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In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

Background: Desmoplastic melanoma (DM) is a subtype of melanoma with high tumor mutation burden (TMB) due to ultraviolet light damage. A previously published retrospective review of patients with PD-1 blockade treated DM suggested this cancer may be highly responsive to PD-1 blockade (Eroglu et al. Nature 2018). S1512 is the first prospective study investigating PD-1 blockade with pembrolizumab in patients with DM. 1512 Cohort A results were presented and demonstrated a 59% complete pathologic response rate with neoadjuvant pembrolizumab in patients with resectable DM (Kendra et al. ASCO 2022). Herein, we present results from S1512 Cohort B in patients with metastatic DM. Experimental procedures: Patients aged ≥18 with metastatic DM received pembrolizumab 200 mg q3 weeks. Eligibility criteria included: Zubrod PS 0-2, no central nervous system metastases, autoimmune disease, or steroid ≥10 mg of prednisone. The primary endpoint was complete response rate (CR) assessed per RECIST 1.1, with the assumption that CR of 20% or higher indicates that the treatment is of interest. A single stage design with 21 eligible patients would have an alpha of 8.5% (when the true CR is 5%) and a power of 82%. Tumor assessments were performed every 9 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), and toxicity assessment. Biopsies were analyzed by whole exome sequencing (WES) for mutational load and oncogenic driver mutations. Summary of data: 27 eligible patients were enrolled in Cohort B. 93% were male, 70% had Zubrod PS 0, median age 75 (range 59-90). Median number of cycles received: 15 (range 1-34). At the time of data cutoff, 3 patients remain on protocol treatment with pembrolizumab. Treatment was discontinued due to: 2 years of therapy (4), adverse event (AE) (8), physician and patient choice (6), progressive disease (4), and under review (2). Objective response rate (including both confirmed and unconfirmed partial and complete responses) was 85% (95% CI: 66%-96%), with 7/27 CR (26%) and 16/27 PR (59%). Grade 3 or higher adverse events were reported in 10 patients. WES analysis was available for 16 patients. Both baseline (N=10) and on-treatment biopsies (N=12) were evaluated for canonical genetic drivers of melanoma; 7 patients had tumors with loss of function (LOF) mutations in NF1, and all had mutations in TP53, with no case having activating mutations in BRAF or NRAS, consistent with the known genetic alterations in DM. The median TMB in baseline biopsies was 79.4 Mut/Mb (range 34.3-159). Conclusion: Patients with metastatic DM are exceptional responders to single agent PD-1 blockade with pembrolizumab. Based on this data, the pathologic subtype of melanoma can be used as a predictive biomarker of response to single agent pembrolizumab. Funding: U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Citation Format: Kari Kendra, Shay Bellasea, Zeynep Eroglu, Siwen Hu-Lieskovan, Katie M. Campbell, William Carson, David Wada, Jose A. Plaza, Jeffrey Sosman, Gino K. IN, Alexandra Ikeguchi, John Hyngstrom, Andres Brohl, Nikhil I. Khushalani, Joseph Markowitz, George Negrea, Samer Kasbari, Gary C. Doolittle, Umang Swami, Toni Roberts, Sapna P. Patel, Elad Sharon, James Moon, Michael C. Wu, Antoni Ribas. S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT009.

Background: Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is approved for adult HLA-A*02:01+ patients with unresectable or metastatic uveal melanoma (mUM). In the Ph2 IMCgp100-102 study of pts with previously treated mUM (NCT02570308), tebentafusp demonstrated a median OS of 16.8 months and 1-year OS of 61% after a minimum 2 yrs of follow-up, nearly double the historical observed rates.12, Here we present the final analysis of OS of the Ph2 IMCgp100-102 study. Methods: 127 HLA-A*02:01+ 2L+ pts with mUM were dosed weekly with intravenous tebentafusp following intra-patient dose escalation of 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Primary objective was overall response rate and secondary objectives included safety and OS. OS was estimated by Kaplan-Meier method. Survival for ctDNA evaluable patients was assessed. Analyses are based on a 17 Oct 2022 database lock. Results: With a median follow-up of 46 months, median OS was 16.8 (95% CI: 12.3-21.3) months, consistent with previous reports. Estimated 1-yr, 2-yr, 3-yr and 4-yr OS rates were 61%, 36%, 21% and 11%, respectively. ctDNA clearance by week 9 (n=12) was associated with 100% 1-yr, 73% 2-yr, 45% 3-yr and 23% 4-yr survival. OS for patients with poor prognostic factors compared favorably relative to historical benchmarks (Table 1). Mean and median duration of treatment was 9.9 and 5.6 months. Majority of pts who received a subsequent line of therapy received immunotherapy (48/72; 67%) followed by liver-directed therapy (14/72; 19%). No new safety signals were identified. Conclusions: This study provides the longest follow-up of OS for a soluble TCR therapeutic to date. Tebentafusp continued to show unprecedented survival benefit for 2L+ mUM pts, including the poorest prognostic groups, with estimated OS rates that remain nearly double the historical rates observed in this population at a median follow-up of ~4 years. Early ctDNA clearance was associated with indication of survival benefit. 1. Carvajal et al. Nat Med 2022 2. Sacco et al. J Immunother Canc 2021 Table 1. OS in Ph2 IMCgp100-102 versus historical benchmarks Ph2 IMCgp100-102 Historical benchmarks*,† Population 1-yr 2-yr 3-yr 1-yr 2-yr 3-yr Overall 2L+ 61% 36% 21% 37% 15% 9% Subgroups Age ≥ 65 yrs 51% 31% 25% 38% 12% 6% LDH > ULN 44% 22% 11% 23% 8% 3% Baseline largest liver lesion ≥ 3cm 52% 26% 14% 32% 11% 4% *OS benchmark for 2L+ patients calculated from Rantala et al 2019 †OS benchmarks for pt subgroups (all lines of therapy) estimated from digitized OS curves presented in Khoja et al. 2019 Citation Format: Joseph J. Sacco, Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M. Piulats, Matthew Rioth, Douglas B. Johnson, Jason J. Luke, Erique Espinosa, Serge Leyvraz, Laura Collins, Chris Holland, Michelle L. McCully, Takami Sato. Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT223.

