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Purpose To report 3 cases of reversible epitheliopathy induced by A166—a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. Methods Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. Results After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. Conclusion A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib–drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. NCT02124148 (date of registration 28 April 2014).

BackgroundATRC-101 is an engineered version of an immunoglobulin G1 antibody that was discovered in a patient with non-small cell lung cancer (NSCLC) experiencing stable disease while being treated with anti–programmed death-1 therapy. ATRC-101 targets a tumor-specific ribonucleoprotein complex containing polyadenylate binding protein-1, which has been found to be present in the majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples tested. Target immunoreactivity and single-agent activity have been observed in mouse models. Preclinical data suggest that ATRC-101 stimulates both innate and adaptive immune activity against tumors.MethodsATRC-101-A01 is a phase 1b trial (3+3 dose escalation with expansion cohorts) in patients with solid tumors treated with ATRC-101 monotherapy every 2 or 3 weeks (Q2W or Q3W), or ATRC-101 in combination with pembrolizumab, until unacceptable toxicity or disease progression at doses of 0.3–30 mg/kg, pending dose-limiting toxicities. The primary objective is safety and secondary objectives are to characterize the pharmacokinetic profile, immunogenicity, and anti-tumor activity of ATRC-101, and to determine the recommended dose for expansion. Pharmacodynamic studies will also be performed to evaluate changes from baseline in specific immune cell populations and cytokine levels in blood and tumors. Results from the ATRC-101 0.3–30 mg/kg monotherapy Q3W cohorts are presented in this abstract (data cutoff: July 16, 2021).ResultsTwenty-four participants with solid tumors (13 colorectal, 5 ovarian, 3 breast, 2 NSCLC, 1 acral melanoma) aged 27–75 years with a median 5 lines of prior therapy were treated Q3W in five dose cohorts. No dose-limiting toxicities were observed. Eight participants (33%) experienced grade ≥3 treatment-emergent adverse events. The maximum serum concentration of ATRC-101 and treatment exposure appeared to be dose proportional. Stable disease was observed in eight patients and best response per RECIST v1.1 was associated with expression of the ATRC-101 target. Multiple biomarkers, such as treatment-associated changes in the composition of CD3+, CD4+, and CD8+ T cells in the blood, and serum cytokines/chemokines, including those predicted to activate antigen-presentation pathways, support the proposed mechanism of action of ATRC-101 and will be presented.ConclusionsThese first-in-human data suggest a manageable safety profile for ATRC-101 Q3W, with no dose-limiting toxicities observed. Pharmacokinetics appear to be dose proportional. Enrollment in the Q2W monotherapy dose-escalation cohort and at the 30 mg/kg dose level Q3W is continuing. Trial sites have been activated to test ATRC-101 in combination with pembrolizumab, and combination with chemotherapy is also planned.Trial RegistrationTrial Registration: NCT04244552Ethics ApprovalThis study was approved by the institutional review board or ethics committee as required for each participating site.

BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200-1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received ≥2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in ≥10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for ≥24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (±8%) at doses ≥ 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored ≥1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, -3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270). Citation Format: Philippe Aftimos, Patrick Neven, Mark Pegram, Catharina Willemien Menke-van der Houven van Oordt, E. Claire Dees, Carolien Schröder, Agnes Jager, Iurie Bulat, Linnea Chap, Marina Maglakelidze, Erika Hamilton, Massimo Cristofanilli, Susanna Ulahannan, Jorianne Boers, Ramsha Iqbal, Adrian Crijanovschi, Curt D Wolfgang, Wenli Tao, Christina Sipes, Rajesh Malik, Sarika Jain. Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-04.

Purpose:TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity.Patients and Methods:This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti–PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability.Results:Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab.Conclusions:Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.

Background Tebotelimab, also known as MGD013, is an investigational, Fc bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells.1 Margetuximab, an investigational Fc-engineered anti-HER2 monoclonal antibody, has similar HER2 binding and antiproliferative properties to trastuzumab, but with enhanced Fc-mediated effector function. In vitro studies have demonstrated upregulation of LAG-3/PD-L1 expression on immune cells after margetuximab exposure, along with enhanced lytic activity of immune cells primed by margetuximab in the presence of tebotelimab. Methods This study characterizes safety, PK/PD, and preliminary antitumor activity of tebotelimab plus margetuximab in patients with advanced HER2+ malignancies. A one-step 3+3 dose escalation phase of tebotelimab (300 and 600 mg) combined with margetuximab 15 mg/kg, both every 3 weeks, was followed by cohort expansion of patients with breast, gastric or gastroesophageal, and other HER2+ tumors. Results At data-cutoff, 31 patients (2.0 median lines of prior therapy; 64.5% with prior HER2-directed therapy) were treated. Median duration of treatment is 10.3 weeks with 17 patients remaining on treatment. No maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) occurred in 23/31 (74.2%) patients, most commonly diarrhea (n=6), nausea, ALT increased (n=5, each), AST increased, and myalgia (n=4, each). The rate of Grade 3 TRAEs was 19.4%, with no Grade 4–5 TRAEs observed. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies and were manageable with supportive treatment. Among 20 response-evaluable patients (i.e., received on-treatment scan), 8 objective responses (6 confirmed) per RECIST v1.1 have been observed, including a confirmed complete response (cholangiocarcinoma) and 7 partial responses (breast [2], microsatellite stable colorectal cancer [2], esophageal adenocarcinoma [1], ovarian cancer [1], and microsatellite stable gastroesophageal junction carcinoma).1 Immunohistochemistry (IHC) of available baseline tumor specimens (n=17) demonstrated low PD-L1 expression with combined positive scores of either 0 (n=16) or 1 (n=1, colorectal cancer). Investigations into other potential correlative biomarkers, including LAG-3 and PD-1 by IHC and gene expression profiling by NanoString, remain ongoing. Conclusions Tebotelimab in combination with margetuximab has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity, with a preliminary overall response rate (ORR) of 40% (8/20) [including unconfirmed responses] among late-line patients with various advanced HER2+ malignancies. Trial Registration NCT03219268 Ethics Approval This study was approved by each Institution’s Ethics Board prior to enrollment of subjects. Reference Luke J, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD–1 and LAG–3, in patients with unresectable or metastatic neoplasms. J Clin Oncol38: 2020 (suppl; abstr 3004).

Background VT1021, a cyclic pentapeptide, reprograms myeloid-derived suppressor cells (MDSCs) and induces the production of thrombospondin-1 (Tsp-1) in the tumor microenvironment (TME). Tsp-1, via binding to CD36 and CD47, induces apoptosis in tumor and endothelial cells, blocks the ‘do-not-eat-me’ signal, increases the M1:M2 macrophage ratio and activates cytotoxic T lymphocytes (CTLs). Preclinical studies showed robust anti-tumor activities of VT1021 in multiple animal models. Methods This is a first-in-human, Ph 1/2, open-label, multicenter dose escalation and expansion study in advanced solid tumors. The primary objectives are to determine the recommended Phase 2 dose (RP2D) and characterize the safety and tolerability of VT1021. Secondary objectives are to characterize the adverse event (AE) profile, evaluate pharmacokinetics (PK), and describe preliminary efficacy. Exploratory objectives include evaluation of pharmacodynamic effects of VT1021 in tumor, TME, and peripheral blood. The expansion phase focuses on ovarian, pancreatic, triple negative breast cancer, glioblastoma, and a basket cohort with high CD36-expressing tumors. Results In the escalation phase, 46 subjects received between 0.5–15.6 mg/kg of VT1021 by IV infusion twice weekly. VT1021 has been well tolerated through all doses tested. One patient dosed at 1.0 mg/kg developed a grade 3 infusion reaction and 3 patients dosed at 1.0, 6.6, and 8.8 mg/kg respectively developed grade 2 infusion reactions. Other drug related AEs included grade 1–2 fatigue (n=7), nausea (n=4), constipation (n=2), increased aspartate aminotransferase (n=2) and blood bilirubin (n=2), hypomagnesaemia (n=2), and dizziness (n=2). Dose proportionality was observed in PK analysis. Among 28 evaluable subjects, one partial response (thymoma, 372+ days on treatment) and 11 stable disease (SD) in 9 different solid tumors have been observed for a disease control rate of 43%. Seven of eleven SDs had high CD36 AND high CD47 expression with an average duration of 162 days on study. VT1021 induced Tsp-1 production in peripheral blood cells at most dose levels. In addition, on-study biopsies exhibited increased Tsp-1 expression in the TME by activation of p53 in MDSCs, increased CTL infiltration, increased M1:M2 macrophage ratio, and reduced regulatory T cells in the TME. The RP2D was declared to be 11.8 mg/kg and enrollment in tumor-specific expansions is on-going. Conclusions Through all doses tested, VT1021 was safe and well tolerated, with dose proportional PK properties. In addition, VT1021 has demonstrated activities in reprogramming the TME which resulted in a high disease control rate in subjects with tumors expressing both high CD36 and high CD47. Trial Registration NCT03364400 Ethics Approval The study was approved by Northwestern University Medical School institutional review board (IRB), approval number 00000418, Horizon Oncology Center IRB, approval number 00001313, South Texas Accelerated Research Therapeutic IRB, approval number 00003657, University of Oklahoma Health Sciences Center IRB, approval number 00006075, Cleveland Clinic IRB, approval number 00000536, Florida Cancer Specialists IRB, approval number 00006075, Case Western IRB, approval number 00000536, Beth Israel Deaconess Hospital and Dana Farber Cancer Institute IRB, approval number 00000753 and MD Anderson IRB, approval number 00006023.

