Faculty Bibliography

Background: Systemic anticancer therapy (SACT) options for aNSCLC continue to increase each year with approvals of more effective therapies that improve long-term outcomes, as seen with immunotherapies (IO). We aimed to examine real-world trends in SACT distribution and sequence from first- to second-line (1L-2L) for EGFR/ALK-negative nonsquamous aNSCLC from 2011-2018 at US community oncology practices.
Method(s): This study used the nationwide Flatiron Health de-identified, EHR-derived database (cutoff: 31Jan2019). Eligible patients were adults with aNSCLC, nonsquamous histology with known EGFR/ALK-negative status, who initiated 1L SACT from Jan2011-Jun2018. SACT regimens were assigned to mutually exclusive classes in hierarchical order, from highest to lowest: (1) PD1/PD-L1 inhibitor (anti-PD1/L1)-based, (2) EGFR/ALK TKI-based, (3) platinum-based chemotherapy (PBC) combination with vascular endothelial growth factor inhibitor (PBC+VEGF), (4) PBC only, (5) single agent chemotherapy, (6) others. 2L regimens were examined for patients initiating 1L SACT only through 2017 to enable sufficient follow-up. Results were stratified by year and by pre-IO/post-IO years of 1L initiation, defined as 2011-2014/2015-2018, respectively, based on earliest IO approval for 2L therapy in Mar2015.
Result(s): For 1L, in the pre-IO period, most patients were prescribed PBC (53%) or PBC+VEGF (30%), and post-IO, most were prescribed PBC (43%), anti-PD1/L1 (25%), or PBC+VEGF (23%). Among patients prescribed 1L therapy, the percentages who received 2L therapy were 50%-62% post-1L PBC; 56%-62% post-1L PBC+VEGF; and 28%-38% post-1L anti-PD1/L1 (table). A substantial percentage (25%) of those initiating 1L anti-PD1/L1 in 2017 were still on therapy at cutoff. [Figure presented]
Conclusion(s): Changing trends in real-world prescribing of 1L-2L SACT for EGFR/ALK-negative nonsquamous aNSCLC from Jan2011-Jun2018 include decreasing use of PBC in 1L and 2L, decreasing use of PBC+VEGF in 1L, and, increasing use of PD1/PD-L1 inhibitors in 1L and 2L. Slightly more than one-half of patients with nonsquamous aNSCLC prescribed 1L PBC are subsequently treated with 2L therapy. Keywords: nonsquamous NSCLC, real-world therapy trends, Immunotherapy
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Background: Tumor heterogeneity is known to be implicated in chemotherapeutic resistance and poor prognosis for non-small cell lung cancer (NSCLC). In this study we sought to evaluate the role of computer extracted features reflecting the intrinsic cellular morphological diversity (ICMD) of tumors from digitized H&E stained images of early-stage NSCLC patients. Additionally, we sought to evaluate the association of these ICMD features in adenocarcinomas with the ALK and EGFR mutational status.
Method(s): Two cohorts, D1 and D2, of digitized H&E stained tissue microarray images (TMA) of NSCLC, n=395 and n=91, respectively, were used for modeling the ICMD predictor. A pretrained deep learning model was used for segmentation of nuclei, and clusters of proximally located nuclei were identified. The ICMD features were then extracted as the variations in shape, size, and texture measurements of nuclei within the clusters. A Cox proportional hazard model using the ICMD features was then trained for lung adenocarcinomas (LUAD, n=270), and squamous cell carcinomas (LUSC, n=216), separately, and was validated on independent cohort from (D3) The Cancer Genome Atlas (TCGA) (n=473) to predict Overall Survival (OS). Univariate and multivariate analyses were performed on (D3).
