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Purpose: Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC., Materials and Methods: Whole-slide images (WSIs) of hematoxylin and eosin-stained core biopsies from 165 (pCR in 60 and non-pCR in 105) and 78 (pCR in 31 and non-pCR in 47) patients with TNBC were used to train and validate the model. The model extracts morphometric features from WSIs in an unsupervised manner, thereby generating clusters of morphologically similar patterns. Downstream ranking of clusters provided regions of interest and morphometric scores; a low score close to zero and a high score close to one represented a high or low probability of response to NAC., Results: The predictive ability of AI score for the entire cohort of 78 patients with TNBC ascertained by receiver operating characteristic analysis demonstrated an area under the curve (AUC) of 0.75. The AUC for stages I, II, and III disease were 0.88, 0.73, and 0.74, respectively. Using a cutoff value of 0.35, the positive predictive value of the AI score for pCR was 73.7%, and the negative predictive value was 76.2% for non-pCR patients., Conclusion: To our knowledge, this study is the first to demonstrate the use of an AI tool on digitized hematoxylin and eosin-stained tissue images to predict the response to NAC in patients with TNBC with high accuracy. If validated in subsequent studies, these results may serve as an ancillary aid for individualized therapeutic decisions in patients with TNBC., Competing Interests: Hassan MuhammadEmployment: Pathomiq

Purpose: To develop a novel artificial intelligence (AI)-powered method for the prediction of prostate cancer (PCa) early recurrence and identification of driver regions in PCa of all Gleason Grade Group (GGG)., Materials and Methods: Deep convolutional neural networks were used to develop the AI model. The AI model was trained on The Cancer Genome Atlas Prostatic Adenocarcinoma (TCGA-PRAD) whole slide images (WSI) and data set (n = 243) to predict 3-year biochemical recurrence after radical prostatectomy (RP) and was subsequently validated on WSI from patients with PCa (n = 173) from the University of Wisconsin-Madison., Results: Our AI-powered platform can extract visual and subvisual morphologic features from WSI to identify driver regions predictive of early recurrence of PCa (regions of interest [ROIs]) after RP. The ROIs were ranked with AI-morphometric scores, which were prognostic for 3-year biochemical recurrence (area under the curve [AUC], 0.78), which is significantly better than the GGG overall (AUC, 0.62). The AI-morphometric scores also showed high accuracy in the prediction of recurrence for low- or intermediate-risk PCa-AUC, 0.76, 0.84, and 0.81 for GGG1, GGG2, and GGG3, respectively. These patients could benefit the most from timely adjuvant therapy after RP. The predictive value of the high-scored ROIs was validated by known PCa biomarkers studied. With this focused biomarker analysis, a potentially new STING pathway-related PCa biomarker-TMEM173-was identified., Conclusion: Our study introduces a novel approach for identifying patients with PCa at risk for early recurrence regardless of their GGG status and for identifying cancer drivers for focused evolution-aware novel biomarker discovery., Competing Interests: Wei HuangStock and Other Ownership Interests: PathomIQResearch Funding: PathomIQTravel, Accommodations, Expenses: PathomIQ Ramandeep RandhawaLeadership: PathomIQ IncStock and Other Ownership Interests: PathomIQ IncTravel, Accommodations, Expenses: PathomIQ Inc Parag JainEmployment: PathomIQStock and Other Ownership Interests: PathomIQPatents, Royalties, Other Intellectual Property: Patents pending in the area of biomarker discovery using AI on histopathology data for patient outcome prediction Samuel HubbardResearch Funding: PathomIQ Jens EickhoffConsulting or Advisory Role: Five Prime Therapeutics, Syneos Health, AbbVie, AIQ Solutions, PathomIQResearch Funding: Sanofi Pasteur (Inst) Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon Therapeutics (I)Consulting or Advisory Role: Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GmbH, Harbour BioMed, SpringWorks Therapeutics, Gilead Sciences, Mirati Therapeutics, EcoR1 Capital, Cadila Pharmaceuticals (I), Oxford BioTherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Dynavax Technologies (Inst), Pfizer (Inst), Loxo (Inst), Corvus Pharmaceuticals (Inst), Plexxikon (Inst), Jounce Therapeutics (Inst), Advenchen Laboratories (Inst), Incyte (Inst), Taiho Pharmaceutical (Inst), Bayer (Inst), Astex Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Genome & Company (Inst), Moderna Therapeutics (Inst), ADC Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Elevation Oncology (Inst), Vincerx Pharma (Inst), Day One Therapeutics (Inst)Travel, Accommodations, Expenses: Bayer George WildingLeadership: Senex Biotechnology, PathomIQ, AIQ SolutionsStock and Other Ownership Interests: Senex Biotechnology, PathomIQ, AIQ Solutions Hirak BasuStock and Other Ownership Interests: Colby Pharmaceutical, PathomIQPatents, Royalties, Other Intellectual Property: Issued patents: 9,023,837 8,466,130 7,491,849 7,453,011 7,235,695 7,186,825 7,026,347 6,982,351 6,794,545 5,880,161 5,541,230Travel, Accommodations, Expenses: Drishti Hirak BasuStock and Other Ownership Interests: Colby Pharmaceutical, PathomIQPatents, Royalties, Other Intellectual Property: Issued patents: 9,023,837, 8,466,130, 7,491,849, 7,453,011, 7,235,695, 7,186,825, 7,026,347, 6,982,351, 6,794,545, 5,880,161, 5,541,230Travel, Accommodations, Expenses: Drishti Rajat RoyEmployment: PathomIQ IncLeadership: PathomIQ IncStock and Other Ownership Interests: PathomIQ IncResearch Funding: PathomIQ Inc (Inst)Patents, Royalties, Other Intellectual Property: Two Patents pendingTravel, Accommodations, Expenses: PathomIQ IncNo other potential conflicts of interest were reported.