Purpose:Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor.Patients and Methods:Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient–derived xenograft (PDX) mouse models. In the phase Ib trial, following dose escalation, the initial expansion arm (E1, solid tumors) explored prexasertib 105 mg/m2 intravenously every 14 days + samotolisib 200 mg orally twice daily. Subsequent expansion arms evaluated samotolisib 150 mg twice daily in patients carrying PIK3CA mutations (E2, solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed.Results:Prexasertib + samotolisib inhibited cell proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib + samotolisib exhibited synergistic or additive effects in 30 of 38 PDX single-mouse (“n = 1”) models, and provided rationale for clinical evaluation. In the phase Ib study, 53 patients were enrolled (escalation, n = 13; E1, n = 9; E2, n = 15; and E3, n = 16). No dose-limiting toxicities (DLT) were observed during escalation; however, DLT-equivalent toxicities were observed in E1, leading to samotolisib dose reduction (150 mg twice daily) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 (PIK3CA) and 25% for E3 (TNBC).Conclusions:Prexasertib + samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.

BackgroundOne barrier to treating pancreatic cancer is the immunosuppressive tumor microenvironment (TME). VT1021 is a cyclic peptide derived from prosaposin and stimulates thrombospondin-1 (Tsp-1) production in myeloid derived suppressor cells. Tsp-1 binds to CD36 on macrophages to convert M2 macrophages to anti-tumorigenic M1 macrophages; on tumor cells to induce apoptosis; and increases the CD8+/Treg ratio. Tsp-1 also binds to CD47 on tumor cells to block the ”do not eat me signal”. In a recently completed phase I/II clinical study (NCT03364400), VT1021 had no major adverse events and a predictable pharmacokinetic profile.MethodsTo evaluate potential predictive biomarkers of VT1021, CD36/CD47 levels were analyzed on pre-treatment biopsy samples and on-study tumor biopsies collected during the treatment using immunohistochemistry (IHC). Samples were stained and scored by software-based image analysis and manual review (figure 1). Induction of Tsp-1 in circulating peripheral blood mononuclear cells (PBMCs) by ELISA was correlated with Tsp-1 induction in on-study biopsy samples via IHC, and with clinical responses. To be considered ”evaluable”, subjects completed ≥1 cycle of VT1021 treatment and tumor imaging during cycle 2.ResultsIn the pancreatic cancer expansion study, 21 of 32 enrolled subjects (66%) had dual high (DH) expression of CD36/CD47. There were 5 subjects with stable diseases among 15 evaluable subjects with disease control rate of 33%. Of the 13 subjects with measurable disease, all 5 subjects with reduction of tumor burden were DH CD36/CD47 and remained on study for an average of 105 days. Moreover, paired tumor biopsies revealed increased Tsp-1 expression, CTL infiltration and M1:M2 ratio among subjects that obtained disease control with DH baseline CD36/CD47 expression.To identify other solid tumor indications that could benefit from VT1021 treatment based on CD36/CD47 expression, commercially available tumor tissue microarrays from 16 different indications were evaluated. Several indications demonstrated high percentage of DH CD36/CD47, including gastric (59%), head and neck (57%), and pancreatic cancers (56%).Abstract 369 Figure 1Expression intensities of CD36/CD47 in subjects with pancreatic cancerConclusionsPancreatic cancer subjects who were DH for CD36/CD47 were more likely to have a reduction in tumor burden and stay on study longer than non-DH subjects. Increased Tsp-1 induction in circulating PBMCs and in the TME was confirmed. Remodeling of the TME by VT1021 to be more immune sensitive via CTL and M1 accumulation was demonstrated. Based on these findings, the DH expression of CD36/CD47 could be a useful predictive biomarker to stratify subjects for inclusion in future trials in pancreatic cancer, and in other solid tumor indications.Trial RegistrationTrial RegistrationNCT03364400

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. Preclinical data have demonstrated that RMC-4630 can shrink tumors carrying certain mutations in the RAS pathway such as KRASG12C, NF1LOF, and BRAFClass3. Longitudinal circulating tumor DNA (ctDNA) was isolated from blood using GuardantOMNI in 80 patients with relapsed/refractory solid tumors in the phase 1 dose-escalation trial of RMC-4630 (NCT03634982) to characterize and confirm RAS pathway mutations and to evaluate molecular responses in patients receiving RMC-4630 monotherapy. Safety, PK and efficacy findings from this study are reported in a separate abstract. 78 of 80 patients had baseline somatic mutations detected in plasma, of which 60 were either KRASG12X, NF1LOF, or BRAFClass3; 48 of these 60 patients also had on-treatment ctDNA assessments and these patients constitute the population reported here. 9 of 48 patients (19%) had KRASG12C detected at baseline, available scan results and a ctDNA sample after 4 weeks of receiving RMC-4630. A decrease in KRASG12C variant allele frequency (VAF) was detected in 5/9 patients (56%) with clearance in 1 patient with a partial response. Decrease in KRASG12C VAF was associated with change in tumor volume (PCC=0.85, p=0.008), preceding scan results by approximately 1 month, suggesting that change in KRASG12C VAF may be an early measure of drug activity or possibly response. 5 of 48 patients (10%) had NF1LOF detected at baseline. A decrease, or stability in NF1LOF VAF on treatment compared to baseline was detected in 4 (80% of all NF1LOF patients). The decrease in NF1LOF VAF was not associated with change in tumor volume and may represent effects of RMC-4630 on a subclone harboring NF1LOF. One patient had a detectable BRAFClass3 mutation at baseline, which decreased in VAF on treatment compared to baseline. Of the remaining patients there were 12 KRASG12D, 9 KRASG12V and other KRASG12X. The majority progressed with an increase in VAF of all mutations including KRASG12X, suggesting that the KRASG12X-containing clone is responsible for escape from single agent RMC-4630. In most instances the increase in KRASG12X VAF in blood preceded determination of clinical progression. Longitudinal assessment of ctDNA indicates that some patients with RAS-addicted tumors undergo a molecular response on treatment with the SHP2 inhibitor RMC-4630. Citation Format: Josie L. Hayes, Marianna Koczywas, Sai-Hong Ignatius Ou, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Ariel Chen, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Eric Haura. Confirmation of target inhibition and anti-tumor activity of the SHP2 inhibitor RMC-4630 via longitudinal analysis of ctDNA in a phase 1 clinical study [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 LB054.

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. In preclinical models, SHP2 inhibition not only directly inhibited tumor growth through suppression of tumor-intrinsic RAS signaling, but also resulted in transformation of the tumor immune microenvironment, characterized by an increase in CD8+T cell infiltrates and selective depletion of pro-tumorigenic M2 macrophages. In this study, we evaluated pharmacodynamic biomarkers in blood and tumors from patients in the RMC-4630 phase I monotherapy clinical trial (NCT 03634982) by using flow cytometry and immunohistochemistry (IHC). Safety, PK and efficacy data are reported in a separate abstract. Longitudinal analysis of immune cell phenotyping in blood was conducted in 35 patients. There was a trend for lower pre-study monocytic myeloid-derived suppressor cell (mMDSC) to be associated with a better clinical outcome on RMC-4630 therapy. While the proportion of circulating T cell and B cell populations did not change, both blood mMDSC and total monocytes were significantly reduced during RMC-4630 administration. Furthermore, tumor volumes changes, and the proportion of patients with SD versus PD, positively correlated with the ratio of mMDSCs to total monocytes on RMC-4630 treatment. Inhibition of pERK was observed in a subset of patients. Three paired tumor biopsies from efficacy-evaluable patients, including 1 PR, 1 SD and 1 PD, were available for tumor microenvironment analysis by multiplexed-IHC assays. Increase in tumor infiltrating T cells in the tumors of one patient with a PR and another with SD was observed on RMC-4630 therapy. Inhibition of tumor PD-L1 expression and a decrease in M2 macrophages was also observed on treatment in the tumor biopsy of the PR patient. Collectively, the preliminary clinical biomarker data supports the preclinical observations that SHP2 inhibition with RMC-4630 modulates both innate and adaptive anti-tumor immunity. Citation Format: Ariel Yung-Chia Chen, Eric Haura, Jose Pacheco, Marianna Koczywas, Michael Gordon, Susanna Ulahannan, Howard A. Burris, Sai-Hong Ignatius Ou, Judy S. Wang, Jonathan W. Riess, Caroline McCoach, Anna Capasso, Elsa Quintana, Josie Hayes, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Pasi A. Janne. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630 [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 LB050.