Background: Patients with advanced melanoma primarily refractory to single agent PD-1 blockade therapy have an option of receiving the CTLA-4 blocking antibody ipilimumab, but if ipilimumab should be given as a single agent or in combination with the anti-PD-1 nivolumab has not been established prospectively. Methods: Patients aged >18 with metastatic or unresectable melanoma without objective response to anti-PD-1 therapy given without CTLA-4 therapy were randomized 3:1 to receive either ipilimumab 3mg/kg + nivolumab 1mg/kg q3 wks x4 cycles followed by nivolumab 480mg q4wks (ipi/nivo) up to 2 years, or ipilimumab 3mg/kg q3weeks x4 cycles (ipi). Additional key eligibility criteria included ECOG Performance Statue (PS) 0-2, no active central nervous system metastases, autoimmune disease, or need for steroids at doses of >10 mg of prednisone or the equivalent. The primary endpoint was progression free survival (PFS). Disease assessments were performed every 12 weeks until progression. Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. All patients were to submit a fresh tumor biopsy and whole blood for correlative endpoints prior to cycle 1 and again at week 5. Results: 92 eligible patients were enrolled, 69 to ipi/nivo, 23 to ipi. Median age was 64 and 69 in the ipi/nivo and ipi arm respectively. 67% and 65% were male. 65% of patients in both arms had ECOG PS of 0. With a median follow up of 25.3 months, the hazard ratio (HR) for PFS was 0.63 (90% CI 0.41, 0.97) with a statistically significant 1-sided p-value of 0.04 favoring ipi/nivo. The 6-month PFS estimates were 34% (90% CI: 25%-44%) and 13% (4%-27%) for ipi/nivo and ipi respectively. ORR was 28% for ipi/nivo (95% CI 17%-40%) and 9% for ipi (95% CI: 3%-34%). With a median follow up of 24.4 months, 39/69 patients in the ipi/nivo arm and 12/23 patients in the ipi arm had died. 12-month OS was 63% (90% CI 52%-72%) in the ipi/nivo arm and 57% (38%-71%) months in the ipi arm. HR for OS was 0.94 (90% CI 0.54, 1.62) in favor of ipi/nivo with a p-value of 0.42. Adverse event rates were similar in both arms. One treatment related death was reported in the ipi/nivo arm due to disseminated intravascular coagulation and one treatment related death was reported in the ipi arm due to colonic perforation. Conclusions: This is the first prospective randomized study comparing ipi/nivo to ipi alone in patients with melanoma without response to anti-PD1 therapy. Ipi/nivo was associated with improved progression free survival as compared to ipi alone. The response rate of 28% to ipi/nivo as compared to 9% to ipi alone implies that patients who do not respond to PD-1 alone can be rescued with ipi/nivo. The toxicity of combination therapy was manageable. Ipi/nivo is an appropriate standard in patients with metastatic melanoma who do not respond to single-agent PD-1 therapy. ClinicalTrials.gov Identifier: NCT03033576 Funding: NIH/NCI grants: U10CA180888, U10CA180819, U10CA180821, U10CA180868; Other grants: SU2C-AACR-CT06-17 Citation Format: Ari M. Vanderwalde, James Moon, Kari Kendra, Nikhil I. Khushalani, Frances Collichio, Jeffrey A. Sosman, Alexandra Ikeguchi, Adrienne I. Victor, Thach-Giao Truong, Bartosz Chmielowski, David C. Portnoy, Michael C. Wu, Kenneth F. Grossmann, Antoni Ribas. S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT013.

