Article
Oncology
T. L. Peters, T. Patil, A. T. Le, K. D. Davies, P. M. Brzeskiewicz, H. Nijmeh, L. Bao, D. R. Camidge, D. L. Aisner, R. C. Doebele
Summary: EGFR mutant non-small cell lung cancer patients initially respond well to EGFR-targeted therapy but often develop acquired resistance, which requires broad molecular testing to understand the resistance mechanisms and develop new treatment options.
NPJ PRECISION ONCOLOGY
(2021)
Article
Oncology
Yasir Y. Elamin, Jacqulyne P. Robichaux, Brett W. Carter, Mehmet Altan, Hai Tran, Don L. Gibbons, Simon Heeke, Frank Fossella, Vincent K. Lam, Xiuning Le, Marcelo Negrao, Monique B. Nilsson, Anisha Patel, R. S. K. Vijayan, Jason B. Cross, Jianjun Zhang, Lauren A. Byers, Charles Lu, Tina Cascone, Lei Feng, Rajyalakshmi Luthra, Francis A. San Lucas, Geeta Mantha, Mark Routbort, George Blumenschein, Anne S. Tsao, John Heymach
Summary: This study reports the efficacy of poziotinib in treating NSCLC patients with EGFR exon 20 mutations and highlights the importance of insertion location in determining drug sensitivity. The study found that near-loop insertions were more sensitive to poziotinib than far-loop insertions. Furthermore, potential mechanisms of acquired resistance were identified.
Review
Oncology
Susan L. Feldt, Christine M. Bestvina
Summary: Targeted therapy against genetic abnormalities in non-small cell lung cancer that has spread has improved patient outcomes. However, resistance eventually develops, and this paper summarizes the research on changes in the MET gene that occur after EGFR-targeted therapy. Medications targeting MET and combination therapies targeting both EGFR and MET show promise for overcoming this resistance. Larger trials are ongoing to assess the potential benefit for patients.
Article
Oncology
Min Yu, Xiaoyu Li, Xueqian Wu, Weiya Wang, Yanying Li, Yan Zhang, Shuang Zhang, Yongsheng Wang
Summary: EGFR-TKI treatment can lead to menstrual abnormalities and abnormal vaginal bleeding in premenopausal female NSCLC patients, which may be associated with decreased progesterone level, reduced EGFR activation, and tissue factor (TF) expression in endometrial tissues.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu, Chiao-En Wu
Summary: A novel nomogram was created in this study to help physicians suggest the optimal treatment for EGFRm+ NSCLC patients. The nomogram was based on pretreatment factors and stratified patients into five different risk groups for progression-free survival (PFS) and overall survival (OS). This risk stratification can provide additional information for clinicians and patients in determining the optimal therapeutic options.
Review
Biochemistry & Molecular Biology
Keigo Kobayashi, Aaron C. Tan
Summary: The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. However, drug resistance remains a challenge in the long-term management of patients. This review highlights the role of intratumoral heterogeneity and drug-tolerant persister (DTP) cells in NSCLC resistance mechanisms. Changes in the tumor microenvironment, chromosomal instability, and extrachromosomal DNA (ecDNA) also contribute to intratumoral heterogeneity and drug resistance. Comprehensive genomic profiling has provided valuable insights into primary resistance mechanisms in the context of tumor heterogeneity. Understanding these mechanisms is crucial for developing individualized anticancer therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, General & Internal
Hongxue Meng, Lan Huang, Jiahui Wang, Yingxu Zhou, Meng Wang, Zhaoyang Yang, Xuan Hong
Summary: A retrospective analysis of 67 patients with EGFR mutations who were switched to osimertinib after receiving first-generation EGFR-TKIs revealed that female patients and those who experienced isolated progression during first-line treatment may exhibit a better response to osimertinib. Additionally, a low frequency of the EGFR T790M allele in plasma samples may predict poor efficacy of osimertinib and shorter progression-free survival (PFS).
