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PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (< 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.

9085 Background: Aberrant activation of the RAS-RAF-MEK-ERK pathway is common in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objective is to identify a recommended Phase 2 dose. Subjects with relapsed/refractory solid tumors were eligible for Phase 1A with any molecular feature and for Phase 1B if the tumor demonstrated RAS or BRAF mutations. ASTX029 was administered orally daily on a continuous basis in 21-day cycles. Phase 1A was a modified 3+3 dose-escalation design based on dose-limiting toxicity (DLT) events. Phase 1B subjects were treated at the recommended dose for expansion (RDE) based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Disease response was evaluated by RECIST v1.1. Results: 76 subjects were treated with at least one dose of ASTX029 in Phase 1A (n = 56) and Phase 1B (n = 20). In Phase 1A, ASTX029 was evaluated from 10 mg to 280 mg daily. Two subjects experienced grade 2 central serous retinopathy (CSR) within a few days of dosing at the 280 mg daily dose level (one event was declared a DLT). Both subjects recovered to baseline within days of dose interruption. CSR is an expected AE based on the class of drugs. At the selected RDE dose level of 200 mg daily, the mean PK exposure was 109% of target exposure (13,022 ng*hr/ml), defined as the level expected to have biological activity based on mouse models. As of the data cut-off of February 7, 2022, the most frequent grade ≥2 AEs experienced by subjects (≥5%) assessed as related to ASTX029 included ocular AEs (n = 6: all Grade 2); nausea (n = 7: all Grade 2); diarrhea (n = 6: 5 Grade 2, 1 Grade 3); fatigue (n = 4: all Grade 2); rash (n = 4, 3 Grade 2, 1 Grade 3). There were 52 serious AEs, all unrelated to ASTX029 except for one subject with Grade 3 malaise. Four subjects had a partial response, including KRAS-G12A BRAF-D549N non-small cell lung cancer (NSCLC; Phase 1A: 120 mg treated 20.0 months); KRAS-G12D pancreatic cancer (Phase 1A: 200 mg treated 2.1 months); KRAS-G13D NSCLC (Phase 1B; treated 10.6 months); KRAS-G12S NSCLC (Phase 1B; treated 10.4 months and ongoing). In all, two partial responses were observed out of 3 NSCLC subjects enrolled in Phase 1B. Phospho-ERK and phospho-RSK were evaluated for PD effect on fresh tumor biopsies obtained at baseline and cycle 2. A PD effect and decreased cell proliferation (Ki-67) were observed in 6 of 9 and 3 of 8 evaluable Phase 1B samples, respectively. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1 study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily continuously for investigation in the Phase 2 study. PK and PD data suggest target exposures are achieved with preliminary clinical activity, especially in KRAS-mutated NSCLC. Clinical trial information: NCT03520075.

2507 Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.

9585 Background: Tebentafusp (tebe) is the first T cell receptor therapeutic to demonstrate overall survival (OS) benefit in a randomized Phase 3 study vs investigator’s choice (IC) [ NCT03070392 ]. OS benefit was also observed in patients (pts) with best objective response (BOR) PD (HR 0.43), and in pts who had tumor growth ≥20% as best change in tumor size (HR 0.41), suggesting tebe-treated pts may exhibit atypical radiological responses and could benefit from treatment beyond radiographic progression (TBP), a well-established concept in immuno-oncology. Here we analyzed tumor kinetics and clinical benefit in pts treated with tebe beyond initial radiographic progression (TBP). Methods: 378 mUM pts were randomized 2:1 to tebe vs. IC. BOR was assessed by investigators using RECIST v1.1. TBP was permitted until: 1) additional ≥20% increase in tumor burden with absolute increase of ≥5 mm, or 2) unequivocal PD of non-target lesions; or 3) new non-measurable lesions. A Cox model adjusted for baseline covariates and for covariates at time of progression for TBP-eligible pts was used to compare survival post progression between those who did (TBP) and did not receive TBP (non-TBP). Stepwise selection of covariates (using p < 0.1 as the entry and staying criterion) was applied. Analysis performed on data cut-off 13Oct2020. Results: 183 tebe pts were eligible for TBP per protocol; 60% (109/183) received TBP with median duration of 8 wks. 21% of all tebe doses were administered as TBP. The proportion of pts with new lesions at initial progression (44% vs 57%) and median time to initial progression (2.9 mo vs 2.9 mo) were similar between TBP and non-TBP pts. Pts receiving TBP were more likely to have favorable key prognostic factors at baseline or at time of progression. After adjusting for these differences, a numerical benefit in post-progression OS favoring TBP was observed (HR 0.67, 95% CI [0.38,1.19]). Serial review of radiographic time points identified initial progression of sum of target lesions followed by stabilization for > 3 months after initial progression in some TBP pts. Safety profile during TBP was consistent with that expected for pts established on tebe and no pts experienced an AE leading to treatment discontinuation. Conclusions: An OS benefit observed for tebentafusp among mUM patients who have initial radiographic progression demonstrates that RECIST assessment underestimates benefit. In a post-hoc analysis of OS following initial radiographic progression, continued treatment with tebentafusp was associated with numerically longer OS after adjusting for key prognostic variables. Tebentafusp treatment beyond progression was tolerated without new safety signals and, in some patients, was associated with radiological stabilization of sum of target lesions for > 3 months following the initial progression. Clinical trial information: NCT03070392.

TPS6596 Background: Immune checkpoint inhibitors (ICI) extend survival for patients with advanced cancer, particularly melanoma and lung cancer, though responses are heterogeneous and treatment may be complicated by immune-related adverse events that are important for patients and their caregivers to recognize. The aim of this trial is to evaluate the feasibility and preliminary efficacy of an educational video and question prompt list (QPL) in improving patients’ and caregivers’ understanding of what to expect from immunotherapy. Methods: In this randomized controlled trial of a novel educational intervention to improve immunotherapy knowledge, we will enroll 140 adult patients with advanced melanoma or lung cancer (small cell or non-small cell) who have a plan to initiate therapy with an ICI and their caregivers. Patients assigned to the intervention will receive a link to a video about the risks and benefits of ICI treatment developed by the study team as well as an ICI-focused QPL that includes questions about the goal and likelihood of benefit of ICIs. We will enroll the first ten patients in an open pilot and we will refine the intervention and study procedures based on pilot findings. We will randomize the remaining 130 patients to receive either the intervention or a usual care control. Randomization will be carried out using the permuted block approach with stratification by cancer type, and patient-caregiver dyads will be assigned to the same study arm. Participants on both arms will complete surveys at enrollment (baseline), 72 hours post-enrollment, and 6 weeks post-enrollment. The primary outcome of the study is feasibility of intervention delivery, defined as 70% of approached patients enrolling in the trial and 80% of enrolled patients watching the video, reviewing the QPL and completing the first assessment. We will also evaluate the preliminary efficacy of the intervention in 1) improving patient and caregiver knowledge, measured by a survey of knowledge questions that we developed and previously pilot tested with a sample of 105 patients; 2) enhancing patient-clinician communication, assessed by evaluating the number of questions patients asked in audio-recorded visits with their oncology clinicians after reviewing the QPL; and 3) reducing anxiety, measured by the State and Trait Anxiety Index. We will assess change in knowledge scores and anxiety from baseline to 72 hours post-enrollment and 6-weeks post-enrollment using the analysis of covariance model, adjusting for baseline scores and relevant covariates. The number of questions asked by patients and caregivers will be assessed by coding transcripts of oncology visits and comparing between arms using the negative binomial model. Study accrual to the open pilot phase began in February 2021. Current enrollment: n = 5. Clinical trial information: 04670445.

