ROS1 Fusion-positive Non-small Cell Lung Research Articles

Additional reporting of diffuse and homogeneous ROS-1 SP384 immunoreactivity enhances prediction of ROS1 fusion-positive non-small cell lung cancer.

ROS-1 immunohistochemistry (IHC) is a common method for screening ROS1 fusion in the clinical management of non-small cell lung cancer. The interpretation criteria for ROS-1 SP384 IHC, however, remain unestablished. Sixty-five non-small cell lung cancer cases underwent AmoyDx ROS1 fusion real-time polymerase chain reaction (PCR) study and ROS-1 SP384 IHC tests, which were retrieved for analysis. ROS-1 IHC tests were interpreted based on the established classifiers as well as the presence of diffuse homogeneous immunoreactivity. The diagnostic accuracies of these ROS-1 IHC interpretation methods were evaluated by comparing them with the ROS1 real-time PCR results. Previous ROS-1 IHC classifiers demonstrated high sensitivity for positive ROS1 real-time PCR results (100%), but they showed low specificities (25%-50%) and overall accuracies (58%-72%). In contrast, the diffuse homogeneous ROS-1 immunoreactivity predicted positive ROS1 real-time PCR results with much higher specificity (94%) and overall accuracy (95%), albeit with a slightly lower sensitivity (97%). Some cases that showed discrepancy between diffuse homogeneous ROS-1 immunoreactivity and real-time PCR results involved rare ROS1::LDLR fusion and suboptimal IHC staining. A 3-tier reporting system for ROS-1 SP384 IHC testing combining previous interpretation criteria and diffuse and homogeneous immunoreactivity may better predict ROS1 fusion status without decreasing specificity.

Serial Cell-Free DNA Sequencing in ROS1 Fusion-Positive Lung Cancers During Treatment With Entrectinib.

Patients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored. In patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria. Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non-ROS1 alterations (TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non-ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1. Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

Entrectinib as first-line vs. second-line therapy in ROS1 fusion-positive non-small cell lung cancer: a cost-effectiveness analysis.

The concept of cost-effectiveness is crucial for the optimal allocation of scarce healthcare resources. However, the cost-effectiveness of entrectinib in ROS1 fusion-positive non-small cell lung cancer (NSCLC) has not been evaluated. We aim to evaluate the cost-effectiveness of entrectinib as a first-line treatment compared to its reservation for second-line therapy or the exclusive use of chemotherapy in ROS1 fusion-positive advanced NSCLC. A Markov model was created to assess the clinical outcomes and healthcare costs associated with these three treatment approaches. Cost and utility values were obtained from established literature and cost databases. To test model robustness, probabilistic and univariate sensitivity analyses were conducted. In the first-line setting, where entrectinib was administered as the initial therapy, it yielded an extra 0.07 quality-adjusted life years (QALYs) at an incremental cost of $73,453, leading to an incremental cost-effectiveness ratio (ICER) of $1,090,594.30 per QALY compared to chemotherapy. Conversely, in the second-line setting, when entrectinib was used as a second-line therapy following chemotherapy, it provided an extra 0.11 QALYs at an incremental cost of $53,480, resulting in an ICER of $494,290.39 per QALY compared to chemotherapy. Furthermore, the analysis revealed that the cost of entrectinib and utility values of progressed disease were the most influential factors for the ICER. Considering the current pricing of entrectinib, it is not deemed cost-effective as a first-line or second-line therapy for patients with ROS1 fusion-positive advanced NSCLC when compared to chemotherapy. Alternatively, reserving entrectinib exclusively for second-line therapy might strike a balance between healthcare expenditures and patient outcomes.

Economic Evaluation of Targeted Therapies for Anaplastic Lymphoma Kinase- and ROS1 Fusion-Positive Non-Small Cell Lung Cancer in India.