Result(s): In (D3), high risk patients predicted by the ICMD features had significantly poorer survival (HR (95% CI) = 1.48 (1.06-2.06), p=0.021 for LUSC, HR (95% CI) = 1.59 (1.11-2.29), p=0.006 for LUAD) in univariate analysis. In multivariate analysis, controlling for major clinical variables, ICMD was independently associated with 5-year OS (p<0.016). (See Table 1) We also found that ICMD features were associated with driver mutations ALK (p=0.0204) and EGFR (p=0.0017) in LUAD. [Figure presented]
Conclusion(s): Computer extracted image features of cellular diversity were able to predict OS in NSCLC and were also associated with the ALK and EGFR mutational status. Future work will entail evaluating ICMD features in predicting added benefit of adjuvant therapy in early stage NSCLCs as well as correlating with gene expression data. Keywords: digital pathology, Early stage non-small cell lung cancer, computational pathology
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Background: HER2 (ERBB2) TMD mutations have recently been described as novel solo actionable drivers in NSCLC responsive to afatinib in small series. However, dual occurrence of de novo EGFR or HER3 (ERBB3) TMD mutations together with HER2 TMD mutations, which may have implications for dimerization patterns and treatment, has not been described.
Method(s): Hybrid-capture based comprehensive genomic profiling was performed on blood-based circulating tumor DNA (n=5,200) or FFPE tissue (n= 45,780) samples collected during clinical care from 50,980 unique NSCLC patients.
Result(s): HER2 TMD mutations were identified in 0.12% (60/50,980) of cases and included V659E (n=33), V659D (n=8), G660D (n=15), V659E+G660R, V659_I661>VVEGI, G660E>R, and S653C (1 each). Within this subset, the median age of patients was 61 years (range 33-91) and 62% were female. No co-occurring known NSCLC driver alterations were detected, except one case with EGFR exon 19 deletion and one case with EGFR L858R and lung co-primary tumors noted. However, co-occurring HER3 (I649R) or EGFR (G652R) TMD mutations were found in 18% (11/60) and 5.0% (3/60) of cases, respectively. Notably, these ERBB3 or EGFR TMD mutations only co-occurred with HER2 TMD V>D (8/9 cases) or G>D (7/15 cases), but not with V>E changes (0/34 cases; p=0.0002). HER2 amplification co-occurred with V659E in 15% (5/34) of cases, and G660D mutation was seen with the oncogenic extracellular domain S310F mutation in one case. Importantly, neither EGFR G652R nor ERBB3 I649R was found in the absence of a HER2 TMD mutation. Preliminary modelling studies suggest formation of a salt-bridge which would increase propensity for HER2/HER3 and HER2/EGFR heterodimerization favoring receptor activation. Two patients in this series with V659E were previously reported to have responded to afatinib and 1 patient with G660D+I649R did not respond to afatinib. Updated clinical data for these patients and others treated with HER2-tageted therapies will be presented.
Conclusion(s): HER2 TMD mutations (V659D/E or G660D/R) are uncommon but targetable driver alterations in NSCLC. In cases with HER2 TMD V>D or G>D, a de novo co-existing EGFR or HER3 TMD mutation was frequently observed (88% and 47%, respectively), which may explain differential dimerization preference and in turn response to ERBB inhibitors. We hypothesize that dual HER2/HER3 or HER2/EGFR TMD mutants may be more aggressive than single HER2 TMD mutants due to the arginine-aspartic acid interaction, and these dual mutants may require combined kinase inhibitor + antibody therapy to block dimerization. Studies utilizing models to further characterization these co-alterations are in progress. Keywords: HER2, transmembrane domain, Receptor tyrosine kinase
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Background: Recently majority of patients with advanced non-small cell lung cancer (NSCLC) without targetable mutations are treated with immune checkpoint inhibitors (ICI). Since there are currently no validated biomarkers for predicting benefit of immunotherapy (IO), there is an unmet clinical need for development of such biomarkers. The tumor vasculature is a key component of the tumor micro-environment that can influence its behavior and therapeutic refractoriness. We aimed to evaluate the prognostic and predictive potential of quantitative vessel trotuosity (QVT), in the NSCLC patients treated with ICI drugs. Two hypotheses were established: first, the QVT on pre-treatment CT scans of NSCLC patients are associated with overall survival (OS). Second, the prognostic QVT features can lead to identify the patients who will benefit from IO.
