Article
Oncology
Luiz Henrique Araujo, Bianca Mendes Souza, Laura Rabelo Leite, Sabrina A. F. Parma, Natalia P. Lopes, Frederico S. V. Malta, Maira C. M. Freire
Summary: KRAS G12C mutation frequency is higher than other driver mutations in colorectal and non-small cell lung cancer, suggesting KRAS testing should be considered for all patients regardless of clinical or demographic characteristics.
Article
Oncology
Gabriela Palma, Faisal Khurshid, Kevin Lu, Brian Woodward, Hatim Husain
Summary: Patients with tumors harboring KRAS G12C mutations have poor prognosis, but targeted therapies like sotorasib and Adagrasib have shown promising overall response rates. While single agent efficacy is observed, combination approaches may offer better outcomes.
NPJ PRECISION ONCOLOGY
(2021)
Review
Oncology
Cian O'Leary, Grace Murphy, Yong Yeung, Ming Tang, Vikram Jain, Connor G. O'Leary
Summary: Non-small-cell lung cancer (NSCLC) is a common and often fatal malignancy, with Kirsten rat sarcoma virus (KRAS) mutation being a commonly mutated oncogene in NSCLC. Recently developed KRAS G12C inhibitors have overcome the therapeutic hurdle of targeting KRAS mutations. While these medications show substantial response rates in heavily pre-treated NSCLC patients, phase-3 evidence has not yet demonstrated an overall survival benefit compared to standard-of-care chemotherapy. Additionally, these medications may have a negative interaction with immunotherapies, leading to higher hepatotoxicity rates. Despite these limitations, these medications represent an important advancement in targeted and personalized oncological treatment, and future trials may provide further meaningful outcomes for guiding treatment in this patient cohort.
Article
Oncology
Cloud P. Paweletz, Grace A. Heavey, Yanan Kuang, Emily Durlacher, Thian Kheoh, Richard C. Chao, Alexander I. Spira, Konstantinos Leventakos, Melissa L. Johnson, Sai-Hong Ignatius Ou, Gregory J. Riely, Kenna Anderes, Wenjing Yang, James G. Christensen, Pasi A. Janne
Summary: This study reports on early ctDNA changes of KRAS G12C in lung cancer patients and suggests that ctDNA changes can be used as a potential measure for early prediction of clinical response.
CLINICAL CANCER RESEARCH
(2023)
Review
Oncology
Wade Iams, Meridith L. Balbach, Sharon Phillips, Adrian Sacher, Christine Bestvina, Vamsidhar Velcheti, Xiao Wang, Melina E. Marmarelis, Nan Sethakorn, Ticiana Leal, Paul E. Sackstein, Chul Kim, Andrew Robinson, Kathan Mehta, Robert Hsu, Jorge Nieva, Tejas Patil, Ross Camidge
Summary: In this study, a retrospective analysis of 396 patients with KRAS G12C mutant NSCLC was conducted, revealing a median progression-free survival of 4.6 months among patients treated with docetaxel in the second-line setting, consistent with the recently reported CodeBreak 200 dataset.
CLINICAL LUNG CANCER
(2023)
Article
Medicine, General & Internal
Oliver Illini, Hannah Fabikan, Maximilian Johannes Hochmair, Christoph Weinlinger, Dagmar Krenbek, Luka Brcic, Ulrike Setinek, Angelika Terbuch, Gudrun Absenger, Selma Konjic, Arschang Valipour
Summary: This study retrospectively assessed the clinicopathological features and standard-of-care treatment responses in patients with KRAS(G12C)-mutated advanced non-small cell lung cancer. The study highlights the poor outcomes in this patient population and emphasizes the need for new treatment options and specific molecular testing.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Oncology
Arielle Elkrief, Biagio Riccuiti, Joao Alessi, Teng Fei, Hannah L. Kalvin, Jacklynn Egger, Hira Rizvi, Rohit Thummalapalli, Guiseppe Lamberti, Andrew Plodkowski, Matthew D. Hellmann, Mark G. Kris, Maria E. Arcila, Marina K. Baine, Charles M. Rudin, Piro Lito, Marc Ladanyi, Adam J. Schoenfeld, Gregory J. Riely, Mark M. Awad, Kathryn C. Arbour
Summary: This study aimed to define the clinical outcomes of first-line chemo-immunotherapy in patients with non-small cell lung cancer with KRASG12C mutations and to examine the significance of PD-L1 tumor proportion score and comutation status (KEAP1 and STK11) on outcomes.
Article
Oncology
Markus Y. Wu, Eric W. Zhang, Matthew R. Strickland, Dexter P. Mendoza, Lev Lipkin, Jochen K. Lennerz, Justin F. Gainor, Rebecca S. Heist, Subba R. Digumarthy
Summary: KRAS G12C mutations in lung cancer are important oncogenic mutations that exhibit distinct primary tumor imaging features and patterns of metastasis compared to lung cancers driven by other genetic alterations. These unique imaging features may provide clues to the presence of KRAS G12C NSCLC and potentially guide management strategies in the future.