Targeted therapies, such as crizotinib and ceritinib, have shown promising results in treating non-small cell lung cancer (NSCLC) with specific oncogenic drivers like anaplastic lymphoma kinase (ALK), c-ros (ROS1) oncogene, etc. This study aims to assess the cost-effectiveness of these therapies for patients with NSCLC in India. The Markov model consisted of three health states: progression-free survival, progressive disease, and death. Lifetime costs and consequences were estimated for three treatment arms: crizotinib, ceritinib, and chemotherapy for patients with ALK- and ROS1-positive NSCLC. Incremental cost per quality-adjusted life-year (QALY) gained with crizotinib and ceritinib was compared to chemotherapy and assessed using a willingness-to-pay threshold of one-time per capita gross domestic product in India. The total lifetime cost per patient for ALK-positive NSCLC was ₹332,456 ($4,054 US dollars [USD]), ₹1,284,100 ($15,659 USD), and ₹2,337,779 ($28,509 USD) in the chemotherapy, crizotinib, and ceritinib arms, respectively. The mean QALYs lived per patient were 1.20, 2.21, and 3.34, respectively. For patients with ROS1-positive NSCLC, the total cost was ₹323,011 ($3,939 USD) and ₹1,763,541 ($21,507 USD) for chemotherapy and crizotinib, with mean QALYs lived per patient of 1.16 and 2.73, respectively. Nearly 92% and 81% reduction in the price of ceritinib and crizotinib is required to make it a cost-effective treatment option for ALK- and ROS1-positive NSCLC, respectively. Our study findings suggest that the prices of ceritinib and crizotinib need to be reduced significantly to justify their value for inclusion in India's publicly financed health insurance scheme for treatment of patients with locally advanced/metastatic ALK- and ROS1-positive NSCLC, respectively.

Mechanisms of resistance to tyrosine kinase inhibitor treatments in patients with ROS1 fusion-positive non-small cell lung cancer.

9062 Background: ROS1 rearrangement was found in about 1% non-small cell lung cancer (NSCLC), and the fusion proteins created during this process will result in the successive activation of the ROS1 kinase domain. NSCLC patients with ROS1 gene fusions were considered a unique subtype highly sensitive to related tyrosine kinase inhibitor (TKI) treatments. However, the acquired TKI resistance was the major hurdle preventing patients from getting prolonged treatment benefits. Methods: 107 patients diagnosed with advanced or metastatic NSCLC harboring ROS1 fusion were retrospectively recruited. All patients were treated with crizotinib as first-line treatment, and 21 patients received lorlatinib after crizotinib progression. Samples were collected at baseline, after crizotinib progression, and after lorlatinib progression, which all underwent targeted DNA sequencing. TKIs binding to mutated ROS1 fusion proteins was simulated using molecular dynamics simulations. Results: The most witnessed fusion partner of ROS1 was CD74 (58%), followed by SDC4 (14%), EZR (11%), and SLC34A2 (9%). The median progression-free survival was 12.9 months for crizotinib and 6.4 months for lorlatinib. Patients with CD74-ROS1 and SLC34A2-ROS1 had significantly longer PFS than those with other ROS1 fusion types when treated with crizotinib. Patients with baseline TP53 mutations showed worse PFS compared to TP53 wild-type (WT) patients (P < 0.001, HR: 0.19, 95%CI: 0.09-0.39) under crizotinib treatment. An accumulation of both on-target (baseline vs. post-crizotinib vs. post-lorlatinib: 0% vs. 43% vs. 62%) and off-target resistant mutations (baseline vs. post-crizotinib vs. post-lorlatinib: 22% vs. 26% vs. 43%) after multiple TKI treatments was observed. A total of ten on-target resistance mutations were detected after TKI therapies, with 4 first-reported mutations (ROS1 L2010M, G1957A, D1988N, L1982V). According to the molecular dynamics simulation results, ROS1 L2010M mutations (happening in the ROS1 kinase ATP binding cassette) maybe resistant to lorlatinib, entrectinib, cabozantinib, and crizotinib. ROS1 G1957A may lead to resistance to cabozantinib. Moreover, all four novel on-target mutations may lead to resistance to crizotinib. Conclusions: In summary, CD74- and SLC34A2-ROS1 patients showed better crizotinib efficacy with different resistance mutation patterns. Patients of these subtypes are potential beneficiaries of molecular testing after crizotinib progression, directing future treatment strategies. Multiple TKI treatments may lead to the accumulation of both on-target and off-target resistance mutations. In addition, 4 novel ROS1 on-target mutations identified underwent molecular dynamics simulations, unveiling potential resistance to different TKIs, which can provide vital information for future ROS1 fusion-positive NSCLC patient treatment selections.

