ROS1-rearranged Non-small Cell Lung Cancer Research Articles

Association of PD-L1 expression and clinical outcomes in ROS1 - rearranged advanced non-small cell lung cancer treated with crizotinib

BackgroundProgrammed cell death ligand 1 (PD-L1) is more readily expressed in ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancer (NSCLC) compared to NSCLC cases lacking driver gene mutations. Prior research has established a link between PD-L1 expression and reduced effectiveness of EGFR or ALK inhibitors in EGFR or ALK-positive NSCLC. Nonetheless, the relationship between initial PD-L1 levels and the clinical impact of first-line crizotinib therapy in ROS1-rearranged NSCLC is still uncertain.MethodsFrom January 2016 to December 2021, a total of 246 patients with ROS1 positive tumors were collected. Out of these, 82 patients with advanced ROS1-rearranged NSCLC, who were treated with crizotinib as their initial therapy, were selected for the study. The study aimed primarily to evaluate the objective response rate (ORR) and progression-free survival (PFS), and secondarily to assess disease control rate (DCR) and overall survival (OS).ResultsOf the 82 advanced ROS1-rearranged NSCLC patients, 38 exhibited PD-L1 positivity, subdivided into 11 with high and 27 with low expression levels, while the remaining 44 showed no PD-L1 expression. The ORR for all included patients was 80.5%. No statistically significant variance in ORR was observed among ROS1-rearranged NSCLC patients across differing PD-L1 expression statuses. However, there was a statistically significant difference in DCR between PD-L1 negative group (100%) and high expression group (90.9%) (p=0.04). The median PFS spanned 26.4 months for the PD-L1 negative group, 16.6 for the low expression group, and 13.7 for the high expression group (p=0.001). Additionally, a notable statistical disparity was also observed in median PFS between the PD-L1 negative and positive groups (p=0.02). For the entire study population, the median OS was 53.0 months (95% CI 43.8 - 62.2). In the PD-L1-negative group, the median OS reached 57.2 months, compared to 53.0 months in the PD-L1-positive group, a difference lacking statistical significance (p=0.43).ConclusionsOur results suggest that for ROS1-positive NSCLC patients receiving crizotinib as first-line therapy, PD-L1 expression may serve as a negative prognostic marker for PFS rather than OS.

ROS1 Positive Non-Small Cell Lung Cancer Patient with Brain Metastases Who Overcame Crizotinib Resistance with Lorlatinib: Case Report

Background: ROS1-positive patients account for 1-2% of non small cell lung cancer (NSCLC) cases. Crizotinib is the first tyrosine kinase inhibitor (TKI) indicated in first line treatment of ROS1-rearranged NSCLC. However, crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. Case report: We report a case of a 43-year-old female patient with no medical history, diagnosted with stage IVB NSCLC including asymptomatic brain metastasis, and harboring ROS1 rearrangement. Within the first three months of starting crizotinib, the patient showed on CT scan evaluation new bone and brain metastases. Lorlatinib in the second line revealed a noteworthy improvement in metastasis and primary lesion. Conclusion: Brain metastases frequently occur in ROS1-rearranged NSCLC at the time of diagnosis and treatment course. However the efficacy of crizotinib might not translate to intracranial control of the disease, one of the cause of resistance to this drug.

Real-World Outcomes of Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer

Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74–ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib’s sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.

Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

O7-3 Phase II study of brigatinib in patients with TKI-naive ROS1-rearranged non-small cell lung cancer (NSCLC): Barossa study

O7-3 Phase II study of brigatinib in patients with TKI-naive ROS1-rearranged non-small cell lung cancer (NSCLC): Barossa study

Activity of ceritinib in crizotinib-resistant ROS1-rearranged non-small-cell lung cancer patients.

