ROS1 Fusion-positive NSCLC Research Articles

Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer.

The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

1290P Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC

1290P Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC

OA03.06 Repotrectinib in Patients with ROS1 Fusion-positive (ROS1+) NSCLC: Update from the Pivotal Phase 1/2 TRIDENT-1 Trial

OA03.06 Repotrectinib in Patients with ROS1 Fusion-positive (ROS1+) NSCLC: Update from the Pivotal Phase 1/2 TRIDENT-1 Trial

390P Entrectinib in Japanese patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC and NTRK-fp solid tumours

Entrectinib is a ROS1/TRK tyrosine kinase inhibitor (TKI) with CNS activity. In an integrated analysis of three phase I/II trials (ALKA-372-001 EudraCT 2012-000148-88; STARTRK-1 NCT02097810; STARTRK-2 NCT02568267), entrectinib showed overall response rates (ORRs) of 67% in pts with ROS1-fp NSCLC and 61% in pts with NTRK-fp solid tumours (data cutoff: 2 Aug 2021). We present primary data for the subset of Japanese pts from STARTRK-2.

EP08.02-013 Prognostic Utility of the ALI (Advanced Lung Index) in Crizotinib-Treated ALK and ROS1Fusion-Positive NSCLC

The tumour microenvironment, impacted by chronic systemic inflammation, is recognized as playing a significant role in cancer development, progression, and outcome. Blood component-based prognostic indices have shown association with outcome in NSCLC, but evaluation of these indices in relation to targeted systemic therapy remains largely underexplored, with performance status relied upon to help determine treatment suitability. This study sought to evaluate the potential of the Advanced Lung Index (ALI) as a prognostic marker in ALK and ROS1 fusion-positive NSCLC treated with crizotinib.

EP08.02-120 MET Alterations at Presentation in NSCLC Patients Harboring EGFR Mutations and ALK, RET and ROS1 fusions

Although EGFR-mut and ALK, RET and ROS1 fusion-positive NSCLC patients are treated first-line with tyrosine kinase inhibitors (TKIs), some present intrinsic resistance and could benefit from combined treatments.To determine the frequency of MET gene amplification, MET mutations and MET mRNA high expression baseline in a large cohort of EGFR-mut and ALK, ROS1 and RET fusion-positive NSCLC patients; (ii) To analyze paired biopsies of EGFR and fusion positive patients showing MET amplification at progression to targeted therapies.

Abstract 1106: Detection of MET alterations at the DNA, RNA and protein levels in NSCLC patients progressing on ALK and ROS1 targeted therapies

Abstract Background: ALK and ROS1 fusion-positive NSCLC patients derive clinical benefit from tyrosine kinase inhibitors (TKIs) but ultimately relapse. Acquired resistance mechanisms include on-target secondary mutations or copy number gains and activation of bypass signaling. Although MET amplification has been described as a bypass resistance mechanism to ALK and ROS1 inhibitors, there are limited data on MET gene and protein overexpression. Aims: (i) detection of MET alterations at the DNA, mRNA and protein levels in ALK and ROS1 fusion-positive NSCLC patients progressing on TKIs, and (ii) establishment of primary cultures using samples from those patients. Methods: MET alterations were studied in 12 patients after progression on TKIs, 10 ALK and 2 ROS1 fusion-positive. Informed consent was obtained from all patients. NGS and FISH were used to detect resistance mutations and amplifications. MET mRNA expression levels were determined by nCounter. Total and phospho-MET levels were assessed by IHC and Western blotting. Results: A total of 21 samples were available from the 12 patients, including tumor biopsies (n=5), plasma (n=10), pleural effusions (n=3) and cerebrospinal fluids (n=3). MET alterations were detected in 4 patients, 3 ALK fusion-positive progressing on lorlatinib and one ROS1 fusion-positive patient progressing on crizotinib. The 3 ALK fusion-positive patients had MET amplification detected in liquid biopsy (n=2) or tumor tissue (n=1), collected after progression on lorlatinib. In the patient with tissue biopsy available, the increased MET copy number was in line with the presence of MET protein and RNA overexpression. MET amplification was not present on the pre-treatment biopsy available for one of the 3 patients. In primary cultures established from pleural effusion samples of 2 ALK fusion-positive patients, MET amplification was maintained, particularly if the cells were cultured in presence of an ALK TKI. Although the ROS1 fusion-positive patient had no MET amplification after progression on crizotinib, MET and phospho-MET upregulation were detected by IHC. These alterations were also present in primary culture that could be established from a pleural effusion sample of the patient. Conclusions: We found MET alterations in 4 out of 12 (33%) fusion-positive patients after progression on TKIs. Three of them had MET amplification and one MET protein overexpression in the absence of MET copy number gain. Despite the small size of the cohort, our results suggest that testing not only at the DNA but also at the RNA and protein levels, discovers amplification-negative patients with MET alterations who may derive benefit from a MET targeted therapy. Finally, our findings highlight the potential of pleural effusion as a source of material for the establishment of primary cultures. Citation Format: Núria Jordana-Ariza, Nadine Reischmann, Carlos Esparré, Ruth Román, Cristina Aguado-Esteban, Silvia García-Román, Christopher Stroh, Andrés Aguilar Aguilar, Rafael Rosell, Niki Karachaliou, Miguel A. Molina-Vila. Detection of MET alterations at the DNA, RNA and protein levels in NSCLC patients progressing on ALK and ROS1 targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1106.

Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion–Positive NSCLC

IntroductionEntrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion–positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion–positive NSCLC with the central nervous system (CNS)–only progression post-crizotinib is reported. MethodsAdults with ROS1 fusion–positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020. ResultsThe efficacy-assessable population comprised 168 ROS1 TKI–naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8–35.9). The ORR was 68% (95% confidence interval [CI]: 60.2–74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3–93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response). ConclusionsEntrectinib is active and achieves prolonged survival in ROS1 TKI–naïve patients with ROS1 fusion–positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.

111P Entrectinib in Chinese (mainland China, Hong Kong, Taiwan) patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC and NTRK-fp solid tumours

Entrectinib is a CNS-active tyrosine kinase inhibitor (TKI) of ROS1 and TRK. Latest results from an integrated analysis of 3 phase 1/2 trials (ALKA-372-001 EudraCT 2012-000148-88; STARTRK-1 NCT02097810; STARTRK-2 NCT02568267) show that entrectinib has efficacy in pts with ROS1-fp NSCLC (objective response rate [ORR] 67.1%; 1 May 2019 cutoff) and NTRK-fp solid tumours (ORR 61.2%; 31 Aug 2020 cutoff). We report primary results for the subset of Chinese (mainland China, HK, Taiwan) pts from STARTRK-2 (17 Jun 2021 cutoff). Adult Chinese pts with ROS1- and TRK- TKI-naïve, ROS1-fp locally advanced/metastatic NSCLC or NTRK-fp solid tumours were enrolled. Tumour responses were assessed by blinded independent central review (BICR) per RECIST v1.1 after 4 wks and every 8 wks thereafter. ORR, duration of response, intracranial (IC) efficacy, time-to-event outcomes, and safety were assessed. The efficacy-evaluable analysis set included 38 pts with ROS1-fp NSCLC and 21 pts with NTRK-fp tumours (NSCLC, 11; sarcoma, 5; colon, 2; breast, 1; salivary, 1; thyroid, 1) with ≥6 mos follow-up. Median survival follow-up was 28.5 mos for pts with ROS1-fp NSCLC and 10.6 mos for pts with NTRK-fp tumours. ORR was 63% (ROS1-fp NSCLC) and 81% (NTRK-fp tumours); overall and IC outcomes (Table) are consistent with the overall study population. In pts with/without investigator-assessed baseline CNS metastases, overall ORR was 58.3%/65.4% (ROS1-fp NSCLC) and 100%/76.5% (NTRK-fp tumours). In the safety-evaluable analysis set, most treatment-related adverse events (TRAE) were grade 1/2 and non-serious. Discontinuation rates due to TRAEs were 5.6% (ROS1-fp NSCLC) and 0% (NTRK-fp tumours) and no deaths due to TRAEs occurred. In Chinese pts with locally advanced/metastatic ROS1-fp NSCLC or NTRK-fp solid tumours, with or without baseline CNS metastases, entrectinib induced deep and durable responses.Table: 111PROS1-fpNTRK-fpOverall (N=38)Intracranial (n=8)†Overall (N=21)Intracranial (n=5)†ORR*, n (%) 95% CI24 (63)46.0–78.23 (38)8.5–75.517 (81)58.1–94.65 (100)47.8–100.0CR4 (11)1 (13)1 (5)5 (100)PR20 (53)2 (25)16 (76)0SD5 (13)01 (5)0PD3 (8)01 (5)0Non-CR/non-PD4 (11)4 (50)1 (5)0Missing/unevaluable2 (5)1 (13)1 (5)0Median time to event, months (95% CI)Duration of response*11.1 (7.5–21.5)30.9 (22.5–NE)NE (11.1–NE)‡NE (5.8–NE)‡Progression-free survival*17.7 (9.6–22.9)13.6 (2.8−NE)30.3 (13.7–NE)‡NE (6.7–NE)‡Overall survival40.2 (21.4–NE)–NE (NE)‡–ORR for NTRK-fp NSCLC patients was 82% *BICR assessed; †Baseline CNS metastases by BICR; ‡Data are not yet matureNE, not estimable Open table in a new tab

Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data inROS1+ NSCLC

Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n=94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n=65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9-17.4) months for entrectinib; 8.8 (6.2-9.9) months for crizotinib (weighted hazard ratio: 0.72 [0.51-1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1-19.9) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.

PRO41 The Economic and Quality of Life impact of Entrectinib on CNS metastasis control

Most anticancer drugs cannot achieve adequate CNS exposure due to being P-gp substrates, a key efflux transporter of the blood–brain barrier. Entrectinib is a weak P-gp substrate and achieves CNS therapeutic levels. Crizotinib and larotrectinib (inhibitors of the same class) are strong P-gp substrates with poor CNS exposure. Therefore, the potential economic and patient quality of life value of entrectinib in targeting and resolving CNS metastases is patient and healthcare system relevant. Entrectinib is a potent and selective inhibitor of ROS1/TRK/ALK tyrosine kinase activity in vitro with systemic and CNS activity. Intracranial ORRs of 79.2% and 62.5% were observed in adult patients with ROS1 fusion positive NSCLC and NTRK fusion positive solid tumours, respectively, who had measurable baseline CNS metastases. For ROS1-positive NSCLC, the median intracranial PFS was 12.0 months, while for NTRK it was 10.1 months. Published costs incurred by patients with early brain metastases vs. patients without were applied to the average duration in which the cohort was free of CNS metastases (ie. in the CNS Progression Free state). Similarly, the QALY benefit was estimated by applying literature EQ-5D utility estimates for patients with CNS metastases vs. the utilities derived from the entrectinib trials for patients without CNS metastases; again, informed by the average duration of the CNS Progression Free state. The CNS effect of entrectinib could result in significant cost savings of $62K and $58K USD per patient with baseline CNS metastases and ROS1-positive NSCLC or NTRK solid tumours respectively. Similarly, resolving CNS metastases with entrectinib would contribute additional QALYs of 0.24 and 0.28 per patient for ROS1-positive and NTRK solid tumours respectively. Entrectinib has demonstrated important CNS clinical benefit relative to other available treatments, which could lead to significant healthcare system cost savings and substantial quality of life improvements for patients.

1287P Efficacy and safety of entrectinib in locally advanced/metastatic ROS1 fusion-positive NSCLC: An updated integrated analysis

1287P Efficacy and safety of entrectinib in locally advanced/metastatic ROS1 fusion-positive NSCLC: An updated integrated analysis

1288P Efficacy of entrectinib in patients with NTRK or ROS1 fusion-positive NSCLC with CNS metastases at baseline

1288P Efficacy of entrectinib in patients with NTRK or ROS1 fusion-positive NSCLC with CNS metastases at baseline

Abstract C084: Crizotinib resistance mechanisms and potential therapeutic strategies to overcome the resistance in ROS1-rearranged non-small cell lung cancer

