Sotorasib for lung cancers with KRAS p.G12C mutation

BACKGROUND: Sotorasib showed anticancer activity in patients with METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treate

Efficacy and immune modulation of KRAS G12C inhibitor sotorasib in murine KRAS G12C mutant non-small cell lung cancers with major co-occurring genomic alterations

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Clinical validation of Guardant360 CDx as a blood-based companion diagnostic for sotorasib

OBJECTIVES Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis

The sensitivity to chemotherapy of KRASG12C-mutated colorectal cancer has been investigated to verify whether the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care in the near future. To this aim, the present retrospective study was designed to assess the performance of irinotecan vs. oxaliplatin in the first-line treatment of KRASG12C-mutated mCRC patients and provide support for first-line decision making. In this setting of patients treated with FOLFIRI or FOLFOX +/ bevacizumab, irinotecan and oxaliplatin were compared using a propensity-score-matched analysis. the survival superiority of irinotecan was demonstrated over oxaliplatin in KRASG12C-mutated patients, while no differences were observed in a control cohort of KRASG12D-mutated patients. this should be considered when investigating chemotherapy plus targeted agent combinations.background: KRAS(G12C)-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS(G12C)inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. methods: a multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/ bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRAS(G12D)-mutated patients were analysed as control. results: one hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. however, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. no difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRAS(G12C)-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations

Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras-driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision-cut slices from Kras-driven non-small-cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen-activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short-term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3-kinase-mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology-associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations

Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast.

The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells' expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non-small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified

Mutations Defining Patient Cohorts With Elevated PD-L1 Expression in Gastric Cancer

The immunotherapy agent pembrolizumab has been approved for gastric cancer (GC) patients with recurrent or advanced disease who are PD-L1 positive. Mutations in the primary lesion may drive the expression of immune targets thereby priming the tumor to therapeutic sensitivity. In this study, we aimed to uncover mutations associated with elevated PD-L1 expression in GC patients. Data from 410 GC patients were available, including the mutational spectrum of 39,916 genes and expression values of 20,500 genes. PD-L1 gene expression was compared to the mutational status of each gene separately by using a Mann-Whitney U-test and a Receiver Operating Characteristic test. Only mutations with a prevalence over 5% were considered. Significance was accepted in cases of p < 1E-05 and a fold change over 1.44. Mutations in 209 genes were associated with increased PD-L1 expression. These mutations were enriched in genes related to microtubule-based movement (p = 3.4E-4), cell adhesion (p = 4.9E-4), response to DNA-damage (p = 6.9E-4), and double-strand break-repair (p = 1.6E-3). Mutations in TTK (p = 8.8E-10, AUC = 0.77), COL7A1 (p = 2.0E-9, AUC = 0.74), KIF15 (p = 2.5E-9, AUC = 0.75), and BDP1 (p = 3.3E-9, AUC = 0.74) had the strongest link to elevated PD-L1 expression. Finally, we established a decision tree based on mutations in PIK3CA, MEF2C, SLC11A1, and KIF15 capable to separate patient sub-cohorts with elevated PD-L1 expression. In summary, we identified mutations associated with elevated PD-L1 expression that facilitate the development of better prognostic biomarkers for GC, and might offer insight into the underlying tumor biology

Using State Space Exploration to Determine How Gene Regulatory Networks Constrain Mutation Order in Cancer Evolution

Cancer develops via the progressive accumulation of somatic mutations, which subvert the normal operation of the gene regulatory network of the cell. However, little is known about the order in which mutations are acquired in successful clones. A particular sequence of mutations may confer an early selective advantage to a clone by increasing survival or proliferation, or lead to negative selection by triggering cell death. The space of allowed sequences of mutations is therefore constrained by the gene regulatory network. Here, we introduce a methodology for the systematic exploration of the effect of every possible sequence of oncogenic mutations in a cancer cell modelled as a qualitative network. Our method uses attractor identification using binary decision diagrams and can be applied to both synchronous and asynchronous systems. We demonstrate our method using a recently developed model of ER-negative breast cancer. We show that there are differing levels of constraint in the order of mutations for different combinations of oncogenes, and that the effects of ErbB2/HER2 over-expression depend on the preceding mutations