Method(s): This study include 128 patients with advanced NSCLC. All patients underwent a baseline contrast CT imaging. Patients who did not receive IO drugs after 2 cycles due to a lack of response or progression as per RECIST were classified as non-responders. The dataset was splitted into a discovery (N=64) and validation sets (N=64). A set of 74 QVT features pertaining to tortuosity and curvature of tumor vasculature was extracted in CT scans. The initial set of QVT features were reduced to 8 features using least absolute shrinkage and selection operator (LASSO) in conjunction with OS data of the patients. Then, cox proportional hazard model was used to determine the contribution of each feature for categorizing survival groups. The weighted sum of selected 8 features gave a risk score (QRS) per patient. Patients in validation set were stratified based on QRS using the cutoff and feature weights learned in the discovery set. Prognostic features in conjunction with a linear discriminant machine learning model and OS were used to build a model to predict the response to IO. The prognostic features were also used for unsupervised clustering of the patients.
Result(s): The QRS risk score was able to stratify patients into two survival groups in validation set (Fig1. a-b) with p-value=0.022, Hazard ratio (HR)=0.47 and concordance index (CI)=0.61. The response prediction model yielded an AUC of 0.64+/-0.03 (Fig1.c). The agreement between patients with high OS and positive response to therapy was found to be 0.62 on unsupervised clustering method (Fig1. d). [Figure presented]
Conclusion(s): The CT extracted QVT features was found to be prognostic of OS and also showed predictive value that could be used to identify patients who will benefit from IO.
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Background: Carboplatin, pemetrexed and pembrolizumab (C/P/P) is currently approved for patients with advanced non-squamous carcinoma of the lung (NS-NSCLC) based on superior survival outcomes noted in KEYNOTE-189. Since clinical benefit was observed across all PD-L1 expression categories, there are currently no robust predictive biomarkers that can identify subsets of patients likely to derive benefit from this regimen. We sought to evaluate whether radiomic features extracted from within and outside the nodule on pre-therapy CT scans could predict response to C/P/P.
Method(s): We retrospectively identified 52 patients with stage IV NS-NSCLC who received C/P/P. Of these, 6 were excluded because of non-evaluable thoracic lesions. Lung tumors were contoured on 3D SLICER software by an expert reader. Textural and shape radiomic features were extracted from intra/peritumoral regions using MATLAB 2018b platform (Mathworks, Natick, MA). The primary endpoint of our study was RECIST response and secondary end point was overall survival (OS). A linear discriminant analysis classifier (LDA) was used to predict response across 100 iterations of threefold cross validation in the dataset. Performance of classifier on response was measured by area under receiver operating characteristic curve (AUC). To build the multivariate radiomic signature for OS, least absolute shrinkage and selection operator (LASSO) Cox regression model was used and a risk score was computed according to a linear combination of selected features. Patients were divided into high-risk or low-risk groups based on median risk score.
Result(s): The top five radiomic features (intra/peritumoral textural patterns) predictive of response to C/P/P were identified by mRMR feature selection method. LDA classifier using these features could discriminate responders from non-responders with an AUC of 0.77 +/- 0.05. The radiomic risk score was calculated using a linear combination of top six selected features from LASSO with corresponding coefficients. In a multivariate Cox proportional hazards model using a combination of clinicopathologic and radiomic features, the radiomics signature was found to be significantly associated with OS (averaged on 100 iteration of CV) (HR 10.42; 95% CI: 4.18-26; P = 4.92e-07). Kaplan-Meier survival analyses according to the radiomics signature risk-score showed significantly worse survival in the high risk category.
Conclusion(s): Textural features within and outside the nodule on pre-treatment CT images of patients with NS-NSCLC treated with C/P/P were predictive of responses and OS. Additional validation of these quantitative image-based biomarkers in independent cohorts is warranted. [Figure presented] Keywords: Radiomics, Biomarker, chemoimmunotherapy
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Background: Immune checkpoint inhibitors (ICI) are a promising and novel approach to treating chemotherapy refractory advanced NSCLC as well as first-line combination therapy in certain NSCLC. Nivolumab, a PD-L1 inhibitor is a promising ICI showing durable benefit with low toxicity in these patients. While PD-L1 positivity is an established tissue based biomarker for response to Nivolumab, studies have shown response rates ranging from 20-50%. Recent research has shown that TILs have been implicated in cancer aggressiveness as well as immune response. In this work, we go beyond simply counting TILs, and apply novel computer-extracted features characterizing the interaction and spatial co-localization of TILs and cancer nuclei (SpaTIL) in stratifying patients based on OS following nivolumab therapy.
