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3. Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer

Author

Hong, David S, Gopal, Ajay K, Shoushtari, Alexander N, Patel, Sandip P, He, Aiwu R, Doi, Toshihiko, Ramalingam, Suresh S, Patnaik, Amita, Sandhu, Shahneen, Chen, Ying, Davis, Craig B, Fisher, Timothy S, Huang, Bo, Fly, Kolette D, and Ribas, Antoni

Subjects
Cancer, Clinical Research, Immunization, Clinical Trials and Supportive Activities, Lung, Vaccine Related, Lung Cancer, Genetics, Adult, Antibodies, Monoclonal, Humanized, Carcinoma, Non-Small-Cell Lung, Humans, Immune Checkpoint Inhibitors, Immunoglobulin G, Lung Neoplasms, Melanoma, Tumor Microenvironment, utomilumab, 4-1BB, CD137, immune checkpoint inhibitor, melanoma, NSCLC, 4-1BB/CD137, Immunology, Medical Microbiology
Abstract

Section headClinical/translational cancer immunotherapy.BackgroundThe goal of this study was to estimate the objective response rate for utomilumab in adults with immune checkpoint inhibitor (ICI)-refractory melanoma and non-small-cell lung cancer (NSCLC).MethodsUtomilumab was dosed intravenously every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ T cells from healthy donors were stimulated with anti-CD3 ± utomilumab and compared with control.ResultsPatients with melanoma (n=43) and NSCLC (n=20) received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two (50.8%) patients experienced treatment-related AEs, mostly grade 1-2. Objective response rate: 2.3% in patients with melanoma; no confirmed responses for patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had stable disease; respective median (95% confidence interval, CI) progression-free survival was 1.8 (1.7-1.9) and 3.6 (1.6-6.5) months. Utomilumab exposure increased with dose. The incidences of antidrug and neutralizing antibodies were 46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity appeared to be blunted at higher doses.ConclusionsUtomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.

Published
2022

4. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.

Author

Bakhoum, Mathieu F, Francis, Jasmine H, Agustinus, Albert, Earlie, Ethan M, Di Bona, Melody, Abramson, David H, Duran, Mercedes, Masilionis, Ignas, Molina, Elsa, Shoushtari, Alexander N, Goldbaum, Michael H, Mischel, Paul S, Bakhoum, Samuel F, and Laughney, Ashley M

Subjects
Human Genome, Biotechnology, Genetics, Cancer, 2.1 Biological and endogenous factors
Abstract

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.

Published
2021

5. The features and management of acquired resistance to PD1-based therapy in metastatic melanoma

Author

Hepner, Adriana, Versluis, Judith M., Wallace, Roslyn, Allayous, Clara, Brown, Lauren Julia, Trojaniello, Claudia, Gerard, Camille Lea, Jansen, Yanina JL, Bhave, Prachi, Neyns, Bart, Haydon, Andrew, Michielin, Olivier, Mangana, Joanna, Klein, Oliver, Shoushtari, Alexander N., Warner, Allison Betof, Ascierto, Paolo Antonio, McQuade, Jennifer Leigh, Carlino, Matteo S., Zimmer, Lisa, Lebbe, Celeste, Johnson, Douglas B., Sandhu, Shahneen, Atkinson, Victoria, Blank, Christian U., Lo, Serigne N., Long, Georgina V., and Menzies, Alexander M.

Published
2024
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7. Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response

Author

Kasago, Israel S., Chatila, Walid K., Lezcano, Cecilia M., Febres-Aldana, Christopher A., Schultz, Nikolaus, Vanderbilt, Chad, Dogan, Snjezana, Bartlett, Edmund K., D’Angelo, Sandra P., Tap, William D., Singer, Samuel, Ladanyi, Marc, Shoushtari, Alexander N., Busam, Klaus J., and Hameed, Meera