INTERNATIONAL JOURNAL OF CLINICAL PRACTICE
(2021)
Article
Oncology
Maya N. White, Zofia Piotrowska, Kevin Stirling, Stephen V. Liu, Mandeep K. Banwait, Kristen Cunanan, Lecia V. Sequist, Heather A. Wakelee, Daniel Hausrath, Joel W. Neal
Summary: Combining osimertinib with chemotherapy in EGFR-mutated non-small cell lung cancer patients who progressed on EGFR-targeted monotherapy showed favorable safety and central nervous system outcomes, with efficacy outcomes similar to historical controls.
CLINICAL LUNG CANCER
(2021)
Article
Oncology
Li Sun, Yi-Jia Guo, Jun Song, Yan-Ru Wang, Shu-Ling Zhang, Le-Tian Huang, Jian-Zhu Zhao, Wei Jing, Cheng-Bo Han, Jie-Tao Ma
Summary: The neoadjuvant EGFR-TKI therapy shows feasibility in treating patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Further phase III clinical trials are needed to confirm these findings and explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Soon Hin How, Chong Kin Liam, Muhammad Adil Zainal Abidin, Harissa H. Hasbullah, Lye Mun Tho, Gwo Fuang Ho, Ibtisam Muhamad Nor, Yong Kek Pang, Kean Fatt Ho, Muthukkumaran Thiagarajan, Roziana Ariffin, Azlina Samsudin, Azza Omar, Sin Nee Tan, Choo Khoon Ong, Sing Yang Soon, Mau Ern Poh
Summary: This study describes the management and outcomes of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting. The results suggest that the choice of first-line therapy, time on each line of treatment, and subsequent treatment options may adversely affect the overall survival of patients.
CANCER MANAGEMENT AND RESEARCH
(2022)
Review
Oncology
Xiuning Le, Monique Nilsson, Jonathan Goldman, Martin Reck, Kazuhiko Nakagawa, Terafumi Kato, Luis Paz Ares, Bente Frimodt-Moller, Katharina Wolff, Carla Visseren-Grul, John V. Heymach, Edward B. Garon
Summary: The VEGF and EGFR pathways play crucial roles in EGFR-mutant NSCLC, and dual inhibition of these two pathways can significantly improve patient outcomes.
JOURNAL OF THORACIC ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Kamrine E. Poels, Adam J. Schoenfeld, Alex Makhnin, Yosef Tobi, Yuli Wang, Heidie Frisco-Cabanos, Shaon Chakrabarti, Manli Shi, Chelsi Napoli, Thomas O. McDonald, Weiwei Tan, Aaron Hata, Scott L. Weinrich, Helena A. Yu, Franziska Michor
Summary: In this study, a computational model was used to identify an optimal dosing schedule for combination therapy of osimertinib and dacomitinib, which was confirmed tolerable and effective in an ongoing phase I clinical trial.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Wenqian Li, Hanfei Guo, Lingyu Li, Jiuwei Cui
Summary: The study found that adjuvant EGFR-TKI application was more cost-effective compared to chemotherapy for early-stage EGFR-mutant NSCLC patients, and sensitivity analysis confirmed the stability of the model.
FRONTIERS IN ONCOLOGY
(2021)
Article
Medicine, Research & Experimental
Dan Yan, Justus M. Huelse, Dmitri Kireev, Zikang Tan, Luxiao Chen, Subir Goyal, Xiaodong Wang, Stephen Frye, Madhusmita Behera, Frank Schneider, Suresh S. Ramalingam, Taofeek Owonikoko, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Summary: Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI). Activation of MERTK is associated with OSI resistance and inhibition of MERTK kinase can resensitize resistant cells to OSI.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Oncology
Chun-Ta Huang, Chih-An Lin, Te-Jen Su, Ching-Yao Yang, Tzu-Hsiu Tsai, Chia-Lin Hsu, Wei-Yu Liao, Kuan-Yu Chen, Chao-Chi Ho, Chong-Jen Yu
Summary: This study investigates the utility of droplet digital PCR (ddPCR) for detection of the T790M mutation in plasma circulating tumor DNA (ctDNA) and explores its impact on prognosis. The results show that ddPCR can effectively detect the T790M mutation and predict disease progression and patient survival in advance. Therefore, the plasma-based detection technology using ddPCR is of significant importance for the treatment and prognosis of EGFR-mutant non-small cell lung cancer.