As a second-generation selective oral anaplastic lymphoma kinase inhibitor, ceritinib is an effective first-line treatment for c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC). Its efficacy and safety for the treatment of crizotinib-resistant ROS1-rearranged NSCLC were explored in the study. A retrospective single-center study was conducted to investigate the efficacy of ceritinib in crizotinib-resistant ROS1-rearranged NSCLC. The objective response rate was the primary objective, while the disease control rate, progression-free survival and adverse events were secondary objectives. From December 2015 to October 2021, a total of 246 patients with ROS1-rearranged NSCLC were screened, 12 (4.9%) of whom were treated with ceritinib after the development of crizotinib resistance. Among the 12 crizotinib-resistant patients included, 3 displayed the efficacy of partial response and 3 had the efficacy of stable condition. The objective response rate, disease control rate and median progression-free survival of all patients were 25% (95% confidence interval [CI]: -3.7% to 53.7%; 3 of 12 patients), 50% (95% CI: 16.8% to 83.2%; 6 of 12 patients), and 10.5 months (95% CI, 5.7 to 15.3 months), respectively. In addition, of the 6 patients with brain metastases, an intracranial disease control rate of 66.7% (95% CI:12.5% to 120.9%) was obtained. The research results reveal that ceritinib can be a treatment option for ROS1-rearranged NSCLC patients after the development of crizotinib resistance.

Efficacy of Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With ROS1-Rearranged Advanced Lung Adenocarcinoma: A Multicenter, Retrospective Cohort Study.

Immune checkpoint inhibitors (ICIs) exert robust antitumor activity in non-small-cell lung cancer (NSCLC) without actionable mutations. Apart from isolated case reports, the efficacy of PD-1 blockade in ROS1-rearranged NSCLC is currently unknown. This retrospective cohort study included 23 patients with ROS1-rearranged advanced lung adenocarcinoma who received ICI plus chemotherapy regardless of the treatment setting. ICI plus chemotherapy was received as a later-line regimen by 14 patients, as the first-line regimen by six patients, and after chemoradiotherapy by three patients. All three patients who received chemoradiotherapy followed by ICI plus chemotherapy achieved partial response (PR) and had a progression-free survival (PFS) of >17.9 months. Of the six patients who received first-line ICI plus chemotherapy, five patients achieved PR and one had stable disease (SD), with a median PFS of 24.3 months (95% CI, 4.9 to 43.7). Of the 14 previously treated patients who received later-line ICI plus chemotherapy, the Objective Response Rate (ORR) was 28.6%, the Disease Control Rate (DCR) was 92.9%, and the median PFS was 5.8 months (95% CI, 0.2 to 9.4). The median time on ICI therapy was 10.0 months (95% CI, 1.5 to 32.5). The duration of response was 24.3 months (95% CI, 5.4 to 43.2) and 4.8 months (95% CI, 2.3 to 12.7) for first-line (n = 5) and subsequent-line (n = 4) ICI plus chemotherapy, respectively. Of the 10 patients with brain metastasis before receiving ICI plus chemotherapy, four patients achieved intracranial PR and five patients achieved intracranial SD, achieving an intracranial ORR of 40.0% and an intracranial DCR of 90.0%. Our retrospective study provides real-world clinical evidence that ROS1-rearranged NSCLCs benefit from ICI plus chemotherapy in any treatment setting, including patients who present with brain metastasis.

Yes-associated protein 1 mediates initial cell survival during lorlatinib treatment through AKT signaling in ROS1-rearranged lung cancer.

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements.

Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non-small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor-associated fibroblasts, critically affect the sensitivity to targeted drugs. We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1-rearranged colon cancer KM12SM cells and ROS1-rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF-induced entrectinib resistance was reversed by the active-HGF-specific macrocyclic peptide HiP-8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF-producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF-producing fibroblasts. Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co-administering inhibitors of resistance-inducing growth factors may maximize the therapeutic efficacy of entrectinib.

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC

ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease.

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK, ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK, ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK-rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases.This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

977P Phase II study of brigatinib in patients with tyrosine kinase inhibitor (TKI)-naïve ROS1-rearranged advanced non-small cell lung cancer (NSCLC): Barossa cohort 1