Published
2023
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8. Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Amaria, Rodabe N., Postow, Michael, Burton, Elizabeth M., Tezlaff, Michael T., Ross, Merrick I., Torres-Cabala, Carlos, Glitza, Isabella C., Duan, Fei, Milton, Denái R., Busam, Klaus, Simpson, Lauren, McQuade, Jennifer L., Wong, Michael K., Gershenwald, Jeffrey E., Lee, Jeffrey E., Goepfert, Ryan P., Keung, Emily Z., Fisher, Sarah B., Betof-Warner, Allison, Shoushtari, Alexander N., Callahan, Margaret, Coit, Daniel, Bartlett, Edmund K., Bello, Danielle, Momtaz, Parisa, Nicholas, Courtney, Gu, Aidi, Zhang, Xuejun, Korivi, Brinda Rao, Patnana, Madhavi, Patel, Sapna P., Diab, Adi, Lucci, Anthony, Prieto, Victor G., Davies, Michael A., Allison, James P., Sharma, Padmanee, Wargo, Jennifer A., Ariyan, Charlotte, and Tawbi, Hussein A.

Published
2022
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10. Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial

Author

Carvajal, Richard D., Butler, Marcus O., Shoushtari, Alexander N., Hassel, Jessica C., Ikeguchi, Alexandra, Hernandez-Aya, Leonel, Nathan, Paul, Hamid, Omid, Piulats, Josep M., Rioth, Matthew, Johnson, Douglas B., Luke, Jason J., Espinosa, Enrique, Leyvraz, Serge, Collins, Laura, Goodall, Howard M., Ranade, Koustubh, Holland, Chris, Abdullah, Shaad E., Sacco, Joseph J., and Sato, Takami

Published
2022
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11. Improved prediction of immune checkpoint blockade efficacy across multiple cancer types

Author

Chowell, Diego, Yoo, Seong-Keun, Valero, Cristina, Pastore, Alessandro, Krishna, Chirag, Lee, Mark, Hoen, Douglas, Shi, Hongyu, Kelly, Daniel W., Patel, Neal, Makarov, Vladimir, Ma, Xiaoxiao, Vuong, Lynda, Sabio, Erich Y., Weiss, Kate, Kuo, Fengshen, Lenz, Tobias L., Samstein, Robert M., Riaz, Nadeem, Adusumilli, Prasad S., Balachandran, Vinod P., Plitas, George, Ari Hakimi, A., Abdel-Wahab, Omar, Shoushtari, Alexander N., Postow, Michael A., Motzer, Robert J., Ladanyi, Marc, Zehir, Ahmet, Berger, Michael F., Gönen, Mithat, Morris, Luc G. T., Weinhold, Nils, and Chan, Timothy A.

Published
2022
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12. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Author

Nguyen, Bastien, Fong, Christopher, Luthra, Anisha, Smith, Shaleigh A., DiNatale, Renzo G., Nandakumar, Subhiksha, Walch, Henry, Chatila, Walid K., Madupuri, Ramyasree, Kundra, Ritika, Bielski, Craig M., Mastrogiacomo, Brooke, Donoghue, Mark T.A., Boire, Adrienne, Chandarlapaty, Sarat, Ganesh, Karuna, Harding, James J., Iacobuzio-Donahue, Christine A., Razavi, Pedram, Reznik, Ed, Rudin, Charles M., Zamarin, Dmitriy, Abida, Wassim, Abou-Alfa, Ghassan K., Aghajanian, Carol, Cercek, Andrea, Chi, Ping, Feldman, Darren, Ho, Alan L., Iyer, Gopakumar, Janjigian, Yelena Y., Morris, Michael, Motzer, Robert J., O’Reilly, Eileen M., Postow, Michael A., Raj, Nitya P., Riely, Gregory J., Robson, Mark E., Rosenberg, Jonathan E., Safonov, Anton, Shoushtari, Alexander N., Tap, William, Teo, Min Yuen, Varghese, Anna M., Voss, Martin, Yaeger, Rona, Zauderer, Marjorie G., Abu-Rustum, Nadeem, Garcia-Aguilar, Julio, Bochner, Bernard, Hakimi, Abraham, Jarnagin, William R., Jones, David R., Molena, Daniela, Morris, Luc, Rios-Doria, Eric, Russo, Paul, Singer, Samuel, Strong, Vivian E., Chakravarty, Debyani, Ellenson, Lora H., Gopalan, Anuradha, Reis-Filho, Jorge S., Weigelt, Britta, Ladanyi, Marc, Gonen, Mithat, Shah, Sohrab P., Massague, Joan, Gao, Jianjiong, Zehir, Ahmet, Berger, Michael F., Solit, David B., Bakhoum, Samuel F., Sanchez-Vega, Francisco, and Schultz, Nikolaus