Editorial Material
Oncology
Christina Guo, Udai Banerji
Summary: KRAS mutations play a critical role in cancer, with drugs targeting KRAS(G12C) mutations showing potential efficacy. Clinical trials targeting non-G12C mutated KRAS driven cancers with the dual RAF-MEK inhibitor VS-6766 have shown early single agent activity.
BRITISH JOURNAL OF CANCER
(2021)
Review
Pathology
Rajwanth Veluswamy, Philip C. Mack, Jane Houldsworth, Ehab Elkhouly, Fred R. Hirsch
Summary: Mutation in the KRAS gene, particularly the G12C mutation, is a common oncogenic driver in non-small cell lung cancer. Recent advances in molecular modeling have led to the development of direct inhibitors targeting mutant KRas(G12C), offering new therapeutic options for patients with lung adenocarcinoma.
JOURNAL OF MOLECULAR DIAGNOSTICS
(2021)
Article
Multidisciplinary Sciences
Tereza Vaclova, Atanu Chakraborty, James Sherwood, Sarah Ross, Danielle Carroll, J. Carl Barrett, Julian Downward, Elza C. de Bruin
Summary: The study investigates the co-occurrence of additional KRAS mutations with KRAS G12C in non-small cell lung cancer (NSCLC) tumors and its impact on cellular response to G12C-specific inhibitors. The results show that KRAS c.35G>T mutation most frequently co-occurred with KRAS G12C and led to cellular resistance to G12C inhibitors. Therefore, comprehensive genotyping of KRAS tumors is necessary for optimal patient selection for treatment with a KRAS G12C inhibitor.
SCIENTIFIC REPORTS
(2022)
Article
Pharmacology & Pharmacy
Peter D. Koch, Jeremy Quintana, Maaz S. Ahmed, Rainer H. Kohler, Ralph Weissleder
Summary: Multiple potent covalent inhibitors for mutant KRAS G12C have been described and some are in clinical trials, with the potential for developing companion imaging probes. A series of fluorescent companion imaging drugs for KRAS G12C have been synthesized and tested, showing potential for specific fluorescence imaging. A two-step procedure using click chemistry has been successful in directly imaging mutant KRAS G12C in cancer cells, providing a useful tool for further research.
ADVANCED THERAPEUTICS
(2021)
Editorial Material
Oncology
Sarina Z. W. Heng, Regina Hoo, Daniel S. W. Tan
Summary: Negrao and colleagues demonstrated that coalterations in KEAP1, SMARCA4, and CDKN2A genes were linked to poor clinical outcomes in patients with KRAS (G12C)-mutated non-small cell lung cancer treated with sotorasib or adagrasib. Their study emphasizes the potential of integrating high-resolution real-world genomic data with clinical outcomes to enable risk-stratified precision therapies.
Article
Multidisciplinary Sciences
Xiaowen Wang, Hong Zhang, Russell Sapio, Jun Yang, Justin Wong, Xin Zhang, Jessie Y. Guo, Sharon Pine, Holly Van Remmen, Hong Li, Eileen White, Chen Liu, Megerditch Kiledjian, Dimitri G. Pestov, X. F. Steven Zheng
Summary: The study reveals a crucial role of nuclear SOD1 in ribosome biogenesis and proliferation in KRAS-driven lung cancer.
NATURE COMMUNICATIONS
(2021)
Review
Oncology
Alessandro Di Federico, Ilaria Ricciotti, Valentina Favorito, Sandra Vietti Michelina, Pietro Scaparone, Giulio Metro, Andrea De Giglio, Federica Pecci, Giuseppe Lamberti, Chiara Ambrogio, Biagio Ricciuti
Summary: The recent development of direct KRAS(G12C) inhibitors has improved outcomes in KRAS mutant cancers, but acquired resistance still occurs. The mechanisms of acquired resistance are heterogeneous, involving both on-target and off-target resistance, including mutations in KRAS and other pathways. Understanding and overcoming resistance is important for targeted therapies.