Barossa is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. We report the results of the cohort 1, in which TKI-naïve ROS1-rearranged NSCLC patients were enrolled. Patients with advanced, TKI-naïve ROS1-rearranged advanced NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoints were PFS, OS, and safety. The sample size was set at 28 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 50% and 75%, respectively. Between September 2019 and May 2020, 28 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 65 (38-81) years; women, n=18 (64%); ECOG PS of 0-1, n=28 (100%); never smoker, n= 16 (57%); tumor histopathological type: adenocarcinoma, n=27 (96%); brain metastasis, n=8 (29%). The median duration of follow-up for PFS was 9.3 months. Seventeen patients (61%) continued study treatment at the data cutoff date of 30 Nov 2021. The primary endpoint was met as 19 patients achieved PR with ORR at 67.9% (90%CI, 50.6-82.1%). Another 3 patients achieved SD and the disease control rate was 78.6% (95%CI, 59.0-91.7%). The PFS and OS were not yet mature: the median PFS was 12.0 months (95% CI, 5.8-not evaluable). Twenty-five out of the 28 patients remained alive at the data cutoff. Grade 3 pneumonitis, which was considered treatment-related, was observed in 3 patients (10.7%), and all 3 cases resulted in treatment discontinuation. Pneumonitis was improved with steroid therapy in all 3 patients. Other grade ≥3 TRAEs were CPK increased (28.6%), hypertension (21.4%), AST increased (10.7%), ALT increased (7.1%), nausea (3.6%), hyperglycemia (3.6%). No treatment-related deaths were observed. Brigatinib demonstrated encouraging antitumor activity in patients with TKI-naïve ROS1-rearranged advanced NSCLC. The safety profile of brigatinib was consistent with previous studies.

Current state of the art on the diagnosis and the role of target therapy for treatment of ROS1-rearranged non-small cell lung cancer: a narrative review

Current state of the art on the diagnosis and the role of target therapy for treatment of ROS1-rearranged non-small cell lung cancer: a narrative review

MET Exon 14 Skipping Mutations: Essential Considerations for Current Management of Non–Small-Cell Lung Cancer

MET Exon 14 Skipping Mutations: Essential Considerations for Current Management of Non–Small-Cell Lung Cancer

Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001.

ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. gov: NCT00585195.

Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.

Cost-effectiveness analysis of first-line treatment with crizotinib in ROS1-rearranged advanced non-small cell lung cancer (NSCLC) in Canada

IntroductionWhile no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC.MethodsA Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations.ResultsIn the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib.ConclusionsAvailable data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

P45.13 Efficacy and Safety of Crizotinib in Real-World ROS1-rearranged NSCLC: A Retrospective Canadian Cohort

ROS1-rearranged non-small cell lung cancer (NSCLC), present in 1-2% of diagnoses, is a genetically distinct type of NSCLC which can be successfully managed through the use of targeted therapy, specifically the first-generation ALK-inhibitor, crizotinib, which doubles as highly effective inhibitor of aberrant ROS1 activity. Clinical trials have shown crizotinib to be safe and effective; however, the use of crizotinib and its safety and efficacy in real-world ROS1-rearranged populations requires further exploration. Consequently, this study initiated a retrospective, observational, population-based investigation into the safety and efficacy of crizotinib in ROS1-rearranged NSCLC patients diagnosed and treated in Alberta, Canada. Alberta patients with advanced or metastatic ROS1-rearranged NSCLC, receiving crizotinib as their first targeted ROS1-inhibitor between January 2014 and June 2020 were identified. Demographic, clinical, treatment and outcome data were extracted from the institutional Glans-Look Lung Cancer Research Database. 21 ROS1-rearranged crizotinib-treated patients were identified: median age was 51.6 years, 67% female, 86% never-smokers. 96% had metastatic disease at crizotinib initiation (38% M1c stage), 67% ECOG < 2, and 57% of patients had previous exposure to systemic chemotherapy (including platin-pemetrexed) and/or immunotherapy. 38% of patients were alive, 29% with crizotinib therapy ongoing, at the time of analysis. One-year survival was 47% following crizotinib initiation; median OS and PFS were 33.3 and 10.6 months, respectively. Disease control rate was 62%, while 14% showed primary resistance to crizotinib. ECOG was not significantly associated with outcome or clinical response. Adverse events (AE) were reported in 52% of patients, most common were gastrointestinal (29%) or investigational disorders (14%), and primarily grade 1 or 2. 19% of patients experienced grade 3+ AE and subsequently terminated crizotinib. Treatment breaks +/- dose modifications occurred in 16%. Patients remained on crizotinib for a median 6.9 cycles before discontinuation. Progressive disease was the most common reason for crizotinib termination (40% of crizotinib discontinuations); upon termination 24% received additional systemic treatment (range 1-3), all receiving additional ROS1-inhibitors. 33% of crizotinib terminations were due to death. 29% of patients had brain metastases at crizotinib initiation and 14% developed brain metastases while on crizotinib, predominantly managed with radiotherapy (67%). Presence/absence of brain metastasis did not significantly impact outcome, but baseline brain metastases resulted in a shorter duration of use and lower rate of clinical response to crizotinib. 48% had high PD-L1 expression (>50%) and 29% received immunotherapy (all prior to crizotinib initiation), with mPFS of 10.1 weeks and DCR of 33%. PD-L1 expression nor immunotherapy use had a significant impact on survival. This real-world study suggests crizotinib therapy for ROS1-rearranged NSCLC in a Canadian clinical setting is an effective, safe and tolerable therapy; however, this real-world cohort was unable to completely meet the outcomes found in crizotinib-treated ROS1-rearranged clinical trial cohorts. As a real-world population, lack of ROS1 testing, delayed access to crizotinib and heavy pre-treatment resulted in high disease burden and early failures on crizotinib, likely impacting crizotinib efficacy. This reinforces the need for real-world data alongside clinical trial data and highlights the need for expeditious access to appropriate targeted therapies in this population.