Published
2022
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13. Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma

Author

Sacco, Joseph J, primary, Carvajal, Richard D, additional, Butler, Marcus O, additional, Shoushtari, Alexander N, additional, Hassel, Jessica C, additional, Ikeguchi, Alexandra, additional, Hernandez-Aya, Leonel, additional, Nathan, Paul, additional, Hamid, Omid, additional, Piulats, Josep M, additional, Rioth, Matthew, additional, Johnson, Douglas B, additional, Luke, Jason J, additional, Espinosa, Enrique, additional, Leyvraz, Serge, additional, Collins, Laura, additional, Holland, Chris, additional, and Sato, Takami, additional

Published
2024
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14. Mucosal Melanoma

Author

Henderson, Michael A., Balch, Charles M., Garbe, Claus, Shoushtari, Alexander N., Lian, Bin, Cui, Chuanliang, Guo, Jun, Balch, Charles M., editor, Atkins, Michael B., editor, Garbe, Claus, editor, Gershenwald, Jeffrey E., editor, Halpern, Allan C., editor, Kirkwood, John M., editor, McArthur, Grant A., editor, Thompson, John F., editor, and Sober, Arthur J., editor

Published
2020
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15. Durable complete response in a patient with leptomeningeal melanoma after treatment with dabrafenib, trametinib, and nivolumab.

Author

Lochrin, Sarah E., Buonocore, Darren J., Young, Robert J., Kaley, Thomas J., Postow, Michael A., Wolchok, Jedd D., Shoushtari, Alexander N., Momtaz, Parisa, Betof Warner, Allison S., and Callahan, Margaret K.

Subjects
NIVOLUMAB, MELANOMA, BRAF genes, PROGNOSIS, LYMPH nodes, LUNGS
Abstract

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple‐drug regimen may be considered a viable option in fit patients. This case highlights the potential for long‐term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Author Correction: Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Amaria, Rodabe N., Postow, Michael, Burton, Elizabeth M., Tetzlaff, Michael T., Ross, Merrick I., Torres-Cabala, Carlos, Glitza, Isabella C., Duan, Fei, Milton, Denái R., Busam, Klaus, Simpson, Lauren, McQuade, Jennifer L., Wong, Michael K., Gershenwald, Jeffrey E., Lee, Jeffrey E., Goepfert, Ryan P., Keung, Emily Z., Fisher, Sarah B., Betof-Warner, Allison, Shoushtari, Alexander N., Callahan, Margaret, Coit, Daniel, Bartlett, Edmund K., Bello, Danielle, Momtaz, Parisa, Nicholas, Courtney, Gu, Aidi, Zhang, Xuejun, Korivi, Brinda Rao, Patnana, Madhavi, Patel, Sapna P., Diab, Adi, Lucci, Anthony, Prieto, Victor G., Davies, Michael A., Allison, James P., Sharma, Padmanee, Wargo, Jennifer A., Ariyan, Charlotte, and Tawbi, Hussein A.

Published
2023
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21. Clinical outcomes in metastatic uveal melanoma treated with PD‐1 and PD‐L1 antibodies

Author

Algazi, Alain P, Tsai, Katy K, Shoushtari, Alexander N, Munhoz, Rodrigo R, Eroglu, Zeynep, Piulats, Josep M, Ott, Patrick A, Johnson, Douglas B, Hwang, Jimmy, Daud, Adil I, Sosman, Jeffrey A, Carvajal, Richard D, Chmielowski, Bartosz, Postow, Michael A, Weber, Jeffrey S, and Sullivan, Ryan J

Subjects
Prevention, Rare Diseases, Clinical Research, Cancer, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, 6.1 Pharmaceuticals, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, Female, Follow-Up Studies, Humans, Male, Melanoma, Middle Aged, Mucous Membrane, Neoplasm Staging, Nivolumab, Prognosis, Programmed Cell Death 1 Receptor, Retrospective Studies, Skin Neoplasms, Survival Rate, Uveal Neoplasms, atezolizumab, immunotherapy, nivolumab, pembrolizumab, uveal melanoma, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundAntibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized.MethodsFifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined.ResultsOf 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity.ConclusionsPD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society.

