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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.

Purpose:BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.Patients and Methods:We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Results:Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.Conclusions:The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.

Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.

Purpose: Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs. Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease). Results: Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events. Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

TPS775 Background: While there have been tremendous advances in cancer treatment, critical challenges remain including limited ability of drugs to successfully reach the tumor, short half-life, and low retention rate on site. Local control of non-metastatic pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable anatomy, for whom enhanced local downsizing of disease could improve symptoms and increase overall survival (OS). Targeted therapies with reduced systemic toxicity are needed for the treatment of PDAC since current therapies have not provided meaningful advances. PTM-101 is a paclitaxel-impregnated absorbable product which is designed for direct, sustained release of the therapeutic agent at the tumor site. Preclinical animal studies demonstrate that PTM-101 results in enhanced drug levels in the tumor compared with comparable systemic paclitaxel dosing leading to tumor reduction, metastasis inhibition and survival benefit (Indolfi et al, 2016). Large animal (i.e. pigs) and human cadaver studies show that PTM-101 can successfully be deployed to the peritumoral pancreatic surface by a standard laparoscopic procedure. Further, large animal studies show no evidence of neutropenia, pancreatitis, severe fibrosis or scarring, or infection after placement of PTM-101. Methods: This Phase I trial will assess the addition of PTM-101 prior to mFOLFIRINOX in 6 subjects with newly diagnosed borderline resectable or locally advanced PDAC. The primary objective is to assess the safety, toxicity and feasibility of a single administration of PTM-101. It is hypothesized that PTM-101 will be readily implanted during diagnostic laparoscopy and will result in clinically meaningful delivery of paclitaxel directly towards the tumor area with good tolerance and minimal local systemic exposure of drug. Patients enrolled and treated on study will be monitored closely for local and systemic toxicities as well as preliminary signals of efficacy. Enrollment is in progress and 3 patients have been enrolled and completed prospective follow up at the time of abstract submission. Clinical trial information: ACTRN12621000881831 .

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.

2603 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia using an accelerated "3+3" design. Patients (pts) with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles. Treatment continuation beyond cycle 4 is possible if subject is deriving an ongoing clinic benefit. The safety, tolerability and preliminary efficacy data will be analyzed. Results: Between 29 Jul 2020 and 30 Dec 2021, a total of 20 patients with various advanced solid tumors were enrolled including 0.03 mg/kg (n = 3), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1.0 mg/kg (n = 8) and 3.0 mg/kg (n = 3). The median age was 60 years (range 33-75). Baseline ECOG scores were 0 (13 pts) and 1 (7 pts). 8 pts had received prior immunotherapy (anti-PD-1/PD-L1 or anti-PD-1+CTLA-4mAb). Dose escalation has been completed and only one dose-limiting toxicity relating to YH003 was observed at 1.0 mg/kg (grade 3 transaminitis). The maximum tolerated dose (MTD) was not reached. 13 (65%) pts experienced any grade treatment related adverse events (TRAEs). The most common (≥ 10%) TRAEs were infusion reaction, pyrexia, fatigue, nausea, diarrhea, transaminitis. Most TRAEs were grade 1 or 2. Only 3 (15.0%) pts experienced Grade 3 TRAEs including one each of neutropenia (YH003 0.3 mg/kg), transaminitis (YH003 1.0 mg/kg) and elevated lipase (Toripalimab 0.1 mg/kg). Only 2 pts have permanently discontinued treatment due to TRAEs including grade 3 transaminases increased and grade 2 hepatitis. There were no ≥grade 4 TRAEs and drug related serious adverse events (SAEs) were not observed. Among 14 pts assessable for response, the overall response rate (ORR) was 14.3% (2/14) and disease control rate (DCR) was 35.7% (5/14). One partial response (PR) occurred in a pt with anti-PD1/anti-CTLA4 refractory ocular melanoma with liver metastases (YH003 0.1 mg/kg) who continued on treatment for > 1 year. The other PR occurred in a pt with Non-Small Cell Lung Carcinoma (YH003 1.0 mg/kg) who continued on treatment for almost 9 months. Conclusions: YH003 was well tolerated up to 3.0 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors. Patients and Methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. Results: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. Conclusions: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

Importance Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participants The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Interventions Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Results Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. Conclusions and Relevance This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. Trial Registration ClinicalTrials.gov Identifier:NCT02923934

BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration numberNCT02407990.

