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Introduction: FRα is overexpressed in 80% of OC and endometrial carcinoma (EC), with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with Sutro’s cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF+™) platform, which uses the non-natural amino acid pAMF. STRO-002 has a drug-antibody ratio (DAR) of 4 and contains the proprietary tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant therapeutic efficacy in OC xenograft models. Toxicology studies demonstrate dose-dependent and reversible neutropenia when STRO-002 is administered to cynomolgus monkeys. No ocular toxicity was observed. Herein we report additional preclinical efficacy in PDX models and preliminary safety experience of STRO-002 in patients (pts) with OC. PDX model methods: FRα expression was evaluated in EC PDX models by IHC. Single agent efficacy of 10 mg/kg STRO-002 was assessed in models with negative, low (+), medium (++) and high (+++) FRα expression. Phase 1 trial methods: STRO-002-GM1 is a first-in-human Phase I, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, relapsed or refractory OC and EC. STRO-002 is given IV over an hour on Day 1 of each 21-day cycle until disease progression. Results: Statistically significant efficacy was observed in 60% of the FRα-positive PDX models tested, with STRO-002 response appearing to positively correlate with FRα expression levels. Though high FRα PDX models showed the highest response rates, some models with low and medium FRα also exhibited good responses. 5 pts with OC have completed at least one cycle (21 days) of STRO-002 at 3 dose levels: 0.5, 1.0, and 1.8 mg/kg and are evaluable for safety and toxicity. Median age is 63 (r, 52-64). Median ECOG performance status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-8). Four pts have received PARP inhibitors. Median number of STRO-002 doses administered is 2 (r, 1-5). 3 additional pts have been treated at the 2.9 mg/kg dose level and continue in the first cycle. No grade ≥ 3 treatment-related adverse events (TRAEs) have been observed. 93% of AEs are grade 1 or 2. The most common TRAEs in ≥20 % of pts includes nausea, vomiting, abdominal pain, fatigue and insomnia. Four grade 3 events occurred in 2 pts after completion of the first cycle and were related to disease progression, including small intestine obstruction, gross hematuria, dehydration and vomiting. 2 pts have discontinued due to disease progression. 6 pts remain on treatment and dose escalation is ongoing. Conclusions: STRO-002 is the first ADC generated with cell-free protein synthesis technology and site-specific conjugation of a novel hemiasterlin linker-warhead to be tested in pts with solid tumors. The potent anti-tumor activity of STRO-002 in PDX models further supports the clinical development of this agent. The preliminary safety profile in 5 OC pts treated with STRO-002 is encouraging. MTD has not been reached, no DLTs have been observed and dose escalation is continuing. Updated results will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186. Citation Format: Denise Uyar, Russell J Schilder, R Wendel Naumann, Fadi S Braiteh, Erika Hamilton, Sami Diab, John Moroney, Richard T Penson, Jennifer Smith, Cristina Abrahams, Michael Palumbo, Venita DeAlmeida, Shannon Matheny, Arturo Molina. Antitumor activity of STRO-002, a novel anti-folate receptor-α (FRα) antibody drug conjugate (ADC), in patient-derived xenograft (PDX) models and preliminary phase I dose escalation safety outcomes in patients with ovarian carcinoma (OC) [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 C095. doi:10.1158/1535-7163.TARG-19-C095

Background Real-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA. Methods We performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease. Results This analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P

Importance Atezolizumab (anti–programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. Objective To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. Design, Setting, and Participants Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). Interventions Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. Main Outcomes and Measures Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. Results Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. Conclusions and Relevance Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. Trial Registration clinicaltrials.gov Identifier:NCT01375842

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment.