Published
2016

22. The efficacy of anti‐PD‐1 agents in acral and mucosal melanoma

Author

Shoushtari, Alexander N, Munhoz, Rodrigo R, Kuk, Deborah, Ott, Patrick A, Johnson, Douglas B, Tsai, Katy K, Rapisuwon, Suthee, Eroglu, Zeynep, Sullivan, Ryan J, Luke, Jason J, Gangadhar, Tara C, Salama, April KS, Clark, Varina, Burias, Clare, Puzanov, Igor, Atkins, Michael B, Algazi, Alain P, Ribas, Antoni, Wolchok, Jedd D, and Postow, Michael A

Subjects
Clinical Trials and Supportive Activities, Cancer, Clinical Research, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Female, Follow-Up Studies, Humans, Liver Neoplasms, Male, Melanoma, Middle Aged, Mucous Membrane, Neoplasm Staging, Nivolumab, Prognosis, Programmed Cell Death 1 Receptor, Retrospective Studies, Skin Neoplasms, Survival Rate, acral melanoma, anti-programmed cell death receptor 1, immunotherapy, mucosal melanoma, nivolumab, pembrolizumab, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundTherapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described.MethodsA multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method.ResultsSixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity.ConclusionsResponse rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society.

Published
2016

23. The association between tumor mutational burden and prognosis is dependent on treatment context

Author

Valero, Cristina, Lee, Mark, Hoen, Douglas, Wang, Jingming, Nadeem, Zaineb, Patel, Neal, Postow, Michael A., Shoushtari, Alexander N., Plitas, George, Balachandran, Vinod P., Smith, J. Joshua, Crago, Aimee M., Long Roche, Kara C., Kelly, Daniel W., Samstein, Robert M., Rana, Satshil, Ganly, Ian, Wong, Richard J., Hakimi, A. Ari, Berger, Michael F., Zehir, Ahmet, Solit, David B., Ladanyi, Marc, Riaz, Nadeem, Chan, Timothy A., Seshan, Venkatraman E., and Morris, Luc G. T.

Published
2021
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24. Long-Term Survival Follow-up for Tebentafusp in Previously Treated Metastatic Uveal Melanoma

Author

Sacco, Joseph, Carvajal, Richard, Butler, Marcus, Shoushtari, Alexander N, Hassel, Jessica, Ikeguchi, Alexandra, Hernandez-Aya, Leonel, Nathan, Paul, Hamid, Omid, Piulats, Josep, Rioth, Matthew, Johnson, Douglas B, Luke, Jason, Espinosa, Enrique, Leyvraz, Serge, Collins, Laura, Holland, Chris, Sato, Takami, Sacco, Joseph, Carvajal, Richard, Butler, Marcus, Shoushtari, Alexander N, Hassel, Jessica, Ikeguchi, Alexandra, Hernandez-Aya, Leonel, Nathan, Paul, Hamid, Omid, Piulats, Josep, Rioth, Matthew, Johnson, Douglas B, Luke, Jason, Espinosa, Enrique, Leyvraz, Serge, Collins, Laura, Holland, Chris, and Sato, Takami

Abstract

BACKGROUND: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM. PATIENTS AND METHODS: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed. RESULTS: 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing. CONCLUSIONS: This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

Published
2024

27. Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors

Author

Valero, Cristina, Lee, Mark, Hoen, Douglas, Weiss, Kate, Kelly, Daniel W., Adusumilli, Prasad S., Paik, Paul K., Plitas, George, Ladanyi, Marc, Postow, Michael A., Ariyan, Charlotte E., Shoushtari, Alexander N., Balachandran, Vinod P., Hakimi, A. Ari, Crago, Aimee M., Long Roche, Kara C., Smith, J. Joshua, Ganly, Ian, Wong, Richard J., Patel, Snehal G., Shah, Jatin P., Lee, Nancy Y., Riaz, Nadeem, Wang, Jingming, Zehir, Ahmet, Berger, Michael F., Chan, Timothy A., Seshan, Venkatraman E., and Morris, Luc G. T.