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node regulating RAS signaling. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Here we report data from the dose-escalation phase of this study. A total of 104 patients were dosed across three schedules: daily dosing (n = 49) and two intermittent dosing schedules, twice weekly on D1D4 (n = 31) or D1D2 (n = 24). Based on PK and tolerability, the recommended phase 2 dose and schedule (RP2DS) was determined to be 200 mg D1D2, delivering a 400 mg weekly dose intensity. Of the 80 efficacy evaluable patients, there was 1 CR (NF1LOF uterine carcinosarcoma), 1 PR (KRASG12C NSCLC), and 1 unconfirmed PR (KRASG12D NSCLC). Tumor regressions were observed in another 11 patients (-2.4% to -27.1%). Disease control rate was 61% (23/38) in patients with KRASMUT NSCLC and 80% (12/15) in KRASG12C NSCLC specifically. The safety and tolerability profile of RMC-4630 were consistent with the mechanism of action and RAS pathway inhibition. The most frequent adverse events (AEs) were edema (48%), diarrhea (47%), fatigue (36%), anemia (34%), and thrombocytopenia (33%). Most AEs were grade 1 or 2 and were manageable. Intermittent dosing with either D1D2 or D1D4 weekly was generally better tolerated than daily dosing at an equivalent weekly dose intensity. Plasma concentrations of RMC-4630 after dosing with 200 mg D1D2 were above those predicted to be clinically active based on preclinical models. Cmax reached and often exceeded the ‘apoptotic threshold' defined as plasma exposures that were associated with induction of tumor regressions in preclinical models. Trough concentrations at the end of each week were at or around the EC50 for RAS pathway inhibition in tumor which is predicted to be sufficient to allow normal tissue recovery and therefore maintain tolerability with sustained dosing up to 6 months. Sequential analysis of pERK levels in peripheral blood cells and paired pre- and on-treatment tumor biopsies showed evidence of RAS pathway inhibition. Tumor and blood-based immune-oncology biomarkers showed preliminary evidence of anti-tumor immune activation. Longitudinal analysis of circulating tumor DNA indicated molecular responses consistent with anti-tumor activity in tumors carrying specific driver mutations in the RAS signaling pathway. An expansion cohort of patients with gynecologic cancers with NF1LOF is underway with monotherapy at the RP2DS. RMC-4630 continues to be evaluated in combination with the MEK inhibitor cobimetinib (Cotellic), the KRASG12C(OFF) inhibitor sotorasib, the PD1 inhibitor pembrolizumab (Keytruda) and the EGFR inhibitor osimertinib (Tagrisso). Additional combination studies are also planned. Citation Format: Marianna Koczywas, Eric Haura, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Richa Dua, Zhengping Wang, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari, Xiaolin Wang, S Ignatius Ou. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers [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 LB001.

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Background & Aims Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Methods Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. Results No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1–51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8 + T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). Conclusions Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8 + T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Lay summary Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. Clinical trial number ClinicalTrials.gov: NCT01853618.

Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells (1). MGD013 demonstrates in vitro ligand blocking properties and improved T-cell responses beyond that observed with anti-PD-1 and anti-LAG-3 benchmark antibodies alone or in combination. PD-1 targeted therapy with nivolumab in patients (pts) with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) has yielded modest efficacy (2). LAG-3, highly expressed in DLBCL (3), has emerged as another therapeutic target of interest in this population with continued unmet need. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose, PK/PD, and antitumor activity of MGD013 in pts with advanced solid and hematologic malignancies. R/R DLBCL pts are being treated at the recommended Phase 2 dose of 600 mg every two weeks in Cohort Expansion. Results: At data-cutoff, 17 DLBCL pts received MGD013 (2.5 median prior lines of therapy, 41.2% with prior CAR-T therapy). Treatment-related adverse events (TRAEs) occurred in 11/17 (64.7%) pts, with no same TRAE occurring in > 1 patient except pyrexia (n=3). One grade ≥ 3 TRAE occurred (pneumonia), and no events of tumor lysis syndrome were observed. Among 11 response-evaluable pts (i.e. received at least one on-treatment scan), 1 complete response (CR) and 3 partial responses (PRs) per the Lugano Classification were observed. Analyses of available pre-treatment tumor biopsy samples corresponding to responding pts demonstrated relatively high levels of LAG-3, PD-1, and PD-L1 by IHC. More comprehensive translational analyses were undertaken for the pt with CR, observed after a single MGD013 infusion in a 28-year-old male in relapse 6 months after CD19-directed CAR T-cell therapy. In contrast to a pre-CAR T biopsy specimen demonstrating no LAG-3 or PD-1 expression, IHC analysis of a lymph node specimen biopsied post-CAR T and prior to MGD013 treatment revealed high levels of both LAG-3 and PD-1 on both infiltrating T-cells and malignant B-cells. Consistent with CD19 CAR T resistance, no CD19 expression was evident. MHC class II and PD-L1 expression were observed, which when bound to LAG-3 and PD-1, respectively, form immune checkpoints that can decrease T cell function. Following MGD013 treatment, serum IFN-γ markedly increased to >140-fold above baseline. No significant changes were observed for IL-6 or IL-2. Expansion of circulating CD3+CD8+ and CD3+CD4-CD8- T-cell subsets and associated cytolytic markers (i.e., perforin, granzyme B) were observed following MGD013 treatment. The patient underwent allogeneic stem cell transplant (allo-SCT) and remains in remission 14 months post-MGD013 and 12 months post-allo-SCT. Further correlative biomarker analyses are underway in the ongoing clinical trial. Conclusion: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has preliminarily demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity in R/R DLBCL pts with and without prior treatment with CAR T. Biomarker analyses confirmed expression of both PD-1 and LAG-3 axes in responding pts with evidence of pharmacodynamic responses consistent with the ability of MGD013 to enhance T-cell function. References: 1. Luke JJ, Patel MR, Hamilton E, et al. A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms. J Clin Oncol 38: 2020 (suppl; abstr 3004). 2. Keane C, Law SC, Gould C, et al. LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Adv. 2020;4(7):1367-1377. doi:10.1182/bloodadvances.2019001390 3. Ansell SM, Minnema MC, Johnson P, et al., Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol, 2019. 37(6): p. 481-489. Disclosures Wang: Verastem Oncology: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; Putnam LLC: Honoraria. Asch:Astellas Pharma: Research Funding; Cartesian: Research Funding; Forty Seven: Research Funding; Juno: Research Funding; MacroGenics: Research Funding; MEI Pharma: Patents & Royalties: Provisional patent submitted (I), Research Funding. Hamad:Novartis: Honoraria; Abbvie: Honoraria. Weickhardt:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ulahannan:Merck Co. Inc: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics, Inc.: Research Funding; ArQule, Inc.: Research Funding; Evelo Biosciences, Inc.: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Klus Pharma, Inc.: Research Funding; Isofol: Research Funding; GlaxoSmithKline GSK: Research Funding; Mersana Therapeutics: Research Funding; Macrogenics: Research Funding; Celgene Corporation: Research Funding; Boehringer Ingelheim: Research Funding; Array: Membership on an entity's Board of Directors or advisory committees; Ciclomed LLC: Research Funding; AbbVie, Inc.: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Exelxis: Membership on an entity's Board of Directors or advisory committees. Koucheki:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sun:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Li:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Chen:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Moore:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumrow:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company.

1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .

Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, degrades the ER, and delays tumor proliferation in preclinical models. Preliminary results from Part 1 dose escalation (200-1000 mg once daily) demonstrated that rintodestrant has a favorable safety profile and encouraging antitumor activity in patients (pts) with heavily pretreated ER+/HER2- advanced breast cancer (ABC) (Dees et al., ESMO 2019 [abstract #3587]). Here, we report the pharmacodynamic (PD) analysis in peripheral blood and tumor biopsies from pts who received rintodestrant in Part 1 and 2 (600 and 1000 mg dose expansion) to characterize the pt population and mechanisms of response. Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant in women with ER+/HER- ABC after progression on endocrine therapy. PD analysis included inhibition of ER target engagement with 18F-fluoroestradiol positron emission tomography (FES-PET), mutational profiling (cell-free DNA [cfDNA]), and circulating tumor cell (CTC) enumeration. Tumor biopsies sampled at baseline and 6 weeks on treatment were evaluated for ER degradation (immunohistochemistry [IHC]) and proliferation (Ki67, IHC) to understand the on-target effects of rintodestrant. Results: As of May 13, 2020, 67 pts had been treated. FES-PET data were obtained in 14 pts and showed a decrease in all pts, with maximum standard uptake values (SUVmax) ranging from 70% to 98% after 4 weeks of rintodestrant monotherapy across all doses. Fifty-nine pts were tested for cfDNA at baseline; 95% (n = 56) harbored ≥1 somatic variant (median = 3 mutations per pt). Among pts with somatic variants, 41% had ESR1 mutations, with D538G being the most common (58%). Additionally, 46% and 42% of pts harbored mutations in TP53 and PIK3CA, respectively, and 10% had mutations in both ESR1 and PIK3CA. Similar clinical benefit rates were observed in wild-type vs ESR1 and/or PIK3CA mutant tumors. An analysis of change of variant allele fraction (VAF) in 55 pts between baseline and 2 weeks of treatment revealed that 58% had a decrease in mean VAF, with a decrease in ESR1 VAF in 16/20 pts that had ESR1 mutations at baseline. Furthermore, of 24 pts who had samples collected at baseline and progression, 16 (67%) developed additional variants (median [range]: 2 [1, 15]), including EGFR, ERBB2, TP53, and ESR1. CTC analysis (n = 45) showed the mean value of Epi+CD45- CTCs decreased from 2.8 cells/mL to 1.8 cells/mL after 8 weeks of treatment. Tumor biopsies were collected in 9 pts (5 received 600 mg and 4 received 1000 mg) at baseline and 6 weeks on treatment. Of the 7/9 pts that had a decrease in the ER H-score (median [range]: -27.8% [-33.8%, -3.4%]), 4 had ≥1 variant in ESR1 at baseline. Overall, 4 pts had a decrease in Ki67, with reductions mostly observed in pts who received 600 mg rintodestrant. Additional analyses, including correlations with clinical response, are ongoing and will be presented. Conclusions: Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270). Citation Format: Philippe Aftimos, Marina Maglakelidze, Andor WJM Glaudemans, Erika Hamilton, Linnea Chap, Elisabeth de Vries, Catharina Willemien Menke-van der Houven van Oordt, Agnes Jager, E. Claire Dees, Massimo Cristofanilli, Mark Pegram, Susanna Ulahannan, Patrick Neven, Iurie Bulat, Ruhi Rai, Wenli Tao, Sarika Jain, Andrew P Beelen, Jessica A Sorrentino. Pharmacodynamic analysis from a phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-07.

78 Background: Overexpression of the cell-cell adhesion protein P-cadherin has been associated with a more aggressive cancer cell phenotype, cancer stem cell properties, tumor invasion and metastasis. We determined the safety and recommended Phase II dose of the yttrium-labeled P-cadherin-targeted 90Y-FF-21101 monoclonal antibody (mAb) in patients (pts) with advanced tumors, and focused our expansion study in advanced colorectal (CRC) and pancreatic-biliary cancers (non-CRC tumors). We report the safety, efficacy, and correlative pharmacokinetics (PK)/pharmacodynamics (PD) in this cohort. Methods: Pts enrolled must have progressed on all standard therapies. 25 mCi/m2 (8 mCi/mg mAb) 90Y-FF-21101 was administered intravenously every 12 weeks (wks) until disease progression or unacceptable toxicity. Disease response was assessed based on RECIST v1.1 every 8 wks (1 cycle = 28 days). Serum mAb PK, existence of anti-drug antibodies (ADA) and tumor P-cadherin expression were also evaluated. Results: 31 pts [mean age 63 (range, 39-89); 14F/17M; median number of prior therapies, 3 (range, 1-11)] with CRC (18) and non-CRC tumors [pancreatic (8), cholangiocarcinoma (3), duodenal (2)] received a median of 1 (range, 1-2) dose of 90Y-FF-21101. Median duration on study was 8.1 (3.9 – 27) wks (CRC) and 8 (1.1-17.1) wks (pancreatic-biliary). Myelosuppression was the most common treatment-related adverse event [thrombocytopenia (87%; Grade (Gr) 3/4 in 45%), lymphopenia (74%; Gr 3/4 in 61%), anemia (52%; Gr 3/4 in 13%), leukopenia (32%; Gr 3/4 in 16%)], in addition to fatigue (68%, 1 Gr 3) and nausea (39%, 1 Gr 3). Three pts required dose reduction to 20 mCi/m2 with subsequent infusion after Gr 3/4 thrombocytopenia [(pancreatic (2), CRC (1)]. The clinical benefit rate in pts with CRC based on stable disease (SD) for ≥8 wks is 43.8% (7/16 pts), with a median PFS of 8.1 wks and OS of 27 wks [median PFS, 7.9 wks; OS, 17.1 wks in non-CRC]. Longer-term SD was maintained in 2 pts with CRC for 17-24 wks; one continues on treatment. Enrollment is ongoing in the non-CRC cohort. FF-21101 has a mean t1/2 of approximately 65 hours, and post-treatment ADA titers have been observed in < 5% of pts. Tumor P-cadherin expression analysis by IHC demonstrated H-scores > 150 in 88% (14/16) of CRC pts, 75% (9/12) for non-CRC; 2 CRC pts with SD ≥17 wks had H-scores ≥190. Conclusions: 90Y-FF-21101 administered every 12 wks demonstrated expected toxicities and has been generally well-tolerated, with preliminary evidence of benefit demonstrated in heavily pre-treated pts with advanced CRC. The optimal dose and schedule for this radioimmunotherapeutic will continue to be explored, along with pre-treatment P-cadherin expression as a predictive biomarker for disease response. Clinical trial information: NCT02454010.

BACKGROUND Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..

Background: Heat Shock Protein 90 (HSP90) is a molecular chaperone that aids in folding and trafficking of proteins and is upregulated in cells under stress. HSP90 is overexpressed in cancer cells and exists in the activated configuration within the tumor microenvironment. PEN-866 is a novel small molecule drug conjugate containing a HSP90 targeting moiety that accumulates in tumors and releases its payload SN-38 through a cleavable linker within the tumor cells. The first in human phase 1/2a PEN-866 study was designed to assess safety, pharmacokinetics (PK), and exploratory biomarkers of PEN-866 related to its mechanism of action. Here we describe the evaluation of PEN-866 and the payload SN-38 in plasma and tumors. Methods: Patients with advanced solid malignancies were enrolled in dose escalation cohorts and received PEN-866 IV on days 1, 8, and 15 in 28-days cycles, over a dose range of 16-228 mg/m2. Plasma samples were collected up to 8 days after the first dose and up to 24 hours after the third dose. Non-compartmental analysis was performed to obtain PK parameters. Optional tumor biopsies were collected from two patients and analyzed for PEN-866 and SN-38 concentrations. Results: PEN-866 plasma concentration profile was biphasic with a rapid concentration decline after end of infusion resulting in an average half-life (t½) of approximately 10 hours across all dose cohorts. PEN-866 maximum plasma concentrations (Cmax) ranged from 0.69 to 54 µg/mL and area under the concentration curve (AUC) from 0.80 to 88 h·µg/mL. The Cmax and AUC increased higher than dose proportionally at the lower dose levels which resulted in higher clearance (CL) and volume of distribution (Vd) variability. Free SN-38 AUC's were generally low demonstrating linker stability in circulation and low systemic exposure. PEN-866 and SN-38 levels in patient tumors confirmed accumulation and retention of the conjugate up to 6 days after PEN-866 dose and the targeted release of SN-38. Conclusion: PEN-866 has an extended plasma half-life in patients with advanced solid malignancies and showed good stability in circulation with limited plasma exposure of the payload SN-38. Analysis of tumor biopsies up to 6 days after dosing demonstrated significant accumulation and extended exposures of PEN-866 and SN-38 within the tumor tissue that exceed plasma exposures. Citation Format: Anish Thomas, Kristina Kriksciukaite, Gerald Falchook, Johanna Bendel, Susanna Ulahannan, Christophe Redon, Laura Mei, Kerry Whalen, Jeffrey Bloss, Mark T. Bilodeau. Characterization of PEN-866, a Heat Shock Protein 90 (HSP90) binding conjugate of SN-38, in patient plasma and tumors from the first in human study [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 CT156.

