Featured
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A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results
In an interim analysis of a phase 1/2 trial, a heterologous prime boost vaccine comprised of a chimpanzee adenovirus and self-amplifying mRNA that encodes neoantigens derived from common oncogenic driver mutations in combination with immune checkpoint blockade was safe and elicited neoantigen-specific T cell responses in patients with advanced solid tumors.
- Amy R. Rappaport
- , Chrisann Kyi
- & Karin Jooss
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Article
| Open Access
Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial
In the phase 2 HUDSON study, patients with advanced non-small-cell lung cancer received anti-PD-L1 combined with biomarker-guided therapy targeting ATR kinase, PARP, STAT3 or CD73, leading to encouraging clinical benefit in response to combination of the ATR kinase inhibitor ceralasertib with durvalumab.
- Benjamin Besse
- , Elvire Pons-Tostivint
- & John V. Heymach
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Article
| Open Access
Association between pathologic response and survival after neoadjuvant therapy in lung cancer
Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.
- Julie Stein Deutsch
- , Ashley Cimino-Mathews
- & Janis M. Taube
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Article
| Open Access
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results
In the first stage of the BR.36 adaptive trial in patients with non-small cell lung cancer receiving anti-PD1 immunnotherapy, the primary endpoint of concordance between circulating tumor DNA (ctDNA) molecular response and RECIST response was met. The results will inform the second, ctDNA-directed stage.
- Valsamo Anagnostou
- , Cheryl Ho
- & Janet Dancey
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News & Views |
Precise, pragmatic and inclusive: the modern era of oncology clinical trials
Innovative clinical trial designs with a patient-centered mission are crucial to advancing modern cancer care; the adaptive phase 2 umbrella study CTONG1702 provides one model for this new era of trial design.
- Michael J. Grant
- & Sarah B. Goldberg
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Article |
First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial
Treatment of patients with HER2-mutant non-small-cell lung cancer with the pan-HER inhibitor pyrotinib in a phase 2 trial or compassionate use showed a favorable objective response rate, whereas patients treated in parallel by physician’s choice in a real-world study did not.
- Si-Yang Maggie Liu
- , Hai-Yan Tu
- & Yi-Long Wu
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Research Briefing |
Clinicogenomic landscape of morphological evolution in lung adenocarcinoma
Lung adenocarcinomas (LUADs) encompass a broad spectrum of histological appearances. We use multi-region, prospective and longitudinal sampling from the TRACERx dataset to show the relationship between LUAD morphologies and their underlying evolutionary genomic landscape, as well as clinical risk and the nature of metastatic dissemination.
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Article |
Body composition and lung cancer-associated cachexia in TRACERx
Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.
- Othman Al-Sawaf
- , Jakob Weiss
- & Charles Swanton
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Article |
Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.
- Takahiro Karasaki
- , David A. Moore
- & Mariam Jamal-Hanjani
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News & Views |
Advancing neoadjuvant immunotherapy for lung cancer
The NEOSTAR trial is a key step on route to better outcomes; but the best approach is likely to be an individualized one, reflecting the many factors that influence treatment response.
- Michael Conroy
- & Patrick M. Forde
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Article
| Open Access
A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer
A machine learning model that uses longitudinal ctDNA metrics robustly predicts survival in two phase 3 trials of patients with metastatic NSCLC, which may improve therapy selection and risk stratification.
- Zoe June F. Assaf
- , Wei Zou
- & Katja Schulze
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Article
| Open Access
Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial
The combination of neoadjuvant nivolumab, ipilimumab and chemotherapy showed promising efficacy in patients with resectable non-small cell lung cancer, with higher tumor immune cell infiltration and tertiary lymphoid structures after treatment compared with neoadjuvant nivolumab plus chemotherapy.
- Tina Cascone
- , Cheuk H. Leung
- & Boris Sepesi
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News & Views |
Circulating tumor DNA as a novel prognostic indicator
Circulating tumor DNA (ctDNA) informs predictive biomarkers in non–small-cell lung cancer, but the presence of ctDNA itself could also be a prognostic indicator.
- Ana Vivancos
- & Josep Tabernero
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Article |
Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer
In a prospective international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy, ctDNA detection was associated with shorter survival, independently of clinicopathologic features and metabolic tumor volume.
- Justin Jee
- , Emily S. Lebow
- & Bob T. Li
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Article
| Open Access
Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial
In a single-arm, non-randomized trial, neoadjuvant atezolizumab therapy in a large cohort of patients with resectable non-small cell lung cancer was safe and the study met its primary end point of major pathological response ≥15%.
- Jamie E. Chaft
- , Filiz Oezkan
- & Justin D. Blasberg
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Article
| Open Access
Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial
Results from EMPOWER-Lung 3 demonstrate increased overall survival with cemiplimab plus platinum-doublet chemotherapy compared to cemiplimab as first-line treatment in patients with advanced non-small cell lung cancer, irrespective of PD-L1 expression.
