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Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild type-sparing third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for advanced non-small cell lung cancer (NSCLC). The study aimed to evaluate the effects of food and race on the pharmacokinetics (PK) of lazertinib from a healthy volunteer trial and PK data from NSCLC patients with EGFR mutation.An open-label, single-dose, two-period, single-sequence crossover study was conducted in healthy subjects with two race groups (non-Asian and Asian). Subjects orally received a single dose of lazertinib 240 mg in fasted and fed state (high-fat meal) in each period separated by a 21-day washout. An open-label, multicenter, phase 1/2 study was conducted in Asian and non-Asian patients with NSCLC. Patients were given oral lazertinib 20-320 mg once daily in fasted state continuously in 21-day cycles. PK parameters were evaluated using non-compartmental analysis.A total of 24 healthy subjects (12 non-Asians and 12 Asians) and 52 NSCLC patients (22 non-Asians and 30 Asians) were evaluated. The change in the overall systemic exposure of lazertinib at fed state was less than 15%. Non-Asians showed 58-76% of the systemic exposure than Asians in healthy subjects. In contrast, there were no significant differences in systemic exposure by race both after single and multiple doses among NSCLC patients.Lazertinib can be taken with or without food considering the comparable systemic exposures related to food. Although effect of race was not consistent across studies, there was no evidence for dose adjustment based on race.

PDF - 260KB, Supplementary Figure 1. Validation of the Docetaxel-resistant prostate cancer cell line DU145-Rx. Supplementary Figure 1. Validation of the Docetaxel-resistant prostate cancer cell line DU145-Rx. Supplementary Figure 3. Co-treatment-induced cell death in Docetaxel-resistant DU145-Rx cells is associated with enhanced autophagy. Supplementary Table 1. SILAC ratios of up- or down-regulated tyrosine phosphorylation sites.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated efficacy in patients withPlain language summary Osimertinib is the standard-of-care treatment for patients with non-small-cell lung cancer caused by mutations in the EGFR. However, patients will eventually see their disease return because their tumors will develop new mutations that are resistant to osimertinib treatment. Amivantamab is a new antibody treatment that blocks the EGFR and another receptor called the MET receptor, to stop the growth of lung tumor cells. In an ongoing clinical trial, called the CHRYSALIS study, when amivantamab was given with lazertinib (another drug that blocks the EGFR), lung tumors shrank in patients whose lung cancer had not been previously treated. A new clinical trial called the MARIPOSA study (NCT04487080) aims to compare the antitumor activity and safety of the amivantamab + lazertinib combination versus osimertinib alone in patients with

We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B-cell lymphoma (DLBCL) cell of origin (COO) in the phase III PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non-germinal centre B cell-like (non-GCB) DLBCL by IHC, the concordance with GEP for non-GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell-like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non-GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged

Background: Among post-osimertinib (osi), chemotherapy-naïve patients (pts) treated with amivantamab (ami) and lazertinib (laz) in CHRYSALIS Cohort E, NGS of baseline ctDNA and tumor tissue revealed pts with identified EGFR/MET-based resistance (eg, EGFR C797S or MET amplification) were slightly more likely to respond versus those without EGFR/MET-based resistance (ORR=47% vs 29%), but about half of responders had unknown resistance mechanisms (Bauml JCO 2021; 39:15_suppl, 9006). In CHRYSALIS-2 Cohort A (NCT04077463), ami + laz demonstrated an ORR of 33% in the post-osi and platinum-based chemotherapy population (Shu JCO 2022; 40:16_suppl, 9006). This analysis investigated whether EGFR/MET-dependent resistance by ctDNA correlated with response. Methods: Cohort A examined ami + laz in EGFR exon19del or L858R mutated advanced NSCLC whose disease progressed on osi as well as platinum-based chemotherapy. ORR was verified through blinded independent central review. Plasma samples were collected prior to treatment; ctDNA was analyzed by Guardant360. Results: A total of 162 pts were enrolled; of these, 110 (68%) had analyzable ctDNA data, with most common mutations observed in EGFR and TP53. Twenty-eight (25%) pts had resistance categorized as EGFR/MET-dependent and 31 (28%) as EGFR/MET-independent; no genetic resistance mechanism was identified in 51 (46%). The ORR was 29% and 26% in EGFR/MET-dependent and independent pts, respectively. ORR in pts with an unknown resistance mechanism was 39% (Table). Conclusions: Among pts who progressed on osi and platinum-based chemotherapy, genetic profiling of osi resistance by ctDNA did not predict response, with many responders having unknown resistance mechanisms. These results suggest alternative biomarker approaches are needed to identify pts most likely to benefit from ami + laz. Table. ORR by type of resistance mechanism Resistance mechanism n PR ORRa EGFR/MET-dependentb 28 8 29% EGFR/MET-independent 31 8 26% Unknown 51 20 39% All patients 110 36 33% aResponses were assessed by blinded independent central review per RECIST v1.1. bIncludes co-occurring ‘independent’ resistance mechanisms. EGFR, epidermal growth factor receptor; MET, mesenchymal epithelial transition factor; ORR, objective response rate; PR, partial response. Citation Format: Rachel E. Sanborn, Saiama N. Waqar, Byoung Chul Cho, Benjamin Besse, Koichi Goto, Yongsheng Wang, Se-Hoon Lee, Melina E. Marmarelis, Yuichiro Ohe, Dong-Wan Kim, Antonio Calles, Joel Neal, Christina S. Baik, Pasi A. Janne, Joshua C. Curtin, Bharvin Patel, Mike Gormley, S. Martin Shreeve, Joshua M. Bauml, Roland E. Knoblauch, James Chih-Hsin Yang. Analysis of ctDNA next generation sequencing (NGS) for predicting response to amivantamab and lazertinib among patients with EGFR-mutant NSCLC after progression on osimertinib and platinum-based chemotherapy (CHRYSALIS-2 Cohort A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2166.

Objective: DNA amplifications of the cMET locus (METamp) are rare (1-6%) in non-small cell lung cancer (NSCLC). The ability to efficiently identify patients with METamp could accelerate development of cMET-targeting therapies by identifying patients for enrollment efficiently. We developed a self-supervised deep learning algorithm (SSDL) to predict METamp status using H&E stained whole slide images (WSI). Methods: Three datasets (CDtrain, CDNGS, CDFISH) consisting of data from 1,436 advanced NSCLC patients (1 slide/pt) were used to develop an SSDL algorithm to predict METamp status. The METamp+ status across datasets was standardized for CDtrain (n=788, METamp+ Prevalence=15%), CDNGS (n=186, 19 positive, 167 negative, Prev=10%) as harboring ≥5 copies of the gene using NGS(Next Generation Sequencing) and for CDFISH (n=462, 36 positive, 426 negative, Prev=8%) as MET CN gain to centromere 7 ratio (CEN) ≥2.5. The datasets were divided into a discovery set (CDtrain) for training and held-out test sets (CDNGS, CDFISH) for validation. To improve robustness of SSDL, we first pre-trained ResNet34 with Simple Contrastive Learning, using >25k WSIs from diverse sources. During the training phase, 4-fold cross validation was applied on CDtrain. The first 3-layers of ResNet34 were frozen while the final layer and an attention-based aggregation system were trained for METamp prediction. The performance was assessed using sensitivity, specificity, AUC, positive predictive value (PPV), and negative predictive value (NPV) on the test sets. Predictions from the model were binarized using two separate thresholds selected from CDtrain, resulting in a High-Sensitivity model (SSDLSens = 90% Sensitivity) and High-Specificity model (SSDLSpec = 90% Specificity). Each model’s potential impact on patient enrollment is presented below. Results: The trained SSDL models achieved an average cross-validation AUC of 0.77±0.04 across folds. The final trained model with the highest cross-validated AUC was chosen for METamp status prediction on the test sets. The selected model maintained predictive performance on CDNGS (AUC=0.82) and CDFISH (AUC=0.75) test sets. The SSDLSpec model had a PPV more than twice the baseline prevalence in both CDNGS (PPV=27%), and CDFISH (PPV=29%), providing a significant enrichment in METamp+ patients. The SSDLSens model correctly classified ~55% of METamp‒ in CDNGS and CDFISH with NPV of ≥97%. These results suggest a potential reduction in genetic screening by 50% while maintaining high sensitivity. Conclusions: The SSDL model robustly predicted METamp status in independent patient cohorts, regardless of METamp definitions (i.e., by NGS or FISH). We demonstrate the ability to classify patients with high sensitivity or specificity, which can help reduce genetic testing or surface potentially eligible patients for trials, respectively. Citation Format: Chaitanya Parmar, Oscar M. Carrasco-Zevallos, Joshua C. Curtin, Darshana Govind, Bing Xia, S. Martin Shreeve, Songbai Wang, Timothy Jatkoe, Patricia Raciti, Levon Demirdjian, Joel Greshock, Kristopher Standish, Stephen S.F. Yip. Prediction of MET amplification from H&E images in non small cell lung cancer using self-supervised deep learning and its role in clinical trial enrollment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6554.