Abstract ROS1 rearrangement was observed in about 1 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. To date, crizotinib, an ALK/ROS1 inhibitor was approved and widely used for the treatment of ROS1 rearranged NSCLC. However, the tumor relapses within a few years due to the emergence of crizotinib resistance by the secondary mutations in ROS1 kinase domain (e.g. G2032R) or other unidentified mechanisms. In this study, we explored crizotinib resistance mechanisms using ENU mutagenesis screening and the analysis of crizotinib resistant patient’s pleural effusion. We found several secondary mutations in ROS1 kinase domain including previously reported mutations. From a crizotinib resistant patient’s specimen, no secondary mutation in ROS1 was observed. By establishing a cell line from the specimen, we performed kinase inhibitor screening combined with crizotinib, and found that a combination of crizotinib with dasatinib or a few other tyrosine kinase inhibitors can suppress the growth. These results suggested that a bypass pathway mediated resistance through Src family kinase conferred resistance in this crizotinib resistant case. For overcoming the secondary ROS1 mutations mediated crizotinib resistance, we characterized several ROS1 inhibitors including a new selective ROS1/NTRK inhibitor DS-6051b in preclinical models of ROS1-rarranged cancers by newly establishing cell lines from TKI naïve ROS1 fusion positive NSCLC patients, or developing resistant mutation harboring HCC78 (SCL34A2-ROS1) or Ba/F3-CD74-ROS1 cell line models. Using these preclinical models, we demonstrated that DS-6051b induced dramatic growth inhibition of both wild type and G2032R mutant ROS1–rearranged cancers in vitro and in vivo, suggesting that DS-6051b might be effective in treating wildtype and crizotinib resistant mutant ROS1-rearranged lung cancer. This study revealed that potential resistance mechanisms in ROS1-rearranged NSCLC are similar to those identified in ALK rearranged NSCLC, and next-generation ROS1 inhibitor provides future promising therapeutic strategies to overcome the secondary mutation mediated resistance. Citation Format: Ryohei Katayama, Bo Gong, Makoto Nishio, Naoya Fujita. Crizotinib resistance mechanisms and potential therapeutic strategies to overcome the resistance in ROS1-rearranged non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C084. doi:10.1158/1535-7163.TARG-19-C084

444PD - Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1/TRK fusion-positive solid tumors (TRIDENT-1 study)

444PD - Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1/TRK fusion-positive solid tumors (TRIDENT-1 study)

LBA28 - Genomic landscape of entrectinib resistance from ctDNA analysis in STARTRK-2

BackgroundEntrectinib is a small molecule inhibitor of ROS1 and TRKA,B,C, with deep and durable responses observed in ROS1 fusion-positive NSCLC (ROS1+) and NTRK1,2,3 fusion-positive solid tumours (NTRK+). Despite clinically meaningful activity, progression on entrectinib eventually occurs. Understanding the mechanisms of resistance could inform subsequent new personalised therapeutic options in these patients. MethodsBlood samples were collected at baseline and at the time of progression from most patients in the NTRK+ and ROS1+ patient populations enrolled on STARTRK-2 (NCT02568267). These were tested using the Foundation Medicine FoundationOne Liquid NGS-based test that assesses base substitutions, indels and rearrangements from 324 genes (including ROS1 and NTRK1,2,3), as well as copy number alterations from select genes using circulating tumour DNA (ctDNA) extracted from the plasma of patients from pre-treatment and following progression on entrectinib. ResultsOf the 54 patients with NTRK+ tumours, 29 had paired samples at baseline and at progression at the time of data cut-off. Ten patients (34%) had a detectable NTRK solvent front mutation at disease progression (NTRK1: n=5; NTRK3: n=5), which were not detected in the pre-treatment sample. BRAF V600E and KRAS G12D mutations were detected at progression from a pancreatic cancer patient who had a partial response. Of the 53 patients with ROS1+ NSCLC, 18 had paired samples at baseline and at progression at the time of data cut-off. Four CD74-ROS1 and one SLC34A2-ROS1 patients showed the emergence of an acquired ROS1 resistance mutation (G2032R and F2004C/I) at disease progression (28%), which were not present before treatment. One NRAS Q61K mutation was detected at the end of treatment collection sample from a patient who had a partial response. ConclusionsFrom blood analysis, acquired resistance mutations were detected in 34% of NTRK+ solid tumour and 28% of the ROS1+ NSCLC cohorts, all of which were mutations in the kinase domain of the oncogenic driver. One additional patient from each cohort showed the emergence of a mutation in an oncogene within the MAPK pathway. Resistance to entrectinib can occur by multiple mechanisms, which should be studied in larger cohorts. Clinical trial identificationNCT02568267. Legal entity responsible for the studyF. Hoffman-La Roche. FundingF. Hoffman-La Roche. DisclosureR.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 (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati.; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond.. R. Dziadziuszko: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Travels: Roche, AstraZeneca. A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health; Research grant / Funding (institution): Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Research grant / Funding (self): Foundation Medicine; Travel / Accommodation / Expenses: Merck - Food/Beverage, Puma - Food/Beverage; Honoraria (self): Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice. A. Shaw : Honoraria (self), Advisory / Consultancy: ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, Natera, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, and TP Therapeutics; Research grant / Funding (institution): Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and TP Therapeutics. J. Wolf: Advisory / Consultancy, Officer / Board of Directors: AbbVie, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Takeda; Research grant / Funding (institution): BMS, Jannsen, MSD, Novartis, Pfizer. A.F. Farago: Research grant / Funding (institution): AstraZeneca, AbbVie, Genentech, BMS, Merck, PharmaMar, Amgen, Bayer, Loxo, Ignyta; Advisory / Consultancy: Genentech, Bayer, AbbVie, AstraZeneca, Boehringer Ingelheim, Loxo, PharmaMar. L. Dennis: Research grant / Funding (institution), Full / Part-time employment: Foundation Medicine. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. B. Simmons: Full / Part-time employment: Roche. C. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. V. Choeurng: Full / Part-time employment: Genentech, Inc. T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech.

Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]

Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1 fusion-positive non-small cell lung cancer (TRIDENT-1 study).

9011 Background: Repotrectinib is a next-generation ROS1/TRK/ALK TKI inhibiting ROS1 with > 90-fold greater potency than crizotinib. Preclinical studies showed robust kinase inhibitory activity of repotrectinib against all known ROS1 fusion positive resistance mutations, including the most common ROS1 solvent-front mutation (SFM) G2032R. Methods: In this ongoing phase 1 study (NCT03093116), TKI-naïve and TKI-refractory (≥1 TKI) patients (pts) with advanced ROS1/TRK/ALK+ solid tumors received repotrectinib treatment. Endpoints include safety, PK, and confirmed overall response (cORR). Safety analysis for all pts (n = 75) and efficacy analysis for ROS1+ NSCLC pts (n = 28) enrolled on the study was conducted. Results: As of 31-Oct-2018, 75 pts were treated with repotrectinib at dose levels from 40 mg QD to 200 mg BID. Most AEs were manageable and grade (Gr) 1-2. Common ( > 20%) treatment-related AEs were dizziness (49%), dysgeusia (48%), paresthesia (28%), and constipation (20%). Four DLTs (Gr3 dyspnea/hypoxia (n = 1); Gr2 (n = 1) and Gr3 (n = 1) dizziness at 160 mg BID, and Gr3 dizziness (n = 1) at 240 mg QD) occurred and were managed with dose modifications. The MTD has not been reached. Median number of prior TKI treatment was 1 (0-3) with all of TKI naïve and 83% of TKI pre-treated pts received prior chemotherapy. Among 10 evaluable TKI-naïve ROS1+ NSCLC pts, confirmed ORR by Blinded Central Review (BCR) was 90% (95% CI 56 - 100) with median duration of response (DOR) not reached ((range 5.5+ – 14.9+ months (mos)). Among 18 TKI-pretreated pts, confirmed ORR by BCR was 28% (95% CI 10 – 54) with DOR of 10.2 mos. Subgroup analysis showed cORR 44% (95% CI 14 - 79) in 9 prior TKI pts and treated at dose levels of 160 mg QD or above. In 7 pts with measurable target CNS lesions at baseline, the intracranial ORR was 3/3 (100%) with DOR (5.5+; 7.2+; 14.85+ mo) in TKI-naïve pts and 2/4 (50%) with DOR (5.5+;14.8+, mo) in TKI-pretreated pts, respectively. Conclusions: Repotrectinib was well tolerated and demonstrated encouraging overall and intracranial clinical activity in pts with ROS1 fusion-positive NSCLC. Enrollment in phase 1 continues until the RP2D is determined. A global phase 2 study is planned. Clinical trial information: NCT03093116.

Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors

Abstract Background: DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated activity of DS-6051b against tumors harboring ROS1 or NTRK fusion genes in cell culture and xenograft models. The objectives of this first in human (FIH) study are to assess safety and tolerability of DS-6051b in cancer subjects and identify the maximum tolerated dose (MTD) and the tentative RP2D. Pharmacokinetics (PK), QT prolongation, and tumor responses are also assessed in this study (Clinical Trial Information: NCT02279433). Methods: Dose escalation initially followed an accelerated titration design enrolling a single subject at each dose level, and then adopted the modified continuous reassessment method using a Bayesian logistic regression model and escalation with overdose control. Adult subjects with advanced solid tumors harboring ROS1 or NTRK1-3 fusion genes; or with neuroendocrine carcinoma; or with advanced solid tumors with tumor-induced pain are eligible for the study. DS-6051b is orally administered once-daily in 21-day cycles. Tumor assessments are performed every 3 cycles using RECIST 1.1 criteria. Plasma PK samples and time-matched ECG data are collected at multiple time points. Results: A total of 22 subjects have been enrolled at 50, 100, 200, 400, 800, and 1200 mg once daily (QD) dose levels. Enrolled population included 11 subjects with neuroendocrine carcinomas, 9 subjects with advanced solid tumors with tumor-induced pain, 1 subject with ROS1 fusion-positive NSCLC liver metastases, and 1 subject with leiomyosarcoma with a ROS1 point mutation. Two dose-limiting toxicities occurred in subjects who received 1200 mg QD, consisting of grade 3 transaminase elevations. The MTD is 800 mg QD. The most frequent (?20%) TEAEs were diarrhea, nausea, vomiting, dehydration, dizziness, dysgeusia, and fatigue, which were predominantly grade ?2. Cmax and AUC increased with the dose. Plasma terminal half-life was 11-24 hours. Steady state AUC was approximately 3 to 4-fold higher than that of Cycle 1 Day 1. Two subjects showed partial response: One with neuroendocrine carcinoma, who received 800 mg QD (33% decrease in tumor size), and one with ROS1 fusion-positive NSCLC liver metastases, who received 1200 mg QD (44% decrease in tumor size). Notably, the latter subject had progressed on crizotinib (best objective response stable disease) and ceritinib (progressive disease). Conclusions: DS-6051b has been well tolerated up to 800 mg QD in subjects with advanced solid tumors. The observed efficacy signals in two subjects with partial response warrant further evaluation. This trial is now selectively accruing subjects with ROS1 fusion-positive tumors. Citation Format: Kyriakos P. Papadopoulos, Erkut Borazanci, Daniel Von Hoff, Leena Gandhi, Amita Patnaik, Masaya Tachibana, Hamim Zahir, Roohi Gajee, Terri Goldberg, Giorgio Senaldi, Sai-Hong Ou. First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT024.

Abstract 764: Rational combination of PF-06463922 (next-generation ALK inhibitor) with PI3K pathway inhibitors overcomes ALKi resistance in EML4-ALK+ NSCLC models

Abstract Crizotinib (PF-02341066) is a small molecule tyrosine kinase inhibitor of ALK, ROS1 and c-MET that is approved in over 70 countries for the treatment of ALK fusion positive non-small cell lung cancer (ALK+ NSCLC). Crizotinib achieved robust objective response rates of approximately 60% in ALK+ NSCLC and significantly improved progression free survival compared to chemotherapy. The emergence of secondary mutations within the ALK kinase domain or the activation of compensatory signaling pathways in crizotinib and other ALKi refractory tumors prompted searches for next generation of ALKi active against resistance mutations as single agents or in combination with other treatments. Such effort led to our recent discovery of PF-06463922, an ALK/ROS1 inhibitor with greatly improved ALK potency, brain penetration, and broad spectrum activity against all known clinical ALKi-resistant mutations. PF-06463922 is being tested in a Phase I clinical trial in both ALK+ and ROS1 fusion positive NSCLC in treatment naive or ALKi relapsed patients. In our current preclinical study, we explored rational combination strategies to further improve the efficacy of PF-06463922 in ALKi resistant cells or tumors. Our results show that compared to PF-06463922 alone, the combination of this compound with PI3K pathway inhibitors, such as PF-05212384 (PI3K/mTOR), GDC0941 (pan-PI3K) or GDC0032 (beta-sparing) leads to more robust anti-proliferative activity in vitro and greater duration of efficacy in vivo in the ALKi resistant models. These PI3K pathway inhibitors also partially overcome EGF or HGF ligand-induced resistance to PF-06463922. Interestingly, in addition to AKT signaling, both compounds inhibit ERK signaling as well, which may be essential for their enhancement of PF-06463922 cell activity or tumor efficacy in combination settings. Studies are ongoing to identify optimal partners for PF-06463922 combination using isoform selective PI3Ki, AKTi and mTORi. We are also exploring the breadth of efficacy of this combination in overcoming resistance to crizotinib, PF-06463922 or other ALKi. The findings provide important evidence that will help define the clinical development path for PF-06463922. This research effort may ultimately lead to more effective approaches to treat ALKi refractory patients in the clinic. Citation Format: Ping Wei, Ming Qiu, Nathan Lee, Joan Cao, Hui Wang, Konstantinos Tsaparikos, Conglin Fan, Timothy Sargis, Justine Lam, Maruja E. Lira, Goldie Lui, James Hardwick, Valeria Fantin, Paul Rejto, Tod Smeal. Rational combination of PF-06463922 (next-generation ALK inhibitor) with PI3K pathway inhibitors overcomes ALKi resistance in EML4-ALK+ NSCLC models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 764. doi:10.1158/1538-7445.AM2015-764