Published
2021
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29. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium

Author

Andrews, Miles C, Berry, Donald A, Block, Matthew S, Boland, Genevieve M, Bollin, Kathryn B, Carlino, Matteo S, Carvajal, Richard D, Cohen, Jonathan, Davar, Diwakar, Delman, Keith A, Dummer, Reinhard, Farwell, Michael D, Fisher, David E, Fusi, Alberto, Glitza, Isabella C, de Gruijl, Tanja D, Gyorki, David E, Hauschild, Axel, Hieken, Tina J, Larkin, James, Lawson, David H, Lebbe, Celeste, Lee, Jeffrey E, Lowe, Michael C, Luke, Jason J, McArthur, Grant A, McDermott, David F, McQuade, Jennifer L, Mitchell, Tara C, Petrella, Teresa M, Prieto, Peter A, Puzanov, Igor, Robert, Caroline, Salama, April K, Sandhu, Shaneen, Schadendorf, Dirk, Shoushtari, Alexander N, Sosman, Jeffrey A, Swetter, Susan M, Tanabe, Ken K, Turajlic, Samra, Tyler, Douglas S, Woodman, Scott E, Wright, Frances C, Zager, Jonathan S, Amaria, Rodabe N, Menzies, Alexander M, Burton, Elizabeth M, Scolyer, Richard A, Tetzlaff, Michael T, Antdbacka, Robert, Ariyan, Charlotte, Bassett, Roland, Carter, Brett, Daud, Adil, Faries, Mark, Fecher, Leslie A, Flaherty, Keith T, Gershenwald, Jeffrey E, Hamid, Omid, Hong, Angela, Kirkwood, John M, Lo, Serigne, Margolin, Kim, Messina, Jane, Postow, Michael A, Rizos, Helen, Ross, Merrick I, Rozeman, Elisa A, Saw, Robyn P M, Sondak, Vernon, Sullivan, Ryan J, Taube, Janis M, Thompson, John F, van de Wiel, Bart A, Eggermont, Alexander M, Davies, Michael A, Ascierto, Paolo A, Spillane, Andrew J, van Akkooi, Alexander C J, Wargo, Jennifer A, Blank, Christian U, Tawbi, Hussein A, and Long, Georgina V

Published
2019
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31. Next-Generation Sequencing for HLA Genotype Screening and Matching to HLA-Restricted Therapies

Author

Gormally, Michael V., Chen, Monica F., Noronha, Anne Marie, Panageas, Kristalla, Reynolds, Maggie, Kohlasch, Kaelyn, Novak, Bryan, Kee-Velez, Tatiana, Clarke, Nikeysha, Eubank, Michael, Chu, Cynthia, Wilhelm, Clare, Blouin, Amanda, Kyi, Chrisann, Friedman, Claire, Rudin, Charles M., Kris, Mark G., Shah, Ronak, Aggen, David, D’Angelo, Sandra, Shoushtari, Alexander N., Berger, Michael F., Bandlamudi, Chaitanya, Klebanoff, Christopher A., Drilon, Alexander, Schoenfeld, Adam J., and Donoghue, Mark T. A.

Published
2025
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34. A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor

Author

Kelly, Ciara M., Shoushtari, Alexander N., Qin, Li-Xuan, D’Angelo, Sandra P., Dickson, Mark A., Gounder, Mrinal M., Keohan, Mary Louise, Mcfadyen, Chloe, Sjoberg, Ana, Singer, Samuel, DeMatteo, Ronald P., Hwang, Sinchun, Heinemann, M. H., Francis, Jasmine H., Antonescu, Cristina R., Chi, Ping, and Tap, William D.

Published
2019
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37. Treatment of Uveal Melanoma

Author

Shoushtari, Alexander N., Carvajal, Richard D., Rosen, Steven T., Series editor, Kaufman, Howard L., editor, and Mehnert, Janice M., editor

Published
2016
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38. Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Author

