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  • American Association for Cancer Research (AACR)  (18)
  • 1
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    First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 2 ( 2018-02-01), p. 184-195
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 2 ( 2018-02-01), p. 184-195
    Abstract: Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors. Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 184–95. ©2017 AACR. See related commentary by Smalley and Smalley, p. 140. This article is highlighted in the In This Issue feature, p. 127
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-1119
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 18 ( 2018-09-15), p. 4416-4428
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 18 ( 2018-09-15), p. 4416-4428
    Abstract: Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-3649
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 8 ( 2016-08-01), p. 827-837
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 8 ( 2016-08-01), p. 827-837
    Abstract: Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827–37. ©2016 AACR. See related commentary by Teng et al., p. 818. This article is highlighted in the In This Issue feature, p. 803
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-1545
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Abstract 2392: Genomic and immune heterogeneity in synchronous melanoma metastases is associated with differential tumor growth and response to therapy
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2392-2392
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2392-2392
    Abstract: There have been significant advances in the treatment of metastatic melanoma through targeted and immunotherapy, however a significant proportion of patients still progress on these regimens with many experiencing mixed responses. Intense research efforts to better understand resistance are underway, and multiple molecular resistance mechanisms to targeted therapy have been identified. The appreciation of genetic heterogeneity as a contributor to resistance to therapy has grown, though immune heterogeneity has been poorly characterized. The goal of the present study is to better understand the molecular and immune heterogeneity in synchronous melanoma metastases at the time of disease progression. In this study, we prospectively evaluated 32 tumors from 15 patients who were treatment-naïve (n = 4), or had received prior targeted (n = 4) or immunotherapy (n = 7). Whole exome sequencing demonstrated between 4-41% of non-synonymous exonic mutations (NSEM) were restricted to individual tumors within a patient. Deep profiling of infiltrating immune cell subsets by flow cytometry and immunohistochemistry analyses confirmed the immune infiltrate between synchronous metastases to be highly heterogeneous, specifically in regards to CD4 and CD8 T lymphocytes. In aggregate, 92% of these T cell clones were unique to distinct tumors within the same patient, with limited overlap with clones detected in the blood. NetMHC3.4 neoantigen prediction demonstrated a large fraction of predicted neoantigens were restricted to individual tumors, with over 10% of these presenting extremely high predicted affinity. Importantly, analysis of RECIST measurements of individual lesions within the same patient suggested this molecular and immune heterogeneity could contribute to differential tumor growth and response to therapy within the same patient. This has important clinical implications, and suggests a single tumor biopsy may not be sufficiently representative of the molecular and immune landscape of multiple tumors within the same individual. Citation Format: Alexandre Reuben, Christine N. Spencer, Peter A. Prieto, John P. Miller, Xizeng Mao, Wei-Shen Chen, Hannah Cheung, Hong Jiang, Cara Haymaker, Mariana Petaccia De Macedo, Haven R. Garber, Pei-Ling Chen, Vancheswaran Gopalakrishnan, Jacob Austin-Breneman, Courtney W. Hudgens, Jason Roszik, Patrick Hwu, Scott E. Woodman, Lynda Chin, Michael A. Davies, Rodabe N. Amaria, Sapna P. Patel, Alexander J. Lazar, Michael T. Tetzlaff, Karen C. Dwyer, Ignacio I. Wistuba, Padmanee Sharma, James P. Allison, Jianhua Zhang, Andrew Futreal, Zachary A. Cooper, Jennifer A. Wargo. Genomic and immune heterogeneity in synchronous melanoma metastases is associated with differential tumor growth and response to therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2392.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2392
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Abstract 5711: The impact of combination oral azacitidine (CC-486) + pembrolizumab (PEMBRO) on the immune infiltrate in metastatic melanoma (MM)
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5711-5711
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5711-5711
    Abstract: Introduction: Although immune checkpoint inhibitors have improved survival for many with MM, most pts do not respond and median PFS is only 6 months for single agent therapy. Cancers subvert the cellular epigenetic machinery to facilitate immune escape. Epigenetic mechanisms of resistance are potentially reversible by DNA hypomethylating agents (HMA). Based on preclinical models, we hypothesized that CC-486, an oral HMA, will enhance response to PEMBRO in PD-1 naïve pts and reverse resistance in anti-PD-1 refractory pts. The aim of this study is to determine the safety, efficacy, and characterize the pharmacodynamic impact of CC-486 + PEMBRO on immune infiltrates in pts with MM. Experimental: NCT02816021 is an ongoing phase II study of CC-486 + PEMBRO in MM pts who are PD-1 naïve (Arm A) or who have progressed on prior PD-1 directed therapy (Arm B). Pts receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO q3 weeks. Serum and tumor biopsies are obtained at baseline, prior to cycles 3 and 5. Immune