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Patients with interstitial lung disease (ILD), especially those with pulmonary fibrosis, are at increased risk of developing lung cancer. Management of lung cancer in patients with ILD is particularly challenging. Diagnosis can be complicated by difficulty differentiating lung nodules from areas of focal fibrosis, and percutaneous biopsy approaches confer an increased risk of complications in those with pulmonary fibrosis. Lung cancer treatment in these patients pose several specific considerations. The degree of lung function impairment may preclude lobectomy or surgical resection of any type. Surgical resection can trigger an acute exacerbation of the underlying ILD. The presence of ILD confers an increased risk of pneumonitis with radiotherapy, and many of the systemic therapies also carry an increased risk of pneumonitis in this population. The safety of immunotherapy in the setting of ILD remains to be fully elucidated and concerns remain as to triggering pneumonitis. The purpose of this review is to summarize the evidence regarding consideration for tissue diagnosis, chemotherapy and immunotherapy, radiotherapy, and surgery, in this patient population and discuss emerging areas of research. We also propose a multidisciplinary approach and practical considerations for monitoring for ILD progression during lung cancer treatment.

Supplementary Table S1. ALK inhibitors in clinical development. Supplementary Table S2. Summary of clinical characteristics of ALK-positive patients undergoing biopsies at the time of ALK inhibitor resistance. Supplementary Table S3. Paired, post-crizotinib and post second-generation ALK inhibitor biopsies. Supplementary Table S4. Treatment course of ALK-positive patients undergoing post-ceritinib biopsies. Supplementary Table S5. Treatment course of ALK-positive patients undergoing post-alectinib biopsies. Supplementary Table S6. Treatment course of ALK-positive patients undergoing post-brigatinib biopsies. Supplementary Table S7. Resistant biopsies with {greater than or equal to}2 resistance mutations. Supplementary Table S8. Mutations in ceritinib-resistant biopsies. Supplementary Table S9. Mutations in alectinib-resistant biopsies. Supplementary Table S10. Mutations in brigatinib-resistant biopsies. Supplementary Table S11. Single-nucleotide variants identified in patient-derived cell lines. Supplementary Table S12. EMT in ceritinib-resistant biopsies. Supplementary Table S13. Cells seeded for survival assays. Supplementary Table S14. Cells seeded for growth assays.

suppl tables

Supplementary Methods include Enzyme Kinetic Assays and Computational Methods.

Supplementary Figure S1. ALK G1202R versus ALK G1202del. Supplementary Figure S2. ALK G1202del in ALK-rearranged lung cancer. Supplementary Figure S3. Swimmer's plot - alectinib. Supplementary Figure S4. Evaluation of MGH075-2E in drug screen. Supplementary Figure S5. MGH067-1 harbors an ALK rearrangement. Supplementary Figure S6. MGH021-5A. Supplementary Figure S7. MGH051-2C and MGH084-1D. Supplementary Figure S8. MGH049-1A and MGH075-2E. Supplementary Figure S9. MGH034-2A.

Supplementary Figures include Figure S1-S9.

PDF file - 96K, Characteristics of the patients that were analyzed on the exon arrays.

PDF file - 66K, Table S3 shows CD13 and its splice variant expression patterns in 193 AML patients.

Supplementary Tables 1-2

PDF file - 1538K, Figure S1 illustrates CD13 splice variant protein expression and Figure S2 shows representative electropherograms for DNA fragment analysis and capillary electrophoresis.

Overlap between BRAF and NF1 Genetic Alterations

PDF file - 162K, Table S2b is a list of spliced oncogenes and tumor suppressors identified in AML patients and Table S2c is a list of genes spliced in both cohorts analyzed.

Purpose:Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.Experimental Design:We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.Results:By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with ≥2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new ALK mutations on lorlatinib.Conclusions:ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.