Background The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non–small-cell lung cancer (NSCLC) is unclear. Materials and Methods We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. Results A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. Conclusions In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600–mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. Significance: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, p. 16. This article is highlighted in the In This Issue feature, p. 1

BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

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.

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

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.

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .

2033 Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Methods: This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Results: 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for high rates of clinical utility and timeliness. Clinicians sited collaboration and communication as critical to delivery of CGP. Conclusions: Pts undergoing CGP are generally satisfied, and derive value on its use beyond potential therapeutic benefit. Our results suggest that to improve test utility and delivery of CGP with value to pts and investing institution, focus must be placed on addressing the additional barriers to its wider implications including efforts to improve process efficiencies, clinician genomic literacy and decision-making support.

Delta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature. This phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy. Forty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6 + 6 design. Demcizumab (2.5, 5.0, and 7.5 mg/kg) was given once every 3 weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance). Initially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding. This study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5 mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.

Background: Sitravatinib is an investigative, orally bioavailable, spectrum-selective receptor tyrosine kinase (RTK) inhibitor with potential antitumor activity that has been shown to potently inhibit split kinase receptors (eg, VEGFR2, KIT) and TAM receptors (eg, AXL, MER). Inhibition of RTKs by sitravatinib may also modulate effects on the tumor microenvironment to overcome resistance to checkpoint inhibitors, including enhanced M1/suppressed M2 macrophage cytokine response, abrogated negative regulation of antitumor NK cell activity, and depleted regulatory T- and myeloid-derived suppressor cells with enhanced antitumor cytotoxic T-cell activity. Tislelizumab is an investigational, humanized IgG4 monoclonal antibody that has been shown to have high affinity and binding specificity for programmed cell death receptor-1 (PD-1). Combining an agent that has both immune modulatory and antitumor properties with an immunotherapeutic PD-1 checkpoint inhibitor could enhance the antitumor efficacy observed with either agent alone. The primary objective of this trial is to examine the safety and tolerability of sitravatinib combined with tislelizumab in patients with advanced solid tumors. Methods: Adult patients with histologically or cytologically confirmed, locally advanced or metastatic, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or ovarian cancer (OC) are enrolling in the open-label, multicenter, nonrandomized, phase 1b clinical trial. Entry criteria include Eastern Cooperative Oncology Group Performance Status ≤ 1 and adequate end-organ function. All patients will receive sitravatinib 120 mg PO QD in combination with tislelizumab 200 mg IV Q3W until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by the sponsor. Approximately 100 patients are expected to be enrolled in 5 cohorts (n=20 patients per cohort): Cohort A: anti-PD-(L)1 antibody-refractory/-resistant, metastatic, nonsquamous NSCLC; Cohort B: anti-PD-1(L)1 antibody-naive, metastatic, nonsquamous NSCLC; Cohort C: anti-PD-(L)1 antibody-refractory/-resistant, metastatic, clear cell RCC; Cohort D (China only): metastatic or advanced RCC without prior therapy; Cohort E: anti-PD-(L)1 antibody-naive, recurrent, platinum-resistant, epithelial OC. The primary endpoint is to assess safety and tolerability of the combination by monitoring adverse events (AEs) and serious AEs. Secondary endpoints include overall response rate, duration of response, disease control rate, progression-free survival assessed by RECIST version 1.1, and plasma concentrations and derived pharmacokinetic parameters of single- and repeated-dose sitravatinib. Seven patients have enrolled as of 3 January 2019 at the sites in Australia and China. Clinical trial registry number: NCT03666143 Citation Format: Jeffrey Goh, Ben Gao, Ben Markman, Hui Gan, Mark Voskoboynik, Yi-Long Wu, Jun Guo, Qing Zhou, Jun Zhao, Cheng Chen, Jingjun Qiu, Yingying Xu, Liu Yang, Michael Millward. A Phase Ib study to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity of sitravatinib in combination with tislelizumab in patients with advanced solid tumors [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 CT167.