Background FGFR2 gene aberrations (GA) include fusions and mutations/amplifications, with an estimated prevalence of approximately 15% and 5% in iCCA, respectively. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 mutations and amplifications is less well defined, due to ambiguous available preclinical and clinical data. In a non-comparative Phase 2a study (NCT01752920), the potent pan-FGFR inhibitor DZB was administered to iCCA pts expressing either FGFR2-fusion (N=29), FGFR2 mutations/amplifications (N=6) or no FGFR gene aberration (N=9). Here, we present a post-hoc analysis of outcomes of iCCA pts expressing FGFR mutations/amplifications (N=6) or no FGFR GA (N=9) as compared to previously reported data of iCCA pts (N=29) expressing FGFR2 fusions (Mazzaferro et al. 2018 BJC). Methods Pts received 300mg DZB QD PO. Eligibility criteria included a locally confirmed (FISH or NGS) testing of FGFR2 GA (fusions vs mutations/amplifications or no aberrations). Objective responses were determined per RECIST 1.1. Disease control rate (DCR) was defined by the summation of CR, PR and SD, and PFS, calculated from treatment initiation until disease progression or death. Results The table shows the efficacy outcomes in the 3 patient groups. Types of drug-related adverse events were similar across groups. No new safety signals were identified.Table721PTableiCCA patient groupFGFR2 fusion N=29FGFR2 mutation/ amplification N=6No FGFR2 genomic aberration N=9Objective response rate (RECIST 1.1)6 (21%)0 (0%)0 (0%)DCR (PR or SD)24 (83%)4 (67%)2 (22%)Any target lesion diameter reduction18 (62%)4 (67%)0 (0%)Median (95% CI) Progression free survival (PFS), months5.76.71.5(4.0-9.2)(1.0-14.7)(0.7 – NA)% PFS at 3 months83%67%0%% PFS at 6 months47%50%0% Conclusions Anti-tumor efficacy of DZB as measured by DCR and PFS in iCCA patients harboring an FGFR2 GA seems to be similar for patients with FGFR2 fusions and FGFR2 mutations/amplifications, while patients without any detectable FGFR GA appear to derive no benefit from DZB treatment. While the influence of prognostic variables still has to be confirmed, the anti-tumor efficacy of DZB seen in pts with FGFR2 GA other than fusions warrant further clinical investigation. Legal entity responsible for the study Basilea Pharmaceutica International Ltd. Funding Basilea Pharmaceutica International Ltd. Disclosure S. Braun: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd.; Shareholder / Stockholder / Stock options: Ipsen. B. El-Rayes: Advisory / Consultancy: Merrimack; Advisory / Consultancy: BTG; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: RTI Health Solutions; Honoraria (self), Speaker Bureau / Expert testimony: Lexicon; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Cleave Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Hoosier Cancer Research Network; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): PPD; Research grant / Funding (institution): Merck; Research grant / Funding (institution): ICON Clinical Research. W.P. Harris: Advisory / Consultancy: Neo Therma; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Nordion; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Agios. N. Damjanov: Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Honoraria (self): Sirtex Medical. L. Rimassa: Advisory / Consultancy: Bayer; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Italfarmaco; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: ArQule; Advisory / Consultancy: Baxter; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Incyte; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Honoraria (self): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Gilead Sciences; Honoraria (self): Roche. F. Braiteh: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Clovis Oncology; Shareholder / Stockholder / Stock options: Agios; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Insys Therapeutics; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Tesaro; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Regeneron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lexicon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Taiho Pharmaceutical; Travel / Accommodation / Expenses: Heron. S. Lonardi: Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Servier. M. Engelhardt: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd. M. Saulay: Full / Part-time employment: Basilea Pharmaceutica Int. Ltd. B. Schwartz: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: ArQule; Advisory / Consultancy: CIRM. W.L. Shaib: Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Lilly. V. Mazzaferro: Advisory / Consultancy: Terumo Europe NV; Speaker Bureau / Expert testimony: Ipsen AB. K.P. Papadopoulos: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): OncoMed. All other authors have declared no conflicts of interest.

Background C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved in the United States and Europe for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). C may promote an immune-permissive tumor environment, which could enhance response to immune checkpoint inhibitors. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; recommended dose, preliminary clinical activity, and safety of the combination have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C + A vs S in pts with aHCC who have not received prior systemic therapy. Trial design This global, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C + A vs S as first-line treatment for aHCC. C vs S will also be evaluated as a secondary endpoint. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS ≤ 1, and measurable disease per RECIST 1.1. Pts are randomized 2:1:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and a C monotherapy arm (60 mg qd). 740 pts are planned to be enrolled at ∼250 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival (PFS) for C+A vs S are primary endpoints, and PFS for C vs S is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. The first patient was enrolled in December 2018, and enrollment is ongoing. Clinical trial identification NCT03755791 (Other Study ID Numbers: XL184-312). Legal entity responsible for the study Exelixis. Funding Exelixis. Disclosure T. Yau: Advisory / Consultancy: Exelixis; Honoraria (self): Ipsen, Exelixis. L. Rimassa: Advisory / Consultancy: Lilly, Bayer, Baxter, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Eisai, Hengrui, MSD; Honoraria (self): AstraZeneca, AbbVie, Gilead, Roche; Travel / Accommodation / Expenses: ArQule, Ipsen. A-L. Cheng: Advisory / Consultancy, Advisory Board: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Advisory / Consultancy, Consultancy: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Honoraria (self): Bayer, Eisai, and Merck Sharp Dohme, Merck Serono, Novartis, Ono Pharmaceutical, Roche/Genentech, and IQVIA. J-W. Park: Advisory / Consultancy, Advisory board: Astra-Zeneca, Ono, BMS, Bayer, Midatech; Research grant / Funding (self): Ono-BMS, AstraZeneca, Blueprint, Roche, Eisai, Exelixis, Kowa; Advisory / Consultancy, Consultancy: Ono, Genetech, Roche, BMS, Bayer, Ipsen; Honoraria (self): Bayer, Ono, Eisai. F. Braiteh: Shareholder / Stockholder / Stock options: Agios; Bristol-Myers Squibb; Clovis Oncology; Insys Therapeutics; Tesaro; Honoraria (self): Abbott Nutrition; Amgen; ARIAD; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; HERON; Incyte; Insys Therapeutics; Insys Therapeutics; Ipsen; Lexicon; Lilly; Taiho Pharmaceutical; Advisory / Consultancy: Ambry Genetics; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Clovis Oncology; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Ipsen; Lexicon; Lilly; Merck; Merrimack; Pfizer; Regeneron; Sanofi; Speaker Bureau / Expert testimony: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Lilly; Merck; Merck; Merrimack; Pfizer; Taiho Pharmaceutical; Travel / Accommodation / Expenses: - Amgen; AstraZeneca/MedImmune; Bayer; Bayer/Onyx; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Clovis Oncology; Exelixis; HERON; Incyte; Insys Therapeutics; Ipsen; Lexicon; Merrimack; Novartis; Pfizer; Regeneron; Roche/Genentech; Sanofi; Taiho Ph. F. Benzaghou: Full / Part-time employment: IPSEN; Shareholder / Stockholder / Stock options: IPSEN. P. Thuluvath: Honoraria (self): AbbVie; Gilead Sciences; Advisory / Consultancy: AbbVie; Eisai; Gilead Sciences; Speaker Bureau / Expert testimony: AbbVie; Gilead Sciences; Research grant / Funding (institution): AbbVie (Inst); Allergan (Inst); Conatus (Inst); Cymabay Therapeutics (Inst); Eisai (Inst); Sillajen (Inst); Target Pharmasolutions (Inst); Tobira Therapeutics (Inst); Zydus Pharmaceuticals (Inst). S. Hazra: Full / Part-time employment: Exelixis; Shareholder / Stockholder / Stock options: Exelixis. S. Milwee: Full / Part-time employment: Exelixis; Shareholder / Stockholder / Stock options: Exelixis. B. Tan: Research grant / Funding (institution): Exelixis. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Bayer; Bristol-Myers Squibb; eisai; Exelixis; Lilly; Merck; Novartis; Sanofi; Research grant / Funding (institution): Bayer (Inst); Bristol-Myers Squibb (Inst); Lilly (Inst); Merck (Inst); Novartis (Inst). R.K. Kelley: Advisory / Consultancy, funding to institution: Agios, AstraZeneca, Bayer, BMS; Advisory / Consultancy, funding to self: IDMC: Genentech/Roche; Research grant / Funding (institution): Agios, AstraZeneca, Bayer, BMS, Eli Lilly, Exelixis, EMD Serono, Medimmune, Merck, Novartis, QED, Taiho. All other authors have declared no conflicts of interest.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

