ROS1-positive Non-small Cell Lung Cancer Research Articles

Effect of the patient information brochure in communicating the risks associated with crizotinib treatment to patients with non-small cell lung cancer (NSCLC) in Europe.

Crizotinib (XALKORI®) is indicated for anaplastic lymphoma kinase‐positive and ROS1‐positive advanced non‐small cell lung cancer. This study evaluated the distribution of the crizotinib patient information brochure (PIB) in Europe and patient knowledge of the key messages in the PIB. A cross‐sectional survey was conducted in 10 European countries among patients who received crizotinib to ascertain whether each patient received and read the PIB, and his/her knowledge of its key messages on hepatotoxicity, interstitial lung disease/pneumonitis, QTc prolongation, bradycardia, and vision disorders. Of the 341 patients contacted, 40 responded (11.7%), and 39 patients were eligible. A total of 77% of respondents acknowledged receiving the PIB, of which, 93% reported reading it. Knowledge of the individual side effects ranged from 36% to 85%, and precautions for use ranged from 56% to 67%. Understanding the reasons for calling a physician ranged from 54% to 85%. Knowledge of each of the 6 key side effects was greater among readers of the PIB compared to non‐readers or respondents who did not recall receiving the PIB. Approximately three‐quarters of survey respondents recalled receiving the crizotinib PIB and respondents who read the PIB were more knowledgeable of the key side effects of crizotinib than those who did not read or receive. Caution should be taken in generalizing these results because of the potential for selection bias and small sample size. These survey results suggest that the crizotinib PIB may be an effective risk communication tool for crizotinib‐treated patients in Europe.

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer

ObjectivesTo evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily. Materials and methodsPRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM). Results255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %). ConclusionsLorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.

ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

BackgroundWe sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC).MethodsWe searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046.ResultsThirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] –0.16 to 1.46; odds ratio 2.58 (0.76–11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39–0.54]; ceritinib 0.52 [0.42–0.64]; alectinib 300 BID 0.16 [0.08–0.33]; alectinib 600 BID 0.23 [0.17–0.30]; brigatinib 0.23 [0.15–0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17–0.70]; alectinib v. ceritinib 0.30 [0.14–0.64]; brigatinib v. crizotinib 0.49 [0.33–0.73]; brigatinib v. ceritinib 0.43 [0.27–0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39–0.83]) and crizotinib (0.68 [0.48–0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56–2.79]) and alectinib (1.60 [1.00–2.58]) but not ceritinib (1.25 [0.90–1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants.Conclusion(s)Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.

Research progress on targeted treatment in ROS1-positive non-small cell lung cancer

ROS1 fusion gene is a new potential target for molecular targeted therapy of non-small cell lung cancer (NSCLC). In recent years, more and more scholars focus on ROS1 fusion gene. The results of in vitro experiments and clinical research both show that anaplastic lymphoma kinase (ALK) inhibitors have potent anti-tumor activity in ROS1-positive NSCLC patients, but drug resistance is still inevitable. At present, there is no standardized diagnosis and treatment path for ROS1-positive NSCLC. Therefore, further study on the ALK inhibitors of ROS1 is very important, which can provide a new therapeutic idea for targeted treatment and research of NSCLC patients. Key words: Carcinoma, non-small-cell lung; Molecular targeted therapy; ROS1 fusion gene

66P - Brain metastases, treatment patterns and outcomes in ROS1-positive NSCLC patients from US oncology community centers

