Interim results from a phase Ib/II study of pepinemab in combination with avelumab in advanced NSCLC patients following progression on prior systemic and/or anti-PDx therapies.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 75-75 ◽  
Author(s):  
Michael Rahman Shafique ◽  
Terrence Lee Fisher ◽  
Elizabeth E. Evans ◽  
John E. Leonard ◽  
Desa Rae Electa Pastore ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Clinical Benefit ◽  
Tumor Regression ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Semaphorin 4D ◽  
T Cell Infiltration ◽  
Humanized Monoclonal Antibody ◽  
Immune Exclusion

75 Background: Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.

Interim subgroup analysis for response by PD-L1 status of CLASSICAL-Lung, a phase Ib/II study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3011-3011
Author(s):  
Michael Rahman Shafique ◽  
Terrence Lee Fisher ◽  
Elizabeth E. Evans ◽  
John E. Leonard ◽  
Desa Rae Electa Pastore ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
T Cell Activation ◽  
Subgroup Analysis ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Single Agent ◽  
Human Study ◽  
Semaphorin 4D ◽  
Biomarker Analysis

3011 Background: Antibody blockade of semaphorin 4D (SEMA4D, CD100) promotes tumoral dendritic cell and CD8+ T cell infiltration and reduces function and recruitment of immunosuppressive myeloid cells. Importantly, these mechanisms to overcome immune exclusion and suppression have been shown to complement immune checkpoint therapies in preclinical models. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple T cell activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This phase 1b/2, single arm, first-in-human study is designed to evaluate the safety, tolerability and efficacy of pepinemab with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) pts and pts whose tumors progressed following immunotherapy (IOF). Results: Among 21 evaluable ION pts, 5 experienced partial response (PR), 3 pts had clinical benefit ≥ 1 year, and the disease control rate (DCR) is 81%. Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy). We, therefore, performed subgroup analysis for response by PD-L1 status. The objective tumor response (ORR) in the PD-L1 negative and low population ( < 80% TPS by Dako 73-10 assay) appears to be approximately 2-2.5 fold greater with combination therapy than with historical single agent immune checkpoint controls. Notably, 97% of pts who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Among 29 evaluable IOF pts, the combination resulted in 59% DCR, including 2 PR and 7 patients with durable clinical benefit of ≥ 23 weeks. Biomarker analysis of pre- and on-treatment biopsies confirmed increased CD8+ T cell density correlating with response. Surprisingly, analysis of myeloid-derived suppressor cells (MDSCs) revealed a relative paucity of these cells in pretreatment NSCLC biopsies as compared to other cancer indications such as HNSCC. Conclusions: This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented. Clinical trial information: NCT03268057 .

17 Activity sensors for noninvasive monitoring of immune response and tumor resistance during immune checkpoint blockade therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A17-A17
Author(s):  
Quoc Mac ◽  
James Bowen ◽  
Hathaichanok Phuengkham ◽  
Anirudh Sivakumar ◽  
Congmin Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Growth Curves ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Tumor Resistance ◽  
Activity Sensors ◽  
Therapeutic Responses