60th Annual Meeting of the American-Society-of-Hematology (ASH) -- DEC 01-04, 2018 -- San Diego, CA Jurczak, Wojciech/0000-0003-1879-8084; Johnson, Peter/0000-0003-2306-4974; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Leppa, Sirpa/0000-0002-8265-511X WOS: 000468868300004 PubMed: 30901302 PURPOSE Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted. (C) 2019 by American Society of Clinical Oncology Amer Soc Hematol Janssen Global Services; Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748] Supported by Janssen Global Services, which also provided writing and editorial support, and by Memorial Sloan Kettering Cancer Center Support Grant No. P30 CA008748 (A.Y.).

Background Docetaxel, the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC) also enhances the survival of patients with metastatic castration-sensitive prostate cancer (CSPC) when combined with androgen-deprivation therapy. Focal Adhesion Kinase (FAK) activation is a mediator of docetaxel resistance in prostate cancer cells. The aim of this study was to investigate the effect of the second generation FAK inhibitor VS-6063 on docetaxel efficacy in pre-clinical CRPC and CSPC models. Methods Docetaxel-resistant CRPC cells, mice with PC3 xenografts, and ex vivo cultures of patient-derived primary prostate tumors were treated with VS-6063 and/or docetaxel, or vehicle control. Cell counting, immunoblotting, and immunohistochemistry techniques were used to evaluate the treatment effects. Results Docetaxel and VS-6063 co-treatment caused a greater decrease in the viability of docetaxel-resistant CRPC cells, and a greater inhibition in PC3 xenograft growth compared to either monotherapy. FAK expression in human primary prostate cancer was positively associated with advanced tumor stage. Patient-derived prostate tumor explants cultured with both docetaxel and VS-6063 displayed a higher percentage of apoptosis in cancer cells, than monotherapy treatment. Conclusions Our findings suggest that co-administration of the FAK inhibitor, VS-6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer.

Introduction This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non–small cell lung cancer. Methods Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. Results Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene ( EGFR ) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene ( MET ) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. Conclusion The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non–small cell lung cancer and was associated with substantial toxicity.

Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxel-resistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry–based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein–protein interaction networks related to these pathways in docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministration with docetaxel may be used in patients with CRPC to overcome chemoresistance. Mol Cancer Ther; 13(1); 190–201. ©2013 AACR.