BackgroundAs new targeted therapies with CNS penetration and activity for non-small cell lung cancer (NSCLC) with ROS1 gene fusions (ROS1+) emerge, there is a need to characterize the disease course of patients (pts) receiving current treatment, especially in relation to CNS metastases (met). MethodsWe evaluated an anonymized cohort of ROS1+ NSCLC pts from the Flatiron Health electronic health record (EHR)-derived database of US cancer centers (2011–2018). Descriptive statistics were used for clinical and treatment pattern characterization. Kaplan-Meier curves estimated median overall survival (OS), real-world progression-free survival (rwPFS, using physician documentation in the EHR) and rwPFS in the CNS, from 1st-line treatment (1L) after diagnosis of advanced/metastatic NSCLC (aNSCLC Dx). Due to low numbers of pts in some groups, 95% CI are not reported. ResultsWe identified 129 ROS1+ aNSCLC pts who received 1L treatment including crizotinib (n = 52, 40.3%), chemotherapy (n = 34, 26.4%), combination systemic therapy (n = 25, 19.4%), clinical study drug (n = 4, 3.1%), or no treatment (n = 14, 10.9%). For 1L crizotinib (the only approved therapy for ROS1+ NSCLC) after aNSCLC Dx median rwPFS: 8.6 m (95% CI: 6.2–12.1); OS: 19.9 m (95% CI: 15.1–NR). For pts receiving other 1L drugs median rwPFS: 5.9 m (95% CI: 4.1–7.2); OS: 18.1 m (95% CI: 12.9–34.6). There were 24 pts (18%) with CNS met at diagnosis and 20 pts (19%) at follow-up. Most pts with CNS met at or after diagnosis received surgery/radiotherapy (37/44, 84.1%). For CNS met pts who received 1L crizotinib after local treatment (6/11), median rwPFS: 8.0 m; OS: 27 m. From 1L crizotinib, pts with CNS met at follow-up only (10/21 pts with CNS mets who received 1L crizotinib), median rwPFS: 7.2 m; rwPFS-CNS: 9.1 m; OS: 15.1 m. For pts with no CNS mets anytime median rwPFS: 10.0 m; OS: 21.5 m from 1L crizotinib (34/55 pts). ConclusionsIn the US, ROS1+ NSCLC pts receive various 1L treatments after aNSCLC Dx. CNS was a site of metastasis in 44/129 ROS1+ NSCLC pts. Surgery/radiotherapy for CNS mets prior to systemic therapy may be associated with favorable outcomes, however conclusions on the natural history of cancers with rare mutations rely on very small patient numbers. Editorial acknowledgementEditorial support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the studyF. Hoffman-La Roche. FundingF. Hoffman-La Roche. DisclosureM.G. Krebs: Advisory / Consultancy, Officer / Board of Directors: Roche, Achilles Therapeutics, Octimet, Janssen; Research grant / Funding (institution): AstraZeneca, Bayer, BerGenBio, Blueprint, Carrick, Immutep, Incyte, Janssen, Merck, Octimet, Roche; Research grant / Funding (institution): Roche, BerGenBio; Travel / Accommodation / Expenses: AstraZeneca, BerGenBio. L. Perez: Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Roche. A. Surinach: Full / Part-time employment: Genesis Research. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. M. Martinec: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffman-La Roche Ltd. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. N.J. Meropol: Full / Part-time employment: Employed by Flatiron Health, Inc., an independent subsidiary of the Roche Group; Equity interest in Flatiron Health; Shareholder / Stockholder / Stock options: Roche. W. Wong: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. G. Crane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. All other authors have declared no conflicts of interest.

P1.14-15 Lorlatinib in ALK- or ROS1-Positive Non-Small Cell Lung Cancer Patients: Experience from an Early Access Program in Turkey

P1.14-15 Lorlatinib in ALK- or ROS1-Positive Non-Small Cell Lung Cancer Patients: Experience from an Early Access Program in Turkey

1485PD - Safety and efficacy of WX-0593 in ALK-positive or ROS1-positive non-small cell lung cancer