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.[Table: see text]

358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

358Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolongi...

TPS3113Background: Programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Tislelizumab is a humanized I...

TPS548 Background: Neuroendocrine carcinomas (NEC WHO grade 3) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced gastrointestinal (GI) NECs. Extrapolating from small cell lung cancer data, standard practice is to treat GI-NECs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab-paclitaxel. NABNEC aims to establish if the carboplatin and nab-paclitaxel combination is an effective and tolerable treatment for advanced GI-NECs and to enhance our understanding of the biology and imaging characteristics of NECs. Methods: Design: Randomised, non-comparative, stratified, multicentre phase 2 trial. Primary endpoint (n=70): objective response rate (RR) by RECIST 1.1 at 6 months. Secondary endpoints: progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational endpoints include 1) blood and tissue biomarkers (prognostic and/or predictive) correlated with clinical endpoints including circulating tumour cells, mutation profile (whole exome sequencing), DNA methylation profile; 2) correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response and other clinical endpoints. Sample Size: 70 patient’s gives 80% power and 95% confidence to rule out a 30% RR in favour of a clinically relevant RR of 50% at 6 months. Population: Adults with advanced or metastatic non-resectable GI-NEC (includes small cell and large cell NEC). Treatment: Randomisation 2:1 to Arm A IV nab-paclitaxel 100 mg/m2 on Day (D) 1 weekly and IV carboplatin AUC=5 on D1, 3 weekly; and Arm B IV etoposide 100mg/m2 on D1-3, and IV carboplatin AUC=5 on D1, 3 weekly to continue until disease progression or unacceptable toxicity. Assessments: 68Ga Octreotate PET at baseline, CT scan at baseline and every 9 weeks, FDG PET at baseline, 9 weeks then every 18 weeks and QOL questionnaires every 9 weeks until disease progression. NABNEC is enrolling patients at 12/20 planned study sites in Australia and New Zealand. ANZCTR #. Clinical trial information: 12616000958482.