- Miranda Gogishvili
- , Tamar Melkadze
- & Petra Rietschel
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Article
| Open Access
Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial
In a phase 3 trial, selection of non-small cell lung cancer patients based on high blood-based tumor mutation burden did not improve clinical response to the checkpoint blockade inhibitor atezolizumab, as compared with standard of care platinum-based chemotherapy.
- Solange Peters
- , Rafal Dziadziuszko
- & Tony Mok
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Article
| Open Access
Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial
The randomized B-F1RST trial evaluating the clinical utility of blood tumor mutational burden as a predictor of benefit from atezolizumab in patients with advanced lung cancer did not meet its pre-specified primary objective, underscoring the need to further investigate the significance of bTMB as a relevant biomarker for patient selection.
- Edward S. Kim
- , Vamsidhar Velcheti
- & Mark A. Socinski
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News & Views |
Tumor-infiltrating lymphocytes make inroads in non–small-cell lung cancer
A phase 1 trial shows promising anti-tumor activity of tumor-infiltrating-lymphocyte therapy in patients with advanced non–small-cell lung cancer.
- Joshua R. Veatch
- , Sylvain Simon
- & Stanley R. Riddell
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Article |
Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial
Adoptive cell therapy with tumor-infiltrating lymphocytes in metastatic lung cancer patients is safe and elicits antitumor activity, including ongoing complete responses, in association with polyclonal T cell responses against tumor antigens.
- Benjamin C. Creelan
- , Chao Wang
- & Scott J. Antonia
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Article |
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.
- Tina Cascone
- , William N. William Jr
- & Boris Sepesi
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Letter |
Geospatial immune variability illuminates differential evolution of lung adenocarcinoma
Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions
- Khalid AbdulJabbar
- , Shan E. Ahmed Raza
- & Yinyin Yuan
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Article |
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
In a first-in-human phase I trial of patients with advanced lung cancer, infusions of autologous T cells edited to delete the PD-1 gene via CRISPR–Cas9 were well tolerated and did not lead to severe treatment-related adverse events.
- You Lu
- , Jianxin Xue
- & Tony Mok
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Article |
Regenerative lineages and immune-mediated pruning in lung cancer metastasis
Single-cell analysis of lung cancer progression uncovers developmental and regenerative programs co-opted by cancer cells and immune-mediated pruning during metastatic outbreak
- Ashley M. Laughney
- , Jing Hu
- & Joan Massagué
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Letter |
Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration
Results from an expansion cohort of the PROFILE 1001 trial describe the anti-tumor activity of crizotinib in people with non-small-cell lung cancer harboring a MET exon 14 alteration.
- Alexander Drilon
- , Jeffrey W. Clark
- & Paul K. Paik
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Letter |
A clonal expression biomarker associates with lung cancer mortality
TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.
- Dhruva Biswas
- , Nicolai J. Birkbak
- & Angeles Montero
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Letter |
Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse
Pulmonary venous tumor cells disseminating before tumor resection are heterogeneous, predict relapse and seed future metastasis of lung cancer
- Francesca Chemi
- , Dominic G. Rothwell
- & Jason Lester
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Article |
Methionine is a metabolic dependency of tumor-initiating cells
Elevated activity of the methionine cycle is essential for cancer stem cell tumorigenesis and represents a therapeutic vulnerability.
- Zhenxun Wang
- , Lian Yee Yip
- & Wai Leong Tam
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Resource |
Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions
A multi-omics survey of progressive compared to regressive carcinoma in situ lesions provides a molecular map of early lung cancer development.
- Vitor H. Teixeira
- , Christodoulos P. Pipinikas
- & Sam M. Janes
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Letter |
Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer
Nongenetic activation of Aurora kinase A in the majority of patients with non-small-cell lung cancer mediates adaptive resistance to EGFR inhibition and offers an opportunity for combination treatment.
- Khyati N. Shah
- , Roma Bhatt
- & Sourav Bandyopadhyay
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Article |
Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab
A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.
- David R. Gandara
- , Sarah M. Paul
- & David S. Shames
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Article |
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
Tumor-infiltrating CD8+ T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.
- Daniela S. Thommen
- , Viktor H. Koelzer
- & Alfred Zippelius
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Article |
Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer
Poziotinib is a candidate inhibitor for a subset of EGFR or HER2 mutant non–small cell lung cancers that lack effective therapy.
- Jacqulyne P. Robichaux
- , Yasir Y. Elamin
- & John V. Heymach
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Letter |
Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis
Frequent loss-of-function mutations in KEAP1, a master regulator of the NRF2 antioxidant pathway, accelerate mutant KRAS driven lung carcinogenesis, but also impose a dependency of these tumors on glutaminolysis. Using a precision medicine–based approach, this work uncovers a metabolic vulnerability of KRAS–KEAP1-mutant lung cancers that can be therapeutically exploited using currently available glutaminase inhibitors and provides a scientific rationale for patient selection in clinical trials.