BackgroundWX-0593 is a potent ALK inhibitor against ALK and ROS1 rearrangement and a series of crizotinib (CRZ)-resistant mutants. We explored the safety and efficacy of WX-0593 in patients (pts) diagnosed with ALK+ or ROS-1+ malignancies, including non-small cell lung cancer (NSCLC). MethodsIn this ongoing phase I, dose-escalation, multicenter trial (NCT03389815), 54 pts (third-grade class-A hospital confirmed ALK+ or ROS-1+) received WX-0593 (30, 60, 90, 120, 180, 240 or 300mg) orally once daily until disease progression or unacceptable toxicity. Activity and safety were evaluated. ResultsFrom 25 September 2017 to 26 December 2018, 54 pts were enrolled, including 46 with ALK+ NSCLC, 10 with ROS1+ NSCLC (2 with both ALK+ and ROS1+, 38.9% with prior CRZ, 9.3% with prior CRZ and second generation ALK inhibitors). Grade 3 QTc prolongation reported in 300mg cohort was identified as dose-limiting toxicity (DLT). Treatment-emergent adverse events (TAEs) associated with WX-0593 in>20% of pts include: hypercholesterolemia (40.7%), nausea (40.7%), hypertension (37.0%) increased ALT (31.5%), increased AST (29.6%), hypertriglyceridemia (25.9%), hyperlipidemia (25.9%), vomiting 25.9%. Serious adverse events (SAE) occurred in 6 pts (11.1%). No treatment related death occurred. 2 pts (3.7%) had SAE related with WX-0593 treatment, including increased ALT (dose of 180mg), increased AST (dose of 180mg) and chronic heart failure (dose of 300mg). For ALK+ NSCLC (n=46), objective response rate (ORR) was 29/44 (65.9%). The ORR in CRZ-naive pts was 17/21 (81.0%), 8/18 (44.4%) in CRZ pre-treated pts. ORR was 3/10 (30.0%) in ROS1+ NSCLC pts. By 26 December 2018, median progression-free survival was not reached, 39 patients remained on WX0593 treatment.Table1485PD Objective response rate in ALK-positive and ROS1-positive NSCLC patientsTableORR, n / m (%)30mg N=360mg N=390mg N=8120mg N=11180mg N=13240mg N=13300mg N=3totalALK+NSCLCall pts2/2 (100.0)2/3 (66.7)2/5 (40.0)8/10 (80.0)7/10 (70.0)7/11 (63.6)1/3 (33.3)29/44 (65.9)CRZ-naive pts2/2 (100.0)2/3 (66.7)06/7 (85.7)3/4 (75.0)3/4 (75.0)1/1 (100.0)17/21 (81.0)pts with prior CRZ002/4 (50.0)1/2 (50.0)3/5 (60.0)2/5 (40.0)0/28/18 (44.4)pts with prior CRZ and other ALK inhibitor000/11/1 (100.0)1/1 (100.0)2/2 (100.0)04/5 (80.0)ROS1+NSCLCall pts0/101/3 (33.3%)0/12/3 (66.7%)0/203/10 (30.0%) ConclusionsThis study revealed the antitumor activity of WX-0593 in ALK- or ROS-positive NSCLC. Safety profile was acceptable. A phase II trial to evaluate the ORR of 120mg and 180mg once daily is ongoing. Clinical trial identificationNCT03389815. Legal entity responsible for the studyQilu Pharmaceutical Co., Ltd. FundingQilu Pharmaceutical Co., Ltd. DisclosureAll authors have declared no conflicts of interest.

1553P - Crizotinib vs platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer with different ROS1 fusion variants

