholesterolemia (83%) Hypertriglyceridemia (60%) Edema (45%)
Peripheral neuropathy (34%) Cognitive effects (23%) Weight gain (21%)
Dizziness (15%)
Hypercholesterolemia (18%) Hypercholesterolemia (9%) Weight gain (6%)
Lipase elevated (6%) Edema (2%)
Peripheral neuropathy (2%)

Entrectinib
Dysgeusia (41%) Fatigue (28%) Dizziness (25%) Constipation (24%) Nausea (21%) Weight gain (19%) Paresthesia (19%)
Weight gain (5%) Anemia (5%) Fatigue (3%) Diarrhea (1%) Dizziness (1%) Myalgias (1%)

Repotrectinib
AST increased (92%) ALT increased (75%)
LFT elevated (27%) Retinal detachment (7%)
Interstitial lung disease (7%) CPK elevated (7%) Hypoalbuminemia (7%) Anemia (7%)

Repotrectinib
Dizziness (50%) Paresthesia (29%) Constipation (19%) Fatigue (18%) Anemia (12%) Nausea (11%)
Anemia (4%) Dizziness (3%)

 
dose of ceritinib at 450 mg daily resulted in improved toler- ance while maintaining similar clinical efficacy [40].
Lorlatinib

Lorlatinib (Lorbrena®) is a selective ROS1 and ALK TKI with robust CNS penetration and preclinical activity against

 

many ROS1 resistance mutations (39, 49, 50). A recent mul- ticenter, open-label, single-arm phase I/II trial evaluated 69 patients with advanced ROS1-positive NSCLC of which 30% were ROS1 TKI-naïve, 58% were previously treated with crizotinib and 12% were previously treated with one non-crizotinib ROS1 TKI or two or more ROS1 TKIs. Fifty- seven percent had brain metastases at baseline. Among all patients, the ORR was 41% (95% CI, 29 – 53).
Unsurprisingly, lorlatinib’s activity was significantly higher in TKI-naïve patients (ORR 62%; 95% CI, 38–82% and PFS 21.0 months; 95% CI, 4.2–31.9) compared to crizotinib- treated patients (ORR 35%; 95% CI, 21–52% and PFS 8.5 months; 95% CI, 4.7–15.2). Further analysis demonstrated that lorlatinib is unable to overcome the most common ROS1 resistance mutation, G2032R, which may explain these differences. Among patients with baseline CNS dis- ease, intracranial response was achieved in 64% of TKI- naïve patients and 50% of crizotinib-treated patients; me- dian DOR was not reached in either group of responders. Grade 3 or 4 adverse events were observed in 49% of patients with the most common being hypertriglyceridemia (19%) and hypercholesterolemia (14%) (Table 2). No treatment-related deaths occurred.
Entrectinib

Entrectinib (Rozlytrek®) is a multikinase inhibitor with activ- ity against ROS1, ALK, and TRK [41–44]. It has potent in- tracranial activity due to its ability to cross the blood-brain barrier and achieve substantial concentrations in the CNS [43]. In August 2019, entrectinib was granted accelerated ap- proval by the FDA for the treatment of metastatic ROS1+ NSCLC based on data from an integrated efficacy analysis of the STARTRK-1, STARTRK-2, and ALKA-372-001 trials [45–47]. Updated findings were published in 2020 [48•]. In the trials, 53 ROS1+ inhibitor-naïve patients were evaluated for ORR and DOR as coprimary endpoints, and PFS, OS, intracranial (IC)-ORR, IC-DOR, and safety as secondary end- points. Most patients were female (64%), white (59%), never- smokers (59%), had an ECOG PS of 1 (51%), and received at least one prior systemic therapy (68%). Baseline CNS disease was present in 43% of patients. Patients received entrectinib at a dose of at least 600 mg once daily with 12 months of follow- up. The ORR was 77% (95% CI, 64-88%) with median DOR of 24.6 months (95% CI, 11.4-34.8) and median PFS of 19 months (95% CI, 12–37). Among patients with baseline CNS disease, ORR was 74% (95% CI, 52–90) with a median DOR of 12.6 months (95% CI, 6.5-not reached) and median PFS of 13.6 months (95% CI, 4.5-not reached). The IC-ORR was 55% (95% CI, 32–77) with an IC-DOR of 12.9 months, sug- gesting that entrectinib is active both systemically and in the CNS. Among patients without baseline CNS disease, ORR was 80% [61-92] with a median DOR of 24.6 months (95% CI, 11.4-34.8) and median PFS of 26.3 months (95% CI, 15.7–36.6). The median OS was not estimable at a median follow-up of 15.5 months. The degree of response did not differ by upstream ROS1 fusion partner type (CD74 vs non- CD74). The most common grade 3 or 4 adverse events were weight gain (8%) and neutropenia (4%). Serious treatment- related adverse events occurred in 11% of patients, with the