2619 Background: Immune checkpoint inhibitors (ICIs) have made significant improvements in the treatment of cancer patients (pts), but many continue to experience primary or secondary resistance. Here, we leveraged clinical and genomic data to identify prognostic biomarkers in pts treated with ICIs utilizing a pan-cancer approach. Methods: Pts were enrolled to the Total Cancer Care protocol across 18 cancer centers within the Oncology Research Information Exchange Network (ORIEN). RNA-seq was performed on tumors following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM) and were logarithmically normalized. An Auto-Encoder Survival Deep Network (AE-SDN) architecture was developed that combined the reconstruction loss of AE with Cox regression for modeling time to event. For comparison, immunoscore for each pt was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells (Galon, 2020) utilizing CIBERSORTx. The quality of overall survival (OS) predictions was assessed using Harrell’s concordance index (C-index). Log-rank test was used to assess stratified group differences (by ICI or cancer histology) along with Kaplan-Meier (KM) survival analysis of AE-SDN and immunoscore. Results: Pts (n=522) with 4 cancer types including melanoma (n=125), renal cell carcinoma (n=149), non-small cell lung cancer (n=128) and head and neck cancer (n=120) treated with 6 ICI regimens were included in this analysis. ICI regimens were nivolumab (n=219), pembrolizumab (n=202), ipilimumab+nivolumab (n=69), ipilimumab (n=30), avelumab (n=1) and cemiplimab (n=1). The Table summarizes the overall C-index and associated 95% CIs and log-rank P values for the entire cohort (regardless of histology) resulting from our proposed AE-SDN model and the separate estimated immunoscore categorization. AE-SDN top selected genes were mostly related to immunity, carcinogenesis and tumor suppression. The corresponding KM plots showed significantly wider separations of the survival curves in favor of our proposed AE-SDN model relative to the immunoscore with more than 20% improvement in prediction power. Conclusions: Deep network machine learning analysis is a promising approach to identifying relevant prognostic biomarkers in cancer pts treated with ICI. This may lead to novel therapeutic predictive signatures and identification of mechanisms of ICI resistance. Our AE-SDN gene expression signature was significantly prognostic and outperformed the estimated CD3+, CD8+ T Cell immunoscore. Further refinements to our prediction power are ongoing along with more advanced neural network architectures to elucidate related functional pathways. [Table: see text]

2618 Background: Despite the significant improvements in treating cancer with immune checkpoint inhibitors (ICIs), many patients (pts) do not achieve disease control. Using Oncology Research Information Exchange Network (ORIEN) Avatar real-world data conducted under the Total Cancer Care protocol we investigate predictive biomarkers of ICI benefits in pts with advanced malignancies. Methods: Clinical data were normalized as part of ORIEN Avatar. RNA-seq was performed on tumor samples following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM). Gene expressions (GE) were log2(TPM+1) transformed. Mann-Whitney U-test was used to compute differences between groups, and Kaplan-Meier survival analysis was performed. Results: Pts (n=1214) with 27 cancer types treated with ICIs were retrieved from the database, where 1143 and 875 patients were profiled by WES and RNA-seq, respectively. 804 pts had both WES and RNA-seq data. The top six cancer types were renal cell carcinoma (n=206), non-small cell lung cancer (n=173), head and neck cancer (n=157), melanoma (n=154), sarcomas (n=99) and bladder cancer (n=87). The ICI regimens included therapy with atezolizumab (n=87), avelumab (n=12), cemiplimab (n=6), ipilimumab (n=47), nivolumab (n=424), pembrolizumab (n=525) and ipilimumab+nivolumab (n=113). Median overall survival (OS) for the entire cohort was 21.9 months. Patients had significant improvement in OS if ICI was given in the first line ( P

e21505 Background: Uveal melanoma is a rare melanoma subtype with poor outcome from immune checkpoint inhibition (ICI) compared to cutaneous melanoma. UM expresses high levels of Glycoprotein 100 (Gp-100) implicating potential sensitivity to tebentafusp (tebe), a novel immune-mobilizing monoclonal T cell receptor therapy. A recent phase 3 study compared tebe to investigator chosen standard of care (SOC) with crossover at progression. SOC regimens were single agent pembrolizumab, ipilimumab and Dacarbazine with 82% of SOC patients receiving pembrolizumab1. Other single arm studies suggest that survival with combination ICI is superior to single agent. We sought to compare overall survival (OS) of first or second line tebe in relation to combination ICI. Methods: Retrospective chart review at a single institution was conducted on patients with metastatic UM (mUM) treated with tebe on clinical trial between June 2018 and December 2021, either in first [NCT03070392] or second line [NCT02570308] setting. Patients were included if they received ipilimumab plus nivolumab either before or after tebe. Data including patient demographics and factors demonstrated in the phase 2 and 3 trials to correlate with survival including lactate dehydrogenase (LDH), size of largest liver lesion and early onset of rash with tebe were extracted. OS was the main outcome measure and was calculated as the time interval between the date of diagnosis of metastatic disease and date of death. Results: Six patients were identified in our data set as having received both ICI and Tebe, three in each sequence order. Mean characteristics were included in table. OS trended towards improvement in the cohort of patients who received tebe first in sequence both in OS in time from UM diagnosis (42.1 vs 63.5 months) (p = 0.21) and in OS in time from detection of mUM (29.8 vs 42.0 months) (p = 0.28), although neither difference was statistically significant given the small sample size. Conclusions: Our limited data demonstrate longer OS with tebe followed by combination ICI on progression compared to the reverse sequence. This comparison of patients at a single institution is underpowered to show a statistically significant OS difference but does demonstrate a trend in favor of first line tebe similar to the conclusive comparison of tebe and single agent ICI in the randomized trial. Reference: 1. Orloff, Marlana et al. Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in phase 3 randomized trial of first-line metastatic uveal melanoma. (2021): 9526-9526.[Table: see text]