BackgroundROS1 rearrangement, a novel specific molecular subtype of non-small cell lung cancer (NSCLC), has become a validated therapeutic target. However, the efficacy of crizotinib and platinum-based chemotherapy as first-line treatment between different ROS1 fusion variants in advanced Chinese NSCLC patients has not yet been fully elucidated. This study explored which treatment regimen would be better in such patients. MethodsRetrospective real-world analyses of clinical and treatment outcome with ROS1-positive advanced NSCLC patients from multi-center study were explored in China, from Jan 9th 2011 to Jan 1st 2019. The study evaluated first-line regimens including crizotinib treatment and platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS), and second endpoints were the objective response rate (ORR) and overall survival (OS). Kaplan-Meier survival analysis was carried out by using SPSS 16.0. ResultsA total of 102 patients, 75 (73.5%) females and 27 (26.5%) males were enrolled. The median age of patients was 52 years and 99 (97.1%) were identified with adenocarcinoma type. 57 cases were administered crizotinib and 45 received platinum-based chemotherapy. For the first-line treatment, the median PFS was significantly longer for crizotinib treatment compared with platinum-based chemotherapy (median,15.0 vs. 9.7months, p=0.006), respectively. 58 cases were confirmed ROS1 fusion variants by next-generation sequence (NGS) including CD74 fusion (n=32) and non-CD74 fusion(n=26). Patients receiving crizotinib with the CD74 fusion had a significant longer PFS than those by platinum-based chemotherapy (median,18.3 vs. 8.8months, p=0.002); in contrast, a statistical significance was not observed on PFS in the non-CD74 fusion subgroup (12.2 vs. 9.0 months, p=0.544). The ORR of crizotinib treatment was higher than that of platinum-based chemotherapy (80.7% vs. 55.6%, p=0.006). OS was not reached owing to immature data. ConclusionsCrizotinib as first-line treatment tends to have more benefit than platinum-based chemotherapy for advanced Chinese NSCLC patients with CD74 ROS1 fusion variant. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1551P - Brain metastases, treatment patterns and outcomes in ROS1-positive NSCLC patients from US oncology community centers

BackgroundAs new targeted therapies with CNS penetration and activity for non-small cell lung cancer (NSCLC) with ROS1 gene fusions (ROS1+) emerge, there is a need to characterize the disease course of patients (pts) receiving current treatment, especially in relation to CNS metastases (met). MethodsWe evaluated an anonymized cohort of ROS1+ NSCLC pts from the Flatiron Health electronic health record (EHR)-derived database of US cancer centers (2011–2018). Descriptive statistics were used for clinical and treatment pattern characterization. Kaplan-Meier curves estimated median overall survival (OS), real-world progression-free survival (rwPFS, using physician documentation in the EHR) and rwPFS in the CNS, from 1st-line treatment (1L) after diagnosis of advanced/metastatic NSCLC (aNSCLC Dx). Due to low numbers of pts in some groups, 95% CI are not reported. ResultsWe identified 129 ROS1+ aNSCLC pts who received 1L treatment including crizotinib (n=52, 40.3%), chemotherapy (n=34, 26.4%), combination systemic therapy (n=25, 19.4%), clinical study drug (n=4, 3.1%), or no treatment (n=14, 10.9%). For 1L crizotinib (the only approved therapy for ROS1+ NSCLC) after aNSCLC Dx median rwPFS: 8.6 m (95% CI: 6.2–12.1); OS: 19.9 m (95% CI: 15.1–NR). For pts receiving other 1L drugs median rwPFS: 5.9 m (95% CI: 4.1–7.2); OS: 18.1 m (95% CI: 12.9–34.6). There were 24 pts (18%) with CNS met at diagnosis and 20 pts (19%) at follow-up. Most pts with CNS met at or after diagnosis received surgery/radiotherapy (37/44, 84.1%). For CNS met pts who received 1L crizotinib after local treatment (6/11), median rwPFS: 8.0 m; OS: 27 m. From 1L crizotinib, pts with CNS met at follow-up only (10/21 pts with CNS mets who received 1L crizotinib), median rwPFS: 7.2 m; rwPFS-CNS: 9.1 m; OS: 15.1 m. For pts with no CNS mets anytime median rwPFS: 10.0 m; OS: 21.5 m from 1L crizotinib (34/55 pts). ConclusionsIn the US, ROS1+ NSCLC pts receive various 1L treatments after aNSCLC Dx. CNS was a site of metastasis in 44/129 ROS1+ NSCLC pts. Surgery/radiotherapy for CNS mets prior to systemic therapy appeared to result in favorable outcomes, however conclusions on the natural history of cancers with rare mutations rely on very small patient numbers. Editorial acknowledgementLaura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications, funded by F. Hoffmann-La Roche. Legal entity responsible for the studyF. Hoffmann-La Roche. FundingF. Hoffmann-La Roche. DisclosureM.G. Krebs: Advisory / Consultancy, Officer / Board of Directors: Roche, Achilles Therapeutics, Octimet, Janssen; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca, Bayer, BerGenBio, Blueprint, Carrick, Immutep, Incyte, Janssen, Merck, Octimet, Roche; Travel / Accommodation / Expenses: AstraZeneca, BerGenBio. L. Perez: Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Roche. A. Surinach: Full / Part-time employment: Genesis Research. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain Therapeutics; Research grant / Funding (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. M. Martinec: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. N.J. Meropol: Shareholder / Stockholder / Stock options: Roche; Shareholder / Stockholder / Stock options, Full / Part-time employment: Flatiron Health, Inc. W. Wong: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. G. Crane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. All other authors have declared no conflicts of interest.