2510 Background: SAR439459 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR439459 with an anti-PD-1 showed improved anti-tumor activity compared to single agent. Here we report preliminary results of SAR439459 ± cemiplimab in a first in human study. Methods: This is an open-label study (dose escalation and expansion) of SAR439459 ± cemiplimab administered intravenously in adult patients with advanced solid tumors to determine safety and tolerability, the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 ± cemiplimab, pharmacokinetics (PK); pharmacodynamic (PD) and preliminary clinical benefit. In Part 1A, SAR439459 (0.05-15 mg/kg) was administered as monotherapy Q2W in an adaptive Bayesian design with overdose control. In Part 1B, SAR439459 doses cleared from monotherapy were administered in combination with fixed dose of cemiplimab (3 mg/kg Q2W or 350 mg Q3W) in a 3+3 design. Results: As of 31 January 2020, 28 (1A) and 24 (1B) patients with ECOG performance status of 0-1 with a median age of 60.5 and 63 years respectively were enrolled. In Part 1A, 25 patients (89.3%) had at least one treatment emergent adverse event (TEAE) and 15 (53.5%) experienced grade (G)≥ 3 events. In Part 1B, 22 patients (91.7%) had at least one TEAE and 14 (58.3%) experienced G ≥ 3 events. Dose-limiting toxicities (DLTs) were evaluable in 24 and 21 patients respectively. In 1A, 2 DLTs were reported in 2 of 8 evaluable patients in dose level (DL) 4: G5 brain stem hemorrhage in a patient on concomitant low molecular weight heparin treatment and G3 myocardial infarction in a patient with diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and hypertension. In 1B, 1 of 6 evaluable patients in DL5 had DLTs (G3 ALT and AST increase). MTD was not reached in either part. Ten patients had best overall response of stable disease: 6 in 1A and 4 in 1B. The PK of SAR439459 was dose proportional over the dose range tested with no evidence of cemiplimab effect on SAR439459 PK, when given in combination. Treatment with SAR439459 ± cemiplimab led to rapid reduction in total plasma TGFβ level in all dose levels tested and induced CD8 & NK cells expansion and Th1 cytokines production, suggesting peripheral T cell activation. Preliminary results from paired tumor biopsies collected from patients treated with SAR439459 ± cemiplimab in expansion showed trend of TGFβ signaling pathway inhibition and conversion from excluded to inflamed tumor-immune phenotype. Conclusions: SAR439459 ± cemiplimab showed an acceptable tolerability profile overall. MTD was not reached. Peripheral and tumor target engagement and modulation of key immune cells was observed in treated patients. Dose expansion cohorts are currently enrolling selected solid tumor patients. Funding: Sanofi. Clinical trial information: NCT03192345.

9530 Background: Ultraviolet (UV)-induced high tumor mutation burden (TMB) of NACM is associated with response to anti-PD-1 monotherapy (aPD-1). Anatomic location of the primary lesion (reflecting UV exposure) and race (reflecting eumelanin level) may serve as surrogates for TMB and be associated with varying response and irAE patterns. Methods: Pts with advanced NACM receiving aPD-1 between 2009-2019 were retrospectively analyzed from 5 institutions in the US, Australia and China. Best response, survival (PFS and OS), and organ/system-specific irAEs were compared by race (Caucasian [C] vs non-Caucasian [NC]) and primary anatomic site. Results: Among 697 patients, 616 were C, 81 were NC. Complete response rate (CRR) was 24.8% (95%CI, 21.4-28.4) and 2.6% (95%CI, 0.3-9.1) and ORR was 54.9% (95%CI, 50.9-58.9) and 15.6% (95%CI, 8.3-25.6) in C and NC, respectively (both P

3059 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. Several studies demonstrate that 20-50% of BM patients respond to ICI. The reasons behind this wide variability in treatment response is not clear. Therefore, using physiologic imaging, we seek to identify the longitudinal biological changes exerted on BM as a result of ICI administration. Methods: Given the importance of aberrant tumor vasculature in cancer proliferation, we have focused on assessing changes in vascular physiology. We analyzed standard post-contrast and dynamic susceptibility contrast (DSC) MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. As per modified RECIST and RANO criteria for immunotherapy, volumetric increase of > 40% was defined as progressive disease (PD), a decrease of > 60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 35 patients, out of the total cohort of 60, have undergone DSC-MRI analysis. Histologies include 15 with breast cancer, 6 with non-small cell lung cancer, 4 with melanoma, and 10 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 35 evaluable patients include 4 PR, 12 SD, and 19 PD. Thus far, we found that ICI-resistant BM had a 50% increase in cerebral blood flow (CBF), 105% increase in cerebral blood volume (CBV), a 15% increase in mean transit time (MTT), and an 80% increase in vessel caliber at 6 weeks post-treatment. On the other hand, ICI-responsive BM had no change in CBF, a 33% increase in CBV, a 10% decrease in MTT, and no change in vessel caliber. Ongoing analysis to uncover additional vascular changes (e.g. tumor oxygenation, vessel size index) within BM to ICI are pending. Conclusions: Our data provides evidence that effective ICI for BM is associated with unique intra-tumoral vascular physiology. With final analysis, we will uncover other facets of vascular physiology that correlate with ICI response, and may reveal mechanisms of response/resistance within tumors to ICI.