Introduction In the phase 3, double-blind, placebo (pbo)-controlled PHOENIX trial (NCT01855750), 838 patients (pts) with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) were randomized 1:1 to ibrutinib (IBR; 560 mg/day orally) + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or pbo + R-CHOP. IBR + R-CHOP did not improve event-free survival (EFS) in the intent-to-treat (ITT) non-GCB population (hazard ratio [HR] 0.934; 95% confidence interval [CI], 0.726-1.200). However, in an exploratory analysis, pts < 60 years benefited from the addition of IBR (HR 0.579; 95% CI, 0.380-0.881 for EFS), whereas pts ≥ 60 years did not (HR 1.228; 95% CI, 0.887-1.699 for EFS) due to increased toxicity and reduced R-CHOP exposure. Based on evidence that co-expression of BCL2 and MYC by immunohistochemistry (IHC) have a worse outcome with R-CHOP, we examined their clinical prognostic effect in the 2 arms of the PHOENIX trial. Methods Pretreatment formalin-fixed paraffin-embedded biopsy samples were collected. RNA was extracted and profiled with Illumina RNAseq. Raw sequence reads were aligned to the hs37d5 genome build with STAR v2.5.1b, and gene-level quantification was conducted using RSEM v1.2.23. The median transcript per million mapped reads (TPM) values for BCL2 and MYC gene expression across all pts with RNAseq data (n = 766) were used as the cutoffs between high and low expression for each gene. BCL2 IHC data were available from 184 pts, and based on these, the threshold expression value from RNAseq data that could best approximate positive calls from IHC (≥ 50% lymphoma cells positive) was determined. This threshold value was very close to the median level calculated above and therefore supported the use of the median expression levels as the cutoffs to define high and low expressors in the subsequent analyses. The relationship between expression by RNAseq and survival (EFS, overall survival [OS]) in the 2 study arms was analyzed by Kaplan-Meier estimate with Cox regression to determine HRs and log-rank testing to assess significance. Results Based on a cutoff at the median TPM value, the percentage of non-GCB pts with BCL2-high + MYC-high (n = 234, 30.5%) was consistent with previous literature. In the IBR + R-CHOP (n = 386) and pbo + R-CHOP (n = 380) arms, respectively, 123 (31.9%) and 111 (29.2%) pts were MYC-high + BCL2-high by RNAseq. In the pbo + R-CHOP arm, pts with MYC-high + BCL-2-high had worse EFS (HR 1.820; 95% CI, 1.264-2.620; p = 0.0011) and OS (HR 1.662; 95% CI, 1.014-2.724; p = 0.0415) versus those with low expression of 1 or both markers in the ITT population (Figure), consistent with known poor outcomes associated with these genes. However, there was no difference in outcome for high versus low expression of these genes in the IBR + R-CHOP arm in the ITT population. In the ITT population, pts with MYC-high + BCL2-high had better EFS (HR 0.648; 95% CI, 0.423-0.993; p = 0.045) with IBR + R-CHOP versus pbo + R-CHOP, but there was no significant difference in OS (HR 0.783; 95% CI, 0.446-1.372; p = 0.39; Figure). We also examined the outcome of the 97 (30.6%) pts < 60 years of age (n = 317) with MYC-high + BCL2-high and observed an improved EFS and OS with IBR + R-CHOP versus pbo + R-CHOP (HR 0.393; 95% CI, 0.198-0.780; p = 0.0056 for EFS; HR 0.191; 95% CI, 0.055-0.666; p = 0.0037 for OS; Figure). There was no significant difference in EFS or OS in pts < 60 years with MYC-low + BCL2-low or in pts ≥ 60 years with MYC-high + BCL2-high in the 2 arms. Conclusions In this exploratory analysis, IBR was associated with improved EFS in combination with R-CHOP compared with pbo + R-CHOP in pts with MYC-high + BCL2-high expression in the ITT (non-GCB) population, without a significant improvement in OS. In pts aged < 60 years, both EFS and OS were significantly better with IBR, while there was no significant difference in older pts. These data suggest that IBR + R-CHOP may particularly benefit pts with MYC-high + BCL2-high-expressing lymphomas, a hypothesis warranting further testing in other DLBCL cohorts. Disclosures Johnson: Novartis: Honoraria; Genmab: Honoraria; Kite: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Boehringer Ingelheim: Honoraria. Balasubramanian:Janssen: Employment; Johnson & Johnson: Equity Ownership; Gilead Sciences: Equity Ownership; Celgene: Equity Ownership; Vertex: Equity Ownership; AbbVie: Equity Ownership. Hodkinson:Janssen: Employment. Schaffer:Johnson & Johnson: Equity Ownership; Janssen: Employment. Parisi:Janssen: Employment. Shreeve:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sun:Janssen: Employment; Johnson & Johnson: Equity Ownership. Vermeulen:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sehn:Abbvie: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria. Staudt:Nanostring: Patents & Royalties. Younes:AstraZeneca: Research Funding; Biopath: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding; BMS: Research Funding; HCM: Consultancy; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria.