Profile of entrectinib and its potential in the treatment of ROS1-positive NSCLC: evidence to date.

ROS1 inhibition provides impressive survival benefits in ROS1-rearranged non-small cell lung cancer (NSCLC) patients. Crizotinib is the only tyrosine kinase inhibitor (TKI) approved by both FDA and EMA for the treatment of ROS1-positive lung cancer. In addition, several TKI have been tested with preliminary proofs of success in this oncogene-driven disease, either in the post-crizotinib setting or as first-line targeted agents. Here we present the evidence concerning entrectinib, an ALK/ROS1/NTRK inhibitor developed across different tumor types harboring rearrangements in these genes, in the context of ROS1-driven NSCLC. Of interest, in August 2019 entrectinib was granted by FDA accelerated approval for the treatment of ROS1-rearranged NSCLC, as well as of NTRK-driven solid tumors.

Entrectinib: First Global Approval

Entrectinib (Rozlytrek®) is an oral selective inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk)A/B/C [encoded by the genes neurotrophic tyrosine receptor kinase (NTRK) 1, 2 and 3, respectively], c-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK) with central nervous system (CNS) activity developed by Roche for the treatment of various solid tumours harbouring NTRK1/2/3 or ROS1 gene fusions. In June 2019, entrectinib received its first global approval in Japan, for the treatment of adult and paediatric patients with NTRK fusion-positive, advanced or recurrent solid tumours and is under regulatory review for the treatment of adult patients with ROS1-positive non-small cell lung cancer (NSCLC). Entrectinib is also under regulatory review in the USA (PDUFA date 18 August 2019) and EU [Priority Medicines (PRIME) designation] for NTRK-positive solid tumours and ROS1-positive NSCLC. This article summarizes the milestones in the development of entrectinib leading to this first global approval for solid tumours in Japan.

Abstract 3071: Repotrectinib demonstrates promising activities in ROS1 wild-type and solvent-front mutant lung cancer patients-derived preclinical models