Background: Colorectal cancer (CRC) is the third most common cancer in the United States. Aberrant activation of the Wnt signaling pathway is associated with CRC progression. Ring finger protein 43 (RNF43) is a single-pass type 1 transmembrane protein and a key feedback regulator of Wnt. SC-006 is a RNF43 targeted antibody drug conjugate, linked to a pyrrolobenzodiazepine dimer DNA crosslinking agent. Budigalimab (ABBV-181) is a PD-1 targeting, humanized, recombinant immunoglobulin G1 monoclonal antibody with Fc mutations (L234A, L235A) shown to reduce Fc receptor interactions and limit effector function. This open-label, Phase 1 clinical trial assessed the safety and efficacy of SC-006 as monotherapy and in combination with budigalimab in patients with CRC (NCT03035279). Methods: Evaluable patients had histologically or cytologically confirmed advanced metastatic or unresectable CRC. The trial consisted of 2 parts: part A (SC-006-monotherapy, 2 to 12 µg/kg, IV) and part B (SC-006 in combination with budigalimab at a fixed dose of 375 mg/kg IV every 3 weeks [Q3W]). Efficacy was assessed per RECIST 1.1 by radiographic assessments. Results: As of April 2019, 29 patients were enrolled (n=20 in part A and n=9 in part B). All patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs (>20% of patients) are summarized in Table 1. Two patients (7%) had dose-limiting toxicities of grade 4 thrombocytopenia. All 29 patients discontinued from the study, with study drug being discontinued for 76% of patients due to progressive disease. One death occurred in part A due to gastrointestinal hemorrhage with possible relation to SC-006. Serious TEAEs occurred in 8 patients (28%); these included thrombocytopenia and malignant neoplasm progression in 2 patients (7%) each. Progressive disease occurred in 18 patients (62%), stable disease was reported in 10 patients (34%) and the response for 1 patient was not reported. Conclusion: SC-006 dose escalation was limited by thrombocytopenia observed below the predicted efficacious dose, leading to study termination. Table 1.Summary of the Most Common Treatment-Emergent Adverse EventsPart A: SC-006-monotherapyPart B: SC-006+budigalimabTEAEs (>20% patients), n (%)2 ug/kg4 ug/kg8 ug/kg4 ug/kg8 ug/kg12 ug/kg4 ug/kg Q6W+budigalimab8 ug/kg Q6W+budigalimabOverallQ3WQ3WQ3WQ6WQ6WQ6W(N=1)(N=3)(N=1)(N=2)(N=10)(N=3)(N=4)(N=5)(N=29)Thrombocytopenia01 (33)1 (100)1 (50)4 (40)3 (100)1 (25)4 (80)15 (52)Fatigue0001 (50)3 (30)2 (67)3 (75)3 (60)12 (41)Nausea0001 (50)5 (50)1 (33)2 (50)2 (40)11 (38)Edema peripheral01 (33)01 (50)4 (40)02 (50)1 (20)9 (31)Decreased appetite01 (33)01 (50)4 (40)002 (40)8 (28)Dyspnea00004 (40)3 (100)01 (20)8 (28)Vomiting0001 (50)3 (30)1 (33)2 (50)1 (20)8 (28)Constipation0001 (50)3 (30)01 (25)2 (40)7 (24) Citation Format: Katrina S. Pedersen, Amit Mahipal, Andrea Cercek, Susanna Ulahannan, Michael Rossi, Abraham Fong, Daniel Brickman, Johanna Bendell. First-in-human clinical trial of SC-006, a RNF43 targeted antibody-drug conjugate, as a monotherapy and in combination with budigalimab in patients with advanced colorectal cancer [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 CT167.

Introduction: LAG3 is an immune checkpoint receptor, often co-expressed with PD-1 on immune cell surfaces. PD-1 and LAG-3 signaling contribute to immune cell exhaustion in the tumor microenvironment. Dual blockade of PD-1 and LAG-3 is thus expected to improve response versus PD-1 blockade alone. A dose escalation/expansion trial (NCT03156114) is evaluating BI 754111, an anti-LAG-3 mAb, plus BI 754091, an anti-PD-1 mAb, in patients (pts) with advanced solid tumors. Here, we report data in pts with MSS mCRC, for whom checkpoint inhibitors (CPIs) have shown limited activity. We broadly evaluated biomarkers to provide information on mode of action and for their potential to predict responses. Methods: In this dose expansion cohort, pts with PD-(L)1-naïve, previously treated MSS mCRC tumors were enrolled. Pre- and on-treatment tumor biopsies and blood samples for biomarker analyses were collected. Cytokines, including interferon-gamma (IFN-γ), were quantified in plasma samples by multiplexed and high-sensitivity immunoassays. Activated effector memory T cell and other peripheral blood mononuclear cell counts were determined by flow cytometry. PD-L1, LAG-3 and CD8 expression was determined by immunohistochemistry (IHC). Exploratory gene expression analyses to determine immuno-oncology (IO)-related markers were conducted. Results: 40 pts with MSS mCRC received BI 754111 600 mg in combination with BI 754091 240 mg every 3 weeks. Pts had received a median (range) of 3.5 (1–10) prior treatments. To date (Sep 2019), 3 (7.5%) pts achieved a partial response (PR) and 11 (27.5%) had stable disease (SD) as best response. Peripheral blood analysis showed treatment led to coordinated upregulation of pro-inflammatory cytokines in some pts. Pts with greater cytokine induction were more likely to have SD. Also, upregulation of activated CD8 effector memory T cells in peripheral blood was observed in many pts. IHC analysis indicated that, in tumors that had CD8 T cells and PD-L1 expression at the tumor periphery at baseline, treatment led to infiltration of CD8 T cells into the tumor and an increase in PD-L1 expression. Analyses of pre-treatment tumors suggested that high PD-L1 gene expression was associated with clinical benefit. In addition, a treatment-associated increase of the IFN-γ gene signature scores was observed, supporting a treatment-induced activation of the immune system in the tumor; the effect was more pronounced in pts with PR/SD versus those with progressive disease. LAG-3 IHC levels at baseline were not predictive of outcome in this anti-PD-(L)1 naïve setting. Conclusion: BI 754111 plus BI 754091 showed encouraging results in this IO-refractory MSS mCRC population. Biomarker analyses showed activation of the immune system in peripheral blood and the tumor, consistent with other CPIs. Citation Format: Johanna Bendell, Susanna V. Ulahannan, Quincy Chu, Manish Patel, Ben George, Aurélie Auguste, Theresia Leo-Kress, Kai Bernd Stadermann, Nicole Kraemer, Mabrouk Elgadi, Melissa Johnson. A phase I study of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb: Biomarker analyses from the microsatellite stable metastatic colorectal cancer (MSS mCRC) cohort [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 779.

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses >20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .

3004 Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells. MGD013 demonstrates ligand blocking properties consistent with anti-PD-1 and anti-LAG-3 benchmark molecules, and improves T cell responses beyond that observed with benchmark or component antibodies alone or in combination. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and antitumor activity of MGD013 in patients (pts) with advanced solid and hematologic malignancies. Sequential single-pt cohorts were treated with escalating flat doses of MGD013 (1-1200 mg IV every 2 weeks), followed by a 3+3 design. Tumor-specific expansion cohorts are being treated at the recommended Phase 2 dose of 600 mg. Results: At data-cutoff, 50 pts (46% checkpoint-experienced) were treated in Dose Escalation, and 157 pts (32% checkpoint-experienced) in Cohort Expansion. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 146/207 (70.5%) pts, most commonly fatigue (19%) and nausea (11%). The rate of Grade ≥ 3 TRAEs was 23.2%. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies. Mean half-life was 11 days; peripheral blood flow cytometry analyses confirmed full and sustained on-target binding during treatment at doses ≥ 120 mg. Among 41 response-evaluable [RE] dose escalation pts, 3 confirmed partial responses [cPRs] (triple negative breast cancer [TNBC], mesothelioma, gastric cancer) per RECIST 1.1 were observed, while 21 pts had stable disease [SD]. Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2; both cPRs, and 7 with SD among 15 RE pts) and TNBC (n=2; 1 cPR, 1 unconfirmed PR [uPR], and 5 with SD among 14 RE pts). In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2], colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. Objective responses have been observed in several pts after prior anti-PD-1 therapy. Investigations into potential correlative biomarkers including LAG-3 and PD-1 are ongoing. Conclusions: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial information: NCT03219268 .

