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PURPOSE Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

Background A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study. Methods The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients). Results Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule. Conclusions To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.

The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. Significance: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. This article is highlighted in the In This Issue feature, p. 1325

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies., DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.

DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection and repair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents, including chemotherapy, radiation or PARP inhibitors such as olaparib (Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells) and >100x selective against 396 other kinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics in preclinical species. In murine xenograft models, PD was assessed using pRPA (S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor, with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019. Citation Format: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies. Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor [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 DDT01-02.

TPS1112 Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.

Bruton tyrosine kinase (BTK) is an essential kinase in the B-cell receptor (BCR) signalling pathway. Acalabrutinib is a potent and highly selective irreversible BTK inhibitor that received accelerated approval by FDA for the treatment of Relapsed/Refractory Mantle Cell Lymphoma. It is proposed to be combined with the Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor AZD6738, in a Phase I/II proof of concept clinical trial to assess safety and efficacy in patients with B-cell malignancies. ATR is a key regulator of DNA replication, repair and cell cycle checkpoints. The Activated B-Cell (ABC) subtype of Diffuse Large B-Cell Lymphoma (DLBCL) is associated with chronic active BCR signalling, and given our previous identification of sensitivity to AZD6738 in ABC-DLBCL cell lines, we hypothesised that combination with acalabrutinib may have additional therapeutic benefit. Here we report preliminary data to support combination efficacy in models of ABC-type DLBCL. The growth inhibitory and cell kill effect of AZD6738 and acalabrutinib in combination was assessed in 3 ABC and 4 GCB DLBCL cell lines. Combination activity and cell kill was detected specifically in the ABC-type TMD8 cell line. Using flow cytometry, we show that the cell kill effects of the drug combination were dependent on dose and schedule. Single agent treatment with 5 nM acalabrutinib or 0.5 µM AZD6738 for 72 h, caused cell death in 12% and 17% of cells respectively. The equivalent doses given in combination for 72 h induced cell death in 39% of cells, indicative of a greater than additive effect. Cell killing was increased with longer co-exposure to the combination, shown by an increase in cell death from 18% at 24 h, to 30% at 48 h. Acalabrutinib is dosed on a BID schedule, thus we tested whether its activity in combination with AZD6738 was affected by pre- or post-addition of acalabrutinib. A 24 h pre-treatment of cells with acalabrutinib, followed by the combination of AZD6738 and acalabrutinib for 48 h resulted in 20% cell death, whereas 48 h combination treatment followed by 24 h acalabrutinib monotherapy caused a similar 27% increase in death, suggesting that combination efficacy is not dependent on sequence of drug administration. Furthermore, the mRNA expression of BTK target genes in ABC-DLBCL cell lines was modulated by acalabrutinib, however there was no additional modulation to this pathway by the combination with AZD6738, suggesting the two agents kill cells through different mechanisms of action. In the TMD8 xenograft mouse model, daily dosing of AZD6738 (25 mg/kg) with twice daily dosing of acalabrutinib (20 mg/kg) was well tolerated and resulted in complete and durable tumor regressions (8/8 tumors), whereas single agent treatments resulted in tumor growth delay. Collectively, our preliminary data support a rationale for combining BTK and ATR inhibitors for an effective and alternative treatment option in ABC-DLBCL. Citation Format: Lucy A. Young, Oona Delpuech, Brandon Willis, Alexandra Bussey, Zena Wilson, Michelle Dupont, Carlos Grajales, Andrew Bloecher, Todd Covey, Kate Wills, Alan Lau, Simon J. Hollingsworth. Preclinical efficacy of the ATR inhibitor AZD6738 in combination with the BTK inhibitor acalabrutinib in ABC-DLBCL models [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 LB-263.

The poly(ADP-ribose polymerase) (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated ovarian cancers. Olaparib inhibits PARP function during DNA single-strand-break repair and also by trapping of PARP on DNA to create lesions. These complexes cause replication-associated DNA damage including stalling and collapse of DNA replication forks. Cells which have lost BRCA1/2-dependent homologous recombination repair are highly sensitive to olaparib. In addition, other DNA damage response (DDR) pathways mediated by the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP inhibitor treatment. Here we show that olaparib combines synergistically with the orally bioavailable ATR inhibitor AZD6738, in vitro, leading to cell death in ATM-deficient backgrounds. The growth inhibitory and cell kill effect of a range of concentrations of AZD6738 (0.01-1 µM) and olaparib (0.03-3 µM) were assessed using the Loewe model of additivity in the isogenic ATM knockout (KO) and wildtype (WT) FaDu head and neck cancer cell lines. The combination of AZD6738 and olaparib induced cell death in the ATM KO cells across a wide range of concentrations, with 3 µM olaparib plus 1 µM AZD6738 inducing 84% cell kill, in contrast to only 37% growth inhibition in the ATM WT cells. The observed combination synergy in the ATM KO cells is a result of increased DNA replication-associated DNA damage together with abrogation of the G2-M checkpoint activated by olaparib. Olaparib treatment led to a 10 and 20% increase in G2 cells at 24 hours in the ATM KO and ATM WT FaDu cell lines respectively, however co-administration of AZD6738 (0.1-0.3 µM) completely released the olaparib treated cells from the G2 arrest. DNA metaphase spread analysis showed that combination treatment with olaparib (1 µM) plus AZD6738 (0.1 µM) in the ATM KO cells caused 12.8 chromosomal DNA aberrations per cell compared to 4.4 or 3.3 aberrations per cell when treated with olaparib or AZD6738 alone respectively (n = 2). In contrast, in the ATM WT cells the olaparib plus AZD6738 combination treatment caused only 1.5 chromosomal aberrations per cell. Collectively, these data show that olaparib-induced DNA damage activates an ATR-dependent G2-M checkpoint allowing time to repair damaged DNA, and that AZD6738 abrogates this checkpoint, permitting cells to undergo mitosis in the presence of DNA damage leading to increased chromosomal aberrations. These data provide a mechanistic understanding of the combination and supports the clinical line of sight for the development of AZD6738 in combination with olaparib. Citation Format: Rebecca Lloyd, Katarynza Falenta, Paul W. Wijnhoven, Christophe Chabbert, Jonathan Stott, James Yates, Alan Y. Lau, Lucy A. Young, Simon J. Hollingsworth. The PARP inhibitor olaparib is synergistic with the ATR inhibitor AZD6738 in ATM deficient cancer cells [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 337.

Introduction: AZD6738 is a potent inhibitor of the ATR protein kinase that is being tested in patients with solid malignancies. In Phase I dose escalation studies, AZD6738 was dosed as monotherapy (continuous schedule from 40 - 480 mg per day), or in combination (intermittent schedule from 80 - 320 mg per day) with olaparib, durvalumab, carboplatin, or radiation. In those studies, thrombocytopenia was the main dose limiting toxicity and changes in peripheral monocytes and proliferating T-cells were seen with AZD6738, with up to 80% decrease on-drug and return to baseline upon cessation of dosing. This effect on monocytes and proliferating T cells was not observed with either single agent olaparib or durvalumab. Based on these observations, we developed two PKPD models linking AZD6738 dose, AZD6738 plasma exposure, and differential blood cell counts to support dose and schedule selection. Methods and Results: The first model characterized the quantitative relationship between the plasma exposure of AZD6738 monotherapy, and the difference between monocyte decrease (on-target activity) and platelet decrease (on-target toxicity). This model was a sigmoid function and predicted biological activity starting at exposures of 2.5 ug/mL (aligned with the in vitro IC90 in LoVo cells, and obtained in ≥ 50% of patients with 80 mg per day) increasing in a concentration dependent manner to 10 ug/mL (obtained in almost all patients dosed at 480 mg per day), after which negligible monocyte response over platelet decrease was observed. Those data were consistent with the preclinical observations which showed tumour regression after at least 3-day concomitant treatment of olaparib and AZD6738 at exposure maintaining IC90 [1]. The second model was a PK-safety model describing the temporal relationship between circulating platelets and exposure of AZD6738 administered in combination with olaparib dosed at 300 mg twice daily continuously. This model allowed generation of various platelet/ time profiles in the most sensitive patient group (10% of the patients) for different AZD6738 doses and schedules. The simulations indicated that, for doses considered biologically relevant by the first model, a period of 21-days free of AZD6738 is needed to give full recovery of potential thrombocytopenia in a 28-day cycle. Conclusion: Using monocyte and proliferative T-cell decreases as biological activity indicators and platelet decrease as a safety indicator, we quantified the exposure/activity/safety relationship for AZD6738. The recommended Phase II dose of AZD6738 (in combination with olaparib) was then driven by maintaining maximally active exposure consistent with manageable safety. Reference: [1]. 2017 AACR Abstract 2494. Acknowledgements: T.A. Yap (The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK) and J.C. Soria (Institut Gustave Roussy, Paris, France) Citation Format: Alienor Berges, S. Y. Amy Cheung, Andrew J. Pierce, Emma Dean, Brunella Felicetti, Nathan Standifer, Simon Smith, James Yates, Alan Lau, Christine Stephens, Matthew Krebs, Kevin Harrington, Simon J. Hollingsworth. PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor) [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 CT118.