Article
Oncology
Panagiotis A. Konstantinopoulos, Su-Chun Cheng, Jeffrey G. Supko, Madeline Polak, Andrea E. Wahner-Hendrickson, S. Percy Ivy, Brittany Bowes, Hannah Sawyer, Patrice Basada, Martin Hayes, Jennifer Curtis, Neil Horowitz, Alexi A. Wright, Susana M. Campos, Elena Ivanova, Cloud P. Paweletz, Sangeetha Palakurthi, Joyce F. Liu, Alan D. D'Andrea, Prafulla C. Gokhale, Dipanjan Chowdhury, Ursula A. Matulonis, Geoffrey Shapiro
Summary: Combining onalespib with olaparib showed anti-tumour activity in BRCA1-mutated and RB-pathway altered ovarian cancer models. Phase 1 evaluation confirmed the safety of dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg, without affecting the pharmacokinetics of either agent. Although there were no objective responses, disease stabilization for ≥24 weeks was observed in 32% of evaluable patients, including those with BRCA mutations and acquired PARPi resistance or RB-pathway alterations.
BRITISH JOURNAL OF CANCER
(2022)
Article
Oncology
Joseph W. Kim, Rana R. McKay, Marc R. Radke, Shilin Zhao, Mary-Ellen Taplin, Nancy B. Davis, Paul Monk, Leonard J. Appleman, Primo N. Lara, Ulka N. Vaishampayan, Jingsong Zhang, Asit K. Paul, Glenn Bubley, Eliezer M. Van Allen, Serhan Unlu, Ying Huang, Massimo Loda, Geoffrey I. Shapiro, Peter M. Glazer, Patricia M. LoRusso, S. Percy Ivy, Yu Shyr, Elizabeth M. Swisher, Daniel P. Petrylak
Summary: The study investigated the clinical outcomes of combining Cediranib with olaparib in patients with prostate cancer. The results showed that the combination improved radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer compared to olaparib alone. However, it was also associated with a higher incidence of adverse events.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Alexandre Andre B. A. da Costa, Dipanjan Chowdhury, Geoffrey I. Shapiro, Alan D. D'Andrea, Panagiotis A. Konstantinopoulos
Summary: Replication stress is a major cause of genomic instability and a vulnerability of cancer cells. Inhibiting kinases such as ATR, CHK1, WEE1, and MYT1 can target this vulnerability. In addition, inhibiting the DNA damage response can elicit an immune response. Therefore, several inhibitors are being evaluated in clinical trials to overcome therapeutic resistance and promote antitumor immunity by targeting replication stress.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Oncology
John Hilton, Mihaela Cristea, Sophie Postel-Vinay, Capucine Baldini, Mark Voskoboynik, William Edenfield, Geoffrey Shapiro, Michael L. Cheng, Jacqueline Vuky, Bradley Corr, Sharmila Das, Abraham Apfel, Ke Xu, Martin Kozicki, Keziban Unsal-Kacmaz, Amy Hammell, Guan Wang, Palanikumar Ravindran, Georgia Kollia, Oriana Esposito, Shodeinde Coker, Jennifer R. Diamond
Summary: BMS-986158, an experimental anticancer therapy, can block BET protein function to regulate cancer-related genes and inhibit tumor growth. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158. Among the different dosing schedules tested, schedule A (5 days on, 2 days off) showed stable drug levels in the blood, preliminary anticancer effects, and a proportional PK profile.
Article
Oncology
Giuseppe Curigliano, Geoffrey Shapiro, Rebecca S. Kristeleit, Albiruni R. Abdul Razak, Stephen Leong, Maria Alsina, Antonio Giordano, Karen A. Gelmon, Erica Stringer-Reasor, Ulka N. Vaishampayan, Mark Middleton, Anthony J. Olszanski, Hope S. Rugo, Kenneth A. Kern, Nuzhat Pathan, Rachelle Perea, Kristen J. Pierce, Sarah C. Mutka, Zev A. Wainberg
Summary: This study evaluated the efficacy and safety of gedatolisib in combination with other anti-tumour agents in advanced solid tumours. The results showed that the combination therapy of gedatolisib and cisplatin had good clinical activity and acceptable tolerability profile in patients with triple-negative breast cancer, both in first-line and second/third-line settings.