392P A phase II study of SAF-189s in patients with advanced ROS1 fusion-positive non-small cell lung cancer

ROS1 fusions (ROS1+) are enriched in 1-2% of non-small cell lung cancer (NSCLC) cases. SAF-189s is a novel, next-generation ALK/ROS1 inhibitor which overcomes multiple resistance mutations. We explored the efficacy and safety of SAF-189s in phase (Ph) 2 study in patients (pts) with ROS1 fusion NSCLC, with or without ROS1 inhibitor treatment.

Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors.

ROS1 fusion proteins resulting from chromosomal rearrangements of the ROS1 gene are targetable oncogenic drivers in diverse cancers. Acquired resistance to targeted inhibitors curtails clinical benefit and response durability. Entrectinib, a NTRK/ROS1/ALK targeted tyrosine kinase inhibitor (TKI), was approved for the treatment of ROS1 fusion-positive non-small cell lung cancer (NSCLC) in 2019. In addition, lorlatinib and repotrectinib are actively being explored in the setting of treatment-naïve or crizotinib-resistant ROS1 fusion driven NSCLC. Here, we employed an unbiased forward mutagenesis screen in Ba/F3 CD74-ROS1 and EZR-ROS1 cells to identify resistance liabilities to entrectinib, lorlatinib, and repotrectinib. ROS1F2004C emerged as a recurrent entrectinib resistant mutation and ROS1G2032R was discovered in entrectinib and lorlatinib-resistant clones. Cell-based and modeling data show that entrectinib is a dual type I/II mode inhibitor, and thus liable to both types of resistant mutations. Comprehensive profiling of all clinically relevant kinase domain mutations showed that ROS1L2086F is broadly resistant to all type I inhibitors, but remains sensitive to type II inhibitors. ROS1F2004C/I/V are resistant to type I inhibitors, entrectinib and crizotinib, and type II inhibitor, cabozantinib, but retain sensitivity to the type I macrocyclic inhibitors. Development of new, more selective type II ROS1 inhibitor(s) or potentially cycling type I and type II inhibitors may be one way to expand durability of ROS1-targeted agents.

540P Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy

Entrectinib is a potent, CNS-active ROS1/TRK/ALK inhibitor, which induces clinically meaningful responses in pts with ROS1 fusion-positive (ROS1+) NSCLC and NTRK fusion-positive (NTRK+) solid tumours. We conducted an exploratory analysis to determine if number of prior lines of systemic therapy had any impact on response to entrectinib.

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of aphysiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

Abstract CT192: Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2

Abstract Background Entrectinib is a potent inhibitor of ROS1 (in addition to TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumor activity in multiple intracranial tumor models. We present an updated integrated safety and efficacy analysis from three Phase I/II studies of entrectinib (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in patients with locally advanced or metastatic ROS1 fusion-positive NSCLCs. Methods The analysis included patients with ROS1 inhibitor-naïve NSCLC harboring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included patients with ROS1 fusion-positive NSCLC who received ≥1 dose of entrectinib; the integrated efficacy analysis included patients with at least 6 months of follow-up. Tumor assessments were done at week 4 and every 8 weeks thereafter. Blinded independent central review (BICR), RECIST v1.1 was performed. Primary endpoints by BICR: overall response rate (ORR) and duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial responses), DOR in patients with an intracranial response, PFS in patients with baseline CNS disease. Results In the ROS1 safety-evaluable population (n=134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of patients. Patients with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively. In the efficacy-evaluable population (n=53 patients with treatment-naïve, ROS1 fusion-positive NSCLC; median age 53 years, 64% female, 59% never smokers), BICR-assessed ORR was 77% (95% CI 64-88), complete responses n=3 (6%). Median BICR-assessed DOR: 25 mo (95% CI 11-35). Median BICR-assessed PFS: 26 mo (95% CI 16-37) and 14 mo (95% CI 5-NR) for patients without (n=30) and with CNS disease (n=23) at baseline, respectively. In patients with baseline CNS disease (per BICR assessment, n=20), intracranial ORR was 55% (95% CI 32-77) and median intracranial DOR in patients with an intracranial response (n=11) was 13 mo (95% CI 6-not reached). Conclusion Entrectinib is highly active in patients with ROS1 fusion-positive NSCLC, including those with CNS disease. Entrectinib is well tolerated and has a manageable safety profile. Citation Format: Alexander Drilon, Fabrice Barlesi, Filippo De Braud, Byoung Chul Cho, Myung-Ju Ahn, Salvatore Siena, Matthew G. Krebs, Chia-Chi Lin, Tom John, Daniel SW Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Christian Rolfo, Jürgen Wolf, Chenglin Ye, Todd Riehl, Susan Eng, Robert C. Doebele. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 [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 CT192.