BackgroundDespite the curative potential of immune checkpoint blockade (ICB) therapy, only small subsets of patients achieve tumor regression while many responders relapse and acquire resistance. Monitoring treatment response and detecting the onset of resistance are critical for improving patient prognoses. Here we engineered ICB antibody-sensor conjugates known as ICB-Dx by coupling peptides sensing the activity of granzyme B (GzmB), a T cell cytotoxic protease, directly on αPD1 antibody to monitor therapeutic responses by producing a fluorescent reporter into urine. To develop biomarkers that indicate mechanisms of resistance to ICB, we generated B2m-/- and Jak1-/- tumor models and performed transcriptomic analyses to identify unique protease signatures of these resistance mechanisms. We then built a multiplexed library of αPD1-Dx capable of detecting early therapeutic response and illuminating resistance mechanisms during ICB therapy.MethodsFITC-labeled GzmB substrates were synthesized (CEM) and conjugated to αPD1 antibody. B2m-/- and Jak1-/- tumors were generated from WT MC38 cells using CRISPR/Cas9. For tumor studies, 106 cells were inoculated s.c. in B6 mice. Tumor mice were treated with αPD1 or IgG1 isotype conjugates (0.1 mg), and urine was collected at 3 hours. Tumor RNA was isolated with RNEasy kit (Qiagen) and prepared for sequencing with TruSeq mRNA kit (Illumina).ResultsTo synthesize αPD1-Dx, we coupled FITC-labeled GzmB substrates to αPD1 antibody (figure 1a). In MC38 tumors, systemic administration of αPD1-Dx lowered tumor burden relative to control treatment while producing significantly elevated urine signals that preceded tumor regression (figure 1b, c). To investigate the ability to monitor tumor resistance to ICB, we developed knockout tumors to model B2m and Jak1 mutations, which are observed in human patients. in vivo, B2m-/- and Jak1-/- MC38 tumors were resistant to αPD1 monotherapy (figure 1d). Tumor RNA sequencing revealed that gene expression was altered during αPD1 treatment only in WT tumors. Importantly, B2m-/- tumors showed very different expression profiles than Jak1-/- tumors during αPD1 treatment, indicative of unique regulation of resistance (figure 1e). We used differential expression analyses to discover unique protease signatures associated with these two resistance mechanisms. Finally, a multiplexed library of αPD1-Dx engineered to monitor both tumor and immune proteases detected early on-treatment responses and stratified B2m-/- from Jak1-/- resistance with high diagnostic validity (figure 1f).Abstract 17 Figure 1Monitoring response and resistance with ICB-Dx(a) αPD1-Dx can reinvigorate T cell response and monitor protease activities in the tumor microenvironment. (b) Growth curves of WT MC38 tumors treated with αPD1- or IgG1-Dx (ANOVA). (c) Urine signals detect treatment response to αPD1 monotherapy (ANOVA). (d) Growth curves of B2m-/- and Jak1-/- tumors treated with αPD1- or IgG1-Dx (ANOVA). (e) TSNE plot showing RNA profiles of WT, B2m-/-, Jak1-/- tumors treated with αPD1 or isotype control. (f) ROC curves of random forest classifiers built from urine signals that differentiate on-treatment response from on-treatment resistance and B2m-/- from Jak1-/- resistance.ConclusionsWe have engineered activity sensors that accurately detect therapeutic responses and stratify resistance mechanisms noninvasively from urine, thereby potentially expanding the precision of ICB therapy to benefit cancer patients.Ethics ApprovalAll animal studies were approved by Georgia Tech IACUC (A100193)

scholarly journals Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1740
Author(s):  
John J. Park ◽  
Russell J. Diefenbach ◽  
Natalie Byrne ◽  
Georgina V. Long ◽  
Richard A. Scolyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Benefit ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Roc Curves ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Targeted Next Generation Sequencing

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

scholarly journals Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000247
Author(s):  
Brett A Schroeder ◽  
Ralph Graeme Black ◽  
Sydney Spadinger ◽  
Shihong Zhang ◽  
Karan Kohli ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Low Dose ◽  
Cellular Therapy ◽  
Tumor Regression ◽  
High Dose ◽  
Adoptive Cellular Therapy ◽  
Link Type ◽  
T Cell Infiltration ◽  
Ifn Γ

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 62-62 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Joanne F. Chou ◽  
Marc Simmons ◽  
Parisa Momtaz ◽  
Francisco Sanchez-Vega ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Regression ◽  
Acquired Resistance ◽  
Phase Iii ◽  
Her2 Positive ◽  
Cell Responses ◽  
Flat Dose ◽  
Biomarker Analysis ◽  
Secondary Endpoints ◽  
Pre Treatment