Method(s): H&E tissue slides obtained from pre-treatment biopsies of 96 NSCLC patients treated with nivolumab were digitized and included for this study from 3 different institutions with the tumor region annotated by pathologists. Then 85 SpaTIL features related to TIL density, architecture and co-localization with tumor cells have been extracted to represent each patient. The most discriminative and uncorrelated features were selected by Elastic-Net regularized Cox-regression model to predict OS. The model was trained on D1 (n=25) and independently validated in D2 (n=32) and D3 (n=64). Multivariate analysis with clinico-pathologic factors was also performed.
Result(s): The top features consisted of the abundance of TILs around tumor cells and the distribution of the TILs. On the validation set, SpaTIL classifier yielded a HR=3.03 (95%CI=1.1 -8.35; p=0.042) on D2 and HR=4.12 (95%CI=1.87-9.09; p=0.02) on D3 by a log-rank test. On multivariate analysis with stage, smoking, histologic type, total lymphocyte count (See Table 1) SpaTIL was independently prognostic of OS (HR=7.88; 95%CI=1.66 - 37.216; p=0.009). [Figure presented] [Figure presented]
Conclusion(s): Spatial interaction of TILs and cancer are independently prognostic of OS in nivolumab treated NSCLC. Further validation needs to be done to evaluate its utility. Keywords: predictive image signatures, TILs, response to immunotherapy
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Background: The prevalence of autoimmune diseases (AIDs) in patients with lung cancer is approximately 14%. However, patients with pre-existing AIDs have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs) limiting the data on safety and efficacy of these agents. Oncologists are therefore wary to use them in this at-risk population.
Method(s): We conducted a single institution IRB-approved retrospective study to evaluate the safety and efficacy of combination and single agent ICI therapy in patients with pre-existing AIDs and concomitant advanced lung cancer that were treated with ICI from 2011 to 2018. Primary endpoints were incidence of irAEs and AID flares. The secondary endpoint was overall survival (OS).
Result(s): We evaluated records from 29 patients with lung cancer of which 17 (59%) had adenocarcinoma, 10 (34%) had squamous cell carcinoma, two (7%) had small cell cancer, and one (3%) had undifferentiated non-small cell lung cancer. AIDs included rheumatic (72%), gastrointestinal (10%), endocrine (10%) and neurologic (7%). 34% of patients experienced an irAE, though only 7% were severe (grade 3-4 colitis and hepatitis). 66% of patients reported no irAEs at all. The most common irAEs were dermatitis (14%) and colitis (10%). 10% of patients had to permanently discontinue ICIs due to an irAE while 17% temporarily held their ICI. 96% of patients with AIDs were either stable or in remission. AID flares were observed in 28% of patients with 24% requiring treatment. None of the AID flares resulted in permanent discontinuation of ICI therapy. 21% of patients were on immunomodulatory therapies at start of ICI treatment. The use of immunomodulatory medications was not associated with an increased incidence of either irAEs or AID flares. Median OS from ICI initiation was 8.5 months and median PFS was 6 months. There was no statistically significant difference for OS or PFS by presence of irAE or presence of immunomodulatory therapy at start of ICI use.