BRITISH JOURNAL OF CANCER
(2023)
Correction
Oncology
Giuseppe Curigliano, Geoffrey I. I. Shapiro, Rebecca S. S. Kristeleit, Albiruni R. R. Abdul Razak, Stephen Leong, Maria Alsina, Antonio Giordano, Karen A. A. Gelmon, Erica Stringer-Reasor, Ulka N. N. Vaishampayan, Mark Middleton, Anthony J. J. Olszanski, Hope S. S. Rugo, Kenneth A. A. Kern, Nuzhat Pathan, Rachelle Perea, Kristen J. J. Pierce, Sarah C. C. Mutka, Zev A. A. Wainberg
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Funda Meric-Bernstam, James M. Ford, Peter J. O'Dwyer, Geoffrey I. Shapiro, Lisa M. McShane, Boris Freidlin, Roisin E. O'Cearbhaill, Suzanne George, Julia Glade-Bender, Gary H. Lyman, James Tricoli, David Patton, Stanley R. Hamilton, Robert J. Gray, Douglas S. Hawkins, Bhanumati Ramineni, Keith T. Flaherty, Petros Grivas, Timothy A. Yap, Jordan Berlin, James H. Doroshow, Lyndsay N. Harris, Jeffrey A. Moscow
Summary: In the past decade, there have been multiple trials to determine the effectiveness of treating cancer based on specific genomic alterations. However, most patients do not respond to single-agent therapies targeting a single alteration, and drug resistance often develops. To address this, the NCI has developed NCI-ComboMATCH, a study to explore genomically-directed combination therapies and overcome drug resistance.
CLINICAL CANCER RESEARCH
(2023)
Article
Immunology
Lestat R. Ali, Ana C. Garrido-Castro, Patrick J. Lenehan, Naima Bollenrucher, Courtney T. Stump, Michael Dougan, Shom Goel, Geoffrey I. Shapiro, Sara M. Tolaney, Stephanie K. Dougan
Summary: The authors analyzed blood and tumors from breast and ovarian cancer patients treated with PD-1 blockade and CDK4/6 inhibition using single-cell RNA-sequencing and TCR tracking. They found that both therapies enhance T cell effector function and memory. In mouse models of melanoma and breast cancer, the augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade, suggesting sequential therapy as a potentially safe and synergistic strategy in patients.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Oncology
Nami Yamashita, Yoshihiro Morimoto, Atsushi Fushimi, Rehan Ahmad, Atrayee Bhattacharya, Tatsuaki Daimon, Naoki Haratake, Yuka Inoue, Satoshi Ishikawa, Masaaki Yamamoto, Tsuyoshi Hata, Sayuri Akiyoshi, Qiang Hu, Tao Liu, Henry Withers, Song Liu, Geoffrey I. Shapiro, Tomoharu Yoshizumi, Mark D. Long, Donald Kufe
Summary: In certain cancer cells, the chromatin remodeling complex SWI/SNF PBAF's subunit polybromo-1 (PBRM1) drives DNA damage resistance and immune evasion through unclear mechanisms. This study found that MUC1-C is necessary for PBRM1 expression in triple-negative breast cancer (TNBC) cells, and the two proteins form a nuclear complex. Transcriptional and chromatin accessibility analysis showed that MUC1-C and PBRM1 increase the expression of STAT1 and IRF1 by enhancing chromatin accessibility on their respective genes, as well as other genes involved in DNA damage resistance and immune evasion.
MOLECULAR CANCER RESEARCH
(2023)
Article
Oncology
Christian Kollmannsberger, Herbert Hurwitz, Lyudmila Bazhenova, Byoung Chul Cho, David Hong, Keunchil Park, Karen L. Reckamp, Sunil Sharma, Hirak Der-Torossian, James G. Christensen, Demiana Faltaos, Diane Potvin, Vanessa Tassell, Richard Chao, Geoffrey Shapiro
Summary: This phase I study determined the maximum tolerated dose, recommended phase II dose, and safety profile of glesatinib in patients with advanced or unresectable solid tumors. The study found that glesatinib had antitumor activity in patients with tumors harboring overexpression or amplification of MET and AXL, as well as MET-activating mutations or rearrangements. Based on the clinical activity, safety, and pharmacokinetic data, SDD 750 mg twice daily was selected as the preferred formulation and dose of glesatinib.