Purpose: Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers., Materials and Methods: Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR)., Results: By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2., Conclusion: Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer., Competing Interests: Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerViewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Daniel S. W. TanHonoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, PfizerConsulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, PfizerResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche Ulrik N. LassenHonoraria: Bayer, Pfizer, NovartisConsulting or Advisory Role: Bayer, PfizerResearch Funding: BMS (Inst), Roche (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Lilly (Inst) Serge LeyvrazConsulting or Advisory Role: Bayer, ImmunocoreTravel, Accommodations, Expenses: Bayer, Immunocore Jyoti D. PatelConsulting or Advisory Role: AbbVie, AstraZeneca, Takeda Science FoundationResearch Funding: Bristol Myers Squibb (Inst) Lee RosenResearch Funding: Pfizer (Inst), Bayer (Inst), PsiOxus Therapeutics (Inst), Rgenix (Inst) Benjamin SolomonConsulting or Advisory Role: BayerResearch Funding: AstraZeneca/Merck (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/358846 Ricarda NorenbergEmployment: Bayer HealthConsulting or Advisory Role: Bayer Health (Inst) Laura DimaEmployment: Bayer Nicoletta BregaEmployment: BayerLeadership: BayerStock and Other Ownership Interests: BayerTravel, Accommodations, Expenses: BayerOther Relationship: Bayer Lin ShenConsulting or Advisory Role: MSD, Bristol Myers Squib, AstraZeneca, Daiichi Sankyo, Roche, Mingji biopharmaceutical, Harbour BioMed, MerckSpeakers' Bureau: Hutchison Whampoa, MSDResearch Funding: Yaojie Ankang (Nanjing) Technology Co, Ltd (Inst), Baiji Shenzhou (Beijing) Biotechnology Co, Ltd (Inst), Beijing Xiantong Biomedical Technology Co, Ltd (Inst), QiLu Pharmaceutical (Inst), Zaiding Pharmaceutical (Inst) Victor MorenoEmployment: STARTConsulting or Advisory Role: Merck, Bristol Myers Squibb, Bayer, Janssen Oncology, Roche, BasileaSpeakers' Bureau: BayerResearch Funding: AbbVie (Inst), ACEA Biosciences (Inst), Adaptimmune (Inst), Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), BeiGene (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Celgene (Inst), Eisai (Inst), E-therapeutics (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Menarini (Inst), Merck (Inst), Nanobiotix (Inst), Novartis (Inst), Pfizer (Inst), PharmaMar (Inst), PsiOxus Therapeutics (Inst), Puma Biotechnology (Inst), Regeneron (Inst), RigonTEC (Inst), Roche (Inst), Sanofi (Inst), Sierra Oncology (Inst), Synthon (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Tesaro (Inst), Transgene (Inst)Expert Testimony: Medscape/Bayer, NanobiotixTravel, Accommodations, Expenses: Sanofi/RegeneronOther Relationship: Bristol Myers Squibb Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon TherapeuticsConsulting or Advisory Role: Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GmbH, Harbor BioMed, SpringWorks Therapeutics, Gilead Sciences, Mirati Therapeutics, EcoR1 Capital, Cadila PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Dynavax Technologies (Inst), Pfizer (Inst), Loxo (Inst), Corvus Pharmaceuticals (Inst), Plexxikon (Inst), Jounce Therapeutics (Inst), ADC Therapeutics (Inst), Advenchen Laboratories (Inst), Incyte (Inst), Taiho Pharmaceutical (Inst), Bayer (Inst), Astex Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Genome & Company (Inst), Moderna Therapeutics (Inst), ADC Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Elevation Oncology (Inst), Vincerx Pharma (Inst), Day One Therapeutics (Inst)Travel, Accommodations, Expenses: Bayer Jessica J. LinHonoraria: Pfizer, OncLiveConsulting or Advisory Role: C4 Therapeutics, Genentech, Nuvalent, Inc, Blueprint Medicines, Turning Point Therapeutics, Turning Point TherapeuticsResearch Funding: Hengrui Therapeutics (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Neon Therapeutics (Inst), Relay Therapeutics (Inst), Elevation Oncology (Inst), Bayer (Inst), Roche (Inst)Travel, Accommodations, Expenses: PfizerNo other potential conflicts of interest were reported.

This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm)., Materials and Methods: Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway., Results: Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm., Conclusion: Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon Consulting or Advisory Role: Corvus Pharmaceuticals, MedTree, Nodus Therapeutics, Genentech, ShangPharma Innovation, Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GMBH, Harbour BioMed, Cadila Pharmaceuticals Research Funding: Bristol Myers Squibb, Dynavax Technologies, Pfizer, Loxo, Corvus Pharmaceuticals, Plexxikon, Jounce Therapeutics, ADC Therapeutics, Advenchen Laboratories, Incyte, Taiho Pharmaceutical, Bayer, Astex Pharmaceuticals, Seattle Genetics, Amgen, Genome & Company Travel, Accommodations, Expenses: BayerNancy MoorePatents, Royalties, Other Intellectual Property: Nestle NutritionP. Mickey WilliamsResearch Funding: Illumina Patents, Royalties, Other Intellectual Property: I was a co-inventor of the DLBCL cell of origin patent recently filed by the NIHKanwal P. S. RaghavConsulting or Advisory Role: AstraZeneca, Bayer, Eisai, Daiichi SankyoFunda Meric-BernstamEmployment: MD Anderson Cancer Center Honoraria: Mayo Clinic, Rutgers Cancer Institute of New Jersey Consulting or Advisory Role: Genentech, Inflection Biosciences, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, OrigiMed, Xencor, Debiopharm Group, Mersana, Seattle Genetics, Silverback Therapeutics, Immunomedics, IBM, Roche, PACT Pharma, eFFECTOR Therapeutics, Jackson Laboratory for Genomic Medicine, Kolon Life Sciences, Parexel International, Pfizer, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes Speakers' Bureau: Chugai Pharma Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, Abbvie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, GlaxoSmithKline, Seattle Genetics, Millennium Travel, Accommodations, Expenses: Taiho Pharmaceutical, Beth Israel Deaconess Medical CenterStephen LeongEmployment: Merck Sharp & Dohme Stock and Other Ownership Interests: Antares Pharmaceuticals, Spectrum Pharmaceuticals Consulting or Advisory Role: Bristol Myers Squibb Research Funding: Deciphera, Karyopharm Therapeutics, Bristol Myers Squibb, Lilly Travel, Accommodations, Expenses: Genentech/RocheSaiama WaqarResearch Funding: Spectrum Pharmaceuticals, Lilly, Pfizer, Genentech/Roche, Daiichi Sankyo, Newlink Genetics, EMD Serono, Puma Biotechnology, Novartis, Xcovery, Synermore Biologics, Celgene, Vertex, Bristol Myers Squibb, Stemcentrx, Hengrui Therapeutics, Checkpoint Therapeutics, Ignyta, AstraZeneca, ARIAD, Roche, MerckBiswajit DasResearch Funding: IlluminaChris KarlovichStock and Other Ownership Interests: Clovis Oncology Research Funding: Illumina Travel, Accommodations, Expenses: IlluminaChih-Jian LihEmployment: Exelixis Stock and Other Ownership Interests: ExelixisEric PolleyResearch Funding: GRAILRichard SimonConsulting or Advisory Role: AbbVie, Amgen, Janssen, Bristol Myers Squibb, Pfizer, Onco-Nano Travel, Accommodations, Expenses: Amgen No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Gene rearrangements involving NTRK1/2/3 can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized., Methods: We compiled a database of NSCLC cases harboring NTRK fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology., Results: We identified 11 NSCLC cases harboring NTRK gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved NTRK1 (7 cases) and NTRK3 (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS , EGFR , ALK , ROS1 , or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI 0.11-0.40)., Conclusion: NTRK fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions using a multiplexed NGS-based fusion assay., Competing Interests: Relevant conflicts of interest: AFF has received consultant fees from AbbVie, PharmaMar, Loxo Oncology; research funding (to institution) from Loxo