Introduction: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway, which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown using an in vivo tumorigenicity limiting dilution assay to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels, resulting in an antiangiogenic effect. Data from a phase 1b study of carboplatin (C), pemetrexed (P), and demcizumab (D) in patients with 1st-line metastatic non-squamous NSCLC led to this double-blind randomized 3-arm placebo (Pl)-controlled phase 2 study. Methods: Patients with non-squamous NSCLC were randomized (1:1:1) to 1st-line therapy with either Arm 1 -CPPl, Arm 2 -CPD with a single 70-day truncated course of demcizumab or Arm 3 - CPD with two 70-day truncated courses of demcizumab (second course starting on Day 168). CP were given at usual dose and schedule; P/D was given IV on days 1 and 15 in cycles 1-3 and 7-9. The primary endpoint was response rate and secondary endpoints included progression-free survival, survival, safety, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles, and tumor cells. The primary study analyses compared CPPl to the two pooled CPD arms. Results: 82 patients were randomized and all 82 were treated. The median age was 61, the male/female ratio was 40/42, 80 pts had adenocarcinoma, 0 pts harbored EGFR mutation or ALK rearrangement, and 15 were KRAS mutated. The response/clinical benefit rates were 52%/92% and 28%/79% in the CPPl and pooled CPD arms, respectively (response p value = 0.04). The median progression-free survival (PFS) was 8.7 months (95% CI: 5.4-12.5) in the CPPl arm and 5.5 months (95% CI: 4.1-6.9) in the pooled CPD arms (HR = 2.3; 95%CI: 1.1-4.8). The interim median overall survival (OS) for the CPPl and pooled CPD arms was not reached (95% CI: 16.0—NR) and 15.5 months (95% CI: 8.3-NR) (HR= 2.4; 95% CI: 0.94-6.1), respectively. CPD was generally well tolerated with nausea, fatigue, constipation, anemia, and hypertension being the most common reported toxicities. The incidences of the Grade 3 or greater toxicities of special interest with demcizumab therapy were hypertension (8% vs 25%), pulmonary hypertension (0% vs 0%), heart failure (0% vs. 0%), and bleeding (0% vs. 3.4%) in the CPPl and pooled CPD arms, respectively. Conclusions: The addition of either 1 or 2 truncated courses of demcizumab to 1st-line carboplatin and pemetrexed did not improve the efficacy compared to CPPl in patients with 1st-line metastatic NSCLC. CPD therapy was generally well tolerated. Citation Format: Brett Hughes, Andrew Dean, Ben Markman, Luke Dreisbach, Mariano Provencio, Libero Ciuffreda, Rachel Dear, Peter Graze, Alforia Nadal, Baerin Houghton, Teresa Moran, Rachel Roberts, Grace Dy, Taus Alvaro, Alex Martinez Marti, Rainer Brachmann, Robert Stagg, Ramaswamy Govindan. DENALI: a 3-arm double-blind randomized phase 2 study of carboplatin, pemetrexed, and placebo (CPP) versus carboplatin, pemetrexed, and either 1 or 2 truncated courses of demcizumab (CPD) in patients with non-squamous non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A084.

3004 Background: Adenosine production in the tumor leads to immunosuppression through A2aR on infiltrating immune cells. CPI-444 is an oral A2aR antagonist with single agent(SA) anti-tumor activity in pre-clinical models. This phase 1/1b clinical trial uses a 2-step adaptive design to evaluate CPI-444 as a SA and in combination (combo) with the anti-PDL1 antibody, atezolizumab (atezo). We report results of RCC and NSCLC cohorts. Methods: Primary objectives: safety, efficacy and to identify optimal dose/schedule. Step 1 utilized 3 SA and 1 combo cohort to select dose/schedule. Step 2 included disease-specific expansion cohorts including RCC and NSCLC. Eligible pts had selected advanced cancers and failed standard therapies including checkpoint inhibitors. Results: 34 pts have enrolled and 25 pts were evaluable for response (Table 1). Median prior regimens: 3 (range,1-5) and most pts were resistant/refractory to anti PD1/PDL1 therapy (R/R). Most common AEs were Gr 1 nausea (n = 3) and pyrexia (n = 3); Gr 3 tachycardia was the only possibly related SAE. The selected Step 2 doses were CPI-444 100mg BID as a SA and in combo with atezo 840mg IV q2 weeks. The disease control rate (DCR, CR+PR+SD; duration 2 mo to > 8 mo) for pts with RCC and NSCLC cohorts were 86% and 50%, (100% and 43% for R/R pts), respectively. DCRs were similar in the SA and combo cohorts. Of 7 evaluable RCC pts, 1 pt has an ongoing PR (SA cohort, > 4 mo) and 5 have ongoing SD, duration 3 mo to > 8 mo (2 SA, 3 combo). Biopsy of the PR pt showed no detectable tumor and infiltration with CD8+ lymphocytes. In 18 evaluable NSCLC pts, 1 PR (PDL1 negative pt) and 8 SD were seen. PRs and SDs were seen in R/R pts and in PDL1 negative pts in both diseases. Conclusions: CPI-444 is well tolerated and shows anti-tumor activity in RCC and NSCLC pts as a SA and in combo. Pts who are R/R to anti PD1/PDL1 therapy and who are PDL1 negative can also benefit. Clinical trial information: NCT02655822. [Table: see text]