monitoring studies were performed by the Immunotherapy Platform at MD Anderson. Immune cell phenotyping by CyTOF was performed using 36 metal-conjugated antibodies targeting myeloid and T cell surface markers. FCS files were exported and manually gated for lymphocytes using FlowJo (version 10.1) and subjected to multidimensional phenographic analysis. Results: Thirteen pts (Arm A, n=6; Arm B, n=7) have been enrolled. Two of the 3 pts remaining on study are PD-1 naïve and have received 13 and 8 cycles of CC-496 + PEMBRO with partial responses by RECIST1.1 at 6 months, respectively. One pt on Arm B remains on study with stable disease after 4 cycles. The combination was considered safe after a run-in phase (6 pts/arm treated without DLTs) and the study is open to full accrual. The most common grade 3/4 AEs were leukopenia , neutropenia, vomiting, and diarrhea (2 each) with 1 grade 5 AE unrelated to treatment (hepatic rupture/bleeding due to progressive disease). Serum and tumor biopsies from 6 pts (3 per Arm) were available for interim analysis, with additional samples in process. Of these 6 pts, 1 pt (PD-1 naïve) responded to therapy by RECIST1.1. We evaluated the blood and tumor samples by CyTOF. In the tumor samples, we observed an increase in frequency of T cells in 2 PD-1 naïve patients but did not observe similar changes in PD-1 refractory patients in this small cohort. Similar data was found with immunohistochemistry. These changes were not observed in the blood samples. Conclusion: The regimen CC-486 + PEMBRO is not marrow suppressive and is well tolerated. Changes in the peripheral lymphocyte cell populations upon treatment are not necessarily concordant with changes occurring in the tumor. Analysis of collected samples is ongoing and will be presented at the meeting, and will help corroborate initial findings and yield further insight into the effect of this combination on the immune response. Citation Format: Emily Z. Keung, Isabella C. Glitza, Elizabeth Burton, Rodabe N. Amaria, Sapna P. Patel, Adi Diab, Cassian Yee, Michael K. Wong, Wen-Jen Hwu, Patrick Hwu, Scott E. Woodman, Michael T. Tetzlaff, Nallely Trujillo-Conley, Denai R. Milton, Michael A. Davies, Kunal Rai, Irina Fernandez, Jorge M. Blando, Luis M. Vence, Padmanee Sharma, James P. Allison, Jennifer A. Wargo, Hussein Tawbi. The impact of combination oral azacitidine (CC-486) + pembrolizumab (PEMBRO) on the immune infiltrate in metastatic melanoma (MM) [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 5711.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5711
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract 1493: Therapeutic efficacy and tolerability of combined immune checkpoint blockade in metastatic melanoma patients is influenced by the gut microbiome
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1493-1493
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1493-1493
    Abstract: Background: The gut microbiome is increasingly being recognized as a strong modulator of anti-PD1 based cancer immunotherapy. Compelling evidence demonstrates differential bacterial enrichment and diversity in responders (R) versus non-responders (NR), mediated by profound influences on systemic and anti-tumor immune infiltrates. However, this has not been studied in the setting of treatment with combined immune checkpoint blockade (CICB), which is associated with superior response rates, but higher rates of potentially debilitating toxicities. Methods: We assembled a cohort of patients with metastatic melanoma receiving CICB (n=54). All patients were classified as R (n=31, CR + PR) or NR (n=23, SD + PD) based on RECIST v1.1, and as having grade 3 or higher (T; n=29), or less than grade 3 (NT; n=25) immune related adverse event(s) by NCI CTCAE 4.0 criteria. Baseline stool samples were characterized by 16S rRNA sequencing. Correlative analyses of peripheral immune cell populations by flow cytometry (n=12) and circulating T cell repertoire by TCR-sequencing (n=12) were done on matched pre-treatment blood samples. Results: The overall gut microbial landscape in these patients was varied with high abundance of Bacteroidales and Clostridiales. Ordination of beta-diversity distances revealed a lack of clustering by subtype of primary tumor (uveal, mucosal, cutaneous) consistent with no significant effect of the tumor histology. While no apparent response or toxicity associations were evident based on diversity, notable compositional differences were appreciated. Comparison of relative abundances by LEfSe (LDA & gt;2, p & lt;0.05), and pairwise Mann-Whitney tests revealed an enrichment of Bacteroides stercoris (p=0.03), and Parabacteroides distasonis (p=0.04) in R, and Lactobacillales (p=0.005) in NR. Consistent with our prior findings, the median relative abundance of the order Clostridiales was again higher in R (0.34) versus NR (0.26). On the other hand, Bacteroides intestinalis (p=0.01) and Anaerotignum lactatifermentans (p=0.006) were enriched in T and NT, respectively. Importantly, correlative analyses with circulating immune cell subsets revealed distinct associations by differential bacterial enrichment (including positive correlations between overall CD8+ T-cell abundance and R-taxa), and a clustering effect by high or low T-cell repertoire entropy. Conclusion: These findings build on our prior work and support the notion of a close link between the gut microbiome and therapeutic outcomes to checkpoint blockade therapy. Extensive studies are underway in both matched human biospecimens and in pre-clinical models to further understand mechanisms of interactions with immune markers, and to establish causality. Taken together, these data support a critical role for the gut microbiome as both a predictive tool and therapeutic target. Citation Format: Vancheswaran Gopalakrishnan, Miles Andrews, Wei-Shen Chen, Christine Spencer, Luis Vence, Alexandre Reuben, Zachary A. Cooper, Peter A. Prieto, Michael T. Tetzlaff, MA Abdul Wadud Khan, Alexander Lazar, Courtney W. Hudgens, Lauren E. Haydu, Hussein A. Tawbi, Patrick Hwu, Wen-Jen Hwu, Rodabe N. Amaria, Elizabeth M. Burton, Scottt E. Woodman, Adi Diab, Sapna P. Patel, Isabella C. Glitza, Jianhua Zhang, Joseph Petrosino, Robert R. Jenq, Michael A. Davies, Jeffrey E. Gershenwald, Padmanee Sharma, James P. Allison, Andrew Futreal, Jennifer A. Wargo. Therapeutic efficacy and tolerability of combined immune checkpoint blockade in metastatic melanoma patients is influenced by the gut microbiome [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 1493.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1493