3515 Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m2), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m2, 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m2. The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .

518 Background: Fosciclopirox (CPX-POM) is being developed for the treatment of non-muscle invasive and muscle invasive bladder cancer. CPX-POM selectively delivers its active metabolite, ciclopirox (CPX), to the entire urinary tract following systemic administration. In a chemical carcinogen mouse model of bladder cancer, CPX-POM treatment resulted in significant decreases in bladder weight, migration to lower stage tumors, inhibition of cell proliferation as well as Notch 1 and Wnt signaling pathways. Methods: Study CPX-POM-001 (NCT03348514) is US multi-site, Phase I, open-label, dose escalation study characterizing the safety, dose tolerance, pharmacokinetics (PK) and pharmacodynamics of IV CPX-POM in advanced solid tumor patients. The PK of CPX-POM, CPX and ciclopirox glucuronide (CPX-G), were characterized in plasma and urine. Circulating biomarkers of Wnt and Notch, IL-6, IL-8 and VEGF were determined. Results: Nineteen patients were enrolled in the study. The starting dose of 30 mg/m2 was administered once daily on Days 1-5 of each 21-day treatment cycle. Doses were escalated to 1200 mg/m2. The MTD was determined to be 900 mg/m2. Overall, the number of treatment-related AE's tended to increase in frequency with dose, nausea and vomiting being the most common. Grade 3 confusion was observed in the 1200 mg/m2 cohort. Four AE's of Grade 1 confusion at 600 and 900 mg/m2. There was no evidence of QTc prolongation or other ECG abnormality. One patient in the 240 mg/m2 dose cohort, with a diagnosis of indolent primary fallopian tube tumor, achieved a partial response per RECIST 1.1. Metabolism of CPX-POM was rapid and complete. The clearance of CPX was dose proportional and time-independent. At MTD, steady-state 24-hour urine CPX concentrations of 215 µM were achieved. Evidence of Notch and Wnt inhibition was observed. Conclusions: IV CPX-POM was well tolerated with treatment-related AEs primarily CNS-related. At MTD, systemic and urinary CPX exposures exceeding in vitro IC50 values by several-fold. The 900 mg/m2 dose is currently being evaluated in an expansion cohort study in cisplatin-ineligible muscle invasive bladder cancer patients scheduled for cystectomy. Clinical trial information: NCT03348514.

SUMMARY Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations.

A Phase I study of A166, a Novel Anti-HER2 Antibody-Drug Conjugate (ADC), in Patients with Locally Advanced/Metastatic Solid Tumors. Purpose: A166 is an Antibody Drug Conjugate (ADC) targeting HER2-expressing cancer cells, aiming for post trastuzumab/TDM1 population and patients with HER2 expressing cancers not commonly treated with trastuzumab and TDM1. The antibody has the same amino acid sequence as trastuzumab, and it is designed to provide uniform distribution of payload molecules, using an innovative antibody-drug linker and duostatin-5 (an MMAF derivative) as payload. This ongoing phase I, open-label, first-in-human study is evaluating the safety, pharmacokinetics (PK), and dose-limiting toxicities (DLT) of A166 to determine the Maximum-Tolerated Dose (MTD) and/or recommended phase II dose (RP2D). Methods: Patients with advance solid tumors received escalating doses of A166 (0.3, 1.2, 3.6, and 4.8 mg/kg), administered intravenously (IV) every three weeks. Patients must have had documented HER2 positivity defined as positive, or amplified on in situ hybridization (ISH) or next-generation sequencing (NGS), or HER2 expression, defined as at least 1+ by validated immunohistochemistry (IHC) test or an activating HER2 mutation. Dose escalations were guided by a Bayesian logistic regression model (BLRM). Assessments include archival tumor molecular status, PK, and efficacy by Response Evaluation Criteria in Solid Tumors (RECIST). Results: 23 subjects [median age 68 (range 50-83), 17 female, 6 male, PS 0-1], have been treated. All patients had metastatic disease: 7 breast, 7 GC/GEJ/EC; 4 CRC, 5 other (lacrimal gland, vulvar, bladder, NSCLC, and ovarian). HER2 expression was available for all 23 patients: 12 (3+), 2 (2+ and amplified), 7 (amplified), 1 (1+), and 1 (HER2 mutated), and most had received previous HER2 targeted therapies (1-7 lines). No significant > Grade 3 AEs at doses below 3.6 mg/kg have been observed. Based on safety and efficacy outcomes, dose levels (DLs) 3.6 and 4.8 mg/kg were expanded to a total of 7 and 8 patients respectively. In these two cohorts, 4 patients experienced grade 2 ophthalmic toxicities involving the ocular surface (3 keratitis, 1 blurred vision), and 2 had Grade 3 keratitis. Treatment was discontinued (n=3) or delayed (n=3), and patients were treated with topical steroids and aggressive lubrication. All patients have resolved/resolving status of the ophthalmic toxicities, with a duration from onset to recovery/improvement of symptoms of 2-3 weeks. Other common drug-related and reversible Grade 1-2 AEs include blurry vision (n=4), peripheral neuropathy (n=3), anemia (n=2), leukopenia (n=2), thrombocytopenia (n=2). No cardiac or liver toxicities have been noted. Preliminary response assessment found that efficacy is evident at DL 3.6 and 4.8 mg/kg. Of 8 evaluable patients at 3.6-4.8 DL, 4/8 had PR, and 6/8 had DCR. Among PRs, 3 had prior anti-HER2 therapies, including 2/3 with prior TDM1. Conclusion: A166 has been well tolerated and shows promising anti-tumor activity in patients with heavily pre-treated HER2-positive cancers. The ophthalmic AEs have been reversible and manageable with supportive management. A detailed regimen for early diagnosis and intervention has been developed to further investigate the management of these toxicities in future cohorts, and three additional dose levels (6.0, 7.2, 8.4 mg/kg) will be added to the escalation phase. Citation Format: Diana M Lopez, Minal Barve, Judy Wang, Andrea J. Bullock, Eirini Pectasides, Ulka Vaishampayan, Alexander I. Spira, Susanna Ulahannan, Amita Patnaik, Rachel E. Sanborn, Dragan Cicic, Qiuqing Ang, Gregory Bergonio, Jordi Rodon Ahnert. A phase I study of A166, a novel anti-HER2 antibody-drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B005. doi:10.1158/1535-7163.TARG-19-B005

Background: ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1–2 study in patients (pts) with advanced solid tumors or lymphoma (ClinicalTrials.gov NCT02503423). In the ongoing phase 2, ASTX660 has demonstrated preliminary evidence of clinical activity in the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts (Mehta et al, presented at the EHA Conference 2019, abs PS1073). Here, we report overall efficacy and safety data from the solid tumors (head and neck squamous cell carcinoma [HNSCC]; cervical carcinoma and other solid tumors) and lymphoma (diffuse large B-cell lymphoma [DLBCL], PTCL, CTCL,) phase 2 cohorts. Methods: Pts received treatment with ASTX660 orally at the RP2D 180mg/day on days 1 to 7, and 15 to 22 in a 28-day cycle. In the first stage 14 evaluable pts were enrolled in each of the 6 phase 2 cohorts with the option to expand the cohort if activity was observed. The primary endpoint was response rate as assessed by the investigator according to the Lugano criteria (DLBCL and PTCL), Global Assessment (CTCL), or RECIST 1.1 (solid tumors). Adverse events (AEs) were assessed per CTCAE V4.03. Results: As of June 4, 2019, a total of 107 pts have received ASTX660 in the solid tumors and lymphoma phase 2 cohorts (HNSCC n=14; DLBCL n=16; PTCL n=26; CTCL n=23; cervical carcinoma n=14; other solid tumors n= 14). Median age (range) was 61 (23-84) years and median number (range) of prior anticancer regimens was 3 (0-12). Among all pts, the most common related AEs of any grade (≥ 10%) were rash (35%), lipase elevation (34%), amylase elevation (29%), diarrhea (14%), fatigue (14%), AST elevation (13%), nausea (13%), and anemia (11%). Related AEs ≥ Grade 3 occurring in ≥ 5% of pts were rash (18%), lipase elevation (16%) and amylase elevation (9%). As of 4 June 2019, 86 pts (80%) discontinued study treatment: 64 (60%) due to progressive disease, 13 (12%) due to AE, 4 (4%) due to death, 4 (4%) due to withdrawal by participant and 1 (1%) for investigator’s decision. At the time of analysis, the ORR was 36% in the PTCL cohort and 15% in the CTCL cohort. One PR was reported in a pt with metastatic melanoma after 12 cycles of treatment. No objective responses were reported in the HNSCC, DLBCL or cervical cohorts. Accrual in the PTCL and CTCL continues; updated efficacy and safety data will be presented at the meeting. Conclusion: In the phase 2 part of the study ASTX660 monotherapy has demonstrated a manageable safety profile and encouraging activity in PTCL and CTCL warranting cohort expansion. Future plans include evaluation of ASXT660 both as mono- or combination therapy in selected malignancies. Citation Format: Antoine Hollebecque, Sarit Assouline, Felipe Samaniego, Benoit You, Francine Foss, Anca Prica, Sarah W. Gordon, Marc Webster, Martin JS. Dyer, Dima El-Sharkawi, Geoffrey I. Shapiro, Lisa Nabell, Sarah P. Blagden, John Lister, Susanna V. Ulahannan, Yijun Sun, Danna Chan, Roberta Ferraldeschi, Monica Mita. Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 107 patients with solid tumors or lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A072. doi:10.1158/1535-7163.TARG-19-A072