9502 Background: Desmoplastic melanoma (DM) is a rare cancer defined by a dense fibrous collagen matrix. It is associated with high UV exposure leading to a high mutational load. When locally advanced, the standard of care is wide excision and radiation therapy due to its propensity for local relapses. Metastatic DM has a high response rate (RR) to PD-1 blockade therapy (Eroglu et al. Nature 2018). We hypothesized that neoadjuvant treatment with anti-PD-1 monotherapy may induce pathologically confirmed regressions in a high percentage of cases, potentially allowing for less extensive local treatment. Methods: Patients > 18 years old with histologically confirmed resectable (primary, recurrent, or regional lymph node metastasis) DM with clinical evidence of residual disease received pembrolizumab 200 mg q3 weeks (wk) 3 followed by excision. No adjuvant therapy was administered. Primary endpoint: pathological complete response (pCR), with the assumption that pCR of 25% would be considered a positive result worthy of future study. To test this hypothesis, a single arm trial with 25 eligible patients would have a 3.4% probability of a positive result with a true pCR of 5%, and a power of 90% of a positive result if the true pCR is 25%. Secondary endpoints: clinical RR by imaging and clinical exam, median overall survival (OS), and evaluation of safety/tolerability of neoadjuvant pembrolizumab. Adverse events were assessed q3 wk. Disease assessments occurred at baseline and q9 wk. NCT02775851. Results: We enrolled-29 eligible patients with resectable DM. One patient refused treatment and was omitted from further analysis. Median age was 75, 79% were male, primary sites of disease were 72% H&N, 10% torso, 14% extremities, 3% unknown. No patients received prior systemic therapy. Mean time from C1D1 treatment to surgery was 84.2 (range: 52-135) days, mean number of cycles received 3.3 (range: 2-4). 26/27 (93%) of patients underwent wide excision of the resectable disease, of which 14 (54%) underwent sentinel lymph node biopsy. One patient underwent resection of a nodal recurrence thus did not require wide excision. pCR was noted in 15/27 (56%) of patients (95% CI: 35%-75%). One patient without a pCR had a major pathologic response with 0.2 mm residual melanoma. In addition, one patient with a clinical CR did not undergo resection by choice. None became inoperable. Clinical RR was 52% (95% CI: 32%-71%). Median OS has not been reached, with two nontreatment related deaths (acute hypoxic respiratory failure; unknown). No > grade 2 related adverse events were observed. Conclusions: Neoadjuvant pembrolizumab in resectable DM results in a high pCR rate with excellent tolerance, which supports consideration of PD-1 blockade therapy prior to surgery. Funding: U10CA180888 and U10CA180819; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT02775851.

9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.

BACKGROUND The nitrone compound OKN-007 is a novel anti-cancer agent. In glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. METHODS NCT01672463 is a phase 1b trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. OKN-007 was administered by IV. The study comprised a 3 + 3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). RESULTS Median age was 51 years (range, 25–62). No dose-limiting toxicities were observed. The expansion dose was 60 mg/kg. Of 123 adverse events (AEs), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAEs were fatigue (4.1%) and headache (3.3%). Grade 3 TEAEs included headache, urinary tract infection, and increased prothrombin time (0.8% each). Two grade 1 AEs, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. CONCLUSIONS OKN-007 appears safe and, compared to standard therapy, may prolong OS in recurrent glioma.