Oncology, Ignyta, AstraZeneca, AbbVie, Merck, Bristol Myers-Squibb, Novartis. RCD has received consultant/advisory board fees from Ariad, Takeda, AstraZeneca, Spectrum, and Ignyta; licensing fees from Abbott Molecular and Ignyta; stock ownership in Rain Therapeutics. VWZ has received honoraria from AstraZeneca, Roche/Genentech, Takeda, and Biocept, and consultant fees from TP Therapeutics. DLA has received consultant fees from Bristol-Myers Squibb and AbbVie LPL has equity interest and royalties from exclusive license of AMP technology to ArcherDx and has received consultant fees from ArcherDx AJI has received consulting fees for Debiopharm Group, Constellation Pharmaceuticals, Chugai Pharmaceutical, and Roche, research Funding from Blueprint Medicines, and has equity interest and royalties from exclusive license of AMP technology to ArcherDx. SHIO has received consultant/advisory board fees from ARIAD/Takeda, Pfizer, Genentech/Roche, Astra Zeneca, Novartis, Ignyta, Foundation Medicine Inc, member of the speaker bureau of Genentech/Roche, AstraZeneca, ARIAD/Takeda, and Merck; a member of the scientific advisory board of TP Therapeutics Inc and stock ownership in TP Therapeutics Inc. ATS has received consultant fees from Pfizer, Novartis, Ariad/Takeda, Genentech/Roche, Ignyta, Loxo Oncology, Blueprint medicines, KSQ therapeutics, Natera. MMK has received consultant fees from Merrimack Pharmaceuticals and H3 Biomedicine. AD has received consultant/advisory board fees from Ignyta, Loxo Oncology, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad. MST, SK, AIS, TAB, EBH, MEA, RB, NKH, JKL have no relevant disclosures.

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

Purpose: Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies., Patients and Methods: AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD., Results: Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated., Conclusion: This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies., (© 2015 by American Society of Clinical Oncology.)

Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs)., Patients and Methods: We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging., Results: Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis., Conclusion: In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.

Purpose: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction., Patients and Methods: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally., Results: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years., Conclusion: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.

Purpose: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies., Patients and Methods: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size., Results: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels., Conclusion: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.

Lung cancer is the leading cause of cancer deaths in the United States and throughout the world; globally, there are more than 1.1 million deaths each year. Treatment modalities currently employed are significantly limited; 50% of patients experience disease recurrence after surgery, and less than a quarter of patients respond to systemic chemotherapy. These statistics have fueled the search for a safer, more effective treatment modality. Despite significant advances in our understanding of the molecular basis of cancer immunology, many obstacles remain. However, encouraging clinical results in patients immunized with autologous tumor cell vaccines expressing granulocyte macrophage colony-stimulating factor strongly advocate further investigation of immunotherapy in non-small-cell lung cancer (NSCLC). Further studies are needed to demonstrate whether these novel therapies can potentially complement or even replace current therapeutic approaches. We present a review of the various vaccine-based strategies employed to target and treat NSCLC.