Introduction DLBCL is an aggressive disease that can be classified by immunohistochemistry (IHC) into GCB and non-GCB or by gene expression profiling (GEP) into GCB, activated B-cell (ABC), and unclassified subtypes. RCHOP is the standard frontline treatment (tx) for DLBCL with a 60% cure rate. Ibrutinib (ibr), an oral covalent Bruton's tyrosine kinase inhibitor, showed activity in relapsed/refractory ABC DLBCL. This study aimed to analyze if the addition of ibr to RCHOP would improve efficacy in previously untreated patients (pts) with non-GCB DLBCL or the ABC subtype. Methods Pts with centralized IHC-confirmed non-GCB DLBCL were randomized 1:1 to standard RCHOP with either ibr (560 mg/d, po) or placebo (pbo) on a 21-day cycle for 6 or 8 cycles. Pts were stratified by revised International Prognostic Index, region (US/Western Europe vs rest of world), and number of prespecified RCHOP cycles (6 or 8). ABC DLBCL was retrospectively identified using GEP (HTG EdgeSeq cell of origin assay). Primary end point was event-free survival (EFS), defined as time from randomization to progression, relapse from complete response (CR), initiation of tx for PET-positive or biopsy-proven residual disease after ≥ 6 cycles of RCHOP, or death, in the intent-to-treat (ITT) or ABC population. Secondary end points included progression-free survival (PFS), CR rate, overall survival (OS), and safety. Results Overall, 838 pts were randomized to ibr + RCHOP (n = 419) or pbo + RCHOP (n = 419). Median age was 62 years (yrs) with 58.5% < 65 yrs; 67.7% had ABC subtype. Baseline prognostic factors were balanced; slightly more pts ≥ 65 yrs in the ibr + RCHOP arm (45% vs 38%). In the ibr + RCHOP and pbo + RCHOP arms, 80.8% and 90.7% of pts received ≥ 6 cycles of RCHOP; 22.4% and 13.6% discontinued tx (all drugs) with adverse event (AE) being the most common reason (12.2% vs 5.3%). All deaths rate was 16.5% vs 17.2% in the ibr + CHOP vs pbo + RCHOP arm, respectively. In pts < 65 yrs, 90.4% vs 91.1% of pts received ≥ 6 cycles of RCHOP in the ibr + RCHOP vs pbo + RCHOP arm, respectively. Fewer pts ≥ 65 yrs in the ibr + RCHOP arm (69.0%) received ≥ 6 cycles of RCHOP compared with the pbo + RCHOP arm (90.0%). Ibr pharmacokinetics with RCHOP was similar to other studies in B-cell malignancies where ibr was used as a single agent or in combination. Median follow-up was 34.8 months. Ibr + RCHOP did not improve EFS in pts with non-GCB (by IHC) or ABC (by GEP) DLBCL: The hazard ratio (HR) for EFS was 0.934 (95% confidence interval [CI], 0.726-1.200) for the ITT and 0.949 (95% CI, 0.704-1.279) for the ABC subset. Multivariate analysis showed a significant interaction (based on SAP prespecified 1-sided α level p < 0.1) between tx effect and age as a continuous or categorical variable. Efficacy was a function of age: stable benefit seen in younger pts, with a decline with increasing age, and benefit no longer favorable in pts ≥ 65 yrs. Efficacy outcomes favored ibr + RCHOP-treated pts < 65 years with statistically significant risk reduction in EFS (30%), PFS (33%), and OS (43%; Table, Figure). A similar trend was seen in the ABC subset. Multivariate analyses, adjusting for other baseline covariates, confirmed the tx benefit in younger but not elderly pts. Grade ≥ 3 AE rates were 89.9% and 87.1% in the ibr + RCHOP and pbo + RCHOP arms, respectively. Serious AEs (SAEs) were greater in the ibr + RCHOP vs pbo + RCHOP arm (53.1% vs 34.0%), particularly febrile neutropenia and pneumonia, as were AEs leading to RCHOP discontinuation. In pts ≥ 65 yrs, there were more SAEs (67.4% vs 40.6%) and pts who received < 6 cycles of RCHOP (31.0% vs 10.0%) in the ibr + RCHOP vs pbo + RCHOP arm. In pts < 65 yrs, grade ≥ 3 AEs were similar; SAEs were numerically higher (41.5% vs 29.8%) in the ibr + RCHOP vs pbo + RCHOP arm, but the proportion of pts who received < 6 cycles of RCHOP was similar (9.6% vs 8.9%) between arms. Conclusions While the addition of ibr to RCHOP did not improve efficacy in the ITT population, there was a significant interaction between tx and age. Among pts ≥ 65 yrs, unexpected increased toxicity associated with ibr + RCHOP resulted in reduced RCHOP exposure, which may explain in part the worse clinical benefit/risk profile of pts in the ibr + RCHOP vs pbo + RCHOP arm. However, in pts < 65 yrs, the addition of ibr showed clinically meaningful improvement in EFS, PFS, and OS with an acceptable safety profile. Funding Source Sponsored by Janssen. Writing assistance was provided by Liqing Xiao of PAREXEL and funded by Janssen. Disclosures Younes: J&J: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria; Curis: Research Funding; Novartis: Research Funding; Seattle Genetics: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Merck: Honoraria. Sehn:Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Johnson:Takeda: Honoraria, Travel, accommodations, expenses; Incyte: Consultancy; Celgene: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Bristol-Myers Squibb: Honoraria; Kite: Consultancy; Boeringher Ingelheim: Consultancy; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy. Zinzani:Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Hernandez:Servier: Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau. Dührsen:Celgene: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Carey:Janssen Research & Development: Employment. Liu:Janssen Research & Development: Employment, Equity Ownership. Shreeve:Janssen Research & Development: Employment, Equity Ownership. Sun:Janssen Research & Development: Employment, Equity Ownership. Vermeulen:Janssen Research & Development: Employment, Equity Ownership.

Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. (Mol Cancer Res 2009;7(9):1438–45)

Objective VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Methods Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Results Forty-six patients were treated across nine dose levels (12.5–750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

Purpose PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. Patients and Methods Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. Results Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration–time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration–time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [18F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. Conclusion The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.

Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

Metastasis suppressor genes (MSGs) are defined by their ability to inhibit overt metastasis in a secondary organ without affecting tumor growth at the primary site. Over 20 MSGs have been confirmed in vivo. This class of genes is only unified by their capacity to suppress metastasis, as they encode for proteins with a wide range of biochemical activities that are components of a variety of signaling pathways. In addition, metastasis suppressors impinge upon different stages of the metastatic cascade to manifest their suppressive effects. The MSGs KISS1, KAI1, MKK4/7 and Nm23-H1 promote tumor dormancy at the metastatic site, since tumor cells with induced expression of these MSGs disseminate, but do not form overt metastases in the secondary organ throughout the duration of a metastasis assay. Evidence suggests that KISS1 triggers dormancy in solitary, metastatic tumor cells by causing growth arrest of solitary cells at the secondary site. KAI1 induces growth arrest prior to extravasation by binding a vascular endothelial cell surface marker. MKK4, MKK7 and Nm23-H1 appear to promote dormancy of micrometastatic colonies, after disseminated tumor cells have undergone several rounds of proliferation. Other MSGs may also function in tumor dormancy, but so far their role has not been fully elucidated. Therapeutic approaches that either mimic the effects of MSGs or re-establish MSG expression in metastatic lesions may hold promise for the establishment or maintenance of dormancy.

TPS5100 Background: ADT is the standard of care for patients (pts) with metastatic prostate cancer and is frequently used in pts with non-metastatic prostate cancer. Initial ADT achieves responses ...

Preparations of lysed synaptosomes exhibit a high affinity Ca2+/Mg2+ ATPase and ATP-dependent Ca2+ accumulation activity, with a Km for Ca2+ congruent to 0.5 microM, close to the cytosolic concentration of Ca2+. When these membrane suspensions were incubated with cholinergic agonists muscarine or oxotremorine (1-20 microM), both Ca2+/Mg2+ ATPase and ATP-dependent CA2+ uptake were inhibited in a concentration-dependent fashion. Atropine alone (0.5-1.0 microM) had no effect on either enzyme or uptake activity, but significantly inhibited the actions of both muscarine and oxotremorine. No significant effects by cholinergic agonists or antagonists were seen on fast or slow phase voltage-dependent Ca2+ channels or Na+-Ca2+ exchange. These results suggest that activation of presynaptic muscarinic receptors produce inhibition of two processes required for the buffering of optimal free Ca2+ by the nerve terminal. Activation of presynaptic muscarinic receptors have been reported to reduce the release of ACh from nerve terminals. Alterations in intracellular free Ca2+ may contribute to a reduction in transmitter (ACh) release seen following activation of cholinergic receptors.