Background: AZD6738 is a potent selective oral ATR inhibitor. Therapeutic combinations aim to inhibit ATR-dependent cycle arrest and repair induced by the PARP inhibitor Olaparib (Ola), and to exploit DNA damage-induced immune responses with the anti-PD-L1 antibody Durvalumab (Durva). Here we present the results of the ongoing Phase I study D5330C00004 (NCT02264678) dose escalation combinations of AZD6738 with Ola or Durva. Methods: A trial assessing AZD6738 in combination with continuous Ola tablets or Durva IV infusion per 28-day cycle. Pharmacokinetic (PK) and pharmacodynamic evaluations were conducted. Results: 70 pts with advanced cancer were treated with +Ola (45 pts) or +Durva (25 pts). Tumor types included breast, ovary, prostate, pancreas, lung, HNSCC and gastric cancers. +Ola: AZD6738 was assessed in 10 cohorts from 60 mg od to 240 mg bd for 5-14 days (D), co-dosing with Ola 100-300 mg bd continuously. All causality toxicity occurring in ≥20% subjects (pts with ≥G3 events) included: thrombocytopenia (5 pts), anemia (7 pts), neutropenia (6 pts), fatigue (1 pt), decreased appetite (1 pt), nausea, vomiting, constipation, diarrhea and cough. Thrombocytopenia and neutropenia were dose- and schedule limiting toxicities (DLTs). The Recommended Phase 2 Dose is AZD6738 160 mg od D1-7 + Ola 300 mg bd D1-28. Of 39 evaluable pts, 1 RECIST complete response (CR), 5 partial responses (PR) and 1 unconfirmed (uPR) were observed in pts with advanced breast (3 pts), ovarian, prostate, pancreatic and ampullary cancer and BRCA1/2 mutations independent of ATM status. Dose expansions are ongoing in pts with advanced gastric and breast cancer. +Durva: AZD6738 was evaluated in 5 cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks. Toxicity occurring in ≥20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in pts with advanced NSCLC (3 pts) and HNSCC (1 pt), independent of tumor PD-L1 expression. Peripheral monocytes and proliferating T-cells were suppressed; both rebounding to levels ≥ baseline during the off-drug interval. GM-CSF increased reciprocally to on-target decreases in monocytes. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Ola or Durva. Conclusions: The combinations of AZD6738 with Ola or Durva were tolerated in dose escalation with preliminary signals of antitumor activity in pts with advanced solid tumors. Citation Format: Matthew G. Krebs, Juanita Lopez, Anthony El-Khoueiry, Yung-Jue Bang, Sophie Postel-Vinay, Wassim Abida, Louise Carter, Wen Xu, Seock-Ah Im, Andrew Pierce, Paul Frewer, Alienor Berges, S.Y. Amy Cheung, Christine Stephens, Brunella Felicetti, Emma Dean, Simon J. Hollingsworth. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers [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 CT026.

4061Background: This trial was a phase II study with selumetinib (AZD6244)/docetaxel as second-line treatment for metastatic GC patients with MEK signature or RAS gene alterations as part of the GC...

TPS1116Background: Invasive BC is diagnosed in > 255,000 pts in the US annually, and TNBC comprises ≈15% of cases. Alterations in BRCA1/2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose ...

4024 Background: The VIKTORY trial is a biomarker-based umbrella trial in GC. Methods: See table below. Results: From June 2014 to Jan 2017, 432 metastatic gastric cancer patients were enrolled. 124 (28.7%) were treated on one of the associated study protocols. At January 2017, 25 pts were allocated to selumetinib/paclitaxel arm, 25 to AZD1775/paclitaxel arm, 16 to AZD5363/paclitaxel arm, 16 to vistusertib/paclitaxel arm, 4 to savolitinib monotherapy, 19 to savolitinib/docetaxel arm, 19 to phase I AZD6738/paclitaxel arm. Initial efficacy signals have been seen in several arms (selumetinib/paclitaxel, 6 of 21 evaluable patients in PR). Correlative analyses between molecular signatures and treatment response are ongoing and will be presented at the meeting. For vistusertib/paclitaxel in the biomarker negative arm, we found RICTOR amplification as a promising predictive biomarker for response. Two (of three) GC patients with RICTOR amplification achieved PR to vistusertib/paclitaxel. Conclusions: This is one of the first attempts to undertake a biomarker-driven trial in metastatic GC. 28.7% of the patients were guided to one of the parallel arms based on molecular screening outcomes. We were able to identify potential molecular targets in the biomarker-negative arm, for further assessment in new protocols. Clinical trial information: 02299648. [Table: see text]