CURRENT ONCOLOGY REPORTS
(2023)
Article
Oncology
Paul K. Paik, Pang-Dian Fan, Besnik Qeriqi, Azadeh Namakydoust, Bobby Daly, Linda Ahn, Rachel Kim, Andrew Plodkowski, Ai Ni, Jason Chang, Rachel Fanaroff, Marc Ladanyi, Elisa de Stanchina, Charles M. Rudin
Summary: Increased understanding of the mutational landscape of squamous cell lung cancers (LUSCs) has not resulted in effective targeted therapies. This study investigates the potential of TORC1/2 inhibitor TAK-228 in NSCLC models with NRF2-activating alterations and reports positive outcomes in a phase 2 clinical trial. TAK-228 shows promising single-agent activity in LUSC patients with NRF2 activation and highlights the importance of targeting metabolism in NSCLC.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Review
Oncology
Kenta Kawasaki, Natasha Rekhtman, Alvaro Quintanal-Villalonga, Charles M. Rudin
Summary: The review provides a comprehensive overview of the current understanding of NENs in the gastrointestinal system and lung from both clinical and biological perspectives. The authors discuss the commonalities and organ-specific differences of NENs and advocate for a tissue-agnostic approach to drug development, in order to improve patient care by accelerating research across different disease entities.
NATURE REVIEWS CLINICAL ONCOLOGY
(2023)
Article
Oncology
Arielle Elkrief, Alex Makhnin, Khadeja A. Moses, Linda S. Ahn, Isabel R. Preeshagul, Afsheen N. Iqbal, Sara A. Hayes, Andrew J. Plodkowski, Paul K. Paik, Marc Ladanyi, Mark G. Kris, Gregory J. Riely, Franziska Michor, Helena A. Yu
Summary: Primary and acquired resistance to osimertinib in EGFR-mutant lung cancers is a significant challenge. Combining osimertinib and dacomitinib may prevent or reverse on-target resistance, but is associated with increased toxicity. This study highlights the need for better strategies to address on-target resistance in EGFR-mutant lung cancers.
CLINICAL CANCER RESEARCH
(2023)
Article
Urology & Nephrology
Kelly N. Fitzgerald, Cihan Duzgol, Andrea Knezevic, Natalie Shapnik, Ritesh Kotecha, David H. Aggen, Maria I. Carlo, Neil J. Shah, Martin H. Voss, Darren R. Feldman, Robert J. Motzer, Chung -Han Lee
Summary: There is no significant difference in outcomes between immunotherapy-based combinations and tyrosine kinase inhibitor/immune checkpoint inhibitor combination in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), suggesting that the current treatment strategy should not be changed.
Article
Oncology
Noura J. Choudhury, Antonio Marra, Jane S. Y. Sui, Jessica Flynn, Soo-Ryum Yang, Christina J. Falcon, Pier Selenica, Adam J. Schoenfeld, Natasha Rekhtman, Daniel Gomez, Michael F. Berger, Marc Ladanyi, Maria Arcila, Charles M. Rudin, Gregory J. Riely, Mark G. Kris, Glenn Heller, Jorge S. Reis-Filho, Helena A. Yu
Summary: The study explores the potential of identifying and intervening on molecular markers associated with therapeutic resistance to improve patient outcomes in metastatic EGFR-mutant lung cancer treated with first-line osimertinib. Baseline atypical EGFR and concurrent TP53/RB1 alterations are associated with shorter progression-free survival on first-line osimertinib. Tissue-based genomic analysis allows for treatment adaptation based on identified mechanisms of resistance at the time of progression, leading to improved postprogression survival.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Oncology
Ying L. Liu, Beryl L. Manning-Geist, Andrea Knezevic, Luxue Deng, Maria Bromberg, Samuel A. Funt, Jane L. Meisel, Oliver Zivanovic, Kara Long Roche, Yukio Sonoda, Ginger J. Gardner, Rachel N. Grisham, Roisin E. O'Cearbhaill, William P. Tew, Nadeem R. Abu-Rustum, Dennis S. Chi, Carol Aghajanian, Darren R. Feldman
Summary: The objective of this study was to validate the modified international male IGCCCG prognostic model in female patients with germ cell tumors (GCTs). The results demonstrated that the modified IGCCCG model accurately assessed the prognostic risk in female GCTs patients and was associated with clinical outcomes.