6579 Background: Immunotherapy is a novel treatment paradigm that has improved survival for patients with advanced melanoma and lung cancer and poses new risks of immune-related adverse events, which are important for patients to recognize promptly. We aimed to describe patients’ knowledge about the risks and benefits of immunotherapy, and their understanding of the goal of treatment with immunotherapy. Methods: We conducted a cross-sectional study of patients at a single institution who had initiated therapy with an immune checkpoint inhibitor for advanced melanoma, small cell lung cancer, or non-small cell lung cancer in the past 12 weeks. We assessed patients’ knowledge about immunotherapy with a 9-item knowledge questionnaire (score range 0-100; higher score represents greater knowledge). We used the Perception of Treatment and Prognosis Questionnaire to assess patients’ understanding of the goal of their treatment. We used the two-sample t-test to compare knowledge scores and chi-square test to compare goals of therapy between patients with melanoma and lung cancer. Results: A total of 105 patients (57 with melanoma, 48 with lung cancer) completed the study questionnaire. Participants had a median age of 69 years (range 36-89), and 33% (35/105) were female. Participants’ mean knowledge score was 69.0 (SD = 23.3). Overall, 91% (96/105) of patients endorsed that immunotherapy works by turning on the body’s immune system to recognize and attack cancer cells and 33% (35/105) correctly identified that immunotherapy does not kill all rapidly dividing cells. With respect to immunotherapy side effects, 68% (71/105) of patients reported that immunotherapy side effects can affect any organ in the body and 65% (68/105) endorsed that side effects from immunotherapy can occur at any time, even after the treatment ends. Overall, 34% (36/105) of participants reported that the primary goal of their treatment is to cure their cancer. Participants with melanoma had higher mean knowledge scores compared to those with lung cancer (74.7 vs. 62.3, P = 0.003). Participants with melanoma were also more likely to report that the goal of their immunotherapy was to cure compared to those with lung cancer (58% [33/57] vs. 6% [3/48], P < 0.001) and that their oncologist had said that immunotherapy would cure their cancer (19% [11/57] vs. 0% [0/48], p = 0.005). Conclusions: We observed substantial knowledge deficits about immunotherapy and perceptions that immunotherapy is a cure for advanced cancer, particularly among patients with melanoma. These findings underscore the need for interventions to enhance patients’ knowledge about immunotherapy and to help them understand the goal of immunotherapy for patients with advanced cancer.

2504 Background: COM701 is a novel first in class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG), blocking its interaction with its ligand, PVRL2. Blocking of PVRIG leads to enhanced activation of T/NK cells and in mouse models inhibits tumor growth. We report new and updated results on safety/tolerability/pharmacokinetics and antitumor activity from this ongoing study including final results in dose escalation combination cohort, monotherapy expansion cohort (MEC). Methods: We enrolled a total of 51 DLT-evaluable pts: Arm A (COM701 mono dose escalation), 16 pts in 8 cohorts (0.01 – 20 mg/kg IV Q3/4 wks); Arm B (COM701 0.3 – 20 mg/kg + nivolumab (NIVO) 360 mg/480 mg IV Q3/Q4 wks), 15 pts in 5 cohorts; 20 pts in MEC (NSCLC, OVCA, breast, endometrial and CRC) at the recommended dose for expansion(RDFE), 20 mg/kg IV Q4 wks. Key inclusion criteria: Age ≥18 yrs, histologically confirmed metastatic solid malignancy, has exhausted available standard tx, ECOG 0-1, prior ICI permissible (except prior tx with a PVRIG inhibitor). Key exclusion criteria: active autoimmune disease requiring systemic tx, hx inflammatory lung disease. Primary objectives – safety/tolerability of COM701 ± NIVO (AEs, CTCAE v4.03), PK, RDFE. Key secondary/exploratory objectives - antitumor activity of COM701 ± NIVO (RECIST v1.1), evaluation of PVRL2 expression in tumor biopsy, blood cytokines and immunophenotyping. Results: No DLTs were reported in Arms A or B. COM701 PK profile similar in Arm A, 20 mg/kg IV Q4 wks (cohort 8) and Arm B cohort 5 (COM701 20 mg/kg + NIVO 480 mg; all IV Q4 wks). Frequency of TEAEs in safety population (N=54 pts): pts on COM701 mono (N=38)- No AE (4), Grade≤2 (21), G3 (11), G4 (1), G5 (1, PD), pts on combo (N=16) - Grade≤2 (8), G3 (7), G5 (1, PD). Serious TEAE: pts on COM701 mono 11/38, pts on combo 6/16. Most frequent AEs in Arm A: Grade ≤2 fatigue 12/38 pts (31%), nausea 9/38 (23%); Arm B: fatigue 7/16 pts (44%) and AST increased 4/16 pts (25%). Antitumor activity - in Arm A (cohort 8), a pt with platinum resistant primary peritoneal cancer had confirmed PR ongoing 14 months. In Arm B (COM701 10 mg/kg + NIVO 480 mg, all IV Q4 wks), a pt with anal SCCA; confirmed CR, ongoing 18 months, last tx with prior PD on NIVO. In addition, a pt with renal cell CA had confirmed SD [ongoing 13 months, COM701 0.3 mg/kg + NIVO 360mg; IV Q3 wks],] In MEC, 30% (6/20 pts) had best response of SD [1-endometrial, 3 NSCLC, 2 OVCA], 2 pts [NSCLC, OVCA] ongoing at 6/4 months. Overall 16pts had prior tx-refractory disease, 9(56%) had best response of ≥SD. Of 18 pts with prior tx with ICI, 13 (72%) had best response of ≥SD. Datacut 14Dec2020. Conclusions: COM701 ± NIVO well tolerated with no new safety signals. Encouraging signal of antitumor activity including in pts with prior tx with ICI or prior tx-refractory disease. Clinical trial information: NCT03667716..

9527 Background: Tebe is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. In this Phase (Ph) 3, randomized trial of first line (1L) metastatic uveal melanoma (mUM) [NCT03070392], tebe significantly improved overall survival (OS) vs. investigator’s choice (IC) in the intention-to-treat population (ITT). In previous trials, tebe-related skin adverse events (AEs), hypothesized to be on-target, off-tumor activity against gp100-expressing melanocytes, were associated with improved OS. This association was tested prospectively as a co-primary endpoint in the Ph3 study. Methods: 378 1L HLA-A*02:01+ mUM pts were randomized 2:1 to tebe (n = 252) or IC (n = 126). Co-primary endpoints were 1) OS in all randomized pts (ITT) and 2) OS in tebe-randomized pts who develop any grade rash in week (wk) 1 vs. all receiving IC. Rash was defined as composite of preferred AE terms. Melanocyte-related AEs (MRAEs) were defined as pigment change AEs in the skin or hair. Overall study-wide alpha was controlled at 0.05, with 90% assigned to ITT and 10% to rash. This analysis was conducted on the first interim analysis (data extracted Nov-2020). Results: In the 245 tebe treated pts, the characteristic skin related AEs included most frequently rash (at any time) in 201 pts (82%), pruritis in 167 pts (68%), MRAEs in 109 pts (45%) and erythema in 69 pts (28%). While rash, erythema and pruritis mostly occurred in the first 4 weeks, MRAEs occurred after a median of 2.7 mo. Rash captures most pts, 201/227 (89%), who have any of these skin related AEs. Rash occurred in 146 pts (60%) by wk 1; 179 pts (73%) by wk 2; and 195 pts (80%) by wk 3. Tebe pts with wk 1 rash had significantly longer OS vs. the IC arm, HR 0.35 (95% CI 0.23, 0.53), p < 0.0001. The estimated 1-yr OS rates were 83% vs 58%, respectively. When expanded to include tebe pts with rash through wk 3, the 1-yr OS rate of 75% was still numerically higher than IC. The 50 (20%) tebe pts who did not experience rash by week 3 had 1-yr OS rate of 55%. Conclusions: In 1L mUM pts, tebe significantly improved OS compared to IC in the ITT analysis. Week 1 rash, presumed due to tebe redirection of T cells to gp100+ skin melanocytes, was associated with a very strong OS benefit. Therefore, rash may be a marker that the immune system can be mobilized by tebe to target gp100+ cells. The vast majority of tebe pts will develop a rash at some point, and tebe pts without rash may still derive benefit. Clinical trial information: NCT03070392.