Samstein, Robert M., Lee, Chung-Han, Shoushtari, Alexander N., Hellmann, Matthew D., Shen, Ronglai, Janjigian, Yelena Y., Barron, David A., Zehir, Ahmet, Jordan, Emmet J., Omuro, Antonio, Kaley, Thomas J., Kendall, Sviatoslav M., Motzer, Robert J., Hakimi, A. Ari, Voss, Martin H., Russo, Paul, Rosenberg, Jonathan, Iyer, Gopa, Bochner, Bernard H., Bajorin, Dean F., Al-Ahmadie, Hikmat A., Chaft, Jamie E., Rudin, Charles M., Riely, Gregory J., Baxi, Shrujal, Ho, Alan L., Wong, Richard J., Pfister, David G., Wolchok, Jedd D., Barker, Christopher A., Gutin, Philip H., Brennan, Cameron W., Tabar, Viviane, Mellinghoff, Ingo K., DeAngelis, Lisa M., Ariyan, Charlotte E., Lee, Nancy, Tap, William D., Gounder, Mrinal M., D’Angelo, Sandra P., Saltz, Leonard, Stadler, Zsofia K., Scher, Howard I., Baselga, Jose, Razavi, Pedram, Klebanoff, Christopher A., Yaeger, Rona, Segal, Neil H., Ku, Geoffrey Y., DeMatteo, Ronald P., Ladanyi, Marc, Rizvi, Naiyer A., Berger, Michael F., Riaz, Nadeem, Solit, David B., Chan, Timothy A., and Morris, Luc G. T.

Published
2019
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39. Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

Author

Hamid, Omid, primary, Hassel, Jessica C, additional, Shoushtari, Alexander N, additional, Meier, Friedegund, additional, Bauer, Todd M, additional, Salama, April K S, additional, Kirkwood, John M, additional, Ascierto, Paolo A, additional, Lorigan, Paul C, additional, Mauch, Cornelia, additional, Orloff, Marlana, additional, Evans, Thomas R Jeffry, additional, Holland, Chris, additional, Edukulla, Ramakrishna, additional, Abedin, Shaad E, additional, and Middleton, Mark R, additional

Published
2023
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40. Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma:A phase 1 study

Author

Hamid, Omid, Hassel, Jessica C., Shoushtari, Alexander N., Meier, Friedegund, Bauer, Todd M., Salama, April K.S., Kirkwood, John M., Ascierto, Paolo A., Lorigan, Paul C., Mauch, Cornelia, Orloff, Marlana, Evans, Thomas R.Jeffry, Holland, Chris, Edukulla, Ramakrishna, Abedin, Shaad E., and Middleton, Mark R.

Subjects
T-Lymphocytes, Immunotherapy, Immune Checkpoint Inhibitors, Melanoma
Abstract

Background Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. Methods In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A∗02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. Results 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%). Conclusion At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1. Trial registration number NCT02535078.

Published
2023
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41. Mucosal Melanoma

Author

Henderson, Michael A., primary, Balch, Charles M., additional, Garbe, Claus, additional, Shoushtari, Alexander N., additional, Lian, Bin, additional, Cui, Chuanliang, additional, and Guo, Jun, additional

Published
2019
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42. Tebentafusp in Combination With Durvalumab And/or Tremelimumab in Patients With Metastatic Cutaneous Melanoma: A Phase 1 Study

Author

Hamid, Omid, Hassel, Jessica C., Shoushtari, Alexander N., Meier, Friedegund, Bauer, Todd M., Salama, April K.S., Kirkwood, John M., Ascierto, Paolo A., Lorigan, Paul C., Mauch, Cornelia, Orloff, Marlana, Evans, Thomas R. Jeffry, Holland, Chris, Edukulla, Ramakrishna, Abedin, Shaad E., Middleton, Mark R., Hamid, Omid, Hassel, Jessica C., Shoushtari, Alexander N., Meier, Friedegund, Bauer, Todd M., Salama, April K.S., Kirkwood, John M., Ascierto, Paolo A., Lorigan, Paul C., Mauch, Cornelia, Orloff, Marlana, Evans, Thomas R. Jeffry, Holland, Chris, Edukulla, Ramakrishna, Abedin, Shaad E., and Middleton, Mark R.