Background: Randomized comparisons have demonstrated survival benefit of adjuvant immunotherapy in node-positive melanoma patients but have limited power to determine if this benefit persists across various demographic factors. Materials & methods: We assessed the impact of demographic factors on the survival benefit of adjuvant immunotherapy in a database of 38,189 node-positive melanoma patients using the Kaplan–Meier method and Cox proportional hazards models. Results: All assessed demographic factors other than race significantly impacted survival of node-positive melanoma patients in univariate analysis. In multivariable analysis, only the age group interacted with immunotherapy. Conclusion: Analysis of this large database of unselected node-positive melanoma patients demonstrated a positive survival benefit of immunotherapy across all demographic factors assessed and the impact was greater for patients 65 years of age and older., Graphical abstract Stage III melanoma patients who received immunotherapy were at a decreased hazard for death. The protective effect from immunotherapy was greater for those ≥65 years of age compared to those

356154 Background: Combinations of immune checkpoint inhibitors (CPI) blocking PD-1 and CTLA-4 or BRAF/MEK inhibitors have both shown significant antitumor efficacy and overall survival (OS) benefit in patients (pts) with BRAFV600-mutant metastatic melanoma (MM), leading to broad regulatory approval. Little prospective data exists to guide the choice of one over the other as initial therapy or the preferred treatment sequence in this population. The DREAMseq Trial was designed to compare the efficacy and toxicity of the sequence of nivolumab/ipilimumab (N/I) followed by dabrafenib/trametinib (D/T) to the converse sequence.Methods: Eligible pts with treatment-naive BRAFV600-mutant MM were stratified by ECOG Performance Status (PS) 0 or 1 and LDH level and randomized 1:1 to receive Step 1 with either N/I (Arm A) or D/T (Arm B) and at disease progression (PD) were enrolled in Step 2 receiving the alternate therapy, D/T (Arm C) or N/I (Arm D), respectively. Pts received N (1mg/kg)/I (3 mg/kg) q3 wks x 4 doses followed by N 240 IV q2 wks for up to 72 wks (Arms A and D) or D 150 mg po BID and T 2 mg po qD until PD (Arms B and C). In 2019, investigators were given the option to use alternate induction dosing of N (3mg/kg)/I (1 mg/kg) q3 wks x 4 doses for Arms A and D. Cycles were every 6 wks and imaging was obtained at baseline and q12 wks on each arm. Primary endpoint was 2-year OS. At the 4th Interim Analysis with 59% of pts being 2 yrs from enrollment, the DSMC and NCI CTEP recommended halting accrual and releasing the data.Results: Beginning 7/2015, 265 out of a proposed 300 pts were enrolled (133 Arm A and 132 Arm B). Median age was 61 (25-85) and 63% were male. Demographics for Arm A and B were balanced with 67% PS 0 and 60% with normal LDH. As of 7/16/21, at a median follow-up of 27.7 mos, 27 pts had switched to Arm C and 46 to Arm D. Overall Grade 3+ toxicity was 60% in Arm A and 52% in Arm B. Grade 5 treatment-related AEs included 2 on Arm A and 1 on Arm C. ORR to date is: Arm A 46% (52/113), Arm B 43% (49/114), Arm C 48% (11/23) and Arm D 30% (8/27). 37/42 assessed pts in Arm A and 19/37 in Arm B remain in response. Median DOR: Arm A- Not reached; Arm B-12.7 mos (95% CI: 8.2, -) (p

BackgroundTebentafusp, a bispecific fusion protein consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown an overall survival benefit for patients with untreated metastatic uveal melanoma (mUM) in a Ph3 trial (NCT03070392). Metastatic uveal melanoma (mUM) is a historically treatment-refractory tumor with 1-year (yr), 2-yr and 3-yr OS rates of 37%, 15% and 9%, respectively, and median OS of 7.8 months in 2L+ patients.1 In the primary analysis of the phase 2 IMCgp100–102 study (NCT02570308) enrolling patients with previously treated mUM, the 1-year overall survival (OS) rate was 62% with median OS of 16.8 months.2 We present updated OS and safety after 2-year follow-up.Methods127 HLA-A*02:01+ 2L+ mUM patients were dosed weekly with tebentafusp following intra-patient dose escalation: 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Primary objective was ORR and secondary objectives included safety, OS and PFS. Here we present the updated OS and safety (data cut-off 31 Mar 2021).ResultsMedian follow-up was 29.9 mos (range 1.8 – 59.9 mos). With extended follow-up, the 1-yr, 2-yr and 3-yr OS rates were 61%, 37% and 24%, respectively (figure 1). Median OS remained unchanged at 16.8 mos (95% CI, 12.8 – 22.5 mos).Mean and median duration of treatment were 9.5 mos and 5.6 mos (0 – 47.4 mos), respectively. As previously reported, most treatment-related AEs (TRAEs) occurred early on treatment. Beyond 6 months, no TRAE led to treatment discontinuation. No new safety signals, changes in the type or treatment-related deaths were reported. Beyond 12 months, there were a total of 7 Grade (G) 3 or 4 events in 3 (7%) patients, all were temporally related to tumor progression and majority included lab abnormalities. Episodes of rash, a common tebentafusp-related AE early on-treatment, were infrequent after 6 months, with no Grade 3 or 4 events.Abstract 538 Figure 1Kaplan-Meier estimate of overall survival at 2-yr follow-up of IMCgp100-102ConclusionsThis study provides the longest follow-up of OS and safety of a soluble TCR therapeutic to date. Tebentafusp continued to show promising survival for 2L+ mUM patients with estimated 2-yr OS rate of 37%. Tebentafusp’s safety profile was as expected and consistent with primary analysis showing that most adverse events occur early on treatment with incidence and severity decreasing with prolonged exposure.Trial RegistrationNCT02570308ReferencesRantala ES, Hernberg M, Kivela TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res 2019;29:561–568.Sacco JJ, Carvajal R, Butler MO, et al. A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). Ann Oncol 2020;31: S1442–S1143.Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