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

3557 Background: Pts with BRAFm mCRC have an exceedingly poor prognosis. Unlike melanoma, BRAF inhibitor monotherapy has limited activity in BRAFm mCRC. Preclinically, BRAF inhibition results in rapid feedback activation of EGFR and ongoing tumor proliferation, which can be readily overcome by combining BRAF and EGFR inhibition. EViCT examined the safety and efficacy of combining two oral agents targeting BRAF with Vemurafenib (Vem) and EGFR with Erlotinib (Erl), in BRAFm mCRC pts. Herein, we report safety and preliminary efficacy data. Methods: EViCT had 2 parts: a Phase I dose escalation of Erl (cohort 1: 100mg qd; cohort 2: 150mg qd) together with Vem 960mg bd, to determine the maximum tolerated dose (MTD). The Phase II component involved dose expansion at MTD using a Simon 2-stage design to treat 9 pts in stage 1 and 15 pts in stage 2. Cycles were 28 days. Eligible pts had ECOG < 1, < 2 lines of systemic therapy for metastatic disease, and acceptable organ function. Staging CT scans were performed every 2 cycles, response assessed using RECIST 1.1. Primary endoint was clinical benefit rate (CR, PR and SD). A number of pharmacodynamics correlates were assessed including serial ctDNA, FDG-PET and optional tumour biopsies. Pts were treated until disease progression or toxicity requiring discontinuation. Results: Between Jul-2014 and Oct-2016, 30 BRAFm mCRC pts were enrolled. The Phase I Lead-in enrolled 4 pts in cohort 1 and 7 pts in cohort 2. There was 1 DLT (grade 3 hand-foot syndrome) in cohort 2. MTD/Recommended Phase 2 Dose was Erl 150mg qd and Vem 960mg bd, the full dose for each agent. The Phase II expansion enrolled 19 pts. Overall, 23 pts are evaluable for this interim analysis. Median age was 61 years, 11 (48%) pts were male. Most pts had 1(50%) or 2 (41%) lines of prior treatment. Overall response rate was 39% (95%CI = [20%, 61%]), including 5 (22%) confirmed PR, 4 (17%) unconfirmed PR, 3 (13%) stable disease and 11 (48%) progressive disease. Conclusions: Vem and Erl can both be given safely at their individual full doses when used in combination. In BRAFm mCRC, this combination resulted in clear clinical activity. Clinical trial information: ACTRN12614000486628.