GYNECOLOGIC ONCOLOGY
(2023)
Editorial Material
Oncology
Salomon Tendler, Charles M. Rudin
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Review
Oncology
Charles M. M. Rudin, Martin Reck, Melissa L. L. Johnson, Fiona Blackhall, Christine L. L. Hann, James Chih-Hsin Yang, Julie M. M. Bailis, Gwyn Bebb, Amanda Goldrick, John Umejiego, Luis Paz-Ares
Summary: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with limited treatment options. DLL3, a Notch inhibitory ligand, is overexpressed on SCLC cells, making it an attractive therapeutic target. This article discusses the clinical experience with a DLL3-targeting antibody-drug conjugate called Rova-T, as well as other DLL3-targeting agents currently in development, including T-cell engager molecules and CAR T-cell therapy. The challenges and opportunities for DLL3-targeting therapies, such as using DLL3 as a biomarker and exploring combinatorial approaches, are also discussed.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Article
Oncology
Charles M. Rudin, David Balli, W. Victoria Lai, Allison L. Richards, Evelyn Nguyen, Jacklynn Egger, Noura J. Choudhury, Triparna Sen, Andrew Chow, John T. Poirier, William J. Geese, Matthew D. Hellmann, Ann Forslund
Summary: A study found that antigen presentation machinery signature and infiltrating CD8 T cells were correlated with survival in SCLC patients treated with nivolumab, suggesting their potential as biomarkers for predicting immunotherapy efficacy. The study also identified the association between durable benefit from immunotherapy and antigen processing and presentation.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Immunology
Ariella Glasner, Samuel A. Rose, Roshan Sharma, Herman Gudjonson, Tinyi Chu, Jesse A. Green, Sham Rampersaud, Izabella K. Valdez, Emma S. Andretta, Bahawar S. Dhillon, Michail Schizas, Stanislav Dikiy, Alejandra Mendoza, Wei Hu, Zhong-Min Wang, Ojasvi Chaudhary, Tianhao Xu, Linas Mazutis, Gabrielle Rizzuto, Alvaro Quintanal-Villalonga, Parvathy Manoj, Elisa de Stanchina, Charles M. Rudin, Dana Pe'er, Alexander Y. Rudensky
Summary: Traditional roles of regulatory T (T-reg) cells as suppressors of antigen presenting cells and effector T cells have expanded to include tissue maintenance functions, suggesting a broader regulatory role than previously thought. In lung cancer and injury-induced inflammation, T-reg cell depletion led to changes in gene expression in fibroblasts, endothelial and myeloid cells, involving VEGF and CCR2 signaling. Combined T-reg cell depletion and short-term VEGF blockade showed improved control of PD-1 blockade-resistant lung adenocarcinoma progression, highlighting the potential of combination therapies for solid organ cancers.
Editorial Material
Oncology
Charles M. Rudin
Article
Oncology
Subhamoy Chakraborty, Charles Coleman, Parvathy Manoj, Deniz Demircioglu, Nisargbhai Shah, Elisa de Stanchina, Charles M. Rudin, Dan Hasson, Triparna Sen
Summary: Lurbinectedin significantly reduces cell viability in most SCLC models, with the best response observed in POU2F3-driven SCLC cells. We also found that lurbinectedin, either as a single agent or in combination with osimertinib, shows an appreciable antitumor response in EGFR-mutant lung adenocarcinoma models with histologic transformation to SCLC. Transcriptomic analysis revealed the induction of apoptosis, repression of epithelial-mesenchymal transition, and modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in both de novo and transformed SCLC models.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Joy A. Pai, Matthew D. Hellmann, Jennifer L. Sauter, Marissa Mattar, Hira Rizvi, Hyung Jun Woo, Nisargbhai Shah, Evelyn M. Nguyen, Fathema Z. Uddin, Alvaro Quintanal-Villalonga, Joseph M. Chan, Parvathy Manoj, Viola Allaj, Marina K. Baine, Umesh K. Bhanot, Mala Jain, Irina Linkov, Fanli Meng, David Brown, Jamie E. Chaft, Andrew J. Plodkowski, Mathieu Gigoux, Helen H. Won, Triparna Sen, Daniel K. Wells, Mark T. A. Donoghue, Elisa de Stanchina, Jedd D. Wolchok, Brian Loomis, Taha Merghoub, Charles M. Rudin, Andrew Chow, Ansuman T. Satpathy
Summary: Paired scRNA/TCR-seq analysis of T cells from NSCLC patients after ICB reveals clonally linked TFH and tumor-specific CD8+ T cells in tumor draining LNs. Exhausted CD8+ T cells, Treg, and TFH cells show progressive exhaustion trajectories with proximity to the tumor microenvironment. Longitudinal tracking demonstrates the persistence of tumor-specific T cell clones in peripheral blood for years after ICB therapy.
Article
Medicine, Research & Experimental
Janneke E. Jaspers, Jonathan F. Khan, William D. Godfrey, Andrea Lopez, Metamia Ciampricotti, Charles M. Rudin, Renier J. Brentjens
Summary: This study developed a chimeric antigen receptor (CAR) against DLL3 and demonstrated its antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of IL-18 enhanced the potency of DLL3-targeting CAR T cell therapy and increased the activation of CAR T cells and tumor-infiltrating lymphocytes. Human IL-18-secreting anti-DLL3 CAR T cells showed durable responses in multiple SCLC models, and this effect could be further enhanced with anti-PD-1 blockade.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Meeting Abstract
Oncology
Darren R. Feldman, Robert J. Motzer, Andrea Knezevic, Chung-Han Lee, Martin H. Voss, Serge K. Lyashchenko, Hijin Park, Steven M. Larson, Neeta Pandit-Taskar
JOURNAL OF CLINICAL ONCOLOGY
(2023)