Background: Inhibition of the PD-1 pathway is an effective immunotherapeutic approach in a subset of patients with various solid tumors and hematologic malignancies. Blockade of the PD-1 pathway leads to overexpression of other checkpoint receptors, including LAG3, potentially providing an escape pathway for tumor cells. LAG-3 signaling contributes to immune cell exhaustion, preventing T-cell proliferation. Dual blockade of PD-1 and LAG-3 has the potential to synergistically restore T-cell functionality and therefore enhance antitumor immune responses. This Phase I trial is evaluating the combination of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), and BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: This open-label, Phase I study is being conducted in two parts. Part 1 (dose-escalation) enrolled patients with advanced solid tumors; no dose limiting toxicities were reported and BI 754111 600 mg intravenous (iv) every 3 weeks (q3w) in combination with BI 754091 (240 mg iv q3w) was selected for further assessment in part 2 (dose expansion). In part 2, patients are being enrolled in 4 cohorts: 1) anti-PD-(L)1 pretreated non-small cell lung cancer (NSCLC) that progressed after having achieved benefit on previous PD-(L)1; 2) previously treated (anti-PD-[L]1 naïve) MSS mCRC; 3) anti-PD-(L)1 pretreated TMB >10 and/or MSI-h and/or dMMR solid tumors; 4) treatment-naive NSCLC with EGFR and ALK wild type tumors. Primary endpoint for the expansion cohorts is objective response. Safety and pharmacokinetics of the combination were secondary endpoints. The mCRC cohort is fully recruited; other cohorts are open to recruitment. This abstract presents data from the MSS CRC cohort. Results. 40 patients with MSS mCRC were enrolled (27 male [67.5%]; median age 56.5 years [range 25–85]; median of 3.0 prior regimens [range 1–10]) and received BI 754111 600 mg q3w in combination with BI 754091 240 mg q3w. Treatment-related AEs (TRAEs) were reported in 18 patients (45%); most commonly infusion-related reactions (10.0%), myalgia (10.0%), hypothyroidism (7.5%), diarrhea (7.5%) and arthralgia (7.5%). Grade 3/4 TRAEs occurred in 4 patients (grade 3 colitis, grade 3 maculo-papular rash, grade 4 diabetic ketoacidosis [n=2]). Treatment-emergent immune-related AEs occurred in 9 patients; of these, 4 had grade 3/4 events (colitis and maculo-papular rash [grade 3] and diabetic ketoacidosis [grade 4; n=2]). To date, 2 (5%) patients achieved a partial response, and 12 (30%) achieved stable disease. Updates will be presented. Conclusion. BI 754111 + BI 754091 was well-tolerated and showed preliminary activity in patients with previously treated MSS mCRC. Assessment of the combination in other cohorts is ongoing. Citation Format: Johanna Bendell, Susanna V Ulahannan, Quincy Chu, Manish Patel, Ben George, Renee Landsberg, Mabrouk Elgadi, Christine Duffy, Ralph Graeser, Wenbo Tang, Michael Merger, Miaomiao Ge, Melissa Johnson. A Phase I, dose finding study of BI 754111, an anti-LAG-3 antibody, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumors: preliminary results from the microsatellite stable (MSS) metastatic colorectal cancer (mCRC) cohort [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C027. doi:10.1158/1535-7163.TARG-19-C027

3010 Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated with intravenous XMT-1536 using a 3+3 design with a modified Fibonacci escalation. NaPi2b expression by IHC is being examined retrospectively in archived tumors. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT03319628). Results: As of Jan. 28, 2019, 36 pts (22 ovarian, 7 endometrial, 4 NSCLC, 3 other) have received treatment with XMT-1536. Treatment was initially given every 3 weeks (q3w); 20 pts were treated in dose cohorts from 3 to 40 mg/m2. There was one DLT of reversible AST elevation at 40 mg/m2. The dosing interval was then changed to every 4 weeks (q4w), and dose escalation was restarted at 20 mg/m2. There was one DLT of reversible AST elevation at 30 mg/m2 on the q4w schedule. Further followup and dose escalation are ongoing. The most common (≥10% of patients) treatment-related adverse events (TRAEs) have been nausea, fatigue, headache, increased AST, anorexia, increased alkaline phosphatase, fever, increased GGT, myalgia, and vomiting. Grade 3 TRAEs were reversible AST increases in 3 patients and increased GGT, decreased lymphocytes, and systolic congestive heart failure in 1 patient each. Treatment-related serious AEs of fever and systolic congestive heart failure occurred in 1 patient each. Among patients dosed at 20 mg/m2 or higher who had restaging scans (n=20), there were 2 PR, in ovarian cancer pts at 30 mg/m2 q3w and 20 mg/m2 q4w, and 11 SD, with disease control maintained for up to 24 weeks. Patient-level results for NaPi2b expression will be presented. The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1536 has been well-tolerated up to the 30 mg/m2 dose level with early signs of anti-tumor activity. Dose escalation continues in pts with advanced solid tumors likely to express NaPi2b. Clinical trial information: NCT03319628.

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.

e14705 Background: Ciclopirox Prodrug (CPX-POM) is a novel anticancer agent currently being evaluated in patients with advanced solid tumors participating in a First-in-Human, Phase 1 safety, dose tolerance, pharmacokinetics (PK) and pharmacodynamics trial at four US sites. In vitro and in vivo preclinical proof of principle was established in high grade human urothelial cancer cell lines as well as a mouse model of bladder cancer.Methods: A series of in vivo PK studies were conducted in mice, rats and dogs to characterize the absolute bioavailability of CPX following intravenous (IV), subcutaneous (SC) and oral administration of CPX-POM. The single dose and steady-state plasma and urine pharmacokinetics of CPX-POM are also currently being characterized in patients participating in the ongoing Phase 1 trial. Plasma and urine concentrations of the prodrug and metabolites were determined by LC-MS/MS validated in each specie and matrix. Non-parametric pharmacokinetic parameters were generated from resultant plasma and urine drug and metabolite concentration-time data. Results: CPX-POM is rapidly and completely metabolized to CPX in blood via circulating phosphatases in animals and humans. CPX is completely bioavailable following IV CPX-POM administration in mice, rats and dogs. CPX and its major inactive glucuronide metabolite (CPX-G) are extensively eliminated in urine in all animal species. SC administration of CPX-POM demonstrated excellent bioavailability in rats and dogs. Following IV administration of 30-900 mg/m2CPX-POM to patients, the apparent elimination half-life of CPX ranged from 2 to 8 hours, CPX systemic exposure was dose-proportional and time-independent in cancer patients, and a major portion of the dose was eliminated as CPX-G. Conclusions: IV CPX-POM achieves plasma and urine CPX exposures that exceed in vitro IC50 values several-fold at well tolerated doses in animals and humans. CPX pharmacokinetics observed in animals were predictive of human systemic clearance based on allometric scaling. Clinical trial information: NCT03348514.

2508 Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation. Clinical trial information: NCT03005782.

