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Ripretinib is a tyrosine kinase inhibitor (TKI) indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study (NCT02571036), the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Ripretinib 150 mg BID intrapatient dose escalation regimen was offered to patients in the phase 1 and 3 trials (INVICTUS, NCT03353753) after radiologic progression at 150 mg once daily (QD). The BID dose was well tolerated with a similar safety profile to the 150 mg QD (approved dose regimen). In this analysis, the population pharmacokinetics (popPK) of ripretinib and DP-5439, a metabolite TKI with in vitro activity and exposure similar to ripretinib, were characterized and potential covariates influencing exposure were evaluated. The popPK models were developed for ripretinib and DP-5439 using 5284 and 5160 quantifiable concentrations, respectively, from 350 patients pooled from the phase 1 and INVICTUS phase 3 studies. Models were estimated using first-order conditional estimation with interaction method in NONMEM® (version 7.3; ICON, Hanover, MD, USA) and evaluated based on standard goodness-of-fit metrics. A covariate analysis was conducted to assess the sources of variability in ripretinib pharmacokinetics (PK) using a full model approach with backward elimination (significance level = 0.005). Tested covariates included age, body weight, sex, race, tumor type, prior gastrectomy, and mild hepatic impairment and mild to moderate renal impairment. Ripretinib oral PK was well described by a 2-compartment model with zero-order drug release at the absorption site followed by first-order absorption with a modest, linear dose-dependent decrease in relative bioavailability and linear elimination. A high-fat meal was predicted to increase the ripretinib AUC by 36% at 150 mg QD relative to the fasted state. The only covariate effect retained in the final popPK model for ripretinib was 29% lower apparent clearance in females compared with males, resulting in a 40% higher AUC in females. No other covariates were identified for ripretinib. The resulting effect on DP-5439 was similar. PK exposure in patients with mild hepatic impairment or mild to moderate renal impairment was similar to that in patients with normal organ function. There were no clinically meaningful differences in the PK of ripretinib based on age, race, body weight, or tumor type. Based on the safety profile of ripretinib observed in patients with advanced GIST and PK variability, the effects of sex, fasted state, and prior gastrectomy on ripretinib PK were not considered clinically significant. Therefore, ripretinib can be taken with or without food by all patients and no dose adjustment is recommended for patients with mild hepatic impairment or patients with mild to moderate renal impairment. Citation Format: Suzanne George, Filip Janku, Ping Chi, Margaret von Mehren, Neeta Somaiah, Hans Gelderblom, Robin L. Jones, Martine Allard, Adekemi Taylor, Xiaoyan Li, Julie Meade, Vienna Reichert, Rodrigo Ruiz-Soto, Jing Wang, Michael C. Heinrich. Population pharmacokinetics of ripretinib in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT123.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p

Introduction: TSR-042 is a humanized monoclonal antibody targeting programmed death (PD)-1, effectively blocking interaction with its ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients (pts) with advanced solid tumors in the ongoing phase 1 GARNET trial (NCT02715284). Weight based dose escalation (Part 1) and fixed-dose safety studies (Part 2A) have been completed,1 and the study is currently enrolling pts with specific tumor types into expansion cohorts. Here, we present safety and efficacy data from the microsatellite instability-high (MSI-H) endometrial cancer (EC) and non-small cell lung cancer (NSCLC) cohorts, as well as pharmacokinetic (PK) and receptor occupancy (RO) characterization at the recommended phase 2 dose (RP2D). Methods/Procedures: 30 NSCLC pts and 19 MSI-H EC pts with previously treated recurrent or advanced disease were enrolled; median number of prior lines of therapy for metastatic disease was 1.0 for both cohorts. MSI status for EC pts was determined centrally using a next generation sequencing-based assay. Key exclusion criteria included prior therapy with agents targeting anti-PD-1, PD-L1, or PD-L2, and uncontrolled CNS metastases. Pts were treated at the R2PD of TSR-042: 500 mg Q3W for the first 4 cycles and 1000 mg Q6W thereafter. Serum and PBMCs were collected for PK and RO analyses, respectively. Antitumor activity was assessed by investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). RO was assessed using a CD3+ binding assay (direct receptor occupancy).1 Results: Among the 30 NSCLC and 19 MSI-H EC pts, 42 (85.7%) pts reported ≥1 adverse event (AE), with grade ≥3 AEs reported in 13/49 (26.5%) pts. The most common AEs were diarrhea and nausea (11 pts each), arthralgia and fatigue (9 pts each), and cough, decreased appetite, and dyspnea (7 pts each). 25/49 (51.0%) pts reported treatment-related AEs; 11/49 (22.4%) pts had serious AEs; 1 case of grade 3 fatigue and 1 case of grade 3 leukopenia and grade 3 neutropenia were deemed treatment-related. 21 NSCLC and 11 MSI-H EC pts had at least 1 tumor assessment. Among NSCLC pts, 7/21 (33.3%) had a partial response (irPR; confirmed and unconfirmed), and 6/21 (28.6%) had stable disease (irSD); among MSI-H EC pts, 4/11 (36.4%) had irPR, and 2/11 (18.2%) had irSD. TSR-042 demonstrated dose-proportional PK. The maximal achievable RO was observed in pts treated at the RP2D, consistent with the results reported for Parts 1 and 2A.1 Conclusions: These results indicate clinical benefit of TSR-042 in previously treated NSCLC and MSI-H EC patients, with a safety profile similar to other PD-1 inhibitors. PK results were consistent across all patients evaluated and show that maximal achievable receptor occupancy was attained at the RP2D. 1. Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P Citation Format: Victor Moreno, Maria-Pilar Barretina-Ginesta, Wei Guo, Sharon Lu, David Jenkins, Kristen McEachern, Vienna Reichert, Steven Dunlap, Ellie Im, Lucy Gilbert, Ana Oaknin, Charles Leath, III, Janakiraman Subramanian. Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT053.