Purpose: Aurora kinases are associated with high proliferation, poor prognosis, and therapeutic resistance in several human tumor types. AMG 900 is an investigational, oral, highly potent, selective, pan-aurora kinase inhibitor. We evaluated the safety, tolerability, pharmacokinetics, and clinical activity of AMG 900 in pts with advanced solid tumors (NCT00858377). Methods: In the dose escalation phase, eligible pts were ? 18 years old, with advanced solid tumors that were refractory to standard treatment, measurable disease per RECIST, ECOG ? 2, and life expectancy > 3 months. In the dose expansion phase, eligible pts had taxane- and platinum-resistant epithelial ovarian cancer (OC), taxane-resistant triple-negative breast cancer (TNBC), or castration-resistant and taxane- or cisplatin-etoposide-resistant stage IV prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at doses of 1 to 50 mg/day (dose escalation), and at the maximum tolerated dose of 40 mg/day with G-CSF support (dose-expansion). The primary objective was safety. Tumor response was determined per RECIST for all pts and additionally by GCIG CA-125 for pts with OC. Results: Treatment-related AEs were reported by 98 of 105 pts (93.3%). Myelotoxicities were the most common grade ? 3 treatment-related AEs. In the dose escalation (N = 50), 1 pt with OC (30-mg cohort) had a partial response (PR) by RECIST and GCIG. In the dose expansion (N = 55), 3 of 29 pts (10.3%) with OC had a PR by RECIST, and 7 of 29 pts (24.1%) had a PR by GCIG; 72.4% of pts with OC had stable disease (SD), and the disease control rate (PR + SD) was 82.8%. Median (95% CI) duration of response in pts with OC per RECIST was 24.1 (16.1, 34.1) weeks, and median (80% CI) PFS was 31.1 (23.6, 34.1) weeks. See table for additional results. Conclusions: AMG 900 had manageable toxicity with G-CSF support and promising single-agent activity in pts with heavily pretreated taxane- and platinum-resistant OC. Patient demographics, prior therapy, AEs, and best tumor responseDose escalation - advanced solid tumors (N = 50)OC (N = 29)TNBC (N = 14)CRPC (N = 12)Overall (N = 105)Male, n (%)21 (42.0)0 (0.0)0 (0.0)12 (100.0)33 (31.4)Female, n (%)29 (58.0)29 (100.0)14 (100.0)0 (0.0)72 (68.6)White or Caucasian, n (%)35 (70.0)23 (79.3)12 (85.7)11 (91.7)81 (77.1)Age, mean (SD), years56.5 (11.6)61.1 (11.4)54.6 (11.4)67.7 (8.0)58.8 (11.7)Prior lines of anti-cancer therapy, mean (SD)4.9 (3.2)5.3 (4.3)5.8 (3.0)4.5 (2.6)5.1 (3.4)Treatment-related AEs by preferred term (any grade), n (%)Fatigue21 (42.0)15 (51.7)6 (42.9)6 (50.0)48 (45.7)Neutropenia24 (48.0)14 (48.3)4 (28.6)4 (33.3)46 (43.8)Anemia15 (30.0)16 (55.2)6 (42.9)3 (25.0)40 (38.1)Nausea18 (36.0)10 (34.5)5 (35.7)5 (41.7)38 (36.2)Thrombocytopenia15 (30.0)11 (37.9)1 (7.1)2 (16.7)29 (27.6)Diarrhea14 (28.0)10 (34.5)1 (7.1)2 (16.7)27 (25.7)Alopecia13 (26.0)11 (37.9)1 (7.1)1 (8.3)26 (24.8)Decreased appetite11 (22.0)7 (24.1)2 (14.3)4 (33.3)24 (22.9)Vomiting9 (18.0)7 (24.1)5 (35.7)3 (25.0)24 (22.9)Leukopenia19 (38.0)3 (10.3)0 (0.0)1 (8.3)23 (21.9)Best tumor response - RECIST 1.1 criteria (central read), n (%)Complete response0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Partial response1 (2.0)3 (10.3)0 (0.0)0 (0.0)4 (3.8)Stable disease29 (58.0)21 (72.4)7 (50.0)9 (75.0)66 (62.9)Progressive disease12 (24.0)3 (10.3)4 (28.6)1 (8.3)20 (19.0)Unable to evaluate8 (16.0)2 (6.9)3 (21.4)2 (16.7)15 (14.3) Citation Format: Montasser Shaheen, Ben Markman, Michael Carducci, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar Goodman, Erick Gamelin, Vincent Chow, Gloria Juan, Erik Rasmussen, Gregory R. Friberg, Florian D. Vogl, Jayesh Desai. Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT045.