Abstract The ROS1-rearranged non-small-cell lung cancer (NSCLC) is currently treated with ALK/ROS1 tyrosine kinase inhibitor (TKI) crizotinib as a first-line agent. However, resistance invariably develops and subsequent therapeutic option for overcoming them is limited. Therefore, we investigated the antitumor activity of several ROS1-TKIs in ROS1-positive patient-derived preclinical models. In this study, we established 6 patient-derived cells (PDCs) from patients with different types of ROS1 fusion partners as follows: treatment-naïve (YU1078, YU1082 and YU1083), crizotinib-resistant G2032R (YU1079) and crizotinib- or entrectinib- primary resistant (YU1081 and YU1085). Sanger sequencing and whole-exome sequencing were then conducted to determine the characteristics. The in vitro and in vivo antitumor activities of ROS1-TKIs in these PDCs were evaluated by comparing the survival, expression assay, duration of tumor re-emergence and ability to penetrate the blood-brain barrier (BBB). Repotrectinib potently inhibited cell proliferation and ROS1-downstream signaling pathways in YU1078 (CD74-ROS1). In YU1078-derived xenograft models, repotrectinib induced the marked tumor regression and delayed the duration of tumor re-emergence following drug withdrawal compared with crizotinib and entrectinib. Interestingly, both YU1081 (TPM3-ROS1) and YU1082 (SLC34A2-ROS1) with cross primary resistance to other clinically available ROS1-TKIs exhibited high sensitivity to repotrectinib in the concentration range of 100~200 nM. Immunoblot analysis demonstrated that repotrectinib completely suppressed the phosphorylation of ROS1 and STAT3. Notably, repotrectinib showed the selective and highly potency in vitro and in vivo against solvent-front mutant G2032R conferring crizotinib resistance. In G2032R-mutant xenograft models, the response of repotrectinib was still maintained until the end of the experiment (120 days) after drug withdrawal, but loratinib- or cabozantinib-treated tumors rapidly re-emerged. Moreover, repotrectinib induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. As clinical proof of concept, the potent systemic and intracranial activity of ropotrectinib has been observed in patients who had progressed on prior TKIs or TKI-naïve patients, who were enrolled on-going phase 1/2 clinical trial (NCT03093116). Our finding indicated a superior antitumor activity of repotrectinib in both wild-type and mutant ROS1 fusion, providing a rationale that repotrectinib may be an effective subsequent or upfront treatment option for patients with ROS1-positive NSCLC who have relapsed on the available TKIs as well as TKI naïve, including patients with progressive CNS metastases. Citation Format: Dong Hwi Kim, Seok-Young Kim, Hyeong Seok Joo, You Won Lee, Han Na Kang, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho, Miran Yun. Repotrectinib demonstrates promising activities in ROS1 wild-type and solvent-front mutant lung cancer patients-derived preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3071.

Resistance mechanisms and potent-targeted therapies of ROS1-positive lung cancer.

The discovery of targetable mutations, which cause gene rearrangement, led to a major advancement in the treatment of patients with non-small cell lung cancer (NSCLC), and cancers with such mutations can be paired with drugs which specifically target them. c-ros oncogene (ROS1) positive NSCLC is one molecular subtype of NSCLC with a therapeutic target. Currently, different targeted therapies and ROS1 inhibitors have been discovered, but all are in different investigational phases, with only one (crizotinib) which is FDA approved. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) which was discovered to actively inhibit ALK, MET, and ROS1. Crizotinib has shown to be remarkably efficacious against ROS1 lung cancer, prompting ROS1 detection in lung cancer to be quite significant. Sadly, crizotinib resistance in ROS1 is a frequent occurrence which poses a major clinical challenge in the successful treatment of ROS1 lung cancer; hence, the discovery of the second and third generation ROS1 inhibitors is of utmost importance. In this review, we discuss the underlying mechanisms through which ROS1 tumor cells acquire resistance to crizotinib-the first-line drug for ROS1-positive NSCLC, and summarize various new potent drugs which can overcome this resistance and serve as viable alternatives.

Safety and Efficacy Study of TQ-B3101 in Patients With ROS1-positive Non-Small Cell Lung Cancer (NSCLC)

Safety and Efficacy Study of TQ-B3101 in Patients With ROS1-positive Non-Small Cell Lung Cancer (NSCLC)

Crizotinib in Chinese Patients with ROS1-Rearranged Advanced Non‒Small-Cell Lung Cancer in Routine Clinical Practice.

BackgroundApproximately 1–2% of patients with non‒small-cell lung cancer (NSCLC) harbor ROS1 rearrangements. Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET, and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC.ObjectiveOur objective was to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice.MethodsWe included 35 patients with ROS1-positive NSCLC in this retrospective analysis. All received crizotinib 250 mg twice daily between March 2016 and April 2018 at the Fudan University Shanghai Cancer Center. All had histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangements, which were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing. The main outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events.ResultsThe median age of the patients was 51.0 years; 23 (65.7%) were female and 28 (80.0%) were never smokers. All were diagnosed as having adenocarcinoma; eight patients (22.9%) had brain metastases at baseline. The ORR and DCR were 71.4% and 94.3%, respectively. The estimated median PFS was 11.0 months (95% confidence interval [CI] 7.8–14.2). The estimated median OS was 41.0 months (95% CI 22.5–59.5). Elevated transaminases (54.3%), vision disorder (25.7%), elevated blood creatinine (22.9%), diarrhea (20.0%), and vomiting (20.0%) were the most commonly reported adverse effects.ConclusionCrizotinib was effective and well tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The progression sites and patterns, as well as treatments after first disease progression on crizotinib were diverse. Crizotinib beyond progressive disease and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice.