OBJECTIVE This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.

Introduction Despite a clinically relevant, statistically significant survival benefit with nab-paclitaxel plus gemcitabine and FOLFIRINOX vs single-agent gemcitabine for metastatic pancreatic cancer (mPC), little is known regarding their real-world effectiveness. We analyzed patients with mPC using a nationally representative electronic medical records database to address this unmet need. Methods This retrospective analysis of the Navigating Cancer database compared outcomes among patients who received first-line nab-paclitaxel plus gemcitabine, FOLFIRINOX, or gemcitabine for mPC. Effectiveness, safety, and supportive care use were examined. nab-Paclitaxel plus gemcitabine was the reference for statistical comparisons. Results Baseline characteristics were similar except age (oldest patients were in the gemcitabine cohort followed by nab-paclitaxel plus gemcitabine, then FOLFIRINOX). Patients receiving nab-paclitaxel plus gemcitabine (n=122) demonstrated similar time to treatment discontinuation (TTD; median, 3.4 vs 3.8 months; P=0.947) and database persistence (DP; median, 8.6 vs 8.6 months; P=0.534) vs FOLFIRINOX (n=80); however, TTD (median, 3.4 vs 2.2 months; P

Fadi Braiteh,1 Manish B Patel,2 Monika Parisi,2 Quanhong Ni,2 Siyeon Park,2,3 Claudio Faria2 1Comprehensive Cancer Centers of Nevada, University of Nevada School of Medicine, Las Vegas, NV, 2Celgene Corporation, Summit, NJ, 3The Ohio State University, Columbus, OH, USA Introduction: Despite a clinically relevant, statistically significant survival benefit with nab-paclitaxel plus gemcitabine and FOLFIRINOX vs single-agent gemcitabine for metastatic pancreatic cancer (mPC), little is known regarding their real-world effectiveness. We analyzed patients with mPC using a nationally representative electronic medical records database to address this unmet need.Methods: This retrospective analysis of the Navigating Cancer database compared outcomes among patients who received first-line nab-paclitaxel plus gemcitabine, FOLFIRINOX, or gemcitabine for mPC. Effectiveness, safety, and supportive care use were examined. nab-Paclitaxel plus gemcitabine was the reference for statistical comparisons.Results: Baseline characteristics were similar except age (oldest patients were in the gemcitabine cohort followed by nab-paclitaxel plus gemcitabine, then FOLFIRINOX). Patients receiving nab-paclitaxel plus gemcitabine (n=122) demonstrated similar time to treatment discontinuation (TTD; median, 3.4 vs 3.8 months; P=0.947) and database persistence (DP; median, 8.6 vs 8.6 months; P=0.534) vs FOLFIRINOX (n=80); however, TTD (median, 3.4 vs 2.2 months; P

Lessons LearnedThese negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses. Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents.BackgroundEGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5-fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC).MethodsOne-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles.ResultsThe progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71–1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46–2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms.ConclusionsThere was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC.