- Rodrigo Romero
- , Volkan I Sayin
- & Thales Papagiannakopoulos
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Article |
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Resistance to ERK signaling inhibitors in BRAFV600E-mutant melanomas and lung cancers is achieved by parallel convergent mechanisms, including amplification of the mutant allele in extrachromosomal elements, that allow tumors to adapt while maintaining their intratumor heterogeneity. Intermittent treatment with a combination of RAF, MEK and ERK inhibitors imposes a higher selective pressure than sequential therapy and produces the strongest antitumor effects while minimizing toxicity. These findings warrant evaluating the effectiveness of this combinatorial regimen in patients, to improve treatment responses and delay the emergence of drug resistance.
- Yaohua Xue
- , Luciano Martelotto
- & Piro Lito
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Article |
Molecular definition of a metastatic lung cancer state reveals a targetable CD109–Janus kinase–Stat axis
In vivo screening of pro-metastatic factors in a genetically engineered mouse model of lung cancer uncovered the CD109–JAK–STAT3 axis as a key contributor of metastatic dissemination of lung cancer cells. Activation of this pathway predicts poor outcome in patients with cancer, and its pharmacological inhibition dramatically reduces the metastatic ability of tumor cells, suggesting that it might be an effective intervention in patients.
- Chen-Hua Chuang
- , Peyton G Greenside
- & Monte M Winslow
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Article |
Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models
An allosteric inhibitor of acetyl-CoA carboxylase reveals a metabolic liability of non-small-cell lung cancer and slows tumor growth alone and in combination with chemotherapy in mouse models.
- Robert U Svensson
- , Seth J Parker
- & Reuben J Shaw
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News Feature |
Take two: Combining immunotherapy with epigenetic drugs to tackle cancer
- Karen Weintraub
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Article |
RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer
Unraveling the signaling dependencies of EMLK4-ALK fusion–driven lung cancer reveals upfront combination therapy strategies.
- Gorjan Hrustanovic
- , Victor Olivas
- & Trever G Bivona
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News & Views |
Liquid biopsies reveal the dynamic nature of resistance mechanisms in solid tumors
Two new studies demonstrate that so-called 'liquid biopsies' may reveal important genomic information needed to monitor treatment responses, forecast tumor recurrences, and provide a rationale for novel therapeutic strategies in patients with lung cancer and colon cancer.
- Catherine B Meador
- & Christine M Lovly
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Brief Communication |
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M
A mutation conferring resistance to novel irreversible EGFR inhibitors is identified in cell-free plasma DNA from lung cancer patients.
- Kenneth S Thress
- , Cloud P Paweletz
- & Geoffrey R Oxnard
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Article |
Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer
Activation of the insulin-like growth factor 1 receptor may underlie clinical resistance to inhibition of the anaplastic lymphoma receptor kinase in lung cancer.
- Christine M Lovly
- , Nerina T McDonald
- & William Pao
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Technical Report |
An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage
Aaron Newman and his colleagues introduce a next-generation sequencing–based approach for the cost-effective detection and quantitation of tumor-derived circulating DNA in both early- and advanced-stage tumors and with high levels of sensitivity and specificity. CAPP-Seq (cancer personalized profiling by deep sequencing) can simultaneously detect multiple mutations and mutation types, including rearrangements. Here, utility is demonstrated for non–small-cell lung cancer.
- Aaron M Newman
- , Scott V Bratman
- & Maximilian Diehn
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Review Article |
The quest to overcome resistance to EGFR-targeted therapies in cancer
Despite the initial promise of cancer therapies targeted against the epidermal growth factor receptor (EGFR), tumors treated with these agents eventually develop resistance. In this Review, the authors outline the complex mechanisms by which tumors become resistant to EGFR-targeted drugs and antibodies and offer insights into new strategies that might be employed to circumvent therapeutic resistance.
- Curtis R Chong
- & Pasi A Jänne
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Brief Communication |
Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer
The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets.
- Aria Vaishnavi
- , Marzia Capelletti
- & Robert C Doebele
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Brief Communication |
Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies
Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.
- Doron Lipson
- , Marzia Capelletti
- & Philip J Stephens
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Article |
RETRACTED ARTICLE: EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers
The authors identify a set of microRNAs regulated by EGFR and MET that are involved in the oncogenic signaling exerted by these receptors and also modulate the response of tumors to targeted EGFR inhibition. These results shed light on the known contribution of MET to therapy resistance and suggest that MET-regulated microRNAs can be key mediators of its effects and potential markers of clinical utility.
- Michela Garofalo
- , Giulia Romano
- & Carlo M Croce
Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer