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Background Many patients do not respond or eventually relapse on treatment with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors due to secondary or acquired resistance; therefore, there is a need to investigate novel PD-1/PD-L1 inhibitors. Methods This open-label, non-randomised study investigated the safety and anti-tumour activity of BGB-A333, a PD-L1 inhibitor, alone and in combination with tislelizumab in patients with advanced solid tumours with progression during/after standard therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D), safety and tolerability for BGB-A333 alone and in combination with tislelizumab (Phase 1a/1b) and to determine the overall response rate (ORR) with BGB-A333 plus tislelizumab (Phase 2). Results Overall, 39 patients across Phase 1a (N = 15), 1b (N = 12) and 2 (N = 12) were enroled. In Phase 1a, an RP2D of 1350 mg was determined. In Phase 1a and 1b/2, serious treatment-emergent adverse events (TEAEs) were reported in five and eight patients, respectively. Two patients experienced TEAEs that led to death. In Phase 2, the ORR was 41.7% (n = 5/12; 95% confidence interval: 15.17%, 72.33%). Conclusions TEAEs reported with BGB-A333 were consistent with other PD-L1 inhibitors. Encouraging preliminary anti-tumour activity was observed with BGB-A333 in combination with tislelizumab. Clinical trial registration NCT03379259.

Supplementary Figure 1 Growth kinetics for all 786-0 xenografts included in the analysis from Figure 1; Supplementary Figure 2 Details of the in vitro angiogenesis assay; Supplementary Figure 3 Isolation of a sunitinib-refractory sub-line (786-0-R) from the parental 786-0 cell line; Supplementary Figure 4 Anti-angiogenic activity of sunitinib combined with trametinib within an in vitro tubule formation assay; Supplementary Figure 5 Quantification of tumor vessel density in treated tumors; Supplementary Table 1 Genotyping of the original patient sample and each generation of the PDX by STR typing

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC. Mol Cancer Ther; 15(1); 172–83. ©2015 AACR.

Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c isoform is associated with poor prognosis in EC patients. Here we report the establishment of 14 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. Treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with FGFR2c+ showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n=5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206+ M2 macrophages. This data collectively supports the evaluation of FGFR inhibitors in a clinical trial.

BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.Primary ObjectiveTo compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.Study HypothesisPembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers).Trial DesignPhase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no).Major Inclusion/Exclusion CriteriaAdults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded.Primary EndpointsProgression-free and overall survival (dual primary endpoints).Sample SizeAbout 875 patients.Estimated Dates for Completing Accrual and Presenting ResultsEnrollment is expected to take approximately 24 months, with presentation of results in 2022.Trial RegistrationClinicalTrials.gov, NCT03884101.

Background and Objectives: Patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (A-PDAC) are not candidates for surgical resection and are often offered palliative chemotherapy. The ready availability of a safe and effective tumor sampling technique to provide material for both diagnosis and comprehensive genetic profiling is critical for informing precision medicine in A-PDAC, thus potentially increasing survival. The aim of this study is to examine the feasibility and benefits of routine comprehensive genomic profiling (CGP) of A-PDAC using EUS-FNA material. Methods: This is a prospective cohort study to test the clinical utility of fresh frozen or archival EUS-FNA samples in providing genetic material for CGP. The results of the CGP will be reviewed at a molecular tumor board. The proportion of participants that have a change in their treatment recommendations based on their individual genomic profiling will be assessed. Correlations between CGP and stage, prognosis, response to treatment and overall survival will also be investigated. This study will open to recruitment in 2020, with a target accrual of 150 A-PDAC patients within 36 months, with a 2-year follow-up. It is expected that the majority of participants will be those who have already consented for their tissue to be biobanked in the Victorian Pancreatic Cancer Biobank at the time of diagnostic EUS-FNA. Patients without archival or biobanked material that is suitable for CGP may be offered a EUS-FNA procedure for the purposes of obtaining fresh frozen material. Discussion: This trial is expected to provide crucial data regarding the feasibility of routine CGP of A-PDAC using EUS-FNA material. It will also provide important information about the impact of this methodology on patients' survival.

Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.

Background: Inactivation of the Hippo pathway is a common finding in MM and other cancers, leading to constitutive YAP activation, but has thus far been undruggable. NF2 encodes Merlin that activates Hippo kinase resulting in inactivation of YAP, which is the major effector of Hippo signaling. NF2-deficient tumors, often due to inactivating NF2 mutations (NF2m), are dependent on YAP for growth. VT3989 is an oral, highly potent and selective inhibitor of TEAD palmitoylation, which blocks YAP function and has shown promising preclinical activity. Materials and Methods: This FIH trial used a 3 + 3 dose escalation design and evaluated VT3989 from 25 to 200 mg QD continuously and 50 to 200 mg intermittently. Pts with refractory solid tumors, ECOG PS 0-1, serum albumin > 2.5, urinary protein creatinine ratio ≤ 0.5 mg/mg and albumin creatinine ratio ≤ 100 mg/g were enrolled. Objectives were to determine the safety, tolerability and recommended Phase 2 dose (RP2D) of VT3989; to evaluate antitumor activity, pharmacokinetics (PK) and correlate NF2m and other alterations in tumor and ctDNA with response. Results: 67 pts have been enrolled. Median age 63.5y (21-83y), ECOG PS 0:1 13:54 pts. Median prior therapies 3 (range 0-8). Tumor types: 42 MM (29 pleural and 13 non-pleural) and 25 solid tumors including 9 meningioma and 4 sarcoma pts. 34 pts had NF2m (29 somatic and 5 germline). All MM pts had progressed on prior platinum/pemetrexed; all but 2 had prior immune checkpoint inhibitors. VT3989 is safe and well tolerated with no dose limiting toxicities. No MTD was defined up to 200 mg QD. The most common AEs are proteinuria, albuminuria and peripheral edema, mainly observed with the continuous schedule. There were 7 possibly related G3 AEs (fatigue, ALT, AST, dehydration, dyspnea, hypotension and peripheral edema) and 1 G4 cardiomyopathy. No pt developed decreased renal function or nephrotic syndrome. VT3989 has a 12-15 day half-life, dose proportional PK and reaches steady state within 2 weeks. Seven pts (6 refractory MM and 1 NF2m sarcoma) achieved RECIST v1.1 partial responses (PRs) with 4 confirmed, 3 unconfirmed (1 pending). 3 PRs in MM pts are ongoing up to 18+ months. The clinical benefit response rate (PR + SD > 8 weeks, per protocol) in MM pts is 57%. Of the 6 MM pts (1 pericardial, 1 pleural/peritoneal and 4 peritoneal) with PR, 2 have NF2m, 3 are wildtype, and 1 is unknown. Conclusions: VT3989 is safe and well tolerated with durable RECIST v1.1 antitumor responses in pts with advanced MM and NF2m cancers, providing the first early clinical proof-of-concept for effectively drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in pts with MM and NF2m tumors. Citation Format: Timothy A. Yap, David J. Kwiatkowski, Jayesh Desai, Ibiayi Dagogo-Jack, Michael Millward, Hedy L. Kindler, Anthony W. Tolcher, Sophia Frentzas, Archie W. Thurston, Len Post, F Andrew Dorr. First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT006.

Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-02.

Background With the rapid influx of novel anti‐cancer agents, phase I clinical trials in oncology are evolving. Historically, response rates on early phase trials have been modest with the clinical benefit and ethics of enrolment debated. However, there is a paucity of real‐world data in this setting. Aim To better understand the changing landscape of phase I oncology trials, we performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes, and treatment outcomes. Methods and results We analyzed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30–89) with an equal sex distribution. Among 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty‐six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty‐two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment‐related adverse events. There was one treatment‐related death (0.5%). Of 190 response‐evaluable patients, 7 (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The median overall survival for our cohort was 8.0 (95% CI: 6.8–9.2) months. Conclusion The profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatment‐related toxicity was relatively uncommon, and treatment‐related mortality was rare.

Background: Toll-like receptors (TLRs) play a key role in innate immune cell recognition of foreign pathogens, stimulating innate and adaptive immune responses. TLR agonists amplify tumor antigen-specific immune responses in the context of anti-PD-1 therapy. TransCon TLR7/8 Agonist is designed as a long-acting prodrug to provide localized delivery of resiquimod, a potent TLR7/8 agonist. TransCon TLR7/8 Agonist has the potential to improve on challenges of pattern recognition receptor agonist treatments by providing prolonged high local concentrations of resiquimod and promoting potent anti-tumoral responses while reducing systemic drug exposure and related adverse events. TransCon TLR7/8 Agonist comprises 3 main components: resiquimod, a polymeric hydrogel microparticle carrier, and a linker bound permanently to the hydrogel microparticle carrier on one end and transiently to resiquimod on the other. TLR-mediated T cell activation induces PD-1 expression on T cells, providing a clear rationale to study TransCon TLR7/8 Agonist alone and in combination with pembrolizumab (pembro). Intratumoral TransCon TLR7/8 Agonist is expected to stimulate innate and adaptive immune response in the tumor microenvironment and further enhance the activity of checkpoint inhibitors like pembro. Methods: transcendIT-101 is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced, unresectable, recurrent, or metastatic solid tumors. All patients must have at least 2 measurable lesions by RECIST 1.1 that are predesignated as target-injected and target non-injected lesions, respectively. The primary objectives are to evaluate the safety, tolerability, define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembro. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of TransCon TLR7/8 Agonist alone (Part 1) or with 200 mg intravenous pembro in solid tumors where pembro monotherapy may have clinical activity (Part 2). Each part will enroll ≈20 patients. Part 3 Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon TLR7/8 Agonist at the RP2D determined in Part 2 combined with pembro. Currently planned expansion cohorts are 1) head and neck squamous cell carcinoma, 2) other HPV-associated tumors (anal, vulvar, cervical, penile, vaginal). Each cohort will be analyzed using a Simon 2-stage design and will enroll ≈50 patients. Secondary objectives are TransCon TLR7/8 Agonist pharmacokinetics and its antitumor activity using ORR, duration of response, time to response by RECIST 1.1 and itRECIST; progression-free survival; overall survival. Recruitment started March 2021 and is ongoing (NCT04799054). Citation Format: Diwakar Davar, Stina M. Singel, Gil Nyamuswa, Tuan-Anh Tran, Yang Wu, Jaspreet Grewal, Morteza Aghmesheh, Alexander Spira, Vinod Ganju, Jamie Rand, Sophia Frentzas, David Bajor, Nashat Gabrail. transcendIT-101: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT252.

2641 Background: HBM4003 is a fully human heavy chain only monoclonal antibody (HCAb) to CTLA-4, which has been engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. In the Phase 1 dose escalation part, HBM4003 showed favorable safety and efficacy profile in patients (pts) with advanced solid tumors. Here, we present the updated data from the dose escalation part and most recent safety and clinical activity data from three expansion cohorts of pts with advanced hepatocellular carcinoma (HCC), melanoma, and renal cell carcinoma (RCC). Methods: In the dose-escalation part, pts were enrolled into 3 dose levels (DL): 0.3mg/kg QW (28-day cycle), 0.45mg/kg Q3W (21-day cycle), and 0.6mg/kg Q3W (21-day cycle). In the dose-expansion part, pts with advanced HCC, melanoma, and RCC received 0.45 mg/kg Q3W (21-day cycle). Tumor measurements were performed every 6 weeks for up to 12 months and subsequently every 12 weeks per RECIST v1.1. Results: In total 60 pts were included for this analysis, including 24 pts with advanced solid tumors in the dose escalation part and 36 pts in the dose expansion part: 18 pts with HCC, 4 pts with melanoma, and 14 pts with RCC, from 12 sites in mainland China, 5 sites in Australia, and 1 site in Hong Kong. 46 pts (77%) received ≥ 2 lines of previous systemic therapies and 37 pts (62%) received previous PD-1/PD-L1 treatment. For the HCC cohort, 19 pts were treated in dose-escalation (1 pt, 0.45 mg/kg Q3W) and dose-expansion parts. All 19 pts received previous PD-1/PD-L1 therapy. 12 pts were evaluable for efficacy. Two had stable disease (SD), 2 pts had partial response (PR) as best response. For 12 evaluable pts, ORR was 16.7% and disease control rate (DCR) was 33.3%. For the RCC cohort, 19 pts were treated in dose-escalation and dose-expansion parts; 18 pts were evaluable for efficacy. Eight had SD as best response; the DCR was 44.4%. Overall, the most common treatment-related adverse event (TRAE) (incidence ≥ 10%) of all grades was rash (16 [26.7%] pts). At the 0.45 mg/kg Q3W DL, the most common TRAE of all grades was hepatic function abnormalities (12 [27.9%] pts) and rash (12 [27.9%] pts). 30 (69.8%) pts reported Gr 1 or 2 TRAEs. Gr ≥3 TRAEs occurred in 4 (9.3%) pts. 1 pt reported Gr 4 TRAE: blood creatine phosphokinase increased. No Gr 5 TRAE was reported. TRAE leading to discontinuation occurred in 4 pts. In mouse model, only tumor infiltrating lymphocytes Treg was depleted upon HBM4003 treatment while no Treg change in blood and spleen. In pts, Treg depletion was observed only in tumor tissue on day 21 post dosing. Overall, HBM4003 demonstrated dose proportional pharmacokinetics and low immunogenicity. Conclusions: HBM4003 showed a favorable safety profile, promising antitumor activity and intratumoral Treg depletion in pts with advanced solid tumors at the 0.45 mg/kg Q3W DL. Clinical trial information: NCT04135261.

TPS2688 Background: The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are stress-inducible, surface glycoproteins that are up-regulated on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D) expressed on Natural Killer (NK) cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface which enables tumor cells to evade immune cell recognition and destruction by NKG2D-expressing cells. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized, clinical-stage, MICA/MICB-specific IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB thereby exposing tumor cells for immune destruction through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022). In mice bearing MICA/MICB-expressing human tumor xenografts, CLN-619 treatment yielded robust anti-tumor activity at low doses. MICA/MICB is expressed in a wide range of solid tumors. Therefore, CLN-619 is expected to have broad anti-tumor activity. Methods: CLN-619 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study as monotherapy, and in combination with pembrolizumab, in patients with advanced solid tumors. Cohort expansion in patients with specific indications as monotherapy and in combination with pembrolizumab will be conducted. The phase 1 study explores ascending intravenous doses of CLN-619 as monotherapy (0.1, 0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg) and in combination with pembrolizumab (200 mg) in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy. At the RP2D, CLN-619 monotherapy will be evaluated in non-small cell lung and cervical cancer. In parallel, a cohort of patients will be administered CLN-619 in combination with pembrolizumab. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress (NCT05117476) and has completed accrual of three participants at the first dose level. Clinical trial information: NCT05117476.

TPS2671 Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant “non-CD25” IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Methods: This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an escalating single aldesleukin dose in sequential escalation cohorts. In Arm C, AU-007 is evaluated in combination with aldesleukin, both given Q2w. AU-007 is administered at a fixed dose with an escalating dose of aldesleukin in sequential cohorts. The Phase 2 cohort expansion portion of the study evaluates the initial efficacy at the RP2D defined in escalation cohorts A, B, and C in 3 matching expansion cohorts of up to 20 patients each. Patients with advanced melanoma, RCC and other tumors including, but not limited to, Merkel Cell Carcinoma, NSCLC, and urothelial cancer are eligible. Enrolment to the study commences in Australia, with US sites planned to open later in 2022. Clinical trial information: CT-2021-CTN-03938-1.

TPS1112 Background: The overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood samples will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.

Worldwide, gastric cancer is the fifth most prevalent cancer and third leading cause of mortality. Gastric cancer is a heterogenous disease and our understanding of this disease is rapidly expanding. Subsequently, the treatment landscape is also changing. Chemotherapy plus or minus trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)-positive disease has been the main treatment option until recently. Notably, a role for immunotherapy is being defined. Current relevant biomarkers clinically utilized for treatment selection are HER2, DNA mismatch repair/microsatellite instability, and programmed death-ligand 1. It is anticipated ongoing research will identify clinically relevant biomarkers to assist in treatment decision-making and identify new drug targets, ultimately improving patient outcomes. In this chapter, we describe four patient cases that highlight the heterogenous nature of gastric cancer, also demonstrating that despite the poor prognosis of advanced gastric cancer, patients can achieve durable disease control.

Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. Toxicity is assessed by NCI CCTCAEv5 and tumor response is assessed by RECISTv1.1. CNS exposure is evaluated in in select patients with confirmed CNS disease involvement via CSF collection. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥ G2) is observed, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). DOSE ESCALATION: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD EXPANSION: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). An update on the progress of this trial will be presented.

Background Checkpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance.1 The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer.2 IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models.3 4 AMG 256 is a mutated IL-21 cytokine fused to an anti-PD-1 antibody to combine IL-21 pathway stimulation with checkpoint inhibition—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors. Methods This is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies. Results N/A Conclusions N/A Acknowledgements • The authors thank the investigators, patients, and study staff who are contributing to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT04362748 Ethics Approval The study was approved by all institutional ethics boards. References Kluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398. Thompson JA, Curti BD, Redman BG, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol 2008;26:2034–2039. Lewis KE, Selby MJ, Masters G, et al. Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology. 2017;7:e1377873. Shen S, Sckisel G, Sahoo A, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol 2020;11:832.

Hepatocellular carcinoma (HCC) is the sixth most common incident and the fourth most common cause of cancer death worldwide. It is strongly associated with chronic Hepatitis B and C infection and excess alcohol intake (1), making treatment of patients with HCC complicated, with the almost uniform presence of concurrent cirrhosis and varying degrees of liver failure, which often fluctuates over time.

BackgroundPlatinum-resistant/refractory epithelial ovarian cancer (PROC) is a high unmet medical need with limited treatment options and a median survival of 12–15 months.1 Single agent PD-(L)1 inhibitors have objective response rates (ORR) of less than 10%.2 3 However, combination of nivolumab plus bevacizumab yields a higher ORR of 16.7% in platinum-resistant patients (pts), indicating synergistic activity between PD-1 inhibition and anti-angiogenic therapy in this disease.4 Here, we present initial efficacy and safety data for AK112, a bispecific antibody targeting PD-1 and VEGF-A, in pts with PROC.MethodsPts with PROC were enrolled in an ongoing Phase 1a/1b study of AK112 (NCT04047290). Tumor assessments based on RECIST v1.1 were performed once every 8 weeks/2 cycles for the first 12 months, and every 12 weeks thereafter.ResultsAs of 16 July 2021, 19 PROC pts, of which 6 had platinum-refractory disease, have received AK112 at doses ranging from 3 mg/kg to 30 mg/kg Q2W. Seventeen pts (89.5%) had ≥2 lines of prior therapy in the recurrent/metastatic setting and 7 pts (36.8%) had prior bevacizumab. Seventeen pts had at least 1 post-baseline tumor assessment. Median duration of follow-up was 4.5 months. ORR was 29.4% (5/17; 2 clear cell, 3 high-grade serous]). Among the 5 responders, 3 pts received 20mg/kg Q2W AK112 and 1 pt each had 3mg/kg and 10mg/kg Q2W AK112. Median duration of response was not reached. One pt, who had clear cell PROC and received prior immune checkpoint inhibitor (ICI) therapy, had tumor shrinkage of 70% and continued treatment for more than 17 months. Another pt, who had high-grade serous ovarian cancer and prior treatment with bevacizumab, had tumour shrinkage of 65% and continued treatment for more than 4 months. Disease control rate (DCR) was 76.5% (13/17), with tumor shrinkage observed in 11 pts (64.7%). Twelve out of 19 (63.2%) pts experienced treatment-related adverse events (TRAEs). Three pts (15.8%) experienced Grade 3 TRAEs (hypertension and transaminitis in 1 pt; and hypertension and colitis). There were no Grade 4–5 TRAEs. Commonly reported TRAEs were hypertension (15.8%), arthralgia (15.8%), fatigue (15.8%), hypothyroidism (10.5%) and rash (10.5%).ConclusionsThe initial results from Study AK112-101 demonstrate that AK112 garners an encouraging anti-tumor activity and a favorable safety profile in patients with platinum-resistant/refractory epithelial ovarian cancer. AK112 will be further evaluated for the treatment of platinum-resistant/refractory epithelial ovarian cancer in a Phase 2 study.AcknowledgementsAkeso Biopharma, Inc would like to thank the patients, investigators and site staff for their participation in this study.Trial RegistrationClinicalTrials.gov Identifier: NCT04047290ReferencesPujade-Lauraine E, Banerjee S, Pignata S. Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J Clin Oncol 2019; 37:2437–2448.Disis ML, Taylor MH, Kelly K, et al. Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial. JAMA Oncol 2019; 5:393–401.Matulonis UA, Shapira-Frommer RS, Santin A, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study. J Clin Oncol 2018; 36: suppl abstr 5511.Liu JF, Herold C, Gray KP, et al. Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial. JAMA Oncol 2019;5:1731–1738.Ethics ApprovalThis study received ethics approval from Bellberry Human Research Ethics Committee (HREC) on 05 Nov 2019 (Application number 2019-05-459-AB). In accordance with ICH Good Clinical Practice Guidelines and the Declaration of Helsinki, study participants gave informed consent voluntarily before participating in this study.

AIMS In the Northern Territory (NT) of Australia, Indigenous women have a lower incidence of breast cancer, but a higher mortality than Non-indigenous women. The aim of this study was to describe and compare breast cancer pathological features related to stage and biological aggression between the two groups. METHODS Subjects were identified by extract from the NT Cancer Registry in two separate cohorts, cohort 1 (1991-2000) and cohort 2 (2001-2010). Data from cohort 1 included age, stage, tumor grade and estrogen receptor status (ER) and treatment completion. Additional pathological variables including tumor size, HER2 status, lymphovascular invasion and derived tumor phenotype were available for cohort 2. Bivariate P values for categoric variables were calculated using Fisher's exact tests. The Wilcoxon rank-sum test was used to compare cohort 2. Logistic regression was used to calculate odds ratios. RESULTS There were 359 (44 indigenous) eligible women in cohort 1 and 526 (100 indigenous) for cohort 2. In cohort 1, in both cohorts, indigenous women were more likely to present at an advanced stage, but there was no difference in ER status or tumor grade. When derived phenotypes were compared, indigenous women were less likely to have better prognosis luminal A tumors, and more likely to have HER2-enriched tumors. CONCLUSION This two decade long comparison of the pathological features of breast cancer between indigenous and nonindigenous women of the NT has confirmed that Indigenous women not only present at a later stage than NI women but are also afflicted by poorer prognosis tumors, particularly HER2 enriched.

Introduction Checkpoint inhibitors are a promising therapy for patients with solid tumors; however, many patients require additional therapies to maximize clinical benefit or overcome resistance. The type-1 cytokine interleukin-21 (IL-21) is a promising candidate for combination and has shown clinical activity in melanoma and renal cell cancer. IL-21 has also shown improved efficacy when combined with anti-programmed death (PD)-1 antibodies in preclinical models. AMG 256 is a bifunctional fusion protein comprising a PD-1-targeting antibody and IL-21 mutein designed to deliver IL-21 pathway stimulation to PD-1+ cells—a strategy that is designed to prime and extend the activity of cytotoxic and memory T cells and induce anti-tumor immunity. This first-in-human (FIH) study will assess safety, tolerability, and estimated dosing of AMG 256 monotherapy in patients with advanced solid tumors. Methods This is a FIH, multicenter, non-randomized, open-label, phase 1 study (NCT04362748) of AMG 256 in patients with advanced solid tumors. The planned sample size is approximately 100 patients in two parts: part 1 will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD), part 2 will evaluate the MTD determined in part 1 to further characterize the safety profile and preliminary tumor response. AMG 256 will be delivered by intravenous (IV) infusion. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status ≤ 2, histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation, and at least one measurable lesion ≥ 10 mm that has not undergone biopsy within 3 months of screening scan. Exclusion criteria include primary brain tumor, untreated or symptomatic brain metastases, currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study, history of solid organ transplantation or major surgery within 28 days of study day 1, live vaccine therapy within 4 weeks prior to study day 1, and active infection requiring oral or IV therapy. The primary endpoints are incidence of dose-limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity (objective response, duration of response, progression-free survival, disease control rate, duration of stable disease, overall survival), and immunogenicity of AMG 256 via incidence of anti-AMG 256 antibodies. Citation Format: Greg Durm, Sophia Frentzas, Erik Rasmussen, Saltanat Najmi, Nooshin Hashemi Sadraei. Design and rationale of a phase 1 study evaluating AMG 256, a novel, targeted, PD-1 antibody x IL-21 mutein bifunctional fusion protein, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT205.

TPS2675 Background: AK119 is a humanized IgG1 monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73, a cell surface enzyme that converts adenosine monophosphate (AMP) into adenosine. Adenosine has been shown to facilitate tumor-mediated evasion. CD73 inhibition may therefore reduce adenosine accumulation and promote anti-tumor immunity. AK104 is a recombinant humanized IgG1 bispecific antibody that simultaneously binds to programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte-associated antigen protein 4 (CTLA-4). Preliminary data from phase I and II studies suggest that AK104 has encouraging anti-tumor activity in selected tumor types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 mAbs. Preclinical studies show that CD73 inhibition synergistically increases the anti-tumor activity of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs). Published early clinical data suggests that anti-CD73 therapy in combination with ICIs produces improved clinical outcomes. Thus, AK119 plus AK104 is postulated to have synergistically enhanced anti-tumor activity compared to the administration of anti-CD73 monotherapy or ICIs alone. Methods: This is a phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced solid tumors that are refractory to standard therapies. The primary objective is to assess safety, tolerability and dose limiting toxicity; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of AK119 in combination with AK104. Secondary objectives are to evaluate antitumor activity, PK and AK119 immunogenicity. The dose-escalation phase will evaluate 5 dose levels of AK119 (1mg/kg to 40 mg/kg Q2W IV) in combination with 6mg/kg AK104 Q2W IV using a 3+3+3 study design. Eligible pts will receive a single dose of AK119 on C0D1 of a 14-day “lead-in” period. Thereafter, from C1D1 pts will receive AK119 in combination with AK104 on a 28-day cycle, until unacceptable toxicity, confirmed progressive disease, subject withdrawal, or for a maximum of 24 months. The “lead-in” period is only applicable for dose-escalation cohorts. Any dose-escalation cohort not exceeding the MTD may be expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, PK/ PD, immunogenicity, and preliminary anti-tumor activity. Cohort 1 is currently in progress with the first patient enrolled in January 2021. For the dose-expansion phase, cohorts of pts with advanced/metastatic pancreatic cancer or MSS/pMMR colorectal cancer will be enrolled. Cohorts of other tumor types may be added based on emerging pharmacodynamic and anti-tumor response data. Clinical trial information: NCT04572152.

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.

1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]

2515 Background: AK112 is a tetrameric bispecific antibody targeting PD-1 and VEGF-A. Published data suggests that the combination of anti-VEGF-A with immune checkpoint inhibitor (ICI) therapy produces complementary and synergistic antitumor effects. Given the strong correlation between VEGF-A and PD-1 expression in the tumor microenvironment, it is postulated that the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificity and produce enhanced antitumor activity, with an improved safety profile, compared to the co-administration of anti-PD-(L)1 and anti-VEGF therapies. Here, we present preliminary safety and efficacy data from a dose escalation study of AK112. Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0.3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose escalation design. Selected dose escalation cohorts were expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and anti-tumor activity. Pts with prior exposure to ICI were eligible. PD studies examined serum VEGF levels and PD-1 receptor occupancy (RO) on circulating T-cells as an indication of target engagement. Results: As of 13 Jan 2021, 29 pts, median age 60 years [30-76], have received AK112 at doses of 0.3 mg/kg (n = 1), 1.0 mg/kg (n = 3), 3.0 mg/kg (n = 3), 10.0 mg/kg (n = 13), 20.0 mg/kg (n = 8), and 30.0 mg/kg (n = 1) Q2W. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts. G3 TRAEs occurred in 10.3% [3/29] and treatment-related SAEs occurred in 3.4% [1/29] of pts. There was no G4 TRAE. No DLT occurred. TRAEs leading to treatment discontinuation occurred in 6.9% of pts [2/29]. Most frequent TRAEs were arthralgia (17%), diarrhea (14%), rash (10%), and fatigue (10.3%). Of the 17 evaluable pts treated at doses ≥ 3 mg/kg Q2W, the ORR was 23.5% (4/17) and disease control rate (DCR) was 64.7% (11/17). Among the 4 responders, a responder (endometrial ca) had not received prior ICI or bevacizumab, 2 responders (ovarian ca, mesothelioma) had received prior ICI therapy; and a responder (microsatellite stable colorectal ca) was previously treated with bevacizumab. Conclusions: AK112, up to 20 mg/kg Q2W (inclusive), can be given safely to pts and demonstrated encouraging anti-tumor activity with an ORR of 23.5% when dosed ≥ 3 mg/kg Q2W in a pt population with various solid tumors resistant/relapsed to standard therapies. Enrolment is currently ongoing at 30.0 mg/kg Q2W and in dose escalation cohorts selected for expansion. Updated data, including PK, serum VEGF, and RO will be presented. Clinical trial information: NCT04047290.