9509 Background: Tebentafusp (tebe) is the first T cell receptor (TCR) therapeutic to demonstrate an overall survival (OS) benefit in a randomized Phase 3 (Ph3) study [ NCT03070392 ]. In Ph2, 42% of pts with best overall response (BOR) of progressive disease (PD) survived > 1 year (yr), suggesting RECIST-based radiographic assessments underestimate OS benefit of tebe. Here we analyzed OS in the Ph3 study in a cohort of pts with BOR of PD by comparing tebe to the control arm of investigator’s choice (IC). Methods: 378 pts were randomized in a 2:1 ratio to tebe vs. IC. BOR was assessed by investigators using RECIST v1.1. Treatment beyond first disease progression (TBP) was permitted for both arms. On the IC arm, only patients receiving pembrolizumab (pembro) continued with TBP and were included in the TBP-related analyses. No crossover to tebe was permitted; investigators were free to choose subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). Kaplan-Meier estimates of OS were based on Day 100 landmark to eliminate immortal time bias and to capture majority of the PDs. Results: By Day 100, PD as BOR occurred in 52% (130/252) of tebe pts (PD-tebe) vs. 60% (76/126) of IC pts (PD-IC). Key baseline characteristics including lactate dehydrogenase, alkaline phosphatase, ECOG performance, age, and sex were similar between PD-tebe vs PD-IC. The proportion of pts with PD due to progression of target lesions (TL), non-TL, or new lesions were also similar between the two groups. More pts received TBP among PD-tebe 53% (69/130) vs PD-pembro 16% (10/61). Median duration of TBP was longer for PD-tebe (7 weeks) vs PD-Pembro (3 weeks). The safety profile of PD-tebe pts during TBP was similar to all tebe-treated pts. OS was superior for PD-tebe vs PD-IC, HR = 0.41 (95%CI 0.25-0.66), even when considering key baseline covariates. While some pts had regression of TL despite diagnosis of PD ( < 10% of pts), the OS benefit remained even when limited to pts with best change of tumor growth of TL, HR 0.46 (0.29, 0.73). 58% (75/130) PD-tebe and 52% (40/76) PD-IC pts received subsequent therapies. In a landmark OS analysis of these pts beginning on 1st day of subsequent therapy, prior tebe was associated with better OS vs. prior IC, HR 0.59 (95%CI 0.36-0.96). Conclusions: Tebe is the first TCR therapeutic to demonstrate an OS benefit in a solid tumor. Surprisingly, a strong OS benefit from tebe is observed even in pts with BOR of PD, suggesting that RECIST-based radiographic assessments do not capture the complete benefit from tebe. The safety profile of tebe during TBP was consistent with that for long-term tebe treatment. Clinical trial information: NCT03070392.

2654 Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.

9538 Background: Percutaneous image-guided cryoablation (cryo) is an established minimally invasive oncologic treatment that modulates the immune microenvironment. We hypothesized that cryo can augment anti-tumor responses in melanoma patients progressing on immune checkpoint inhibitors (ICI). Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryo of an enlarging lesion and ICI continuation for a minimum of 2 additional cycles. Computed tomography was performed at 6-8 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-12 weeks. The primary endpoint was safety and feasibility. Secondary endpoints were overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analyses on pre- and post-cryo tumor biopsy and blood samples were performed. Results: From May 2018 through July 2020, 20 pts were screened, 18 enrolled and 17 treated per protocol. All pts received prior PD-1/PD-L1 monotherapy and 12 (67%) experienced primary resistance to ICI. Median follow-up was 8.5 months. Ablated lesions included lymph nodes (n = 4), lung/pleura (n = 4), soft tissue/bone (n = 3), adrenal (n = 3), chest wall (n = 1), and kidney (n = 1). Peri-procedural events occurred in 3 cases (pneumothorax, diaphragm puncture, osteomyelitis). One pt. with underlying ICI-induced hypophysitis experienced an adrenal crisis post-procedure, which rapidly corrected with stress-dose steroid administration; there were no de novo immune-related adverse events post-ablation and there were no grade 4/5 events. In evaluable pts (n = 17), ORR was 18% and DCR was 47% (3 PR, 5 SD). To investigate the inflammatory state of the tumor microenvironment prior to cryo, PD-1, CD8+ TIL IHC, was performed and will be presented at the meeting. Additional exploratory analyses (serial ctDNA analysis, single cell RNA sequencing, HLA-subtyping) are ongoing. Conclusions: Cryoablation in patients with unresectable melanoma following progression on ICI is feasible with an acceptable side effect profile. Efficacy data of this potentially synergistic approach in metastatic melanoma is encouraging. Correlative analyses are underway to identify biomarkers of response to this novel strategy. Clinical trial information: NCT03290677. [Table: see text]

3092 Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931 .

10020 Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P < .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.

10062 Background: Despite recent successes with immune checkpoint blockade (ICB) in melanoma, the prognosis for most patients remains dire. Whereas small fraction of patients are able to achieve disease control, most do not respond or are limited by immune-related toxicities. Robust non-invasive predictors of ICB response have the potential to guide clinical decision and alter management of patients, however, no such predictors currently exist. Methods: We applied a highly-multiplex Proximity Extension Assay to simultaneously detect > 1000 proteins in the plasma of anti-PD-1 treated melanoma patients. Our cohort comprised 116 patients, 66 responders (R) and 50 non-responders (NR). Additional 65 patients comprised a validation cohort with 30 R and 35 NR, and included 50 patients who developed treatment-related toxicities. Plasma samples were collected at baseline, 6-weeks and 6-months after starting the treatment. A subset of patients had single-cell RNA-seq performed on tumor tissue. Group differences and treatment effects were evaluated by linear model with maximum likelihood estimation for model parameters and Benjamini and Hochberg multiple hypothesis correction. Results: At baseline, 6 significantly differentially expressed (DE) proteins were identified between R and NR. Elevated expression of ST2 and IL-6, two key immunoregulatory proteins were found in NR. At 6-weeks, more dynamic changes occurred and 79 significantly DE proteins were identified between R and NR, including proteins implicated in primary or acquired resistance as IL-8, MIA, TNFR1 and potential novel targets as MCP-4/CCL13, ICOSLG and VEGF. Proteomic changes identified at baseline and 6-weeks were more profound at 6-months, and moreover 238 proteins were confirmed significant between R and NR. Importantly, we were able to leverage these differences to build classifiers of R and NR subsets. We compared mRNA expression of DE proteins within the tumor microenvironment by leveraging scRNAseq data from a subset of these patients. Enriched expression of these genes was uncovered in certain myeloid and exhausted T cell subsets, thus shedding insight into the potential role of these cell subsets in ICB response. Conclusions: Plasma proteomic profiling of anti-PD1 treated patients identified important tumor and immune changes associated with response. Non-invasive means discovery of circulatory protein biomarkers may predict sensitivity to immunotherapy and uncover biological insights underlying primary resistance.