109O - Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2

Background Entrectinib is a potent inhibitor of ROS1 (in addition to TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumor activity in multiple intracranial tumor models. We present an updated integrated safety and efficacy analysis from three Phase I/II studies of entrectinib (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in patients with locally advanced or metastatic ROS1 fusion-positive NSCLCs. Methods The analysis included patients with ROS1 inhibitor-naive NSCLC harboring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included patients with ROS1 fusion-positive NSCLC who received ≥1 dose of entrectinib; the integrated efficacy analysis included patients with at least 6 months of follow-up. Tumor assessments were done at week 4 and every 8 weeks thereafter. Blinded independent central review (BICR), RECIST v1.1 was performed. Primary endpoints by BICR: overall response rate (ORR) and duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial responses), DOR in patients with an intracranial response, PFS in patients with baseline CNS disease. Results In the ROS1 safety-evaluable population (n=134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of patients. Patients with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively. In the efficacy-evaluable population (n=53 patients with treatment-naive, ROS1 fusion-positive NSCLC; median age 53 years, 64% female, 59% never smokers), BICR-assessed ORR was 77% (95% CI 64-88), complete responses n=3 (6%). Median BICR-assessed DOR: 25 mo (95% CI 11-35). Median BICR-assessed PFS: 26 mo (95% CI 16-37) and 14 mo (95% CI 5-NR) for patients without (n=30) and with CNS disease (n=23) at baseline, respectively. In patients with baseline CNS disease (per BICR assessment, n=20), intracranial ORR was 55% (95% CI 32-77) and median intracranial DOR in patients with an intracranial response (n=11) was 13 mo (95% CI 6-not reached). Conclusion Entrectinib is highly active in patients with ROS1 fusion-positive NSCLC, including those with CNS disease. Entrectinib is well tolerated and has a manageable safety profile. Citation Format: Alexander Drilon, Fabrice Barlesi, Filippo De Braud, Byoung Chul Cho, Myung-Ju Ahn, Salvatore Siena, Matthew G. Krebs, Chia-Chi Lin, Tom John, Daniel SW Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Christian Rolfo, Jurgen Wolf, Chenglin Ye, Todd Riehl, Susan Eng, Robert C. Doebele. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 [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 CT192.

OA09 Preliminary Clinical Activity of Repotrectinib (TPX-0005) in Advanced ROS1 Fusion-Positive Non-Small Cell Lung Cancer

OA09 Preliminary Clinical Activity of Repotrectinib (TPX-0005) in Advanced ROS1 Fusion-Positive Non-Small Cell Lung Cancer

OA02.01 Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

OA02.01 Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

OA 14.06 Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

OA 14.06 Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF-06463922, a novel, orally available, CNS-penetrant, ATP-competitive small-molecule inhibitor of ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1(G2032R) mutation and the ROS1(G2026M) gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing to the high-affinity binding. In vivo, PF-06463922 showed marked antitumor activity in tumor models expressing FIG-ROS1, CD74-ROS1, and the CD74-ROS1(G2032R) mutation. Furthermore, PF-06463922 demonstrated antitumor activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma. Taken together, our results indicate that PF-06463922 has potential for treating ROS1 fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for overcoming crizotinib resistance driven by ROS1 mutation.