most common being nervous system disorders (3%) and car- diac disorders (2%) (Table 2). No deaths due to adverse events occurred.
Next Generation Therapies to Combat Resistance Mutations in ROS1+ NSCLC

The inevitable development of resistance mutations in ROS1+ NSCLC treated with first-line TKIs remains a clinical chal- lenge. Currently, second-line therapy after disease progression remains platinum- and pemetrexed-based chemotherapy, which only provides a median PFS of 7 months [49]. To date, there are no approved second-line targeted therapies for crizo- tinib, ceritinib, or entrectinib-resistant ROS1+ NSCLC, but there are promising data from next generation ROS1 inhibitor trials.
Cabozantinib

Cabozantinib is clinically available and approved to treat pa- tients with medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma [50–52]. Preclinical studies suggest that cabozantinib inhibits several ROS1 solvent front muta- tions, including G2032R [53]. One published study reviewed four patients with ROS1+ NSCLC who developed secondary resistance to crizotinib or primary resistance to ceritinib and were trialed on cabozantinib at doses ranging from 40 to 60 mg. The objective response rate was 25%, and PFS time rang- ing from 4.9 to 13.8 months [54]. Unfortunately, there were no tissue samples to identify specific resistance mutations pri- or to cabozantinib, and it is not clear if the responses were due to ROS1 inhibition or other cabozantinib effects. Nonetheless, cabozantinib may play a role as part of second-line treatment of ROS1+ NSCLC.
Taletrectinib (DS-6051b)

In preclinical models, taletrectinib, a dual inhibitor of ROS1 and NTRK1/2/3, was found to be effective in inhibiting the growth of crizotinib resistant ROS1- CD74, L1951R, L2026M, S1986F, and G2032R mutant Ba/F3 cells in vitro [55]. An all comer phase 1 study of patients with ROS1 or NTRK fusions included 6 ROS1+ NSCLC. The ORR was 33% with two additional patients achieving stable disease in ROS1+ NSCLC [56]. In March 2020, the Chinese Drug Evaluation Agency approved taletrectinib for use in an open-label, single-arm, multi-center study phase II clinical trial, which will enroll first- and second-line ROS1+ NSCLC patients [57].
Repotrectinib

In preclinical models, repotrectinib, an inhibitor of ROS1, ALK, and NTRK1/2/3, had potent kinase inhibitory activity against the G2032R and D2033N solvent front mutations in ROS1 as well as improved CNS penetration [58]. The TRIDENT-1 trial (NCT03093116), an ongoing phase 1/2 clinical trial of repotrectinib, recently published preliminary data. This trial included 33 patients with ROS1-positive NSCLC, comprising 11 patients who were TKI naive and 22 patients pre-treated with TKIs (mostly crizotinib), as well as 18 patients with CNS metastases. Patients received escalated doses of repotrectinib from 40 mg daily to 200 mg twice daily. In TKI-naïve patients, overall response rate (ORR) was 82% (9/11). In TKI-pretreated patients, ORR was 32% (7/22), and 55% in patients pretreated with 1 TKI and given a dose of 160 mg QD or above. The ORR in patients with identified G2032R solvent front mutations (n=5) was 40%. The intracranial-ORR was 100% in the subset of 3 with measur- able CNS disease at baseline and the intracranial-ORR with 1 prior TKI treatment was 75%. This trial is ongoing with plans for a Phase 2 TRIDENT-1 registrational study [59].
Conclusion

ROS1+ NSCLC is a unique, molecularly driven form of lung cancer. There are currently three agents approved in the first- line setting, though resistance to available ROS1 inhibitors presents a significant clinical challenge. ROS1-target drugs and their eventual next generation replacements will serve an important role in managing 1–2% of NSCLC harboring activating ROS1 gene fusions.
Declarations

Conflict of Interest None of the authors has any potential conflicts of interest to disclose.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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