FP09.04 Impact of Brain Metastasis Status on Adverse Events (AEs) Requiring Dose Reduction Among Patients Receiving Lorlatinib

Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) and ROS1-rearranged (ROS1+) non-small cell lung cancers (NSCLC) are associated with a propensity towards central nervous system (CNS) dissemination. Lorlatinib is a third-generation tyrosine kinase inhibitor (TKI) that is approved for treatment of metastatic ALK+ NSCLC based on robust intracranial and extracranial activity. Although not approved for ROS1+ NSCLC, lorlatinib is widely used for treatment of this disease based on its promising systemic activity in the post-crizotinib setting, including among patients with brain metastasis.

Response to immune checkpoint inhibition as monotherapy or in combination with chemotherapy in metastatic ROS1-rearranged lung cancers.

9049 Background: ROS1 fusions are oncogenic drivers in various cancers types, including 1-3% of non-small cell lung cancers (NSCLCs). Immunotherapy approvals for NSCLC include ROS1-rearranged carcinomas, but the activity of immune checkpoint inhibition (ICI) as monotherapy or in combination with chemotherapy (chemo-ICI) therapy, as well as the immunophenotypic characteristics of these tumors, have not been described in a large data set. Methods: In this multi-institutional study, patients with ROS1-rearranged NSCLC were identified retrospectively. Tumor PD-L1 expression and tumor mutational burden (TMB) were assessed as part of routine clinical care. In patients who received ICI monotherapy or chemo-ICI in the metastatic setting, time to treatment discontinuation (TTD) and objective response rate (ORR; RECIST v. 1.1) were calculated. TTD was assessed with Kaplan-Meier methods; patients remaining on treatment were censored at last follow up. Results: 184 patients with ROS1-rearranged NSCLC were identified. Among 146 PD-L1 evaluable cases, PD-L1 expression was &lt; 1% in 60 (41%), 1-49% in 35 (24%) and ≥50% in 51 (35%) tumors. Ninety-two of 100 (92%) TMB-evaluable tumors had &lt; 10 mutations/megabase (mut/Mb). TMB was significantly lower for ROS1-rearranged NSCLCs (n = 97) vs. ROS1-wild type tumors (n = 5,380) evaluated with next-generation sequencing using MSK-IMPACT (median 2.6 vs. 5.9 mut/Mb, p &lt; 0.001). Twenty-eight patients received ICI monotherapy and 11 patients received chemo-ICI. The median TTD was 2.1 months (95% CI: 1.0-4.2; n = 28) for single-agent ICI therapy and 10 months (95% CI: 4.7-14.1; n = 11) for chemo-ICI therapy. The ORR was 13% (2/16 RECIST-evaluable; 95% CI: 2-38%) for ICI monotherapy and 83% (5/6 RECIST-evaluable; 95% CI: 36-100%) for chemo-ICI therapy. There was no difference in PD-L1 tumor expression (p = 0.9) or TMB (p = 0.8) between responders and non-responders and no correlation between PD-L1 tumor expression (rho = 0.16, p = 0.6) or TMB (rho = 0.03, p = 0.9) and maximum change in sum of target lesions. Conclusions: Most ROS1-rearranged NSCLCs have low or no PD-L1 expression and low TMB. The activity of checkpoint inhibitor monotherapy is disappointing in ROS1-driven NSCLC. In contrast, combination chemoimmunotherapy can achieve clinically meaningful activity.