Article
Oncology
Meghan J. Mooradian, James M. Cleary, Anita Giobbie-Hurder, Lancia N. F. Darville, Aparna Parikh, Elizabeth I. Buchbinder, Justine V. Cohen, Donald P. Lawrence, Geoffrey I. Shapiro, Harold Keer, Helen X. X. Chen, Susan Percy Ivy, Keiran S. M. Smalley, John M. Koomen, Ryan J. Sullivan
Summary: This study showed that the combination of HSP90 inhibitor AT13387 with dabrafenib and trametinib was safe and led to modest disease control in heavily pretreated patients with BRAF V600E/K-mutant solid tumors. Further research is needed to identify tumor types and resistance mechanisms that are most sensitive to this approach.
Article
Oncology
David S. Hong, Michael Postow, Bartosz Chmielowski, Ryan Sullivan, Amita Patnaik, Ezra E. W. Cohen, Geoffrey Shapiro, Conor Steuer, Martin Gutierrez, Heather Yeckes-Rodin, Robert Ilaria Jr, Brenda O'Connell, Joanna Peng, Guangbin Peng, Nora Zizlsperger, Anthony Tolcher, Jedd D. Wolchok
Summary: This study evaluated the safety and tolerability of a new antitumor drug, IPI-549, and found that it has good antitumor activity when used in combination with PD-1/PD-L1 inhibitors, and with minimal side effects. Therefore, doses of 30 and 40 mg of IPI-549 were chosen for the next phase of the study.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Elizabeth Pan, Wanling Xie, Archana Ajmera, Arlene Araneta, Christina Jamieson, Edmund Folefac, Arif Hussain, Christos E. Kyriakopoulos, Adam Olson, Mamta Parikh, Rahul Parikh, Biren Saraiya, S. Percy Ivy, Eliezer M. Van Allen, Neal I. Lindeman, Bose S. Kochupurakkal, Geoffrey I. Shapiro, Rana R. McKay
Summary: In this study, the synergy between olaparib and radium-223 in metastatic castration-resistant prostate cancer (mCRPC) was demonstrated. A phase I dose escalation study showed that olaparib can be safely combined with fixed dose radium-223, and early clinical benefit was observed. The recommended dose of olaparib was 200 mg orally twice daily with radium-223, which will be further investigated in a phase II study.
MOLECULAR CANCER THERAPEUTICS
(2023)
Article
Multidisciplinary Sciences
James J. Harding, Sarina A. Piha-Paul, Ronak H. H. Shah, Jessica J. Murphy, James M. Cleary, Geoffrey I. Shapiro, David I. Quinn, Irene Brana, Victor Moreno, Mitesh Borad, Sherene Loi, Iben Spanggaard, Haeseong Park, James M. Ford, Monica Arnedos, Salomon M. Stemmer, Christelle de la Fouchardiere, Christos Fountzilas, Jie Zhang, Daniel DiPrimeo, Casey Savin, S. Duygu Selcuklu, Michael F. Berger, Lisa D. Eli, Funda Meric-Bernstam, Komal Jhaveri, David B. Solit, Ghassan K. Abou-Alfa
Summary: In patients with biliary tract cancer, HER2 alterations correlate with poor prognosis. A phase II clinical trial showed that the tyrosine kinase inhibitor neratinib has some efficacy in treating advanced biliary tract cancers with HER2-mutation positive. The objective response rate to neratinib was 16% (95% CI 4.5-36.1%).
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Zahra Talebi, Dominique A. Garrison, Eric D. Eisenmann, Kalindi Parmar, Geoffrey I. Shapiro, Michelle A. Rudek, Alex Sparreboom, Yan Jin
Summary: A rapid, sensitive, and simple UHPLC-MS/MS method was developed and validated for the determination of the PARP inhibitor talazoparib in mouse plasma. The method showed good accuracy and reproducibility, making it suitable for pharmacokinetic studies.