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Your search keyword '"Alvarez, Jacob J. S."' showing total 3 results
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3 results on '"Alvarez, Jacob J. S."'

1. Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities

Author

Chua, Khi Pin, Teng, Yvonne H. F., Tan, Aaron C., Takano, Angela, Alvarez, Jacob J. S., Nahar, Rahul, Rohatgi, Neha, Lai, Gillianne G. Y., Aung, Zaw Win, Yeong, Joe P. S., Lim, Kiat Hon, Naeini, Marjan Mojtabavi, Kassam, Irfahan, Jain, Amit, Tan, Wan Ling, Gogna, Apoorva, Too, Chow Wei, Kanesvaran, Ravindran, Ng, Quan Sing, Ang, Mei Kim, Rajasekaran, Tanujaa, Anantham, Devanand, Phua, Ghee Chee, Tan, Bien Soo, Lee, Yin Yeng, Wang, Lanying, Teo, Audrey S. M., Khng, Alexis Jiaying, Lim, Ming Jie, Suteja, Lisda, Toh, Chee Keong, Lim, Wan-Teck, Iyer, N. Gopalakrishna, Tam, Wai Leong, Tan, Eng-Huat, Zhai, Weiwei, Hillmer, Axel M., Skanderup, Anders J., Tan, Daniel S. W., Chua, Khi Pin, Teng, Yvonne H. F., Tan, Aaron C., Takano, Angela, Alvarez, Jacob J. S., Nahar, Rahul, Rohatgi, Neha, Lai, Gillianne G. Y., Aung, Zaw Win, Yeong, Joe P. S., Lim, Kiat Hon, Naeini, Marjan Mojtabavi, Kassam, Irfahan, Jain, Amit, Tan, Wan Ling, Gogna, Apoorva, Too, Chow Wei, Kanesvaran, Ravindran, Ng, Quan Sing, Ang, Mei Kim, Rajasekaran, Tanujaa, Anantham, Devanand, Phua, Ghee Chee, Tan, Bien Soo, Lee, Yin Yeng, Wang, Lanying, Teo, Audrey S. M., Khng, Alexis Jiaying, Lim, Ming Jie, Suteja, Lisda, Toh, Chee Keong, Lim, Wan-Teck, Iyer, N. Gopalakrishna, Tam, Wai Leong, Tan, Eng-Huat, Zhai, Weiwei, Hillmer, Axel M., Skanderup, Anders J., and Tan, Daniel S. W.

Abstract

Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M(+)) and -negative (T790M(-)) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M(-) tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M(-) tumors. Almost half of resistant tumors were further classified as immune(hot), with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M(-) and T790M(+) disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naive patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Published
2021

2. A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Author

Lai GGY, Yeo JC, Jain A, Zhou S, Pang M, Alvarez JJS, Sim NL, Tan AC, Suteja L, Lim TW, Guo YA, Shen M, Saw SPL, Rohatgi N, Yeong JPS, Takano A, Lim KH, Gogna A, Too CW, Da Zhuang K, Tan WL, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Wang L, Toh CK, Lim WT, Tam WL, Tan SH, Skanderup AMJ, Tan EH, and Tan DSW

Abstract

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC., Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI., Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events., Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients., (© 2022 by the International Association for the Study of Lung Cancer.)

Published
2022
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3. Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

Author

Chua KP, Teng YHF, Tan AC, Takano A, Alvarez JJS, Nahar R, Rohatgi N, Lai GGY, Aung ZW, Yeong JPS, Lim KH, Naeini MM, Kassam I, Jain A, Tan WL, Gogna A, Too CW, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Anantham D, Phua GC, Tan BS, Lee YY, Wang L, Teo ASM, Khng AJ, Lim MJ, Suteja L, Toh CK, Lim WT, Iyer NG, Tam WL, Tan EH, Zhai W, Hillmer AM, Skanderup AJ, and Tan DSW

Subjects
ErbB Receptors genetics, Humans, Protein-Tyrosine Kinases genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Mutation
Abstract

Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M -negative resistance., Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M + ) and -negative (T790M - ) disease., Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M - tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M - tumors. Almost half of resistant tumors were further classified as immune hot , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M - and T790M + disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients., Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2021
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