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 7
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    Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 3 ( 2022-03-01), p. 644-653
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 3 ( 2022-03-01), p. 644-653
    Abstract: We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59–0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61–1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-21-1141
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Abstract 5881: PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5881-5881
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5881-5881
    Abstract: Immune checkpoint inhibitors (ICI) have demonstrated limited success in patients with metastatic uveal melanoma (MUM) with liver involvement due to an immunosuppressive tumor microenvironment (TME) driven in part by myeloid-derived suppressor cells (MDSCs). Toll-like receptor-9 agonists (TLR-9A) have improved ICI response rates in cutaneous melanoma, but delivery challenges have limited their application for MUM. Hepatic arterial infusion (HAI) of TLR-9A using a pressure-enabled drug deliveryTM (PEDDTM) device has the potential to enhance responsiveness to ICI by optimizing delivery to intrahepatic tumors and reprogramming the TME, including elimination of MDSCs.PERIO-01 is an open-label first-in-human Phase 1 trial of SD-101 given by HAI using a PEDDTM in MUM (NCT04935229). The study consists of dose-escalation cohorts of single agent SD-101 alone and with ICI. SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Research blood, tumor and normal liver biopsies are collected serially for correlative studies. At data cutoff, a total of 20 patients were enrolled, with 13 in the single agent dose escalation cohort (2, 4, and 8 mg) and 7 patients with SD-101 (2 mg) + nivolumab. The median age was 65.5 years with an equal gender distribution. Only 2 patients were treatment-naïve and the median number of liver metastases was 5.1. The average number of SD-101 infusions was 5.2. One patient in the combination cohort experienced a serious adverse event related to treatment - asymptomatic Grade 3 increase in liver enzymes. PEDDTM resulted in high drug levels in the liver (up to 2,340 ng/ml at 8mg) with only transient exposure in the periphery ( & lt;4 hours) with one Grade 2 cytokine related syndrome adverse event. Dose-dependent increases in canonical TLR9-associated cytokines (IL-18, IFNγ, IP-10, and soluble CD25) was observed across the 2mg, 4mg, and 8mg single-agent dose levels. Concordant with predicted mechanism of action, PEDDTM HAI administered SD-101 resulted in decreases in liver monocytic MDSCs in 4 of 4 patients with available multiplex immunofluorescence data. NanoString analysis from three patients revealed increases in ISG15, IL-9, IFNα, and IL-2 transcripts and decreases in ARG1 and IDO transcripts, with increased scores for macrophages, activated CD8 T cells, Th1 cells, and Th1 activation. For patients who received 2mg SD-101 + ICI with available liquid biopsy data, 4 of 7 demonstrated decreases in circulating tumor cells and 3 of 5 showing ctDNA decreases after the first cycle. In this first-in-human experience, HAI of SD-101 via PEDDTM was well tolerated and associated with encouraging immunologic activity. Evidence of biologic activity with 2 mg of SD-101 with nivolumab is encouraging and patients are currently enrolling at higher SD-101 dose levels + ICI. Citation Format: Sapna P. Patel, Cara Haymaker, Rahul A. Sheth, Joshua D. Kuban, Joshua Weintraub, Eric Wehrenberg-Klee, Paula Novelli, Carin Gonsalves, Robert Adamo, Virgina Honaker, Laura Timciuc, Tarin Hennegan, Juan C. Amador Molina, Dzifa Duose, Edwin R. Parras Cuenta, Anthony Lucci, Salyna Meas, Vanessa Sarli, Victor G. Prieto, Jason LaPorte, Ann-Marie Hulstine, Ashley Moody, Bryan Cox, David Geller, Diwakar Davar, Kamaneh Montazeri, Marlana Orloff, Steven C. Katz, Richard Carvajal. PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5881.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5881
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract CT009: S1512: High response rate with single agent anti-PD-1 in patients with metastatic desmoplastic melanoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT009-CT009
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT009-CT009
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT009
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 10
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    Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 9 ( 2022-05-02), p. 1911-1924
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 9 ( 2022-05-02), p. 1911-1924
    Abstract: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%–50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown. Experimental Design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products. Results: Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy. Conclusions: Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-1060
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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