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Annals of Oncology : Official Journal... Jan 2024Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor...
Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.
BACKGROUND
Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.
PATIENTS AND METHODS
A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.
RESULTS
All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy.
CONCLUSIONS
Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.
Topics: Humans; Acrylamides; Aniline Compounds; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease Progression; ErbB Receptors; Indoles; Lung Neoplasms; Morpholines; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 37879444
DOI: 10.1016/j.annonc.2023.10.117 -
Nature Sep 2023Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear. Because ICB...
Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear. Because ICB targets cell-cell interactions, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8TCF1T cells and MHCII cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B T cells. On-treatment, responsive tumours contained abundant granzyme B T cells, whereas resistant tumours were characterized by CD15 cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.
Topics: Humans; B-Lymphocytes; Biopsy; CD8-Positive T-Lymphocytes; Granzymes; Histocompatibility Antigens Class II; Immunotherapy; Lewis X Antigen; Neoadjuvant Therapy; Precision Medicine; Prognosis; Randomized Controlled Trials as Topic; T-Lymphocytes; Triple Negative Breast Neoplasms
PubMed: 37674077
DOI: 10.1038/s41586-023-06498-3 -
Nature Mar 2024Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. Here we studied 246,102...
Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8 alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8 cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.
Topics: Animals; Humans; Mice; Adenocarcinoma of Lung; Alveolar Epithelial Cells; Aneuploidy; Carcinogens; Cell Differentiation; Epithelial Cells; Lung Neoplasms; Mutation; Organoids; Precancerous Conditions; Proto-Oncogene Proteins p21(ras); Survival Rate; Tobacco Products
PubMed: 38418883
DOI: 10.1038/s41586-024-07113-9 -
Cancer Cell Feb 2024Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained...
Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; DNA Methylation; Cell-Free Nucleic Acids; Epigenesis, Genetic; Biomarkers, Tumor
PubMed: 38278149
DOI: 10.1016/j.ccell.2024.01.001 -
The Lancet. Digital Health Jul 2023Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg,...
BACKGROUND
Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context.
METHODS
In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics.
FINDINGS
Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features.
INTERPRETATION
This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer.
FUNDING
National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.
Topics: United States; Humans; Carcinoma, Non-Small-Cell Lung; B7-H1 Antigen; Immune Checkpoint Inhibitors; Retrospective Studies; Deep Learning; Lung Neoplasms
PubMed: 37268451
DOI: 10.1016/S2589-7500(23)00082-1 -
Trends in Cancer May 2024Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their... (Review)
Review
Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their identification can inform clinical management by enabling precision oncology, as fusions involving BRAF, FGFR2, RET, NTRK, NRG1, and ALK represent actionable targets in KRAS-WT cancers, and serve diagnostic purposes since fusions involving PRKACA/B represent the diagnostic hallmark of intraductal oncocytic papillary neoplasms (IOPNs). Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Oncogene Proteins, Fusion; Biomarkers, Tumor; Receptor, trkA; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins B-raf; Receptor, Fibroblast Growth Factor, Type 2; Neuregulin-1; Anaplastic Lymphoma Kinase; Gene Fusion
PubMed: 38378317
DOI: 10.1016/j.trecan.2024.01.009 -
Nature Medicine Nov 2023Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 .
Topics: Humans; Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Melanoma; Neoplasm Staging; Nivolumab; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 37845511
DOI: 10.1038/s41591-023-02583-2 -
Abdominal Radiology (New York) Aug 2023This study aimed to characterize the clinical and imaging findings of intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) compared to those of intraductal...
PURPOSE
This study aimed to characterize the clinical and imaging findings of intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) compared to those of intraductal papillary mucinous adenoma/carcinoma (IPMA/IPMC).
METHODS
This multi-institutional retrospective study reviewed the clinical, imaging, and pathological findings of 21 patients with pathologically proven IOPN-P. Twenty-one computed tomography (CT) and magnetic resonance imaging, and seven F-fluorodeoxyglucose (FDG)-positron emission tomography were performed before surgery. The following findings were evaluated: preoperative blood test results, lesion size and location, pancreatic duct diameter, contrast-enhancement effect, bile duct and peripancreatic invasion, maximum standardized uptake (SUVmax) value, and pathological stromal invasion.
RESULTS
Serum carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) levels were significantly higher in the IPMN/IPMC group than in the IOPN-P group. Except in one patient, IOPN-P showed multifocal cystic lesions with solid components or a tumor in the main pancreatic duct (MPD) with dilatation. IOPN-P had a higher frequency of solid parts and a lower frequency of downstream MPD dilatation than IPMA. IPMC showed smaller overall cyst size, more radiological peripancreatic invasion, and worse recurrence-free and overall survival than IOPN-P. The average SUVmax value of IOPN-P was 7.5. Pathologically, 17 of the 21 IOPN-Ps had a malignant component, and six showed stromal invasion.
CONCLUSION
IOPN-P shows cystic-solid lesions similar to IPMC but has lower serum CEA and CA19-9 levels, larger overall cyst size, lower frequency of peripancreatic invasion, and more favorable prognosis than IPMC. Moreover, the high FDG uptake by IOPN-Ps may be a characteristic finding of this study.
Topics: Humans; Carcinoma, Pancreatic Ductal; Retrospective Studies; Fluorodeoxyglucose F18; Carcinoembryonic Antigen; CA-19-9 Antigen; Pancreatic Neoplasms; Pancreas; Cysts; Neoplasm Invasiveness
PubMed: 37358603
DOI: 10.1007/s00261-023-03985-z