•Efficacy of ICIs in NSCLC patients with BRAF mutations remains uncertain.•Our data showed an increased pathological complete response rate in BRAF-mutant NSCLC patients versus BRAF-wt NSCLC ...patients.•The presence of BRAF mutations was associated with better PFS and OS.•Our results suggest a potential avenue for treating BRAF-positive NSCLC patients with ICIs.
Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown.
Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing.
The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78–2.85; P < 0.001).
BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.
For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and ...on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression.
Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1.
Pretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio HR 2.13 95% confidence interval CI: 1.06–4.30, p = 0.031) and overall survival (HR 2.61 95% CI: 1.16–5.91, p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 95% CI: 1.65–7.74, p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations.
Our data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.
Germline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR ...mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer.
We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing.
We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%).
Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval CI: 6.3–NR). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3–NR) and median overall survival was 82.0 months (95% CI: 28.4–NR).
Based on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white women with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC.
To develop a radiogenomic predictive model for non-small cell lung cancer (NSCLC) patients studied through contrast enhanced chest computed tomography (CE-CT) targeting the most frequent gene ...alterations.
A retrospective study of patients with NSCLC imaged with CE-CT before treatment and had their tumor genomics sequenced at our institution was performed. Data was gathered from their imaging studies, their electronic medical records and a web-based database search (cBioPortal.ca). All of the patient data was tabulated for analysis. Two predictive models (M1 & M2) were created using different approaches and a third model was extracted from the literature to also be tested in our population.
Out of 157 patients, eighty were male (51%) and 124 (79%) had a history of smoking. The three most prevalent genes were KRAS, TP53 and EGFR. The M1 radiomics-only model median AUC were 0.61 (TP53), 0.53 (KRAS) and 0.64 (EGFR) and for M1 radiomics + clinical were 0.61 (TP53), 0.61 (KRAS) and 0.80 (EGFR). The M2 radiomics-only model median AUC were 0.63 (TP53), 0.60 (KRAS) and 0.65 (EGFR) and for M2 radiomics + clinical were 0.64 (TP53), 0.62 (KRAS) and 0.81 (EGFR). The external EGFR radiomic model showed an AUC of 0.69 and 0.86 for the radiomics-only and combined radiomics + clinical respectively.
Our study was able to provide robust predictive radiomics model evaluation for the detection of TP53, KRAS and EGFR. We also compared our performance with an already published model and observed how impactful clinical variables can be on models' performance.
Identifying tumor mutations in patients that can’t undergo biopsy is critical for their outcomes.
• Tumor genomic profiling is critical for treatment selection
• CE-CT radiomics produce robust predictive models comparable to those already published
• Clinical variables should be considered/included in predictive models
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