Gene testing in primary immune deficiencies (PIDs) once was limited to expert academic laboratories, but now is easily available to physicians with a broad range of clinical expertise. Such testing can establish or confirm a suspected diagnosis and also may predict future disease risk in advance of clinical signs and symptoms, inform reproductive decision making, and guide clinicians in selecting the most appropriate therapeutic options. This article, based on the authors' experience and a review of the published literature, discusses some of the advances and challenges currently encountered in the clinical molecular genetic diagnosis of PIDs.

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: The chaperone protein HSP90 is required for the stabilization and activation of many client proteins critical to breast cancer growth and aggressiveness, such as HER2, HIF1-α, EGFR, ER, PI3K, AKT, P53 and VEGFR. Ganetespib, a novel triazolone inhibitor of HSP90, has shown activity in breast cancer in both preclinical models (HER2+, ER+/PR+ and TNBC), and in early clinical trials (patients with HER2+ disease, as well as TNBC). Ganetespib has been well tolerated in clinical trials with a favorable safety profile. The ENCHANT-1 trial was designed to further evaluate ganetespib single agent activity in metastatic breast cancer (mBC) and identify potential predictive biomarkers. Methods: The ENCHANT-1 trial is an international, first-line phase 2 study in mBC patients: Cohort A, HER2+ (up to n=35) and Cohort B, TNBC (up to n=35). Patients with previously untreated metastatic disease are eligible for treatment with ganetespib at 150 mg/m2 twice weekly on 3 out of 4 wks. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include early metabolic effects as assessed by PET/CT at week 3. Tissue samples were collected from all pts at baseline prior to initiation of treatment; fresh biopsies at C1D18 and end of treatment were optional. Gene expression will be evaluated using RNAseq to survey mutations and gene expression levels in breast cancer genes. A reverse phase protein microarray assay will be used to map the activated protein signaling architecture of laser capture micro-dissected tumor cells from collected tissue samples to evaluate the level of phosphorylation/activation of HSP90 clients and coordinated signaling pathways. Analysis of ∼150 signaling proteins is planned. Results and Conclusions: The study was initiated in 27 centers globally. At the time of submission, a total of 35 patients were enrolled; TNBC (n= 30) and HER2+ (n=5). In an interim analysis, of the evaluable 4 patients in HER2-positive cohort, 2 had objective response (OR), and 2 stable disease (SD). In the TNBC cohort, of the evaluable 10 patients, 2 had OR, 3 SD and 5 PD. Full molecular analysis to identify biomarkers of response is underway and will be reported at the meeting. Citation Format: Emanuel F. Petricoin, Julia Wulfkuhle, Tamas Hickish, Iman El-Hariry, Vienna Reichert, Vojislav M. Vukovic, David A. Cameron, Ahmad Awada, Neil Spector. Gene expression and proteomic analysis to identify predictive biomarkers of response in the ENCHANT-1 Trial ([NCT01677455][1]), a Phase 2 Proof of Concept study evaluating first-line ganetespib monotherapy in women with metastatic HER2 positive or triple negat [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1612. doi:10.1158/1538-7445.AM2014-1612 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01677455&atom=%2Fcanres%2F74%2F19_Supplement%2F1612.atom