Conclusion(s): In this cohort, patients with pre-existing AIDs and advanced lung cancer reported fewer AID flares (28%) than has been cited in the literature (approximately 50%). IrAEs were seen at an incidence similar to that observed in patients without AIDs. In our cohort, the majority of adverse reactions were manageable and did not require permanent discontinuation of ICI therapy. Furthermore, the presence of irAEs did not detrimentally affect patients' OS or PFS. Based on these findings, we would consider ICI therapy as an option in select patients with pre-existing autoimmunity. Keywords: toxicity, pre-existing autoimmune disease, Immunotherapy
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Background: Information from real-world clinical settings remains limited regarding outcomes of pembrolizumab therapy for advanced NSCLC. Our aim was to examine real-world time on treatment (rwToT) and overall survival (OS) for patients prescribed pembrolizumab monotherapy for previously treated, PD-L1-expressing advanced NSCLC, thus clinically similar to patients in the KEYNOTE-10 (KN010) trial.
Method(s): This retrospective study used Flatiron Health's nationally representative EHR-derived database to identify adult patients with histologically confirmed advanced NSCLC and PD-L1 tumor proportion score (TPS) >=1% previously treated with platinum-containing chemotherapy (and appropriate TKI if nonsquamous NSCLC with EGFR/ALK aberration). Eligible patients initiated pembrolizumab monotherapy from January 1, 2016, to May 31, 2018; those with <6 months of follow-up were excluded. Kaplan-Meier (KM) rwToT and OS were calculated.
Result(s): Median follow-up was 15.6 months (range 6.0-32.8 months). Of 281 eligible patients (56% male), median age was 68 years; 36% had squamous NSCLC; 10% brain metastases; and 57%, 18%, and 25% ECOG performance status 0-1, >=2, and unknown, respectively. Baseline characteristics were similar across PD-L1 TPS distributions. The table summarizes rwTOT and OS by PD-L1 TPS categories. [Figure presented]
Conclusion(s): Real-world patients treated with pembrolizumab monotherapy after platinum-containing chemotherapy for PD-L1-expressing advanced NSCLC experienced rwToT and OS benefits similar to findings in a clinical trial setting, validating KN010 findings and approved indication in second line. Keywords: Pembrolizumab, overall survival, real-world time on treatment
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Background: The SACT options for aNSCLC continue to increase each year with approvals of more effective therapies that improve long-term outcomes, as seen with immunotherapies (IO). Our aim was to examine real-world trends in SACT distribution and sequence from first- to second-line (1L-2L) for squamous aNSCLC from 2011-2018 at US community oncology practices.
Method(s): This study used the nationwide Flatiron Health de-identified, EHR-derived database (cutoff: 31Jan2019). Eligible patients were adults who initiated 1L SACT from Jan2011-Jun2018 for aNSCLC with squamous histology, excluding patients with known EGFR/ALK-positive tumors. Descriptive analyses included patients receiving >=1 SACT dose, assigning all SACT regimens to mutually exclusive classes in hierarchical order (combination regimens assigned by highest component), from highest to lowest: (1) PD1/PD-L1 inhibitor (anti-PD1/L1)-based, (2) EGFR/ALK TKI-based, (3) platinum-based chemotherapy combination with vascular endothelial growth factor inhibitor (PBC+VEGF), (4) PBC only, (5) single agent chemotherapy, (6) others. The 2L regimens were examined for patients with 1L SACT initiation only through 2017 to enable sufficient follow-up. Results were stratified by years and by pre-IO and post-IO years of 1L initiation, defined as 2011-2014 and 2015-2018, respectively, based on the earliest IO approval for 2L therapy in Mar2015.
Result(s): For 1L therapy, in the pre-IO period, most patients were prescribed PBC (80%), and post-IO, most patients were prescribed PBC (68%) or anti-PD1/L1 (21%). Among patients prescribed 1L therapy, the percentages who received 2L therapy were 44%-53% following 1L PBC and 25%-37% following 1L anti-PD1/L1, with 19% of 2017 1L anti-PD1/L1 starts still on 1L therapy (table). [Figure presented]
Conclusion(s): PBC remain the most common 1L SACT prescribed through mid-2018 for patients with squamous aNSCLC at US community oncology practices. Prescribing of PD1/PD-L1 inhibitors as 1L has gradually increased since regulatory approval starting in 2015. Approximately one-half of patients with squamous aNSCLC prescribed 1L PBC are treated with 2L therapy. Keywords: squamous NSCLC, real-world therapy trends, Immunotherapy
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