Background: Programmed cell death protein-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Although both pathways have overlapping elements, each has a distinct mechanism of action. Nonclinical studies have demonstrated that potential synergistic antitumor effects can result from blocking both PD-1 and PD-L1. BGB-A333 is an investigational humanized IgG1 monoclonal antibody against PD-L1 that has antitumor activity in xenograft models. Tislelizumab, a clinical-stage anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, has demonstrated clinical activity in patients with advanced solid tumors. Here we report preliminary results from the phase 1 component of an open-label phase 1/2 study (NCT03379259) of BGB-A333 alone and in combination with tislelizumab in patients with advanced solid tumors. Methods: Phase 1 of this study consisted of two parts. In Part A, patients received single-agent BGB-A333 IV Q3W at increasing doses; in Part B patients received BGB-A333 1350 mg IV Q3W + tislelizumab 200 mg IV Q3W. Eligible patients had unresectable advanced or metastatic cancer and an ECOG performance status of ≤1. Safety/tolerability profile (primary endpoint) was examined by monitoring adverse events (AEs); secondary endpoints included antitumor activity, assessed by RECIST v1.1, and the pharmacokinetic (PK) parameters of each antibody. Results: As of Oct 30, 2019, 15 patients were enrolled in Part A (450 mg, n=3; 900 mg, n=3; 1350 mg, n=6; 1800 mg, n=3) and 12 in Part B. Across both parts, patients were female (n=17/29; 63%); squamous cell carcinoma of either skin or head and neck (n=5) and ovarian cancer (n=4) were the most common tumor types. Thirteen patients (48%) had ≥2 lines of prior systemic therapy. The most common treatment-related AEs (TRAEs) were fatigue (N=5; Part A, n=3; Part B, n=2) and nausea (N=4; n=2 in A and B); the only grade ≥3 TRAE occurring in ≥1 patient was grade 3 maculo-papular rash (N=2; n=1 in A and B). One patient in Part B experienced a fatal AE (acute kidney injury) considered possibly related to study treatment. Of the 15 patients receiving BGB-A333 monotherapy in Part A, three (20%) achieved a confirmed complete response and two (13.3%) achieved a partial response (PR). Two of the 12 (16.7%) patients receiving combination therapy in Part B achieved a PR. The PK of BGB-A333 was comparable to a typical IgG1 antibody, and was similar as a single-agent or in combination with tislelizumab. The PK of tislelizumab was comparable with historical data. Conclusions: BGB-A333, alone or in combination with tislelizumab, was generally well tolerated and demonstrated antitumor activity in patients with advanced solid tumors. Based on these data, expansion cohorts have been initiated. Citation Format: Jayesh Desai, Mark Voskoboynik, Ben Markman, Sophia Frentzas, Paul Foster, Nageshwar Budha, Jing Song, Tarek Meniawy. Preliminary safety and efficacy data of BGB-A333, an anti-PD-L1 monoclonal antibody, alone and in combination with tislelizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT253.

The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularization process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (ie vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26, and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularized desmoplastic tissue columns. Finally, we examined the process of arterialization in lung metastases and found that they became arterialized when their diameter grew to exceed 5mm. In conclusion, our data show that lung metastases can vascularize by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti-angiogenic therapies. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. .

Background: The benefits of multidisciplinary working in oncology are now accepted as the norm and widely accepted as being pivotal to the delivery of optimal cancer care. Central to this are the multidisciplinary meetings (MDMs) and we have evaluated decision outcomes and financial costs of these. Methods: We reviewed the electronic patient records of 551 newly referred patients, discussed at 14 tumour site-specific MDMs for adult solid tumours and lymphoma (paediatric oncology and acute leukaemia were excluded) over a 1-month period, a total of 52 MDMs were studied. In addition, the records of a further 81 patients from 10 different MDMs were reviewed where the treating consultant had clearly recorded their opinion of how the patient should be managed and this was compared with the final MDM's consensus view. We also costed the MDMs utilising two different methodologies. Results: The mean age of the 551 patients in the study was 62 years. In all, 536 (97.3%) patients were treatment naive before MDM discussion and 15 (2.7%) had prior treatment. Median time to treatment after the MDM was 16 days. In 535 (97.1%) cases, the MDM discussions were clearly documented, 16 (2.9%) were not clearly documented. In total, 319 (57.9%) patients were discussed once, and 232 (42.1%) were re-discussed (one to six occasions). In 62 (12.7%) patients, there were delays in MDM discussion, 30 (48.4%) were related to radiology, 26 (41.9%) to histopathology and 6 (9.7%) a combination of both. Adherence to the MDM management plan decision occurred 503 times (91.3%) with 48 (8.7%) deviations. In the smaller cohort of 81 patients, the consultant management plan and MDM consensus was compatible 71 (87.6%) times. On four occasions, there were major alterations in management while six were minor. The cost per month of our MDMs ranged from £2192 to £10 050 (median £5136) with total cost of £80 850 per month and the cost per new patient discussed was £415. Conclusion: Adherence to MDM decisions by health-care professionals occurs in the majority of patients. MDMs are costly, which may have relevance in the currently challenged health-care financial environment. There is a need to improve MDM efficiency without losing the considerable benefits associated with regular MDMs.