e21513 Background: Tebe is a bispecific gp100-targeted T cell receptor fusion protein that can redirect polyclonal T cells to target gp100+ cells leading to T cell activation and release of inflammatory mediators. Hepatocytes do not express gp100 and tebe did not redirect T cells against normal hepatocytes in preclinical in vitro studies. However, since most mUM pts have liver metastases, tebe may result in secondary effects from localized tumor-related inflammation. Here we describe LFT kinetics and outcomes for pts in the IMCgp100-102 study (NCT02570308). Methods: 127 HLA-A*02:01+ pts with 2L+ mUM received tebe, administered weekly at the RP2D following intra-patient dose escalation (C1D1: 20μg; C1D8: 30μg; C1D15+: 68μg). Pts were eligible if ALT/AST ≤ 3 x ULN and bilirubin ≤ 1.5 x ULN. LFTs were measured at baseline (BL) and weekly prior to each dose using local laboratories. AE grading was based on CTCAE v4.03. This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: At BL,125/127 (98%) pts had ALT/AST ≤ grade(G)1 and 122/127 (96%) had liver metastasis. 68/127 (54%) had an increase in post-BL grade for ALT, AST or both. Of these 48/68 (71%) increased to G1, 9/68 (13%) to G2, 7/68 (10%) to G3, and 4/68 (6%) to G4. 67 of these 68 pts (99%) had liver metastasis and most had largest liver metastasis > 3cm (38 pts > 3 cm, 29 pts < 3cm and 1 pt without). ALT/AST increases occurred early in treatment in 36/68 (53%) including at Dose 1 (12/68; 18%), Dose 2 (10/68; 15%), or Dose 3 (14/68; 21%). In the other 32/68 pts (47%), ALT/AST increases occurred at or after Dose 4 (4-65), and most of these events (21/32; 66%) were associated temporally with increase in size of liver metastases. Among the 11 pts with G3/4 ALT/AST increases post-BL, most pts experienced these events early (Doses 1-3) (8/11; 73%) and in the context of either increase in size of liver metastases / disease progression or biliary obstruction (9/11; 82%). Most pts, 60/68 (88%), continued treatment despite an increase in ALT/AST grade. Among 8 pts who discontinued treatment, 3 were due to disease progression and 3 were due to adverse events. Median time for ALT/AST to return to BL was 9 days and there were no temporal increases in albumin or INR. Conclusions: Approximately 1/2 of tebe treated pts experienced an increase in post-BL CTCAE grade for ALT/AST. Among these pts, most ALT/AST increases were mild. Most of the pts with G3/4 ALT/AST increase (9/11) were explained by increase in size of liver metastases or biliary obstruction. Increase in LFT are not unusual at time of disease progression in mUM given high frequency of liver metastases. In summary, ALT/AST increases occurred early in about half of the pts, were generally self-limiting, permitted treatment to continue, and did not appear to impact liver synthetic function (INR/Albumin). Clinical trial information: NCT02570308.

9531 Background: Cytokine-mediated adverse events (AEs) are commonly reported in pts treated with T cell engaging therapies. Tebentafusp (tebe), 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, has shown an overall survival benefit for pts with untreated mUM in a Ph3 trial (NCT03070392). Here we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-102 trial of 2L+ pts with mUM (NCT02570308). Methods: 127 HLA-A*02:01+ 2L+ mUM pts were treated with tebe at the RP2D of 68mcg following intra-patient dose escalation of 20 mcg dose 1 and 30 mcg dose 2. Pts were monitored overnight to allow management of hypotension and other cytokine-related AEs. Because the rate of severe CRS was low in Ph1, prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria [1]. Circulating cytokines in serum were measured before and at 8hr and 12-24hr after dosing for the 1st, 3rd and 4th doses (n=105). This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: The most frequent treatment-related AEs that were likely cytokine-mediated included fever (80%), chills (64%), nausea (59%), hypotension (41%) and hypoxia (4%). In a post-hoc review using ASTCT criteria, 86% of pts (n=109) had any grade CRS. The majority of these 109 pts had either grade (G) 1 (n=42; 33%) or G2 (n=62; 49%), with few G3 (n=4; 3.1%), one G4 (0.8%), and no deaths. Onset of CRS began within 24 hours of administration and G≥2 hypotension or hypoxia typically resolved within 2 days of onset. Most CRS events occurred after the first 3 doses with a marked reduction in the frequency and severity of CRS thereafter; G3-4 CRS was limited to first two doses. Only 2 pts discontinued tebe due to CRS (1 G3 and 1 G4). Treatment of G≥2 CRS included iv fluids (n=45), iv steroids (n=18), oxygen (n=8), and vasopressor use (n=2). No pts received tocilizumab. Tebe induced a transient increase in peripheral cytokines, including IFNγ, IL-10, IL-6 and TNFα, within hours of tebe dosing, which were several fold higher in pts with CRS compared to pts without CRS. Higher levels of TNFα trended with severity of CRS. Conclusions: CRS, a common AE observed with all T cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity even without the use of prophylactic premedications, were reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation. Pts with CRS tended to have greater increases in serum cytokines, consistent with tebe’s proposed mechanism of action. [1] Lee, DW et al. Biol Blood Marrow Transplant 2019. Clinical trial information: NCT02570308.