2529 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) for melanoma and lung cancer. This breakthrough has prompted interest in evaluating ICI in BM of other histologies. However, accurately assessing intracranial response in patients undergoing ICI is a challenge, as current measures cannot distinguish pseudoprogression from true tumor progression. To shed light on potential biomarkers of response, we prospectively use perfusion MRI to identify characteristic vascular signatures in a BM-specific trial of ICI. Methods: As part of an ongoing phase II study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 53 patients have been enrolled, of whom 44 have received at least baseline advanced MR imaging. Histologies include 21 with breast cancer, 5 with non-small cell lung cancer, 4 with melanoma, and 13 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 33 evaluable patients include 4 PR, 10 SD, and 19 PD. On preliminary analysis, there was a correlation between increased tumor cerebral blood volume/flow with tumor progression. Correlation of additional vascular physiologic parameters (e.g. vessel caliber, tissue oxygenation) and volumetric response to patient outcome and standardized response criteria (iRANO) are ongoing. Conclusions: Pembrolizumab likely has anti-tumor efficacy in BM. Our data provides potential evidence that effective ICI is associated with a decrease in perfusion. Ongoing analyses to uncover additional vascular changes – specifically longitudinal metrics reflecting vascular structure and function - within BM to ICI are pending. These findings have potential to illustrate mechanisms of efficacy for ICI and biomarkers of response in this patient population.

3609 Background: Combination BRAF and MEK inhibitor therapy is associated with response in patients (pts) with BRAF mutant (mut) solid tumors; however critical limitations for the durable activity of these agents remains. Preclinically, the addition of heat shock protein 90 (HSP90) inhibitors improves the efficacy of BRAF inhibitor (BRAFi) therapy in both BRAFi -sensitive and resistant mutant cell lines. Methods: CTEP study 9557 (NCT02097225) is a phase I study designed to determine the safety and efficacy of the small molecule HSP90inhibitor, AT13387, in combination with dabrafenib (dab) and trametinib (tram) in patients with BRAF V600E/K mut solid tumors. Prior chemotherapy, immunotherapy, BRAF and/or MEK exposure was permitted. The primary objective was to determine the maximum tolerated dose (MTD). Results: From July 2015 to June 2018, 22 patients with previously treated, metastatic BRAF V600E/K mut solid tumors were enrolled using a 3 + 3 design at four dose levels (DL) (Table). Pts were predominantly female (59%) with a median age of 57.5yrs (37 -75). The most common tumor type was BRAF V600Emut colon cancer (N=12). Dose limiting toxicities (DLTs) occurred in one patient in DL3 and one in DL4, specifically grade 3 myelosuppression and fatigue, respectively. The MTD was Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. Twenty-one of 22 pts were eligible for efficacy assessment. Best response, per RECIST 1.1, was partial response (PR) in 2 pts – one with colon ca (TKI-naïve), one with melanoma (TKI-resistant) - stable disease (SD) in 8 pts, and disease progression (PD) in 11 with a disease control rate (PR + SD) of 47.6% (90% CI: 29% - 67%). Median time to progression was significantly longer in DL3 (3.9 mths; 1.8-9.2) compared to DL1 (1.6mths; 0.9-1.7) or DL2 (1.5; 0.6-3.6). Median PFS and OS were 1.8mths (90% CI: 1.6 – 3.7mths) and 5.1 mths (90% CI: 2.5 -10.6mths), respectively. Median OS was not reached in DL3/4. Correlative data on the expression of the key signaling proteins relating to response will be presented at the meeting. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was determined to be safe with evidence of disease control in a heavily pre-treated population of pts with BRAF V600E/K mut solid tumors. Clinical trial information: NCT02097225 . [Table: see text]

10036 Background: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. This has led to efforts to treat uveal melanoma with MEK inhibition with mixed results. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases which has undergone phase I testing. Methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a total sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts. Two responses were required to continue to the second stage. Results: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 yrs. (34 -76). Sites of metastasis included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with BVD-523 and other ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease (SD) in 4 pts, and disease progression (PD) in 7 patients. Two patients were unevaluable for response due to withdrawing themselves from the study. Median time to progression was 2.0 months (90% CI: 1.8 – 3.6 mos.). There were eight deaths due to disease progression with a median survival time of 6.9 months (90%CI: 3.2 to 8.3 mos.). Analysis of correlative data from pre- and on-treatment biopsies exploring the change in expression of key signaling proteins relating to treatment is underway. Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed on study were consistent with what would be expected with MAPK pathway inhibition. Clinical trial information: NCT03417739.

3116 Background: The mechanistic relationship between clinical benefit and immune-related adverse events (irAEs) in response to immune checkpoint inhibitors (ICIs) remains unclear, with several clinical studies reporting that irAEs are biomarkers of responses. Single-cell RNA sequencing (scRNAseq) analysis of tumors from patients with advanced melanoma before and after treatment with ICIs have identified immune cells that correlate with response to ICIs. We sought to evaluate if these populations were also associated with irAEs. Methods: A published scRNAseq data set generated with the Smart-Seq2 protocol (Sade-Feldman M, et al. Cell 2018.) was re-analyzed, stratified by two definitions of irAEs: (1) toxicity requiring systemic immunosuppression (prednisone > 10mg/day) or (2) systemic immunosuppression and/or endocrinopathy. Unbiased single-cell analysis was performed, followed by sub-clustering of T cell populations. The percentage of cells in each cluster was determined on a per sample basis. Results: 13,184 immune cells from 39 samples collected from 25 patients were re-analyzed. 27 samples were from patients who did not respond to ICIs, while 12 samples came from responding patients. 21 samples came from patients who required immunosuppression, 5 samples from patients with isolated thyroiditis, and 13 samples from patients who met neither irAE criteria. Unsupervised scRNAseq analyses focused on ICI efficacy re-capitulated published associations between response and populations that included B-cells (p < 0.01) and TCF7 expressing T-cells (p < 0.01). While these cell populations were not associated with either definition of toxicity, we observed a non-Treg CD4 expressing T cell population (0.8-10.5% cells/sample) that positively correlated with either definition of toxicity (p < 0.05) but not efficacy. Conclusions: In a patient cohort with advanced melanoma, tumor-infiltrating immune cell populations associated with response to ICI therapy were not associated with irAEs. This suggests that biomarkers of ICI response may not function as biomarkers of irAEs, and ongoing analysis will seek to validate this result. Understanding the differences between ICI response and irAEs may identify new therapeutic targets for maximizing efficacy while mitigating toxicity.