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens.CT scans demonstrated progressing liver, lung and peritoneal metastases and MRI detected multiple intracerebral metastases.New brain metastases secondary to progressive endometrioid endometrial carcinoma.On the basis of her sensitivity to repeated platinum treatment she was treated with the oral poly(ADP)-ribose polymerase (PARP) 1 inhibitor olaparib as part of a phase I trial. Repeat MRI scan at week 10 of treatment showed a significant reduction in the size of the brain metastases without steroid treatment or radiotherapy and the patient reported subjective improvement in tumor-related symptoms. After 8 months of olaparib treatment the patient developed objective disease progression. The tumor biopsy was negative for somatic BRCA1 and BRCA2 mutations, but displayed loss of PTEN, which has been suggested to be another predictive marker for sensitivity to PARP inhibitors. The patient remained alive for 10 months after completing olaparib, having gone on to derive further clinical benefit from repeat exposure to platinum-based therapy.

Introduction: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment. Methods: Data of patients with MM treated at The Drug Development Unit between 2004 and 2010 were collected. The response rate (RR) and time to progression (TTP) for first-line therapy were compared to those of phase I trial therapy. Patients acted as their own controls for statistical analyses. Results: Sixty-five patients were treated in 31 phase I trials. First-line treatment included dacarbazine or temozolomide in 58 (89%) cases and interferon-α in 5 patients (8%) and cisplatin-based treatment in 2 patients (3%). There was no significant difference in either the RR (11 vs. 14%, p = 0.87) or TTP (90 vs. 53 days, p = 0.15) in patients treated with first-line treatment versus phase I treatment, respectively. Conclusion: Phase I clinical trials of molecularly targeted agents show clinical activity that is not dissimilar to that of treatment with existing chemotherapy and cytokine-based treatment.

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.

Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.

The purpose of this study is to: (1) examine whether vessel co-option is associated with a lack of response to anti-angiogenic therapy in advanced colorectal cancer patients, (2) identify whether inhibition of pathways associated with vessel co-option sensitizes to anti-angiogenic therapy in vivo. Sprouting angiogenesis is the process whereby new blood vessels are induced to sprout from existing vessels. The growth of metastatic tumors is considered to require sprouting angiogenesis. This hypothesis has driven the development and clinical application of vascular endothelial growth factor (VEGF) targeted agents, such as bevacizumab. However, responses to such agents in cancer patients, including metastatic colorectal cancer (CRC), are variable. It is not currently clear why this is the case and we have no way of selecting patients suitable for such therapies. Importantly, it is now evident that tumors can also utilize a number of putative ‘VEGF-independent’ angiogenesis mechanisms, the existence of which may limit the efficacy of VEGF-targeted therapy. One such mechanism is ‘vessel co-option,’ whereby tumors engulf existing local blood vessels as they invade into surrounding host tissue. Published studies have reported that this mechanism occurs in ∼28-30% of CRC liver metastases. Here we present data from a retrospective study of patients with CRC liver metatases that were treated with bevacizumab. We demonstrate that, in this patient cohort, the presence of vessel co-option in liver metastases was strongly associated with lack of response to bevacizumab. We also show that a similar result is observed in a mouse model of colorectal cancer liver metastasis. Interestingly, when we disable actin nucleation activity in colorectal cancer cells, vessel co-option is compromised and sensitivity to VEGF-targeted therapy is restored in vivo. These data demonstrate a potential role for vessel co-option as a negative predictive biomarker for anti-angiogenic therapy and also have consequences for the development of novel therapies for targeting tumor angiogenesis. Citation Format: Sophia Frentzas, Victoria L. Thompson, Peter B. Vermeulen, Shane Foo, Gina Brown, David Cunningham, Andrew R. Reynolds. Vessel co-option in colorectal cancer liver metastases mediates resistance to VEGF-targeted therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2014-2997

8564 Background: Dacarbazine (DTIC) and interferon (IFN) are two agents currently used in the treatment of malignant melanoma (MM). They have modest response rates (RR) and marginal improvement in time to progression (TTP) or survival. The recently published results of targeted agents such as ipilimumab and PLX4032 are encouraging, and will one day replace these agents as front line treatment. We hypothesize that clinical outcomes of patients (pts) with MM treated with targeted therapies on phase I clinical trials are equivalent to those seen with agents such as DTIC or IFN. Methods: We analyzed the outcomes of 65 patients with MM that had undergone treatment in our phase I clinical trials unit between 2005-2010. All pts had received at least one previous line of systemic treatment and acted as theis own controls. RR and TTP on previous treatment was compared to RR and TTP on the phase I trial. Differences were studied by a Chi-squared test and the log-rank test respectively. A Cox analysis was performed ...

2040 Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II. [Table: see text]