Abstract

BACKGROUND: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. METHODS: In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. RESULTS: 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tu

Published
2023

43. Abstract CT223: Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM)

Author

Sacco, Joseph J., primary, Carvajal, Richard D., additional, Butler, Marcus O., additional, Shoushtari, Alexander N., additional, Hassel, Jessica C., additional, Ikeguchi, Alexandra, additional, Hernandez-Aya, Leonel, additional, Nathan, Paul, additional, Hamid, Omid, additional, Piulats, Josep M., additional, Rioth, Matthew, additional, Johnson, Douglas B., additional, Luke, Jason J., additional, Espinosa, Erique, additional, Leyvraz, Serge, additional, Collins, Laura, additional, Holland, Chris, additional, McCully, Michelle L., additional, and Sato, Takami, additional

Published
2023
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45. Data from Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis

Author

Li, Jun, primary, Duran, Mercedes A., primary, Dhanota, Ninjit, primary, Chatila, Walid K., primary, Bettigole, Sarah E., primary, Kwon, John, primary, Sriram, Roshan K., primary, Humphries, Matthew P., primary, Salto-Tellez, Manuel, primary, James, Jacqueline A., primary, Hanna, Matthew G., primary, Melms, Johannes C., primary, Vallabhaneni, Sreeram, primary, Litchfield, Kevin, primary, Usaite, Ieva, primary, Biswas, Dhruva, primary, Bareja, Rohan, primary, Li, Hao Wei, primary, Martin, Maria Laura, primary, Dorsaint, Princesca, primary, Cavallo, Julie-Ann, primary, Li, Peng, primary, Pauli, Chantal, primary, Gottesdiener, Lee, primary, DiPardo, Benjamin J., primary, Hollmann, Travis J., primary, Merghoub, Taha, primary, Wen, Hannah Y., primary, Reis-Filho, Jorge S., primary, Riaz, Nadeem, primary, Su, Shin-San Michael, primary, Kalbasi, Anusha, primary, Vasan, Neil, primary, Powell, Simon N., primary, Wolchok, Jedd D., primary, Elemento, Olivier, primary, Swanton, Charles, primary, Shoushtari, Alexander N., primary, Parkes, Eileen E., primary, Izar, Benjamin, primary, and Bakhoum, Samuel F., primary

Published
2023
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46. Supplementary Tables 1-3 and Supplementary Figures 1-4 from Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071

Author

Piperno-Neumann, Sophie, primary, Larkin, James, primary, Carvajal, Richard D., primary, Luke, Jason J., primary, Schwartz, Gary K., primary, Hodi, F. Stephen, primary, Sablin, Marie-Paule, primary, Shoushtari, Alexander N., primary, Szpakowski, Sebastian, primary, Chowdhury, Niladri Roy, primary, Brannon, A. Rose, primary, Ramkumar, Thiruvamoor, primary, de Koning, Leanne, primary, Derti, Adnan, primary, Emery, Caroline, primary, Yerramilli-Rao, Padmaja, primary, and Kapiteijn, Ellen, primary

Published
2023
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47. Supplementary Data PDF from Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis

Author

Li, Jun, primary, Duran, Mercedes A., primary, Dhanota, Ninjit, primary, Chatila, Walid K., primary, Bettigole, Sarah E., primary, Kwon, John, primary, Sriram, Roshan K., primary, Humphries, Matthew P., primary, Salto-Tellez, Manuel, primary, James, Jacqueline A., primary, Hanna, Matthew G., primary, Melms, Johannes C., primary, Vallabhaneni, Sreeram, primary, Litchfield, Kevin, primary, Usaite, Ieva, primary, Biswas, Dhruva, primary, Bareja, Rohan, primary, Li, Hao Wei, primary, Martin, Maria Laura, primary, Dorsaint, Princesca, primary, Cavallo, Julie-Ann, primary, Li, Peng, primary, Pauli, Chantal, primary, Gottesdiener, Lee, primary, DiPardo, Benjamin J., primary, Hollmann, Travis J., primary, Merghoub, Taha, primary, Wen, Hannah Y., primary, Reis-Filho, Jorge S., primary, Riaz, Nadeem, primary, Su, Shin-San Michael, primary, Kalbasi, Anusha, primary, Vasan, Neil, primary, Powell, Simon N., primary, Wolchok, Jedd D., primary, Elemento, Olivier, primary, Swanton, Charles, primary, Shoushtari, Alexander N., primary, Parkes, Eileen E., primary, Izar, Benjamin, primary, and Bakhoum, Samuel F., primary

Published
2023
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