3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

Squamous metaplasia is commonly detected in pancreatic parenchyma; however, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis.Surveillance, Epidemiology, and End Results (SEER) registries were examined identifying pancreatic SCC and adenocarcinoma cases from 2000 to 2012. Age-adjusted incidence rates were calculated. Patients with SCC versus adenocarcinoma were compared by clinical features and relative survival outcomes.We identified 214 patients with SCC and 72,860 with adenocarcinoma. For SCC, incidence rates tripled between 2000 and 2012. Significantly higher SCC incidence rates were observed in older age groups, blacks, and males. Greater proportion of patients with SCC than those with adenocarcinoma had poorly differentiated histology (73.0% vs 43.7%, P0.001). In both subtypes, majority of patients had stage IV disease, 59.0% for adenocarcinoma versus 62.6% for SCC. The 1- and 2-year relative survival rate was significantly lower in patients with SCC versus adenocarcinoma. The 1-year relative survival was 14.0% (95% confidence interval, 9.5%-19.4%) for SCC, compared with 24.5% (95% confidence interval, 24.2%-24.8%) for adenocarcinoma.Although primary pancreatic SCC is a rare neoplasm, incidence rates for this subtype are increasing. Relative to adenocarcinoma, pancreatic SCC is characterized by poorly differentiated histology and worse survival.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors.The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib.Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105.A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study.TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

Background: Signet ring carcinoma (SRC) is a distinct histological phenotype of adenocarcinoma. There are only a few published studies specifying the epidemiology of SRC with extragastric presentation. The purpose of our study was to define the most common primary sites of extragastric SRC, determine the incidence, and to compare survival by primary site and disease stage. Methods: The Surveillance Epidemiology and End Result (SEER) database was examined from 2000 to 2012 in order to identify SRC histology (8490) and determine its most common primary sites, incidence, and survival by site and stage. The five most common primary extragastric sites were identified by utilizing ICD-0-3/WHO 2008 classification. Age-adjusted incidence rates for extragastric SRC were calculated and compared to gastric SRC. Relative survival (RS) and overall survival (OS) at 1 and 3 years were analyzed by primary site and stage using Kaplan-Meier method. Chi-square test was used for categorical variables. Results: A total of 24,522 histologically confirmed cases of SRC were identified, and SRC comprised 0.5% of all malignant neoplasms. Among cases with known histological grade, 89.7% had poorly differentiated tumors. Overall, digestive system origin was recorded for 90% of SRC cases. Approximately half (44.2%) of primary SRC tumors were detected outside of the stomach. The most common primary sites for extragastric SRC were colon (40.5%), esophagus (11.9%), rectum (9.8%), lung/bronchus (7.3%), and pancreas (4.7%). The incidence rates for common extragastric SRC were much lower than for gastric SRC, and were higher for males than females (p Conclusion: Our study indicated that extragastric SRC most commonly occurs in the colorectum, esophagus and lung/bronchus. We confirmed that the primary site substantially impacts survival. Thus, development of unique molecular or histologic markers may help to identify the organ of origin and thereby determine prognosis in these phenotypically similar neoplasms. Citation Format: Chul Kim, Susanna Ulahannan, Julius Strauss, Jaydira Del Rivero, Austin Duffy, Tim F. Greten, Oxana V. Makarova-Rusher. Epidemiology and survival in patients with extragastric signet ring carcinoma. [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 3421.

220 Background: Although squamous metaplasia is commonly detected in pancreatic parenchyma, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. Methods: Using SEER-18 database primary code C25 in conjunction with histology codes for SCC (8052-8053, 8070-8078, 8083-8084) and for adenocarcinoma (AC) (8052-8053, 807-8078, 8083-8084), we identified cases diagnosed from 2000 to 2012. Age-adjusted incidence rates and trends over time were calculated. Patients with SCC were compared with AC by clinical features (TNM categories and histological differentiation), and 1-year and 2-year relative survival (RS) outcomes. Chi-square tests for categorical variables and t-tests for continuous variables were conducted. Kaplan-Meier method was used to estimate RS and Z-test was used to compare RS rates. SEERStat and GraphPad were used for analysis. Results: We identified 214 patients with microscopically confirmed SCC and 72,860 patients with AC. SCC constituted less than 1% of all cases of primary pancreatic cancer; however, age-adjusted incidence rates for this subtype tripled between 2000 and 2012. The annual percent increase of SCC incidence rate was 5.5%. Significant differences were observed by age, gender and race: older age groups, blacks and males had higher SCC incidence rates. Compared to AC, a greater proportion of patients with SCC had poorly differentiated histology (15.8% vs. 30.4%, p < 0.01). Similar to AC, the majority of patients with SCC had stage IV disease at diagnosis, 54.3% for AC vs. 56.4% SCC. The 1-year and 2-year relative survival rates were significantly lower in patients with SCC than AC. The 1-year relative survival rate was 15.8% (95%CI = 10.4-22.3) for SCC, compared with 24.7% (95%CI = 24.3-25.1) for AC, p < 0.001. Conclusions: Although primary squamous pancreatic carcinoma is a rare neoplasm, incidence rates for this subtype are markedly rising. Relative to adenocarcinoma, pancreatic squamous cell carcinoma is characterized by poorly differentiated histology and worse survival.

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Primary liver cancer is the sixth most common cancer worldwide, with HCC representing the majority of the cases. In the U.S., HCC rates are higher among Hispanics, Asians and blacks than among whites. Whether the higher risks are due to different distributions of risk factors is not clear. Thus, we conducted an analysis of HCC risk factors by race/ethnicity in the SEER-Medicare database for the years 2000-2009. Methods: HCC cases (n = 8,116), identified by ICD-O morphology codes 8170-8175, were compared to a 5% random sample of cancer-free persons in the SEER areas (n = 313,525). Risk factors examined included type II diabetes (DM II), obesity, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related disorders. Multivariate logistic regression analyses, which adjusted for age, location, gender, income and date of diagnosis as well as the other risk factors were used to compare risk factors by racial/ethnic group. Results: Risk factors by race/ethnicity | Risk factor | White | Black | Asians | Hispanics | |:----------------- | ------- | ---------------- | ------ | ---------------- | ---- | | | N 6,120 | N 668 | N 971 | N 357 | | | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | | Obesity | 6.3 | 1.06 (0.9-1.2) | 5.5 | 1.0 (0.7-1.5) | 0.7 | 0.2 (0.1-0.8) | 7.8 | 1.2 (0.7-1.9) | | DM II | 44.5 | 2.9 (2.8-3.1) | 41.8 | 1.3 (1.1-1.6) | 38.1 | 1.8 (1.5-2.1) | 54.6 | 2.0 (1.5-2.7) | | HBV | 1.8 | 3.8 (2.6-5.7) | 3.6 | 1.6 (0.7-3.7) | 17.7 | 17.1 (11.8-25.0) | 2.0 | 1.4 (0.2-11.1) | | HCV | 16.8 | 19.7 (17.1-22.6) | 34.0 | 36.8 (28.0-48.6) | 31.1 | 21.4 (15.4-29.9) | 22.7 | 16.0 (9.2-28.1) | | Alcohol cirrhosis | 11.4 | 4.7 (3.7-5.8) | 7.6 | 4.5 (2.4-8.5) | 4.0 | 3.8 (1.3-11.7) | 17.1 | 3.3 (1.7-6.8) | | Alcohol NOS | 13.1 | 2.7 (2.2-2.9) | 13.2 | 1.6 (1.1-2.4) | 3.7 | 2.0 (1.0-4.1) | 14.8 | 1.6 (0.8-3.0) | | Cirrhosis NOS | 33.3 | 45.5 (41.2-50.4) | 24.1 | 17.9 (12.3-25.9) | 36.8 | 36.9 (26.2-52.0) | 44.8 | 27.6 (18.9-40.3) | NOS not otherwise specified. Conclusion: Major HCC risk factor profile is differ across race/ethnical groups. While diabetes is most common risk factor overall, it is most prevalent in Hispanics. HCC related to HCV is more common in blacks and Asians, and to HBV in Asians. Citation Format: Oxana V. Makarova-Rusher, Sean F. Altekruse, Timothy S. McNeel, Barry I. Graubard, Austin G. Duffy, Susanna V. Ulahannan, Tim F. Greten, Katherine A. McGlynn. Risk factors for hepatocellular carcinoma (HCC) by race/ ethnicity in the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2015-875

e17591 Background: Background: Curative treatments are less frequently used in racial/ethnic minorities with hepatocellular carcinoma (HCC) leading to worse survival. It is unknown if any progress was made in reducing these disparities in the past decade. Methods: Patients with HCC (histology 8170-8175, topography C22.0) were identified in SEER 18 database 2000-2011, analyzed by ethnicity/race (Hispanics and non-Hispanic (NH) whites, Asians, blacks and American Indians/Alaska Natives (AI/AN) and divided into 3 time intervals (2000-2003, 2004-2007, and 2008-2011). Treatment variables included curative (transplantation, resection, and ablation) and palliative. Statistical analysis was performed using Chi-Square and Kaplan-Meier tests. Relative survival (RS) was calculated to adjust for differences in background mortalities. Results: We identified 40148 patients with race/ethnicity as follows: NH whites (N 19584), NH Asians (N 7444), NH blacks (N 5228), NH AI/AN (N 443) and Hispanics (N 7449). The analysis s...

639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.