2538 Background: Despite therapeutic advances, the median overall survival for patients with recurrent, high-grade gliomas remains poor. Thus, there is an urgent need for efficacious new therapies. The nitrone compound, OKN-007 (disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is a promising novel anti-cancer agent. In orthotopic glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. Methods: NCT01672463 is a phase Ib trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. Patients with recurrence, adequate performance status and organ function, receiving clinically appropriate doses of steroids, with a life expectancy greater than 8 weeks were eligible. OKN-007 was administered by IV. The study comprised a 3+3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until recurrence (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Median age was 51 years (range, 25-62). No dose-limiting toxicities were observed and 60 mg/kg was chosen for the expansion dose. Of 123 adverse events (AE), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAE were fatigue (4.1%) and headache (3.3%). No drug-attributable grade 4 or 5 AE were observed. Grade 3 TEAE included headache, urinary tract infection, and increased prothrombin time (0.8% each). Only two grade 1 AE, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. Conclusions: OKN-007 appears safe for patients with recurrent glioma. The MTD was not reached. Our data suggest that, compared to standard therapy, OKN-007 may prolong OS in recurrent glioma. Based on new data, a trial of OKN-007 plus temozolomide is underway in patients with newly diagnosed glioblastoma (NCT03587038). Clinical trial information: NCT01672463 .

Melanoma is the deadliest form of all skin cancer, and the incidence of melanoma has been rising for the last 30 years. There are only a few reported biomarkers for prediction and prognosis for melanoma, therefore, there is an unmet medical need to identify predictive and prognostic biomarkers. Doublecortin-like kinase 1 (DCLK1) marks a population of tumor-initiating cells in colonic and pancreatic cancers, and it is overexpressed in many solid tumors. Our preliminary studies suggest that DCLK1 is overexpressed in serum samples of melanoma patients and it maybe a novel biomarker for melanoma. In this study we examined DCLK1 expression in melanoma tumor tissues and further evaluated whether its levels in serum could be quantitatively assessed in melanoma patients before and after therapy treatment. Immunohistochemistry (IHC) analysis was performed to detect DCLK1 in a tissue microarray with 60 tumor and normal adjacent tissues (NAT) from melanoma patients. ELISA assay were performed to detect DCLK1 levels in the serum samples of melanoma patients before and after treatment. Western blotting was also performed to detect DCLK1 protein in the serum samples of melanoma patients. Additionally, analysis of DCLK1 and correlative gene expressions was performed using TCGA Melanoma dataset. Here we report that the intensity of DCLK1 staining in melanoma tumor tissues are significantly increased compared to NAT. DCLK1 levels in the serum were elevated in melanoma patients (n=65) compared to healthy volunteers. Patients with higher levels of serum DCLK1 had reduced overall survival compared to patients with lower levels of serum DCLK1. We also compared DCLK1 levels in 10 patients for whom pre- and post- treatment samples were available. Among these patients, seven had elevated DCLK1 before treatment and had a significantly decrease (about 30-50%) in serum DCLK after treatment. Three patients had no change in DCLK1 levels after treatment. Interestingly, the patients with decrease level of DCLK1 post-treatment demonstrated significant clinical responses to therapy, however, the patients with no change in DCLK1 level post therapy showed no clinical improvement (p Citation Format: Dongfeng Qu, Nathaniel Weygant, Parthasarathy Chandrakesan, Kamille Pitts, Randal May, Adam Asch, Alexandra Ikeguchi, Courtney Houchen. DCLK1 is upregulated in melanoma and it is a novel predictive marker for survival and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4034.