BACKGROUND: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. PATIENTS AND METHODS: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). RESULTS: Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. CONCLUSIONS: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. TRIAL REGISTRATION NUMBER: NCT00940225. ispartof: Annals of Oncology vol:28 issue:3 pages:528-534 ispartof: location:England status: published

Introduction: PF-06801591 is a humanized IgG4 monoclonal antibody that binds to programmed cell death (PD-1) receptor, blocking its interaction with PD-1 ligands. In a phase I study (NCT02573259; dose-escalation) of 40 patients (pts) with multiple solid tumor types treated with PF-06891591 intravenously (IV) or subcutaneously (SC), 7 pts showed partial response. PF-06801591 was well tolerated at all doses. Biopsy samples were evaluated for predictive biomarkers and pharmacodynamic effects. Methods: Biopsy samples at baseline and on-treatment (IV:day 29; SC:day 36) were collected from 4 dose cohorts (IV:1, 3 and 10 mg/kg; SC:300 mg). Whole-exome sequencing (WES) and RNA-seq of biopsy tissue were used to estimate tumor mutation burden (TMB) and gene expression. Regression analysis was used to identify TMB/genes/pathways potentially associated with response in baseline tissue. Differential analysis of baseline and on-treatment biopsies identified genes/pathways potentially upregulated by PF-06801591. PD-L1 (clone SP-263; Ventana) expression was evaluated in tumor biopsies by immunohistochemistry (IHC) and pathologist scoring. Results: In a combined WES analysis of samples from baseline biopsies (all doses, n=24 pts), higher TMB was significantly associated with improved objective response (R^2=0.215, P=0.013). From RNA-seq analysis, genes positively associated with response were involved in interferon-gamma (IFNG) and PD-1 signaling, and cell cycle; CTLA4 was among the genes most significantly associated with response (P Conclusion: Based on a mixed set of tumor types with possible sensitivity to anti-PD-1, high TMB, IFNG signaling, and PD-L1 were associated with response to PF-06801591, as reported for other anti-PD-1 antibodies. Albeit based on a small sample size and diverse indication profile, baseline expression of CTLA4 appears to be highly associated with response and PD-L1 RNA levels may be better associated with response than protein expression by IHC. Increased expression of genes/pathways associated with adaptive immune activation in on-treatment biopsies indicates an active, immunomodulatory mechanism with anti-PD-1 therapy. This ongoing study will evaluate predictive biomarkers in dose-expansion cohorts of PF-06801591 in non-small cell lung cancer and urothelial cancer. Acknowledgments Study sponsor: Pfizer. Medical writing support: Chu Kong Liew (Engage Scientific Solutions), funded by Pfizer. Citation Format: Siwen Hu-Lieskovan, Fadi Braiteh, Juneko E. Grilley-Olson, Shobha Potluri, Xiao Wang, Alison Forgie, Vinicius Bonato, Jeffrey Chou, Melissa L. Johnson. Predictive biomarkers and pharmacodynamic changes in tumor RNA expression in a phase I study of anti PD-1 monoclonal antibody PF-06801591 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT046.

Importance We assessed feasibility of monthly subcutaneous administration of PF-06801591, a humanized immunoglobulin G4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1 ligands. Objective To evaluate the safety, efficacy, and pharmacokinetics of PF-06801591 administered intravenously vs subcutaneously. Design, Setting, and Participants Ongoing phase 1, open-label, multicenter, dose-escalation study of 40 patients, 18 years or older, with locally advanced or metastatic solid tumors, enrolled between March 8, 2016, and March 5, 2018, from 4 US medical centers. Interventions An intravenous dose of 0.5, 1, 3, or 10 mg/kg of PF-06801591 was administered every 3 weeks or a subcutaneous dose of 300 mg was administered every 4 weeks. Dose escalation occurred after 2 to 4 patients were enrolled per dose level, with additional patients enrolled in each cohort for further assessment. Main Outcomes and Measures The primary end points were dose-limiting toxic effects and safety. Secondary end points included pharmacokinetics, immunogenicity, PD-1 receptor occupancy, and efficacy. Results Of 40 enrolled patients (12 men and 28 women; mean [SD] age, 61 [13] years) in this phase 1 dose-escalation trial, 25 received PF-06801591 intravenously at escalating dose levels (0.5, 1, 3, or 10 mg/kg) and 15 patients received the monoclonal antibody subcutaneously at a single dose level. No dose-limiting toxic effects were observed. Grade 3 or higher treatment-related adverse events occurred in 4 (16%) patients treated intravenously and 1 (6.7%) patient treated subcutaneously. Immune-related adverse events occurred in 10 (40%) patients treated intravenously and 3 (20%) treated subcutaneously. No dose–adverse event associations were observed during intravenous dose escalation, and no serious skin toxic effects occurred with subcutaneous delivery. Responses were seen in 5 patients receiving PF-06801591 intravenously and in 2 patients treated subcutaneously for an overall objective response rate of 18.4%. Median overall survival was not reached with intravenous dosing vs 10.7 months with subcutaneous administration. Exposure to PF-06801591 increased in a dose-proportional manner over the range of intravenous doses. Median time to maximum observed serum concentration was 8 days after subcutaneous administration. Full PD-1 receptor occupancy was seen in all dose cohorts. Conclusions and Relevance Anti–PD-1 antibody PF-06801591 was tolerable and showed antitumor activity in a variety of tumor types across all dose levels of intravenous and subcutaneous administration. Monthly subcutaneous administration of PF-06801591 offers a convenient, effective alternative to currently available intravenously administered checkpoint inhibitors. Trial Registration ClinicalTrials.gov identifier:NCT02573259

