Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene

A Stochastic Markov Chain Model to Describe Lung Cancer Growth and Metastasis

A stochastic Markov chain model for metastatic progression is developed for primary lung cancer based on a network construction of metastatic sites with dynamics modeled as an ensemble of random walkers on the network. We calculate a transition matrix, with entries (transition probabilities) interpreted as random variables, and use it to construct a circular bi-directional network of primary and metastatic locations based on postmortem tissue analysis of 3827 autopsies on untreated patients documenting all primary tumor locations and metastatic sites from this population. The resulting 50 potential metastatic sites are connected by directed edges with distributed weightings, where the site connections and weightings are obtained by calculating the entries of an ensemble of transition matrices so that the steady-state distribution obtained from the long-time limit of the Markov chain dynamical system corresponds to the ensemble metastatic distribution obtained from the autopsy data set. We condition our search for a transition matrix on an initial distribution of metastatic tumors obtained from the data set. Through an iterative numerical search procedure, we adjust the entries of a sequence of approximations until a transition matrix with the correct steady-state is found (up to a numerical threshold). Since this constrained linear optimization problem is underdetermined, we characterize the statistical variance of the ensemble of transition matrices calculated using the means and variances of their singular value distributions as a diagnostic tool. We interpret the ensemble averaged transition probabilities as (approximately) normally distributed random variables. The model allows us to simulate and quantify disease progression pathways and timescales of progression from the lung position to other sites and we highlight several key findings based on the model

A WIN Consortium phase I study exploring avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer

Genomics; Transcriptomics; Lung cancerGenómica; Transcriptómica; Cáncer de pulmónGenòmica; Transcriptòmica; Càncer de pulmóBackground The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design). Results Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression-free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD-L1 expression and low tumor mutational burden. Conclusions Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post-pembrolizumab progression, and was active at the RP2D, which was well tolerated.This work was supported by the ARC Foundation for Cancer Research, Villejuif, France and Worldwide Innovative Network (WIN) Association––WIN Consortium, Villejuif, France, sponsor of the study. WIN was responsible for the study design, collection, analysis, and interpretation of data as well as writing of the report. The study drugs were provided by Pfizer, as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer. Funded in part by National Cancer Institute grant P30 CA023100 and the Joan and Irwin Jacobs Fund philanthropic fund (RK)

Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy

BACKGROUND: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. METHODS: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. RESULTS: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. CONCLUSION: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls

Prognosis and oncogenomic profiling of patients with tropomyosin receptor kinase fusion cancer in the 100,000 genomes project

INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Limited data exist on the overall survival (OS) of patients with tumors with NTRK gene fusions and on the co-occurrence of NTRK fusions with other oncogenic drivers. MATERIALS AND METHODS: This retrospective study included patients enrolled in the Genomics England 100,000 Genomes Project who had linked clinical data from UK databases. Patients who had undergone tumor whole genome sequencing between March 2016 and July 2019 were included. Patients with and without NTRK fusions were matched. OS was analyzed along with oncogenic alterations in ALK, BRAF, EGFR, ERBB2, KRAS, and ROS1, and tumor mutation burden (TMB) and microsatellite instability (MSI). RESULTS: Of 15,223 patients analyzed, 38 (0.25%) had NTRK gene fusions in 11 tumor types, the most common were breast cancer, colorectal cancer (CRC), and sarcoma. Median OS was not reached in both the NTRK gene fusion-positive and -negative groups (hazard ratio 1.47, 95% CI 0.39-5.57, P = 0.572). A KRAS mutation was identified in two (5%) patients with NTRK gene fusions, and both had hepatobiliary cancer. High TMB and MSI were both more common in patients with NTRK gene fusions, due to the CRC subset. While there was a higher risk of death in patients with NTRK gene fusions compared to those without, the difference was not statistically significant. CONCLUSION: This study supports the hypothesis that NTRK gene fusions are primary oncogenic drivers and the co-occurrence of NTRK gene fusions with other oncogenic alterations is rare

Cetuximab Plus Carboplatin and Paclitaxel With or Without Bevacizumab Versus Carboplatin and Paclitaxel With or Without Bevacizumab in Advanced NSCLC (SWOG S0819): A Randomised, Phase 3 Study

Background EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. Methods We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Findings Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9–39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75–1·12; p=0·40; median 5·4 months [95% CI 4·5–5·7] vs 4·8 months [3·9–5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83–1·04; p=0·22; median 10·9 months [95% CI 9·5–12·0] vs 9·2 months [8·7–10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36–0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46–1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78–1·40; p=0·77; and 1·02, 0·77–1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68–1·14; p=0·34; and 0·99, 0·78–1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85–1·17; p=0·97; and 1·03, 0·88–1·20; p=0·69; respectively). The most common grade 3–4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [\u3c 1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Interpretation Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC

Recognizing Prognostic and Predictive Biomarkers in the Treatment of Non-Small Cell Lung Cancer (NSCLC) with Immune Checkpoint Inhibitors (ICIs)

Immunotherapy plays a central role in the treatment of NSCLC and biomarkers predicting response to ICIs are valuable therapeutic tools. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is integral in therapy selection as its positive predictive nature to ICIs in the metastatic setting is well documented. Tumor mutational burden (TMB) has undergone much study and, while results are somewhat mixed, there is evidence for its positive predictive value with ICI use. Additional markers such as tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), mismatch repair (MMR) and microsatellite instability (MSI), somatic mutations, neutrophil to leukocyte ratio (NLR), smoking history, medication history, and immune-related adverse event (irAE) development can further guide clinicians