Supplementary Figure 1-5

Supplementary Figures

Supplementary Figures

Supplementary Tables

Supplementary methods, figure legends

Supplementary Table 1. Treatment Histories

Supplementary Figure Legends

Purpose: Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets.Experimental Design: We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML.Results: Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34+ cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis.Conclusions: Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease. Clin Cancer Res; 20(5); 1135–45. ©2013 AACR.

supplementary tables, figure legends, methods

Purpose:Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non–small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.Experimental Design:Biopsies from patients with ROS1+ NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.Results:From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%).Conclusions:ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.

PDF file - 68K, Table summarize results of annotation analyses of aberrantly spliced transcripts detected in AML patients as compared to normal donors.

Purpose:Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.Experimental Design:We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.Results:MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy.Conclusions:Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

The NTRK genes encode the TRK proteins. NTRK fusions lead to constitutively active, ligand-independent downstream signaling. NTRK fusions are implicated in up to 1% of all solid tumors and 0.2% of NSCLC. Larotrectinib, a highly selective small molecule inhibitor of all three TRK proteins, has a response rate of 75% across a wide range of solid tumors. Mechanisms of primary resistance to larotrectinib are not well understood. We report a case of a 75-year-old male with minimal smoking history with NTRK fusion-positive metastatic squamous NSCLC with primary resistance to larotrectinib. We suggest subclonal NTRK fusion as a possible mechanism contributing to primary resistance to larotrectinib.

PURPOSE Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established. METHODS We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration–approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival. RESULTS A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors. CONCLUSION This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.

PURPOSE Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies. MATERIALS AND METHODS We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP /CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort. RESULTS The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss ( P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM. CONCLUSION Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.

Enhanced understanding of the molecular events underlying oncogenesis has led to the development of “tumor‐agnostic” treatment strategies, which aim to target a tumor's genomic profile regardless of its anatomic site of origin. A classic example is the translocation resulting in an ETV6‐NTRK3 gene fusion, a characteristic driver of a histologically diverse array of cancers. The chimeric ETV6‐NTRK3 fusion protein elicits constitutive activation of the tropomyosin receptor kinase (TRK) C protein, leading to increased cell survival, growth, and proliferation. Two TRK inhibitors, larotrectinib and entrectinib, are currently approved for use in the metastatic setting for the treatment of advanced solid tumors harboring NTRK fusions. Here we report a rare case of recurrent secretory carcinoma of the breast (SCB) with NTRK3 gene fusion. Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case detailed here is the first to the authors' knowledge of recurrence within 1 year of surgery. We review the molecular findings and potential clinical significance. KEY POINTS: The translocation resulting in the ETV6‐NTRK3 gene fusion is a known oncogenic driver characteristic of secretory carcinoma of the breast (SCB). Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case here with ETV6‐NTRK3 gene fusion had local recurrence within 1 year of surgery. Two tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are approved to treat NTRK fusion–positive tumors, demonstrating sustained high overall response rates in the metastatic setting. Approval of TRK inhibitors necessitates optimization of NTRK fusion detection assays, including detection with liquid biopsies.

Introduction Capmatinib is approved for MET exon 14–altered NSCLC on the basis of activity in targeted therapy–naive patients. We conducted a phase 2 study to assess the efficacy of capmatinib in patients previously treated with a MET inhibitor. Methods Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping alterations received capmatinib 400 mg twice daily. The primary end point was the objective response rate. Secondary end points included progression-free survival, disease control rate (DCR), intracranial response rate, and overall survival. Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms. Results A total of 20 patients were enrolled between May 2016 and November 2019, including 15 patients with MET skipping alterations and five patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range: 4–374). Two patients (10%) achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among five patients who discontinued crizotinib for intolerance, the DCR was 83%, including two patients with the best tumor shrinkage of −25% and −28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median progression-free survival and overall survival were 5.5 (95% confidence interval: 1.3–11.0) and 11.3 (95% confidence interval: 5.5–not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in postcrizotinib, precapmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib. Conclusions Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially owing to overlapping resistance mechanisms.

Purpose: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non–small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. Experimental Design: Biopsies from patients with ROS1+ NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. Results: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%). Conclusions: ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.