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Inhibition of Hsp90, a key molecular chaperone required for activation of many oncoproteins, can lead to cancer cell death. Ganetespib (G) is a 2nd generation Hsp90 inhibitor (Hsp90i) that has single agent clinical activity in patients with ALK, KRAS, HER2, and BRAF mutations. G also inhibits pathways implicated in resistance to taxanes, including hypoxia pathways (HIF-1α) as well as cell-cycle and DNA repair pathways. Combination of G with docetaxel (D) has shown synergy in NSCLC xenografts and prolongation of progression-free survival (PFS) and overall survival (OS) of patients with NSCLC adenocarcinoma in interim analyses of the GALAXY-1 trial. Methods: Patients enrolled in GALAXY-1 (n=253) receive D 75 mg/m2 on D1 of a 3-week treatment cycle; combination arm patients receive G 150 mg/m2 on D1 and D15 in addition. The co-primary endpoints are PFS in patients with elevated baseline level of serum LDH and PFS in the mutant KRAS population. PFS and OS in all adenocarcinoma patients are key secondary endpoints. Genomic profiling using Affymetrix Oncoscan™ was performed on archival tissues obtained at baseline, with the goal of determining biomarkers predictive of ganetespib activity Results: Tumor tissue samples from 65 patients and 26 matched normal tissues were processed on the Affymetrix OncoScan™ FFPE Express 2.0 Services assay. The OncoScan™ FFPE Express 2.0 assay contains 332941 copy number probes. After removing samples with average call rates lower than 90%, 296522 markers on chromosome 1-22 were selected for copy number analyses. For preliminary evaluation of interactions between copy number aberrations and treatment response in the G arm, a genome scale Kaplan-Meier Estimates PFS analysis at each of 296522 markers was performed. Conclusions: Genomic profiling using OncoScan™ is utilized in the GALAXY-1 trial to identify biomarkers of response/resistance to ganetespib administered in combination with docetaxel. Complete analyses will be presented at the meeting. Note: This abstract was not presented at the meeting. Citation Format: Dean Fennell, Alexey Antonov, Miguel L. Martins, Sanjay Popat, Suresh S. Ramalingam, James Spicer, Vojislav M. Vukovic, Iman El-Hariry, Vienna Reichert, Rafael Rosell. Evaluation of genomic profiling in the GALAXY-1 ([NCT01348126][1]), a randomized Phase 2b study of ganetespib in combination with docetaxel versus docetaxel alone as second line therapy in patients with advanced NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2014-4657 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01348126&atom=%2Fcanres%2F74%2F19_Supplement%2F4657.atom

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Non-small cell lung cancer is a mosaic, comprising several distinct molecular subtypes driven by somatic mutations in so-called cancer genes. Several of these oncogenic mutations confer dependence on HSP90 e.g. EML4-ALK, BRAF, KRAS, KIT. Inhibition of Hsp90 induces apoptosis and can exploit this dependence. Ganetespib (G) is an Hsp90 inhibitor with single agent activity in molecularly defined disease, including EML4-ALK rearrangement, KRAS mutations, HER2 amplification and BRAF mutations. Circulating free DNA (cfDNA) is present at low levels in plasma of healthy individuals allowing detection of somatic mutations by deep sequencing. The aim of this work was to determine the mutational spectrum of patients enrolled into the GALAXY trial using this liquid biopsy strategy. Methods: We performed a prospective exploratory analysis to identify plasma-borne somatic mutations as predictors of clinical outcome with G in GALAXY, a randomized trial, comparing G + docetaxel (D), to D alone in 2nd line advanced NSCLC patients. Plasma samples were collected from approximately 200 patients with adenocarcinoma at baseline prior to initiation of treatment, and during cycles 1 and 2. cfDNA samples were evaluated using the Ion AmpliSeq™ Cancer Panel on the Ion Torrent |PGM platform to survey 739 amplicons in 46 cancer genes at up to 6000x depth. Results: CfDNA targeted sequence analysis of the first 38 patients revealed multiple concurrent mutations in client proteins including the HSP90 client proteins BRAF, PDGFR and KIT, demonstrating the feasibility of this method. Sequencing of a larger cohort is underway. Longitudinal sampling of plasma has been conducted to monitor temporal evolution of the penetrance of mutations. Summary: Ultra-deep re-sequencing of multiple somatic mutations in circulating cfDNA is feasible, and can potentially enable identification of G sensitive subgroups. This represents a new approach to biomarker discovery in the context of phase II trials. Citation Format: Dean Anthony Fennell, L. Miguel Martins, Iman El-Hariry, Vojo Vukovic, Florentina Teofilovici, Vienna L. Reichert, Jacqui Shaw. Ultra-deep sequencing of circulating free DNA to identify predictive, mutated HSP90 clients in the GALAXY TrialTM ([NCT01348126][1]): a randomized phase IIB/III study of ganetespib (STA-9090) in combination with docetaxel versus docetaxel alone in subjects wit [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2012. doi:10.1158/1538-7445.AM2013-2012 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01348126&atom=%2Fcanres%2F73%2F8_Supplement%2F2012.atom