Melanoma is the deadliest form of skin cancer, and the incidence of melanoma has been rising for the last 40 years. There is a paucity of readily available tools to predict for melanoma progression and response to therapy, leaving an unmet medical need to identify predictive and prognostic biomarkers. Doublecortin-like kinase 1 (DCLK1) is overexpressed and marks a population of tumor-initiating cells in colonic and pancreatic cancers. It regulates key oncogenes, pluripotency factors, angiogenic factors, and epithelial mesenchymal transition (EMT) related transcription factors. In this study, we evaluated whether DCLK1 can be detected in the bloodstream and if its levels in serum samples could be quantitatively assessed in melanoma patients. ELISA assay was performed to detect DCLK1 levels in the serum samples of melanoma patients before and after treatment with either targeted agents or immune checkpoint inhibitors. Western blotting was also performed to detect DCLK1 protein in the serum samples of melanoma patients. Immunohistochemistry (IHC) analysis was performed to detect DCLK1 in the same patients' tumor tissues. Additionally, analysis of DCLK1 and correlative gene expression profiles was performed using TCGA Melanoma dataset. Here we report that the intensity of DCLK1 staining in melanoma tumor tissues is increased compared to normal tissues. DCLK1 levels in the serum were elevated in melanoma patients (n=20) compared to healthy volunteers. Next, we compared DCLK1 levels in 10 patients for whom pre- and post- treatment samples were available. Among these patients, seven had elevated DCLK1 before treatment and had a significant decrease (about 30-50%) in serum DCLK after treatment. Three patients had no change in DCLK1 levels after treatment. The patients with a decrease in their level of DCLK1 post-treatment demonstrated radiologic response to therapy as well, while the patients with no change in DCLK1 level post therapy showed either no improvement or progression (p Citation Format: Dongfeng Qu, Nathaniel Weygant, Parthasarathy Chandrakesan, Kamille Pitts, Randal May, Sripathi Sureban, Adam Asch, Alexandra Ikeguchi, Courtney Houchen. Serum DCLK1 levels are elevated in melanoma patients and it is a novel predictive marker for survival and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3611.

The abi-1 gene encodes a protein that binds and is phosphorylated by the Abelson protein tyrosine kinase. Constructs expressing a full-length abi-1 cDNA, and a smaller cDNA arising from an alternatively spliced form, were generated and tested for their effect on transformation of NIH3T3 cells by the Abelson murine leukemia virus. Overexpression of both forms of the protein strongly inhibited transformation by the wild-type P160 strain of the virus, but not by the non-interacting mutant P90A strain. The inhibition required the SH3 domain of Abi-1, suggesting that a direct interaction was required for the effect. Rare breakthrough P160 transformants of the Abi-1 overexpressing lines were found to have downregulated Abi-1 protein levels by a post-transcriptional mechanism.

Background: Many factors have been found to impact the treatment outcomes of acute myeloid leukemia (AML) patients including age of patient at diagnosis, race, cytogenetic risk grouping, and white blood cell count. Although these clinical and demographic features might be easy to measure and identify, models using socioeconomic factors predicting treatment outcomes of AML have not been as rigorously explored. This study aims to investigate how some socioeconomic factors may impact the treatment outcomes of patients with newly diagnosed AML. Methods: We retrospectively analyzed patients from January 2000 to June 2012 diagnosed with AML over 18 years of age, who were treated at the University of Oklahoma with induction chemotherapy. 215 AML patients were identified. The AML patient, or next of kin, was contacted and asked to complete a telephone-based questionnaire with 11 questions. A total of 181 patients or next of kin responded to questions regarding marital status, dependency on another, difficulty with transportation, renting hotel/motel for treatment, car ownership, and whether the patient's life was stressful. Simple descriptive statistics were created for all covariates [n (%)] overall. Kaplan-Meier survival curves and log-rank tests of homogeneity identified which covariates were associated with survival (α=0.25) and would be included in a multivariable Cox proportional hazards regression model. In this model, all two-way interactions were explored and backward selection was used to identify the variables included in the final model. If the exclusion of a variable changed the estimate of a significant covariate by ≥ 20%, it was deemed a confounder and retained in the model. A similar approach was used to assess complete remission (CR); however, binary logistic regression models were used to examine the univariate association of each covariate with CR to identify associated variables to include in the multivariable model (α=0.25). Results: The majority of patients were males (61%), married (45%), and achieved CR (64%). The median age was 52 years. Most patients reported not being dependent on another (65%), not having served in the military (94%), and not having difficulty with travel (73%), although most reported owning a car (70%). After adjusting for age and risk grouping, military status is marginally associated with overall survival (OS) (p-value =0.0548). The hazard of death for those in the military is 2.36 times higher for patients with AML relative to those who have never been part of the military (95% CI: 0.98, 5.69). Marital status is not associated with OS. There is a significant association between difficulty with transportation (p-value=0.0440) and CR. Patients who reported difficulty with transportation have 0.35 times the odds of CR (or 65% lower) relative to those who do not report this difficulty (95% CI: 0.13, 0.97). Marital status is marginally significant (p-value=0.0698) when comparing married vs widowed patients. Married patients have 1.35 times the odds of remission relative to those patients who are widowed (95% CI: 0.32, 5.68). Conclusion: There is evidence that those who served in the military have lower OS relative to those who have not. We also find that patients who reported having difficulty with transportation have lower rates of CR. Further exploration of how these variables might be associated with OS and CR is warranted given evidence from this study. Disclosures No relevant conflicts of interest to declare.