89 Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination blockade between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariate logistic regression analyses. External validation was performed on an independent cohort from Massachusetts General Hospital. Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). The odds of colitis were higher in patients treated with ipilimumab either as monotherapy or in combination with nivolumab compared to those treated with pembrolizumab. Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1–0.9). These results were confirmed in the validation cohort of 169 patients of whom 49 developed ICI colitis (29%). Pretreatment neutrophil/lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1–0.9) only in the discovery cohort. Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and GVHD. This observation should be validated prospectively in future studies. [Table: see text]

TPS23 Background: COM701 is a novel 1st-in-class monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2. In preclinical experiments inhibition of PVRIG alone and in combination with a PD-1 inhibitor leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. Novel checkpoint therapies are needed for the treatment of patients with advanced malignancies. We hypothesized that COM701 monotherapy and in combination with nivolumab will be safe and tolerable and demonstrate preliminary antitumor activity in pts with advanced solid malignancies. Methods: This ongoing phase 1 study (NCT03667716) is evaluating the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 or Q4 weekly and in combination with nivolumab 360 mg IV Q3 weekly or 480 mg IV Q4 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed advanced solid malignancy and has exhausted all available standard therapy, ECOG performance status 0-1, prior ICI permissible. Key Exclusion Criteria: Symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day or 28-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Key secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701 as monotherapy and in combination with nivolumab. Study Design: Hybrid accelerated titration and 3+3 study design. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. Analyses of all study objectives are descriptive and hypothesis generating. As of the date of this submission dose level 8 of COM701 monotherapy and dose level 3 of the combination arm are open to enrollment. Updated data will be presented at the conference. Clinical trial information: NCT03667716.

3001 Background: LY3214996 is a selective and potent ERK1/2 inhibitor that has demonstrated tumor growth inhibition in several pre-clinical tumor models with BRAF, RAS, or MAP2K1 mutations. This is the first-in-human Phase 1 Study of LY3214996 in adv CA pts. Methods: The goals of this DE study were to determine a recommended Phase 2 dose (RP2D), safety, pharmacokinetic (PK), and preliminary efficacy of LY3214996 (NCT02857270; I8S-MC-JUAB; Eli Lilly & Co.). Pts with adv CA, ≥18 yrs of age, ECOG ≤1, and with adequate organ function were eligible. Pharmacodynamic (PD) biomarkers including pRSK were evaluated in blood and paired tumor tissue. The DE phase evaluated PO doses using the Bayesian model-based toxicity band method. Results: A total of 51 pts with median age of 62 yrs (range: 21-81) received at least 1 dose of LY3214996 with a median of 3 cycles (range: 1-12). Most pts had a mutation in RAS (N = 33) or BRAF (N = 16) and had a median of 4 prior lines of treatment. The DLTs observed in the study include grade (G) 3 cough and fatigue, G3 dehydration, increased creatinine (Cr), G3 increased CPK, G3 rash > 7 days, and 1 pt with renal failure. TRAEs to LY3214996 occurring in ≥10% of pts included nausea, vomiting, diarrhea, dermatitis acneiform, fatigue, pruritus, and blurred vision. LY3214996 exposures increased with dose. Tumor regression was observed in 7 pts with BRAF/non -BRAF mutant CA including 5 pts who failed prior IO/MAPK inhibitors. Four pts achieved stable disease (2 BRAF, 1 RAS and 1 CRAF mutation) that lasted > 4 mos. Up to 100% pRSK decrease from baseline in tumor was observed. Conclusions: LY3214996 had an acceptable safety profile, favorable PK, and potent tumor PD inhibition at RP2D. This supports further exploration of LY3214996 as monotherapy and in combination in CA pts with activating MAPK pathway alterations. Clinical trial information: NCT02857270.

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

e14243 Background: Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment. Through direct modulation of the tumor, it is theorized that this local therapy may modify the immune microenvironment. We hypothesized that it can augment an anti-tumor response when used concurrently with ICI. Methods: In this phase II single-arm study, pts with advanced lung cancer or melanoma progressing on ICI undergo cryo of an enlarging lesion and ICI is continued for a minimum 2 additional cycles. Computed tomography is performed at 4-6 weeks following cryo to determine tumor response in non-ablated lesions per RECIST1.1, with confirmatory scans at 8-10 weeks. The primary endpoint is safety and feasibility. Secondary endpoints are overall response rate (ORR) and disease control rate (DCR) with DCR defined as the percentage of pts who achieve complete response (CR), partial response (PR), and stable disease (SD). Correlative analysis on pre- and post-cryo biopsy specimen, when evaluable, will be performed. A planned analysis to document preliminary safety and feasibility in the first 11 patients was performed. Results: 11 pts (out of planned 40) have been enrolled. 8 with melanoma, 3 with lung cancer. All pts received prior PD-1/PD-L1 monotherapy with 8 pts treated with pembrolizumab, 2 with nivolumab and 1 with atezolizumab. Treated lesions were in lung (n = 4), bone (n = 3), lymph nodes (n = 2), liver (n = 1) and adrenal gland (n = 1). No immune related adverse events occurred. There was one treatment-related CTCAE grade 3 event (osteomyelitis) but no grade 4/5 events. One pt. experienced grade 3 hyponatremia, unrelated to cryo. In evaluable pts (n = 10), ORR was 10% and DCR was 50% (4 SD, 1 PR). Conclusions: During this scheduled safety analysis, cryo following progression on ICI was feasible and had an acceptable side effect profile. Early efficacy data of this potentially synergistic approach is encouraging but warrants further investigation. Clinical trial information: NCT03290677. [Table: see text]

6634 Background: Immune checkpoint inhibitors (ICI) represent a major leap in the treatment of many cancers. Use has rapidly expanded in recent years, yet it is unknown whether hospitalized patients, who are often sicker than those who were studied in clinical trials, derive benefit from ICI. The primary objectives of this study were to characterize the clinical features and outcomes of inpatients receiving ICI at a single institution, and to identify predictors of survival. Methods: After IRB approval, we conducted a retrospective chart review of inpatients with Stage IV solid tumors receiving ICI between 2015 – 2018 at a tertiary care referral hospital. Patients receiving ICI on clinical trial were excluded. We examined the clinical characteristics, readmission rate, and post-discharge survival. We then conducted a Cox multivariable regression analysis to identify predictors of post-discharge survival. Results: A total of 103 patients with Stage IV solid tumors were treated with ICI as inpatients between 2015 – 2018. Average age was 57 years (range = 26 to 85); 57% were male; 27% had ECOG performance status (PS) 3-4; average Charlson Comorbidity Index score was 8.3. Most common tumor types were melanoma (35%) and lung (22%). Seventy-six percent began ICI as an inpatient and 24% received ICI as continuation of outpatient therapy. Seventeen percent experienced an immunotherapy related adverse event, most commonly colitis and pneumonitis. The 30 day readmission rate was 41%. The median post-discharge survival was 31 days; 47% of patients died during admission or within 30 days of discharge; 14% survived more than 6 months. Factors predictive of shorter post-discharge survival were PS of 3-4 relative to PS 0-2 (HR 2.0, p < 0.004), and lung cancer (HR 2.0, p < 0.024) and other tumor types (HR 2.1, p < 0.004) relative to melanoma. Conclusions: While the majority of inpatients receiving ICI died during admission or within 30 days of discharge, a subset of patients with stage IV disease were alive at 6 months. Tumor type and ECOG PS predict post-discharge survival and may be used to identify inpatients more likely to benefit from ICI. These novel findings, which are unique to a single institution, require additional validation.