62 Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. Oxaliplatin can further enhance T-cells by activating dendritic cells. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off (or 5-FU continuous infusion). The primary endpoint was 6-months PFS; with target accrual of 37 patients. Secondary endpoints included safety, OS, ORR, exploratory biomarker analysis and 89Zr-trastuzumab PET. Results: 100% of the 24 evaluable pts had tumor regression (ranging from -22% to -100%). The RECIST 1.1 ORR was 83% [95%CI: 63%-95%] (17 PR , 3 CRs), median PFS 11.4 [95%CI: 6-15] months. In 31 pts evaluable for toxicity, common ( > 10%) adverse events included Gr 2 fatigue (35%), Gr 2/3 nausea (35%), Gr 2 diarrhea (26%), Gr2 AST/ALT elevation (16%), Gr2 neutropenia (16%). Immune related toxicities observed in 1 pt each: Gr 2 colitis, Gr 3 interstitial nephritis, Gr 3 AST/ALT elevation; and resolved with steroids. Of 21 patients with available material, 6 (29%) expressed PD-L1. Of these 6 patients, 5 had a PR while 1 had a CR. ERBB2 amplification was evident on NGS in 56% of pre-treatment tumors from 25 tested patients, while the remaining were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. Mutations in TP53 and alterations in KRAS occurred in 68% and 16%, respectively. To identify mechanisms of acquired resistance, patients are biopsied at progression. In 6 paired sample analysis, we identified two patients with loss of ERBB2 amp at progression. Conclusions: Updated survival, correlative studies and 89Zr-trastuzumab PET imaging will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.

scholarly journals Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial

2019 ◽  
Vol 7 (8) ◽  
pp. 1237-1243 ◽  
Author(s):  
Shihong Zhang ◽  
Karan Kohli ◽  
R. Graeme Black ◽  
Lu Yao ◽  
Sydney M. Spadinger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Mhc Class I ◽  
Interferon Γ ◽  
Class I ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Phase 0

Phase I Analysis of the Safety and Pharmacodynamics of the Novel Broad Spectrum Histone Deacetylase Inhibitor (HDACi) PCI-24781 in Relapsed and Refractory Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2726-2726 ◽  
Author(s):  
Andrew M Evens ◽  
Weiyun Ai ◽  
Sriram Balasubramanian ◽  
Mint Sirisawad ◽  
Chitra Mani ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Dose Escalation ◽  
Clinical Benefit ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Refractory Lymphoma

Abstract Abstract 2726 Poster Board II-702 Background: PCI-24781 is a novel oral pan-HDACi with potent preclinical anti-tumor activity in lymphoma cell lines and models and has previously demonstrated safety and clinical benefit in solid cancers (Undevia et al, ASCO 2008). In lymphoma cell lines, PCI-24781 was causes increased oxidative stress and NF-κB inhibition that results in caspase-dependent apoptosis (Evens et al, Clin Ca Res 2009). Based in part on this encouraging pre-clinical data, a phase I/II clinical trial was designed for patients with relapsed/refractory lymphoma. Methods: The primary objective of the phase I component of this protocol was to determine the maximum tolerated dose (MTD) for testing in the phase II portion of the trial. PCI-24781 was given orally twice daily at escalating doses of 30–60mg/m2 on a 4-week cycle on two treatment schedules: 5 days/week x 3 weeks (schedule 1) or 7 days/week every other week (schedule 2). A standard 3+3 phase I dose escalation scheme was used. Tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs). Data presented here consists of the completed phase I dose escalation component of the clinical trial. Results: 25 pts enrolled with 7 pts continuing on treatment. The median age was 63 years, while the median number of prior treatments was 3. The histologies included: diffuse large B-cell lymphoma (DLBCL) (9), follicular lymphoma (FL) (4), Hodgkin lymphoma (3), CLL/SLL (2), mantle-cell lymphoma (2), nodal peripheral T-cell lymphoma (2), and cutaneous T-cell lymphoma (1). The best tolerated doses were 30 mg/m2 on schedule 1 and 45 mg/m2 on schedule 2, both with no adverse events (AEs) > grade 2. AEs ≥ grade 3 were thrombocytopenia (n=4) and diarrhea (n=1) and thus were dose limiting. One DLBCL pt with a history of renal insufficiency and renal involvement by lymphoma experienced a serious AE of renal failure, which was deemed possibly related to PCI-24781. Of note, no pericarditis, pericardial effusion, or QT prolongation were seen at any dose level of PCI-24781. Twelve pts were evaluable for response. Two confirmed responses have been seen (1 complete remission (CR), 1 partial remission (PR)), while six patients had stable disease (SD) with the median length of SD being 15 weeks (range, 6–17+). The longest duration of response (CR) was 8 cycles (32+ weeks). Both responses were seen in FL (2/4); one patient (PR) had received prior CHOP, R-ESHAP, and autologous transplant, while the other patient (CR) was rituximab-refractory and had failed 5 prior therapies. Pharmacodynamic monitoring revealed a dose-dependent increase in tubulin acetylation at 4 hours following the first dose, however this did not correlate with response or toxicity. Conclusion: PCI-24781 is a well tolerated pan-HDACi, including complete absence of prolonged QT abnormalities. Preliminary clinical benefit in heavily pre-treated relapsed/refractory lymphoma patients was documented in the phase I portion of this study. Accrual will continue to the phase II component of the clinical trial. Disclosures: Off Label Use: This is a non-FDA approved agent. Balasubramanian:Pharmacyclics: Employment. Sirisawad:Pharmacyclics: Employment. Mani:Pharmacyclics: Employment. Guerra:Pharmacyclics: Employment. Szakacs:Pharmacyclics: Employment. Loury:Pharmacyclics: Employment. Buggy:Pharmacyclics: Employment. Hamdy:Pharmacyclics: Employment, Equity Ownership.