145P - Clinicopathological characteristics and outcome of advanced ROS1-positive non-small cell lung cancer in Asian patients

145P - Clinicopathological characteristics and outcome of advanced ROS1-positive non-small cell lung cancer in Asian patients

Clinicopathological features and clinical efficacy of crizotinib in Chinese patients with ROS1-positive non-small cell lung cancer.

C-ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement forms a novel molecular subgroup of non-small cell lung cancer (NSCLC). The present study explored the clinicopathological features and clinical efficacy of crizotinib in patients with ROS1-positive NSCLC. A retrospective analysis of 2,617 cases of NSCLC diagnosed between January 2013 and December 2016 was performed. ROS1 fusion genes were detected by reverse transcription-quantitative polymerase chain reaction, fluorescence in situ hybridization or next-generation sequencing techniques, and patients positive for the ROS1 fusion gene received oral treatment with crizotinib. The ROS1 fusion was identified in 67 out of 2,617 cases (2.56%), including 21 cases that were male and 46 cases that were female. The median age was 68 years. Among these cases, 59 (88.06%) were adenocarcinoma and 8 were non-adenocarcinoma. According to Tumor-Node-Metastasis (TNM) staging, 4 cases were stage I-IIIa and 63 (94.02%) were stage IIIb-IV. The epidermal growth factor receptor (EGFR) gene status included 60 cases of wild-type, 1 case of co-mutation and 6 unknown cases. Statistically significant differences were identified for sex, TNM staging and EGFR gene status between ROS1 fusion gene-positive and -negative patients (P<0.001). A total of 23 patients received oral treatment with crizotinib, of which 13 (56.52%), 5 (21.74%) and 5 (21.74%) patients demonstrated a partial response, stable disease and progressive disease, respectively. The objective response rate was 56.52% and the disease control rate was 78.26%. Among all patients, the median progression-free survival (mPFS) time was 14.5 months. No differences were revealed in the mPFS time with regard to age, sex, smoking history, performance status score, histopathological type, TNM staging, tumor protein p53 gene status, EGFR gene status and first-line crizotinib treatment, whether by single or multiple factor analysis. The grade 3/4 treatment-associated adverse events included gastrointestinal disturbance, followed by increased transaminase concentration. In conclusion, the rate of ROS1 fusion in NSCLC among the patients is low, and crizotinib is an effective and safe drug for the treatment of ROS1-positive advanced NSCLC.

1380PD - Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations

1380PD - Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations

Crizotinib in ROS1-positive non-small cell lung cancer: an Asian large phase II trial confirms its key-role

The ROS1 oncogene encodes an orphan receptor tyrosine kinase related to anaplastic lymphoma kinase (ALK), along with members of the insulin-receptor family (1). ROS1 rearrangement can be found in several human cancers as cholangiocarcinoma, gastric cancer, ovarian cancer, glioblastoma multiforme, and with therapeutic implications in non-small cell lung cancer (NSCLC) (2-4). As a consequence of the rearrangement, a portion of ROS1, that includes the entire tyrosine kinase domain, is fused with 1 of 12 different pattern proteins (5). The ROS1 fusion kinases resulting from rearrangement are constitutively activated and drive cellular neoplastic transformation.

Crizotinib in ROS1-positive non-small cell lung cancer: an Asian large phase II trial confirms its key-role

Crizotinib in ROS1-positive non-small cell lung cancer: an Asian large phase II trial confirms its key-role