9552 Background: Melanoma is notorious for its high degree of heterogeneity with the implication that metastases in different sites react differently to immunotherapy. We aimed to explore the site-specific response pattern in anti-PD-1 monotherapy treated advanced melanoma patients. Methods: Clinical data was collected retrospectively from advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital (MGH) from Sept 2009 to Dec 2017. Radiological evaluations were carried out by radiologists from the MGH Tumor Imaging Metrics Core using irRECIST 1.1. Statistical analysis was carried out using ANOVA test. Results: Among 61 evaluated patients, 56 (91.8%) had at least one measurable target lesion(s) at baseline, including 35 (57.4%) patients with measurable lymph nodes (LN)/subcutaneous lesion(s), 25 (50.0%) with lung lesion(s), and 21 (34.4%) with liver lesion(s). At week-12 radiological evaluation after anti-PD-1 monotherapy initiation, lesions at different sites responded differently at marginal statistical significance (P = 0.071), namely mean percent changes compared with baseline were 3.75%, 5.12%, and -30.95% for LN/subcutaneous, liver, and lung lesions, respectively. Among patients who had disease under control (CR/PR/SD) (n = 37, 60.7%) by week-12 evaluation, the mean tumor percentage change at week-24 compared with week-12 were -8.94%, -12.18%, and -5.91% for LN/subcutaneous, liver, and lung lesions, respectively (P = 0.479). Conclusions: Although our small sample size limits definitive discrimination in organ site-specific response differences, it appears that lung lesions respond more quickly and to a greater extent compared with LN/subcutaneous and liver lesions in advanced melanoma patients treated with anti-PD-1 monotherapy. We will explore this in a larger, multicenter cohort.

9564 Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.

130 Background: The response of metastatic melanoma to anti-PD1 is heterogeneous. We performed proteomic profiling of patient plasma samples to build a predictor of immunotherapy response and uncover biological insights underlying primary resistance. Methods: 58 metastatic melanoma patients receiving anti-PD1 (Pembrolizumab or Nivolumab) at MGH comprised the initial cohort, and 150 additional patients comprised a validation cohort. Plasma samples were collected (MGH IRB #11-181) at baseline and several on-treatment time-points. Samples were analyzed for 1102 proteins by a multiplex proximity extension assay (Olink Proteomics). A subset of patients had single-cell RNA-seq (Smart-Seq2 protocol) performed on tumor tissue. Group differences and treatment effects were evaluated using linear mixed models with maximum likelihood estimation for model parameters, and Benjamini and Hochberg multiple hypothesis correction. Results: 70 significantly differentially expressed (DE) proteins were identified across the treatment period, including markers of immune activation (PD1, CXCL9, CXCL10, CD25, IL-17a, among others). 38 significantly DE proteins were identified with on-treatment time points between anti-PD1 responders (R) and non-responders (NR), including several implicated in primary or acquired resistance (IL8, MIA, ERBB2, among others). Importantly, we demonstrate the relationship of these serum biomarkers to overall and progression-free survival, and employed statistical learning approaches to build classifiers of treatment response, leveraging early and late on-treatment time points. Analysis of single-cell RNA-seq data (Sade-Feldman et al, Cell, 2018) of tumor tissue from a subset of these patients revealed that gene expression of most proteins predictive of response were enriched among tumor myeloid cells, with the remainder of proteins being reflective of exhausted T cell states. Conclusions: Whole plasma proteomic profiling of anti-PD1 treated patients revealed DE proteins between R and NR that may enable a liquid biopsy to predict anti-PD1 response. These results unveil a putative role of myeloid cells within the tumor microenvironment in anti-PD1 response or primary resistance.

133 Background: Anti-PD-1 monotherapy has dramatically improved the outcomes of patients with advanced melanoma, yet the majority of patients develop therapeutic resistance. A prognostic model is needed to optimally select patients who are most and least likely to benefit. Methods: We performed a retrospective analysis of 141 advanced melanoma patients treated with anti-PD-1 monotherapy at Massachusetts General Hospital from Sept 2009 to Dec 2017. Demographic and clinical characteristics, baseline and early-on-treatment (median 3 weeks after anti-PD-1 monotherapy initiation) routine laboratory variables, and prognostic data were collected and correlated in both univariate and multivariate analyses. Results: Median progression free survival (PFS) and overall survival (OS) were 7.6 months (95% CI 2.3-12.9) and 57.3 months (95% CI 33.3-81.3), respectively. In multivariate analyses, significant independent prognostic variables ( P < 0.05) in favor of longer PFS included cutaneous subtype, low baseline lactic acid dehydrogenase (LDH); low early-on-treatment derived neutrophil-to-lymphocyte ratio (dNLR); high early-on-treatment albumin, basophil, and red blood cell counts (RBCs); those in favor of longer OS included BRAF V600 mutation; low baseline LDH and neutrophil-to-lymphocyte ratio (NLR); low early-on-treatment LDH; high early-on-treatment total protein, basophil, and lymphocyte counts. Prognostic scoring models (total scale: 0-6) were established based on these independent prognostic factors as dichotomous variables, for both PFS (HR 0.555, 95% CI 0.481-0.641, P

e21569Background: Mechanisms underlying immune checkpoint inhibition (ICI) efficacy and toxicity have yet to be fully elucidated and, to date, there are no reliable biomarkers predictive of the dev...

2007Background: Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). Median survival of patients with LMD is approximately 4-6 weeks and there are no effective tr...

3056Background: MAGE-A10 is expressed in 10-50% of urothelial, melanoma, head and neck (HNC), and non-small cell lung cancers (NSCLC). Affinity-enhanced autologous MAGE-A10c796T cells directed towa...

3060Background: Immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1 antibodies represent a paradigm shift in the treatment of many advanced malignancies. However, immune related adverse ef...

3087Background: Immune related hepatitis (irH) occurs in a subset of patients receiving ICIs. Although the pathologic features of irH have been described, no studies have correlated the histologic ...

9564Background: ICI has shown major benefit in cutaneous malignancies including melanoma and Merkel cell carcinoma. Efficacy data in cSCC is, however, limited. Here we report our institutional expe...

9581Background: Immune checkpoint inhibitors (ICI) have revolutionized treatment in metastatic melanoma (MM), but progression occurs in the majority of patients (pts), and the evolution of resistan...

3013Background: IPI-549 is a potential first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms macrophages from an immune-suppressive to an immune-activating phenoty...

9559Background: Prior studies in pts with BRAFmM have shown increased density of tumor infiltrating lymphocytes (TIL) at 2 weeks (wks) with BRAF +/- MEK inhibition(i), but did not fully characteriz...

9540Background: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for BRAF V600 mutant melanoma, but doses and adverse event (AE) profiles were defined in trials conducted largely b...

127 Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.