PURPOSE The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)–rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome ALK resistance mutations. We conducted a phase II study to evaluate the intracranial activity of lorlatinib in patients with CNS-only progression on second-generation ALK inhibitors. METHODS Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability. RESULTS Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events. CONCLUSION Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent.

Clinical venous thromboembolism (VTE) risk prediction scores, such as the Khorana Risk Score, perform poorly in NSCLC, possibly because the tumor molecular subtype is omitted. Previous studies suggest a possible increased VTE risk in ALK-rearranged NSCLC, but data are conflicting.We performed a retrospective cohort study of patients with advanced-stage NSCLC diagnosed between 2009 and 2019. Multivariable, time-to-event analyses modeling the risk of first venous or arterial thrombosis in ALK and non-ALK NSCLC groups, controlling for covariates known to impact thrombosis risk (15 in VTE model and 17 in arterial thrombosis model), were performed using Cox proportional hazards regression and competing-risks regression. Multivariable negative binomial regression modeled the total VTE rate.A total of 422 patients with ALK-rearranged and 385 patients with non-ALK-rearranged NSCLC were included. Patients with an ALK rearrangement were younger, had better performance status, and had lower rates of most thrombotic risk factors but had significantly higher rates of initial VTE (42.7% versus 28.6%, p0.0001), recurrent VTE (13.5% versus 3.1%, p0.0001), and similar rates of arterial thrombosis (5.0% versus 4.4%, p = 0.71) compared with non-ALK NSCLC. VTE risk attributable to ALK was significant (Cox model: hazard ratio 3.70, [95% confidence interval [CI]: 2.51-5.44, p0.001], competing risks: subhazard ratio 3.91 [95% CI: 2.55-5.99, p0.001]). Negative binomial modeling revealed higher VTE rates in patients with an ALK rearrangement (incidence rate ratio 2.47 [95% CI: 1.72-3.55, p0.001]). The OR for recurrent VTE was 4.85 (95% CI: 2.60-9.52, p0.001). Arterial thrombosis risk attributable to ALK was significant (Cox model: hazard ratio 3.15 [95% CI: 1.18-8.37, p = 0.021], competing risks: subhazard ratio 2.80 [95% CI: 1.06-7.43, p = 0.038]).In time-to-event analyses controlling for thrombosis risk factors, the ALK rearrangement conferred a fourfold increase in VTE risk and a threefold increase in arterial thrombosis risk in NSCLC. These patients may benefit from pharmacologic thromboprophylaxis.

Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in EGFR-mutant and ALK fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, ROS1 fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation of RB1 and TP53, and loss of ROS1 fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of “hard” clonal sweep. Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.

Background The clinical features and traditional semantic imaging characteristics of BRAF-mutated non-small cell lung cancer (NSCLC) have been previously reported. The radiomic features of BRAF-mutated NSCLC and their role in predicting cancer stage, however, have yet to be investigated. This study's goal is to assess the differences in CT radiomic features of primary NSCLC driven by BRAF mutation and stratified by tumor-node-metastasis (TNM) staging. Methods Our IRB approved study included 62 patients with BRAF mutations (V600 in 27 and non-V600 in 35 patients), who underwent contrast-enhanced chest CT. Tumor stage was determined based on the 8th edition of TNM staging. Two thoracic radiologists assessed the primary tumor imaging features such, including tumor size (maximum and minimum dimensions) and density (Hounsfield units, HU). De-identified transverse CT images (DICOM) were processed with 3D slicer (Version 4.7) for manual lesion segmentation and estimation of radiomic features. Descriptive statistics, multivariate logistic regression, and receiver operating characteristics (ROC) were performed. Results There were significant differences in the radiomic features based on cancer stages I-IV with the most significant differences between stage IV and stage I lesions [AUC 0.94 (95% CI: 0.86-0.99), P

Purpose: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

Introduction Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Methods Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. Results We detected SMARCA4 genomic alterations in 9% (n = 117 of 1422) and 11% (n = 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n = 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n = 11) or chemotherapy plus immunotherapy (n = 5), median progression-free survival was 38 days and 35 days, respectively. Conclusions BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.