TPS4157 Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). Standard of care for first-line treatment of aHCC is tyrosine kinase inhibition with S or lenvatinib, and phase 3 trials of immune checkpoint inhibitors (ICIs) in first- and second- line aHCC are ongoing. C may promote an immune-permissive tumor environment, which could enhance response to ICIs. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; and dose, preliminary clinical activity, and safety have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C+A vs S in pts with aHCC who have not received prior systemic therapy. Methods: This international, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C+A vs S as first-line treatment for aHCC. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS 0 or 1, and measurable disease per RECIST 1.1. Patients are randomized 6:3:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and an exploratory arm of C monotherapy (60 mg qd). 640 pts are planned at ~200 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival are coprimary endpoints and objective response rate is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. Enrollment in COSMIC-312 is ongoing. Clinical trial information: NCT03755791.

e15607 Background: FGFR2 fusions are prevalent in 13-22% of iCCA and known oncogenic drivers. DZB is a kinase inhibitor with potent pan-FGFR activity. In a non-comparative Phase 2a study, DZB was administered to 29 pts with FGFR2-fusion positive advanced, inoperable iCCA, either as first-line (1L) (n = 2), 2L (n = 13), 3L (n = 10), 4L (n = 2) or 5L therapy (n = 2). The objective response rate (ORR) with DZB was 21%, disease-control rate (DCR) 83% and median PFS 5.7 months (Mazzaferro et al. 2018 BJC). Data from biliary tract cancer studies suggest decreasing treatment effects of chemotherapy with increasing lines of treatment. Here, we present a post-hoc analysis of outcomes of pts treated with DZB in 1L/2L (n = 15) compared to pts treated post-2L (n = 14). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included locally confirmed, positive testing of FGFR2 fusion expression (FISH or NGS), ECOG PS 0-1. Objective responses were determined using RECIST 1.1. Disease control rate was defined as CR, PR or SD. Results: The mean age of pts treated in 1L/2L was 66y and 55y in post-2L; 73% were females in 1L/2L and 50% in post-2L treatment; other demographic variables were balanced between groups (87% vs 86% of liver target lesions, median baseline lesion size of 97.5 mm vs 109.5 mm, ECOG PS0 was 60% vs 71%). Of 15 1L/2L group pts, 12 (80%) had prior platinum-based chemotherapy as compared to all 14 pts in the post-2L group. In the 1L/2L and post-2L groups, ORR was 20% and 21%, DCR was 80% and 86%, and a reduction in sum of the largest diameter of target lesions was observed in 60% and 64% of pts, respectively. Median PFS was 5.5 mo (95% CI, 1.9-11.9) and 6.2 mo (3.6-9.2) for the 1L/2L and post-2L groups, respectively. Types of drug-related adverse events were similar in 1L/2L and post-2L. Conclusions: Anti-tumor efficacy of DZB in iCCA patients measured either by ORR, DCR, tumor shrinkage or PFS was numerically similar irrespective of treatment line. These data suggest that DZB is an effective treatment option that can be applied early in the treatment continuum of iCCA patients or at later stages to offer anti-tumor efficacy and disease control. Clinical trial information: 01752920.

43 Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p < 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p < 0.001 and p < 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMBhigh and TMBlow groups. All 13 pts (100%) with TMBhigh had an OR, while only 2/9 (22%) pts with TMBlow had an OR and 6/9 had PD. The median PFS for TMBhigh pts has not been reached (no progressors, median follow-up > 18 mos), while the median PFS for TMBlow pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25th, 35th, 50th and 75th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.

The case of a patient with metastatic colorectal cancer is presented. This report is the first instance of an ALK fusion in colorectal cancer detected using a ctDNA assay., ALK rearrangements have been observed in 0.05%–2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS, NRAS, or BRAF alterations. Here we present the case of a patient with metastatic CRC who was treatment naïve at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture‐based assays each identified an identical STRN‐ALK fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay. Key Points. Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of KRAS, NRAS, BRAF, and microsatellite instability (MSI) status.ALK rearrangements are rare in CRC, but patients with activating ALK fusions have responded to targeted therapiesALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.

Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.

Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and50%, TC1≥1% and5%, and TC01%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and10%, IC1≥1% and5%, and IC01%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.F Hoffmann-La Roche/Genentech Inc.

Introduction The treatment options for squamous cell non–small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC. Patients and Methods The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC + populations. Results The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC + populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety-evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm. Conclusion Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further.

Introduction: Atezo (anti-PD-L1) + bev + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L non-squamous mNSCLC in the randomized Ph 3 IMpower150 study regardless of PD-L1 expression. This analysis aims to further understand the efficacy of atezo + bev + chemo in key subgroups: PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays, patients with EGFR/ALK genetic alterations and patients with liver metastases at baseline. Methods: Pts received atezo 1200 mg + bev 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (Arm B) or bev + C + P (Arm C) IV q3w. A co-primary endpoint (EP) was PFS in the ITT-WT (EGFR or ALK wild-type pts); a secondary EP was PFS in subgroups defined by PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) with SP142. Retrospective analysis with SP263 was a prespecified exploratory EP. Results: In Arms B and C of the ITT-WT (n = 692), 503 pts had available tumor sections for SP263 testing (BEP). Pt characteristics in the ITT-WT and BEP were similar. A similar PFS benefit was observed for Arm B vs C across all PD-L1 expression subgroups defined by either assay, including pts with PD-L1-negative and PD-L1-low tumors (Table). PFS benefit with Arm B vs C was also observed in patients with EGFR or ALK genomic alterations, including patients with actionable EGFR mutations, and in patients with liver metastases at baseline (Table). Conclusion: PFS benefit with atezo + bev + chemo was observed across all PD-L1 subgroups, regardless of the IHC assay used. Additionally, clinically meaningful PFS benefit was observed in patients with EGFR/ALK genomic alterations, and in patients with liver metastases with this combination. Table. PFS in Biomarker Subgroups and Other Subgroups of Interest in IMpower150Median PFS, moPFSan (%)HRb (95% CI)P ValueArm BArm CITT-WT692 (100%)0.62 (0.52, 0.74) Citation Format: Marcin Kowanetz, Mark A. Socinski, Wei Zou, Mark McCleland, Nancy Yang, Ariel Lopez Chavez, Alexander Spira, Julien Mazières, Fadi Braiteh, David Shames, Alan Sandler, Martin Reck. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups [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 CT076.

187 Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.

[1] Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;/2:/471 8. [2] Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;/9:/327 37. [3] O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003;/101:/3597 605. [4] Pfizer Inc., data on file [5] Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future trial development. Nat Rev Drug Discov 2007;/6:/734 45. [6] Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;/143:/313 4. [7] Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French Sarcoma Group. J Clin Oncol 2007;/25:/1107 13. [8] Blay JY, George S, Casali PG Le Cesne A, Morgan JA, Tyler A, et al. Clinical benefit of continuous daily dosing of sunitinib in patients (pts) with advanced gastrointestinal stromal tumor (GIST). Ann Oncol 2006;17(Suppl 9):508P (Abstract). [9] Escudier B, Roigas J, Gillessen S, Srinivas S, Pisa P, Vogelzang N, et al. Continuous daily administration of sunitinib malate (SU11248)-phase II study in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (MRCC). Ann Oncol 2006;17(Suppl 9):436O (Abstract). [10] Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara Yao VJ, et al. Rapid vascular regrowth in tumours after reversal of VEGF inhibition. J Clin Invest 2006;/116:/ 2610 21.

Palliative care services can decrease physical and psychosocial distress in patients with advanced cancer. However, most patients with cancer die without access to palliative care services (APCS), and patterns of referral are not well understood. The purpose of this study was to determine predictors of patients' access to palliative care.We reviewed patient records from the computerized database at UT M. D. Anderson Cancer Center over 2 (2003 and 2004) to determine differences in characteristics and outcomes between patients with and without APCS. APCS was defined as a palliative care consultation and follow-up or transfer to the palliative care unit.A total of 499 of 1453 (34%) inpatients who died at our cancer center had APCS. There were no significant differences in race, age, or insurance status between the APCS groups. The two major predictors of a low rate of APCS were hematologic malignancies (20% rate of APCS versus 44% for solid tumors, p0.0001) and intensive care unit (ICU) admission (15% versus 52% for non-ICU admission, p0.0001). Patients with hematologic malignancies who were admitted to the ICU had the lowest APCS rate (10%, p0.0001). The median relative cost of care per patient for decedents with APCS was 0.62 compared to non-referred patients (p0.0001).APCS was lower among patients with hematologic malignancies and those admitted to the ICU. APCS resulted in a lower cost of care. Mortality in comprehensive cancer centers is quite variable among different primary malignancies. More research is needed to better define patterns of referral.

Why does it seem that, repeatedly, when a new treatment with a striking effect is discovered in the cancer field, it is effective for a very rare cancer type? For example, groundbreaking therapeutic discoveries have been made for extremely uncommon malignancies such as hairy cell leukemia, chronic myelogenous leukemia, seminoma, gastrointestinal stromal tumor, (del)5q myelodysplastic syndrome, and acute promyelocytic leukemia. In contrast, progress in the most common and most intensively studied tumors—lung, breast, prostate, and colon cancer—has been slow and incremental. We hypothesize that the reason for this phenomenon is that the pathophysiologic basis for a tumor being rare is one and the same as the reason that it may ultimately be so treatable. That is, if a cancer can be derived only via a single aberrant molecular genetic aberration, then it should be both rare and easily targeted by a molecular cancer therapeutic approach. If, on the other hand, many distinct pathways can lead to the development of a specific tumor type, it should occur much more commonly and be significantly more difficult to treat. The corollary to our hypothesis is the prediction that new therapies will continue to show their most salutary effects in rare cancers. Furthermore, only by stratifying the common tumors, especially when using targeted agents, into the molecular subsets of diseases that compose them are we likely to achieve a substantial effect in these disorders. [Mol Cancer Ther 2007;6(4):1175–9]

Summary Background Klebsiella pneumoniae -associated liver abscesses have distinct clinical and epidemiologic features. Methods We report the unusual case of an American patient with a K. pneumoniae -associated liver abscess and septic spread to other organs. We additionally present a comprehensive review of K. pneumoniae -associated liver abscess syndromes in adults. Results We identified three distinct K. pneumoniae liver abscess syndromes: the polymicrobial liver abscess, the monomicrobial cryptogenic noninvasive liver abscess, and the monomicrobial cryptogenic invasive K. pneumoniae -associated liver abscess (CIKPLA) syndromes, with distinct clinical, epidemiologic and outcome features. CIKPLA syndrome typically affects diabetic patients, mainly in Southeast Asia, and is complicated by septic spread to other organs. Conclusions The community-acquired, monomicrobial, K. pneumoniae -associated liver abscess syndromes that typically occur in the USA are mainly noninvasive and affect Asian or Hispanic persons. However, this report provides an alert that CIKPLA syndrome can occur in North America, and physicians need to be aware of it.

Summary Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m 2 every 3 weeks, equivalent to 100 mg/m 2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m 2 , equivalent to 70 mg/m 2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8–8·9) vs 4·2 months (3·3–5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49–0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2–5·6] vs 4·2 months [3·6–4·9]; 0·99, 0·77–1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Funding Merrimack Pharmaceuticals.

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.

Purpose: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non–small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation. Experimental Design: A large pool of NSCLC cases was assayed with well-validated, hybrid capture–based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Δex19) were identified, and available clinical history was reviewed. Results: Pathology reports were available for 250 consecutive cases with classical EGFR Δex19 (amino acids 743–754) and were reviewed to assess previous non-hybrid capture–based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR Δex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed. Conclusions: CGP identifies drug-sensitive EGFR Δex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative. Clin Cancer Res; 22(13); 3281–5. ©2016 AACR.

Objectives The gatekeeper mutation T790M mutation is the responsible for the majority of the resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Other previously described resistance mechanisms include HER2 amplification, MET amplification, PIK3CA mutation, epithelial–mesenchymal transition (EMT), small cell transformation have also been identified. However other resistance mechanisms remains to be discovered. Materials and methods Hybrid-capture based comprehensive genomic profiling (CGP) was performed on pre- and post-EGFR TKI progression EGFR-mutated NSCLC tumor samples during routine clinical care. We identify two paired pre- and post-EGFR TKI progression EGFR-mutated NSCLC patient tumor samples where both post EGFR TKI samples harbored in-frame CCDC6-RET rearrangements but not in the pre-EGFR TKI tumor samples. Furthermore analysis of the clinical database revealed one additional NCOA4-RET rearrangement co-existing with activated EGFR mutation in an EGFR-mutated NSCLC patient who had progressed on afatinib. None of the known resistance mechanisms to EGFR TKI including EGFR T790M, EGFR amplification, HER2 amplification, MET amplification, PIK3CA mutation, BRAF mutation, EMT or small cell transformation was identified in the three post progression samples that now harbored RET rearrangements. Results and conclusions This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI. As such, RET rearrangement may serve as a potential resistance mechanism to EGFR TKI in EGFR-mutated NSCLC.

Background. Gastric cancer (GC) is a major global cancer burden and the second most common cause of global cancer-related deaths. The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy improves survival for ERBB2-amplifiedadvancedGCpatients;however,themajority of GC patients do not harbor this alteration and thus cannot benefit from targeted therapy under current practice paradigms. Materials and Methods. Prospective comprehensive genomic profiling of 116 predominantly locally advanced or metastatic (90.0%) gastric cancer cases was performed to identify genomic alterations(GAs)associatedwithapotentialresponsetotargeted therapiesapprovedbytheU.S.FoodandDrug Administrationor targeted therapy-based clinical trials. Results. Overall, 78% of GC cases harbored one clinically relevant GAormore,withthemostfrequentalterationsbeingfoundinTP53 (50%), ARID1A (24%), KRAS (16%), CDH1 (15%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.5%), PIK3CA (8.6%), MLL2 (6.9%), FGFR2 (6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations were detected in 20.6% of cases, primarily ERBB2, FGFR2, andMETamplification,withERBB2alterationsevenlysplitbetween amplifications and base substitutions. Rare BRAF mutations (2.6%) were also observed. One MET-amplified GC patient responded for 5 months to crizotinib, a multitargeted ALK/ROS1/MET inhibitor. Conclusion. ComprehensivegenomicprofilingofGCidentifies clinically relevant GAs that suggest benefit from targeted therapy including MET-amplified GC and ERBB2 base substitutions. The Oncologist 2015;20:1–9 ImplicationsforPractice:Despitedescriptionofmanypotentiallyclinicallyrelevantgenomicalterationsinretrospectiveresearch studies, these alterations are not regularly assessed in a comprehensive manner in clinical practice.This study demonstratesthe feasibility of prospective comprehensive genomic profiling (CGP) for advanced gastric carcinoma. We demonstrated a high frequency of genomic alterations associated with potential benefit from targeted therapies. CGP in this setting may inform therapeutic options beyond standard of care testing by identifying genomic alterations such as point mutations in the kinase domain of ERBB2 and MET amplification. Genotype-directed management is highlighted by the response of a MET-amplified gastric carcinoma patient to crizotinib.

Introduction. Triple negative breast cancer (TNBC) has a poor prognosis and limited treatment options. Atezolizumab (atezo) is a humanized mAb that inhibits the binding of PD-L1 to PD-1 and B7.1, thus restoring tumor-specific T-cell immunity. Atezo was evaluated in an expansion cohort of mTNBC patients (pts) in a Phase Ia study (NCT01375842). Methods. Enrollment was initially limited to TNBC pts with PD-L1 on ≥5% of tumor-infiltrating immune cells (IC2/3), then opened to pts regardless of PD-L1 status. Pts received atezo IV in 1L or 2L+ q3w at 15 or 20 mg/kg or 1200 mg for 1 y with option to be retreated at PD, or until loss of clinical benefit. ORR was assessed by RECIST v1.1 and irRC, to capture non-conventional responses. Baseline PD-L1 expression on IC was centrally scored as IC0/1/2/3 (VENTANA SP142 assay). Pretreatment tumors and on-therapy biopsies were evaluated for TILs, CD8 T cells and macrophages by IHC. Results. As of Mar 31, 2016, 115 mTNBC pts were safety evaluable; atezo was generally well tolerated. There were no additional safety signals from prior report (Emens AACR 2015). 112 pts with FU ≥12 wk were evaluable for response. Based on irRC, ORR in 1L and 2L+ pts were 26% and 11%, respectively. ORR for PD-L1 IC2/3 pts were 17% vs 8% in IC0/1. mDoR was 21.1 mo (3 to 34+). mOS of responders (n=15) was not reached (4+ to 37+ mo) with no deaths as of data cutoff. mOS of non-responders who lived ≥ 6 wk (n=87) was 9 mo (1+ to 19+ mo). OS rates in all pts at 1, 2, and 3 y were 41%, 22% and 22%, respectively. OS rates at 1, 2, and 3 y for PD-L1 IC2/3 were 45%, 28% and 28%, respectively. Pts whose tumors had >10% TILs or ≥1.35% CD8 in the tumor center trended toward higher ORR and longer OS. Atezo increased intratumoral TILs, CD8, macrophages and IC PD-L1 expression, but no response association was observed. Conclusions. In mTNBC, atezo was well tolerated. Responders showed durable clinical benefit. Response rates were higher in 1L or PD-L1 IC2/3 pts. Baseline TILs and CD8 were associated with greater clinical benefit. Table.EfficacyResponses per RECIST v1.1 (irRC efficacy results presented in text)1L2L+PD-L1 IC2/3PD-L1 IC0/1Alln = 19n = 93n = 71n = 37N = 112ORR, % (95%CI)26% (9, 51)7% (2, 14)13% (6, 23)5% (1, 18)10% (5, 17)CR, n21303PR, n35628SD, n31210415CBR, %42%19%27%16%23%Median (range) DoR, mo21 (8+ to 26+)NE (3 to 13+)21 (3 to 26)NE (10 to 10+)21 (3 to 26+)OS1L2L+PD-L1 IC2/3PD-L1 IC0/1All ptsn = 19n = 94n = 71n = 38N = 1131 y OS (95% CI)63% (37, 89)37% (26, 47)45% (32, 58)37% (21, 53)41% (31, 51)2 y OS (95% CI)47% (14, 80)18% (8, 27)28% (15, 41)NE22% (12, 32)3 y OS (95% CI)NE18% (8, 27)28% (15, 41)NE22% (12, 32)CBR; clinical benefit rate, defined as CR, PR or SD for ≥12 weeks. DoR, duration of response; NE, not evaluable.+, censored. Citation Format: Peter Schmid, Cristina Cruz, Fadi S. Braiteh, Joseph Paul Eder, Sara Tolaney, Irene Kuter, Rita Nanda, Cathie Chung, Philippe Cassier, Jean-Pierre Delord, Michael Gordon, Yijin Li, Bo Liu, Carol O’Hear, Marcella Fasso, Luciana Molinero, Leisha A. Emens. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2986. doi:10.1158/1538-7445.AM2017-2986