Introduction. Nanoparticles (NPs) provide many advantages over small molecule drugs, such as greater solubility, increased duration of exposure, and enhanced tumor delivery, which may lead to improved antitumor activity and reduced toxicity. PK of NPs is complex as the PK is dependent upon the carrier and not the therapeutic entity until the active-drug payload is released. It is important to evaluate the PK of the inactive carrier-associated drug and active released drug. CRLX301 is an investigational NDC containing the payload docetaxel covalently conjugated to a cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that is 10-30 nm in diameter. This study evaluated CRLX301 PK in a phase 1 study in patients with refractory solid tumors. Methods. CRLX301 was administered at 7.5, 15, 30, 60 and 75 mg/m2 IV over 1 h every 21 days. The doses of CRLX301 represent mg of docetaxel. PK studies were performed on days 1-21 of cycles 1, 3 and 6. Plasma samples were processed to measure total (conjugated + released) and released docetaxel. PK parameters area under conc-time curve (AUC0-inf) and volume of distribution (Vd) were estimated. Results were compared to a prior PK study of Taxotere® at 75 mg/m2 IV x 1 every 21 days (Zamboni, et al. CCP 2011). Results. Plasma PK of total and released docetaxel were linear after CRLX301 from 7.5 to 75 mg/m2. CRLX301 plasma PK was similar on cycles 1, 3 and 6 suggesting no accumulation after multiple doses. For CRLX301 at 75 mg/m2 on cycle 1, mean ± SD plasma AUC0-inf of total and released docetaxel were 321,355 ± 9,831 and 3,015 ± 904 ng/mL•h, respectively. Mean ± SD% of docetaxel released from CRLX301 into the plasma was 1.0 ± 0.2%. Exposures of total and released docetaxel in plasma after administration of CRLX301 (7 days) were prolonged compared with Taxotere (24 h). Total docetaxel plasma AUC after CRLX301 at 75 mg/m2 was ∼63-fold greater than for Taxotere. The Vd of CRLX301 total docetaxel and Taxotere were 2.1 ± 0.1 and 74-99 L/m2, respectively. The overall plasma AUC of released docetaxel after CRLX301 (3,015 ± 904 ng/mL•h) was similar to Taxotere (2,000-10,000 ng/mL•h); however, most of the released docetaxel AUC after CRLX301 is associated with exposures at 24-168 h. Early exposures of released docetaxel in plasma after CRLX301 (Cmax = 242 ± 44 ng/mL) were ∼25-fold lower than Taxotere (Cmax = 5,000-8,000 ng/mL). Conclusions. CRLX301 exhibits PK advantages over Taxotere such as higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. CRLX301 exhibits low inter- and intra-patient PK variability. It is anticipated that this unique PK profile of CRLX301 may improve efficacy as well as the tolerability profile when compared to Taxotere. The study continues with dose escalation to further explore the safety, efficacy and PK of CRLX301. Citation Format: William C. Zamboni, Ben Markman, Paul de Souza, E. Claire Dees, Tara Gangadhar, Scott Eliasof, Curran Murphy, Adrian Senderowicz, Hongwei Wang. Pharmacokinetics (PK) of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing the payload docetaxel, in patients with refractory solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2047.

3066Background: BGB-A317 is a humanized IgG4 anti-PD-1 mAb with high specificity and affinity (KD = 0.15 nM) for PD-1. It blocks PD-L1 and PD-L2 binding, and inhibits PD-1-mediated negative signali...

2526Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), di...

669 Background: Imgatuzumab, a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second-line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2-weekly) or cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 IV q-weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run-in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus 6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second-line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC. Clinical trial information: NCT01326000.