Investigation of mechanisms of resistance to ipilimumab therapy with a pre-surgical trial in patients with high-risk, localized prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5081-5081 ◽  
Author(s):  
Jianjun Gao ◽  
John Francis Ward ◽  
Curtis Alvin Pettaway ◽  
Lewis Z Shi ◽  
Sumit Kumar Subudhi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cell ◽  
High Risk ◽  
Clinical Benefit ◽  
In Vitro Studies ◽  
Prostate Tumors ◽  
Inhibitory Pathways ◽  
Surgical Trial

5081 Background: Anti-CTLA-4 therapy ipilimumab (BMS) has led to clinical benefit in patients with metastatic melanoma. However, in multiple clinical trials in patients with prostate cancer, ipilimumab has not demonstrated significant clinical benefit. To identify potential immune inhibitory pathways responsible for resistance to ipilimumab therapy, we evaluated tumor samples from a pre-surgical clinical trial and performed correlative laboratory studies. Methods: We carried out a pre-surgical clinical trial with androgen deprivation therapy (ADT), (leuprolide acetate, Tap Pharmaceuticals) plus ipilimumab in patients with localized, high-risk prostate cancer. Each patient received one injection of leuprolide (22.5 mg) on week 0 and ipilimumab (10 mg/kg) on weeks 1 and 4. Patients then underwent surgery at week 8. Tumor tissues were collected at baseline and then at surgery for flow cytometry, IHC, multiplex immunofluorescence, and gene profiling analyses. In vitro studies were carried out for functional analysis. Results: Sixteen patients completed treatment with ipilimumab plus ADT and surgery. We observed a significant increase of immune cells including T cells and macrophages into prostate tumors after ipilimumab therapy, similar to data observed in ipilimumab-treated melanoma samples. However, compared to melanoma tumors, we found higher expression of PD-L1 and VISTA inhibitory molecules on CD68+ macrophages in prostate tumors. Interestingly, PD-L1 and VISTA were expressed on distinct subset of CD68+ macrophages, with high expression of CD163, suggesting an M2 subtype. In vitro studies demonstrated that engagement of PD-L1 and/or VISTA pathways inhibited T cell responses. Co-culture with monocytes resulted in suppression of T cell function, which can be reversed with anti-VISTA blocking antibody. Conclusions: These data suggest that evolving compensatory inhibitory pathways including PD-L1 and VISTA may mediate resistance of prostate cancer to ipilimumab therapy. Concurrent blockade of other immune checkpoints such as PD1/PD-L1 and/or VISTA may be necessary to provide significant clinical benefits for patients with prostate cancer. Clinical trial information: NCT01194271.

Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9592-9592 ◽  
Author(s):  
Jessica Yang ◽  
Marlana M. Orloff ◽  
Joseph J. Sacco ◽  
Leonel Fernando Hernandez-Aya ◽  
Karla Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Benefit ◽  
Objective Response ◽  
Cell Receptor ◽  
Median Number ◽  
Checkpoint Inhibition ◽  
Melanoma Antigen ◽  
T Cell Infiltration ◽  
Historical Figures ◽  
Baseline Characteristics

9592 Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) > 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting > 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD > 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.

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