3017 Background: Approximately 40-60% of metastatic cutaneous melanoma (CM) patients do not respond to the current immunotherapy (IT) regimens, pointing to other yet unknown factors conferring IT resistance. Based on our recent findings showing that germline expression quantitative trait loci (eQTLs) in immune pathways associate with overall CM survival, in this study we tested whether germline immune-specific eQTLs also impact IT outcomes in CM. Methods: By interrogating a healthy twin cohort expression dataset (MuTHER), we have identified 50 eQTLs most significantly associated with the expression of 265 immune genes. Using the MassARRAY system, these 50 SNPs were genotyped in 138 anti-CTLA-4 treated patients, 59 PD-1 treated patients and 38 patients from combined (COMBO) treatments collected from multi-institutional collaborations. To test the association of SNPs with IT response, logistic regression was performed for each treatment group adjusting by demographic and clinical covariates. Results: We found significant associations with COMBO IT resistance for rs6673928 (OR = 4.249, p = 0.0167), an eQTL in IL10/IL19 which we have recently identified for association with melanoma survival; interestingly, it is a previously established locus associated with the risk of several autoimmune diseases. Additionally, we also identified eQTLs that are associated with IT sensitivity: rs4848306 in IL1-β with resistance to anti-CTLA-4 (OR = 0.373, p = 0.000733) and rs2071304 in SPI1with resistance to anti-PD-1 (OR = 0.3328, p = 0.0271). Conclusions: In this study we report that rs6673928, an eQTL from the IL19/IL10 locus previously shown to predict autoimmunity risk and CM survival, is also a surrogate marker of response to COMBO IT. The associations of rs6673928 with both IT response and CM survival indicate a strong relationship between interleukin pathways and the level of tumor immunogenicity. In addition to its apparent function in immune response, the putative multi-faceted role of this locus in predicting better survival and IT outcomes indicates high potential as a novel clinical target. Additional genetic and functional validation of these findings is currently underway in a large collaborative setting.

e14102 Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major signaling pathways involved in tumorigenesis. Components of these two pathways are frequently mutated in a broad range of tumors. ASN003 is a novel and highly selective small-molecule inhibitor of the RAS-RAF-MEK and PI3K pathways. Methods: The activity of ASN003 was determined using PI3K and BRAF enzymes, and efficacy was studied in human tumor xenograft models in mice. ASN003 is currently being investigated in patients with solid tumors in a Phase 1 trial using an accelerated dose titration design. In Part A, safety and tolerability of ASN003 is being studied in patients with advanced solid tumors. In Part B, safety, tolerability and preliminary efficacy of ASN003 will be evaluated in melanoma, CRC and NSCLC patients with a BRAF, PIK3CA or PTEN mutation. Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: ASN003 showed potent and highly selective inhibition of BRAF and PI3K-α and -δ, and low affinity for PI3K-ß. ASN003 showed strong antiproliferative activity in cell lines and caused significant tumor growth inhibition in xenograft models harboring BRAF and PIK3CA or PTEN mutations. ASN003 showed antiproliferative activity in B-RAF and MEK inhibitor resistant cell lines. ASN003 had a strong antitumor activity in a BRAFV600mutant melanoma PDX model resistant to BRAF inhibitors, vemurafenib and dabrafenib. In humans, to date, ASN003 was well tolerated at 10 and 20 mg QD. Adverse events were mild and peak plasma level of 120 nM at 10 mg QD was achieved with a half-life of > 12 h. Dose escalation is ongoing. Conclusions: ASN003 is a unique small molecule, with highly selective and potent inhibition of BRAF, PI3-α and -δ kinases. ASN003 has strong antitumor activity in various xenograft tumor models harboring both BRAF and PIK3CA/PTEN mutations, and in a BRAF inhibitor resistant melanoma PDX model. To date, ASN003 was well tolerated and achieved good systemic exposure. Updated and detailed clinical, PK and PD results will be presented. Clinical trial information: NCT02961283.

TPS3098 Background: MAGE-A10 is a cancer/testis antigen that has been identified in 42, 26 and 17% of urothelial, melanoma and head and neck tumors, respectively. This study will evaluate the safety and antitumor activity of genetically engineered affinity enhanced autologous MAGE-A10c796T cells directed towards a MAGE-A10 peptide expressed on tumors in the context of HLA *02:01 and/or *02:06. Methods: This first-in-human T cell dose escalation study utilizes a modified 3+3 design to evaluate safety, including dose limiting toxicities (DLT). Secondary objectives include anti-tumor activity (overall response, duration of response, time to response, PFS, OS) and translational research assessments. Patients are screened under a separate protocol (NCT02636855). Those who are HLA*02:01 and/or *02:06 positive and have inoperable or metastatic (advanced) urothelial cancer, melanoma, or squamous cell head and neck tumors with MAGE-A10 expression and meet all other entry criteria are eligible for treatment. Patients must have received standard of care therapies and have progressive disease. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the MAGE-A10c796 TCR, and infused into the subject (Day 1) after receiving lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day, on days -7, -6 and -5). The DLT observation period will be during the first 30 days following the infusion of MAGE-A10c796T for each patient in all groups. Up to 10 patients will be enrolled at the target dose. Disease assessments will be conducted at week 6, 12, 18 and 24, and then every 3 months until confirmation of disease progression. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02989064. [Table: see text]

2508 Background: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head & neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head & neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429.

e14565 Background: Checkpoint inhibition (CPI) has significant and durable effectiveness against a broadening range of cancers and currently is FDA approved for more than 10 different malignancies. With increasing use of CPI, there is a need to understand the range and extent of immune-related adverse effects (irAE). Though certain irAEs, such as colitis and pneumonitis have been well studied, CPI- induced arthritis (CA) has not been widely recognized nor well characterized with data on the subject largely comprised of case reports and small case series. Methods: We retrospectively reviewed 125 patients (pts) with advanced melanoma treated with CPI to define the incidence and clinical features of CA. We identified 20 pts who developed CA during the course of CPI treatment. Cases were included only if active rheumatic signs or symptoms developed after receiving therapy. Demographic data (gender, age), type of CPI, number of CPI cycles, treatment of CA and other irAE manifestations were extracted from the medical chart. Results: 16% of patients treated with CPI developed CA. Among the 20 pts, the average age at CA onset was 70.3 (43, 84) with 75% of pts male. 80% had received anti-PD-1 monotherapy, 15% combination anti-PD-1 + anti-CTLA-4 and 5% monotherapy with CTLA-4 inhibition. The average number of infusions prior to symptom onset was 13.5 (1-48) after a median time point of 6.6mths on therapy. Basic rheumatologic testing (RF, CCP, ANA) was only positive in 10% of cases. 20% of pts were treated with non-steroidal anti-inflammatory drugs alone, whereas 40% required corticosteroids (systemic or injection). The remaining 40% necessitated treatment with disease modifying anti-rheumatic drugs. Conclusions: CA is a debilitating irAE with a higher incidence (16%) than most other irAEs and a negative impact on the quality of life of pts affected. Based on our retrospective review, this irAE tends to delayed in onset and often requires systemic immune suppressants for effective treatment. We posit that this is an under recognized and undertreated irAE. Further work is needed to better define the clinical factors that may affect or predict its development.