2544 Background: Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhib...

Major advances with new molecular agents have translated in the last decade in a survival benefit for those patients with advanced stage cancer and in improved cure rates for those treated in the adjuvant setting. Some of these targeted agents have been approved by the regulatory agencies and are now used in daily clinical practice. Globally, this group of drugs includes monoclonal antibodies and tyrosine and non-tyrosine kinase inhibitors. In general, targeted molecular therapies have a good toxicity profile. Nevertheless, new types of toxicities have been reported with the use of these new agents. The spectrum of adverse events is broad and includes gastrointestinal toxic effects; these require careful clinical management. Diarrhea and hepatotoxicity, the most common adverse events experienced with these treatments, can frequently lead to treatment discontinuation and consequently decreased cancer control. Diarrhea. Diarrhea is one of the most frequent causes of treatment discontinuation with molecular-targeted cancer drugs and it represents a common dose-limiting toxicity. The incidence of drug-induced diarrhea observed with targeted therapies is summarized in the attached table. Diarrhea induced by EGFR tyrosine kinase inhibitors can be easily managed easily by reducing the dose; treatment very rarely has to be ceased entirely. Loperamide is a useful treatment that can decrease intestinal motility, and the guidelines used for irinotecan-related diarrhea can be very well applied. Hepatotoxicity. Hepatotoxicity is a common cause of discontinuation of treatment for some of the tyrosine kinase inhibitors, this being especially the case of imatinib (see attached table). Moreover there are instances of agents whose clinical development has been curtailed due to this particular toxicity. Hepatotoxicity may comprise different biochemical scenarios including cytolysis, characterized by transaminase increase, and cholostasis, typified by increases in bilirubin, alkaline phosphatase and/or gammaglutamiltranspeptidase. The management of hepatotoxicity must be adapted to each patient according to its severity and impact on the disease. Nevertheless, in all cases, other causes of liver pathology need to be rule out, including progression of the malignancy in this organ. In current practice, treatment with tyrosine kinase inhibitors is interrupted when patients exhibit grade 3 or 4 transaminase elevation. When abnormalities return to grade 1 or less, the treatment can be reintroduced at a reduced dose. If the liver toxic effects do not recur within 6–12 weeks, the initial dose may be re-escalated, accompanied by close monitoring by use of liver function tests. For recurrent grade 3 toxicity, guidelines recommend discontinuation of the drug. If grade 2 transaminase increase is observed, the treatment could be continued with caution and a close follow-up and dose reduction may be considered. A rise in bilirubin levels induced by tyrosine kinase inhibitors can be seen quite frequently, but the drug should only be discontinued in case of grade 3 toxicity. As a general principle, patients taking this class of drugs should avoid alcohol consumption as well as other potential hepatotoxic drugs whenever possible. Phase I studies are evaluating the recommended doses of most of these compounds in patients that have mild to moderate liver function impairment. Intestinal bleeding and perforation. Several cases of gastrointestinal perforation have been reported in patients treated with bevacizumab and chemotherapy. Although they have been initially described in patients with metastatic colorectal cancer, the relative incidence seems to be extremely low. The Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry reported gastrointestinal perforation in 1.7% of 1,987 patients with metastatic colorectal cancer. The clinical pattern and severity of perforation seen was variable, ranging from asymptomatic to fatal. Most gastrointestinal perforations occurred within the first 3 months after initiation of treatment. The incidence of perforations was greatest in cases where the primary tumor remained in situ, an endoscopic procedure had recently been performed and those with prior radiotherapy. In some trials conducted in patients with advanced ovarian cancer the incidence of this side effect has been shown to be higher. Elevation of pancreatic enzymes. Some tyrosine kinase inhibitors can rarely induce hyperlipasemia and hyperamylasemia. These abnormalities have been described with sorafenib and sunitinib. In most of the cases this toxicity only deals with biochemical alteration without any clinical effects and can be managed in most cases with close follow-up without discontinuation of the drug. Conclusions: Targeted therapies have emerged as a new cancer treatment strategy with several currently approved specific indications. Novel targeted agents aim to interfere with specific critical properties of the malignant cells with limited impact on the non-neoplastic host cells thereby increasing the therapeutic index in comparison to conventional cytotoxic agents. However, most targeted agents have the best therapeutic index when they are used in combination with standard chemotherapy. Therefore the specific toxicities related to targeted agents have to be analyzed in combination with the toxicities related to cytotoxic chemotherapy. The most frequent digestive system toxicities include diarrhea and hepatotoxicity, although some patients may present with nausea/vomiting, pancreatic toxicity or very rarely gastrointestinal perforation. Multitargeted agents show a more heterogeneous toxicity profile depending on the different proteins targeted for inhibition. The information emerging from prospective randomized studies is increasingly establishing the toxicity profile related to the administration of these targeted agents. Toxicities Drug Diarrhea, all grades (grades 3–4) (%) Hepatotoxicity, all grades (grades 3–4) (%) Gefitinib/Erlotinib/Lapatinib 40–60 (3–13) 11 (2) Sorafenib/Sunitinib 33–53 (5–8) 1–52 (1–3) Cetuximab/Panitumumab 20 (2) - Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN03-04.