Faculty Bibliography

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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Background: The SACT options for aNSCLC continue to increase each year with approvals of more effective therapies that improve long-term outcomes, such as immunotherapies (IO). Our aim was to examine trends in SACT rates from 2011-2018 for patients with aNSCLC and no known EGFR/ALK aberrations at US community oncology practices.
Method(s): We used the nationwide Flatiron Health EHR-derived database (data cutoff: 31Jan2019), which incorporates oncologist-defined, rule-based lines of therapy. Adults with aNSCLC diagnosis date from Jan2011-Jun2018, inclusive, with recorded EHR activity <=90 days after diagnosis, were eligible. Patients with known EGFR/ALK-positive tumors, or nonsquamous histology (NSQ) with unknown or untested EGFR/ALK status, were excluded. We summarized no-treatment and first-line (1L) SACT rates as a proportion of aNSCLC diagnosed from 2011-2018, while limiting 2L and 3L SACT rates to aNSCLC diagnoses from 2011-2016 in order to have sufficient follow-up. Results were stratified by NSQ and squamous (SQ) histology, as well as by pre-IO and post-IO years of aNSCLC diagnosis, defined broadly as 2011-2014 and 2015+, respectively, based on the earliest IO approval for 2L therapy in Mar2015.
Result(s): The figure depicts 1L, 2L, and 3L SACT rates by year of aNSCLC diagnosis for EGFR/ALK-negative NSQ and for SQ. For NSQ, the pre-IO and post-IO no-treatment rates were 28% (2286/8246) and 22% (2520/11,639), respectively. For SQ, the pre-IO and post-IO no-treatment rates were 34% (1781/5200) and 26% (1549/6040). [Figure presented]
Conclusion(s): For both EGFR/ALK-negative NSQ and SQ aNSCLC, 1L SACT rates are trending upward, with no-treatment rates showing substantial drops in the post-IO (versus pre-IO) period. The 2L and 3L SACT rates are variable for both NSQ and SQ; and SACT rates for NSQ tend to be substantially greater than for SQ across all lines of therapy and years of diagnosis. Keywords: real-world treatment rates, Immunotherapy, advanced NSCLC
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Background: Early-Stage non-small cell lung cancer (ES-NSCLC) accounts for approximately 40% of NSCLC cases, with 5-year survival rates varying between 31-49%. Radiomic textural features from pre-treatment CT scans and QH features from H&E stained WSIs have been shown to be independently prognostic of outcome. With diagnostic CT scans and surgical resection, the standard of care in ES-NSCLC, in this work we seek to take a multimodality approach using routine imaging to improve the predictive performance in determining DFS following resection.
Method(s): A retrospective chart review of Stage I and II (ES-NSCLC) pts undergoing surgical resection between 2005-14 with available CT and resected tissue yielded 70 pts. A total of 248 radiomic CT textural features from inside the tumor (Intratumoral -IT) and outside the tumor (Peritumoral - PT) and 242 QH features related to the nuclear shape, texture and spatial orientation and architecture from H&E WSI were extracted. We developed two risk models, Radiomic and QH using the most stable, discriminative and uncorrelated features from CT and WSI respectively determined by Lasso-regularized Cox regression to predict Disease free survival (DFS). Model performances were analyzed using Hazard Ratios (HR), Concordance Index (C-index) and Decision curve analysis. We built a nomogram to calculate the DFS based around the individual models as well as an integration of the QH and Radiomic models.
Result(s): Top 6 Radiomic features included 2 IT and 4 PT features from the Haralick and Collage families. The QH model comprised 6 nuclear shape and graph features. In predicting DFS, While the Radiomic model had a HR of 2.4 (p <0.01) with C-index - 0.67, the QH model had

Background: Early stage non-small cell lung cancer (ES-NSCLC) comprises about 45% of all NSCLC patients, with 5-year survival ranging between 30-49%. Surgical resection is the standard of care curative modality in these patients but about 30-55% of patients often recur following surgery within the first 3 years. There is currently no validated method to stratify patients based on their risk of recurrence following surgery in these patients. In this project, we develop and validate a nomogram using a combination of CT-derived radiomic textural features and clinco-pathologic factors, in order to predict DFS in ES-NSCLC.
Method(s): This study comprised 350 ES-NSCLC patients from two different institutions who underwent surgery (75 patients relapsed). Radiomic textural features were extracted from tumor region (Intratumoral - IT) as well as from the annular ring shaped peritumoral region (PT) with 3mm as a ring thickness and extending 9 mm outside the nodule. A total of 124 features from Gabor, Laws, Laplace, Haralick and Collage feature families were extracted from IT and each PT ring for all patients. The most stable, significant and uncorrelated features were selected from D1 (N=221) and used to build a Lasso-regularized multivariate Cox-regression model to generate a Radiomic Risk Score (RRS) derived from weighted Lasso coefficients. Further, RRS was integrated with clinic-pathologic variables (Lympho-vascular invasion LVI and AJCC stage) which were independently predictive on DFS in multivariate analysis to build a clinical-radiomics score (CRS). A nomogram was constructed to visually assess the CRS and RRS on DFS. Performances were evaluated using hazard ratios (HR), concordance index (C-Index) along with decision and calibration curves to show the differences between the individual and integrated risk scores.
Result(s): Top 14 radiomic features included 6 from IT and 8 from 0-9 mm PT distance. The constructed RRS could predict DFS (n=221, C-index=0.69, HR = 3.8; 95% CI- 2.7-5.6, p<0.05) on training (D1) and (n=129, C-index=0.69,

Background: Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination's efficacy in treatment-naive EGFR-mutant NSCLC.
Method(s): The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334.
Result(s): Section not applicable
Conclusion(s): Section not applicable Keywords: Ramucirumab, CNS metastasis, EGFR
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Background: No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method(s): This global phase 1/2 study (87 sites, 15 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result(s): As of 17-June 2019, 247 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 54 patients (51%) also received prior immune checkpoint inhibitors (ICIs). The majority of PAS responders have been followed for >=6 months from first response. Of the remaining 142 patients, 74 previously treated with platinum-based chemotherapy have not had sufficient follow-up, 56 did not receive prior platinum-based chemotherapy and 12 did not have measurable disease at baseline. Among PAS patients, the investigator-assessed ORR was 70% (95% CI 60-78%, n=73/105, 3 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, ICIs and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 16.6-NR) with a median follow-up of 7.5 months (range 1.9-21.1 months); as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (12 of 70 confirmed responders). The intracranial ORR was 90% (n=9/10: 2 confirmed CRs, 7 confirmed PRs) for patients with measurable brain metastases at baseline. The ORR in evaluable treatment naive RET fusion-positive NSCLC patients was 88% (95% CI 72-97%, n=29/33, 10 PRs pending confirmation). In the safety data set of all 247 patients, 5 treatment-related AEs occurred in >=15% of patients: dry mouth, AST increased, diarrhea, ALT increased, and hypertension. Most AEs were grade 1-2. Only 3 of 247 (1.2%) NSCLC patients discontinued LOXO-292 for treatment-related AEs. Updated data will be presented at the meeting.
Conclusion(s): LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year. Keywords: RET fusion, selective RET inhibitor, NSCLC
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Background: bTMB assays determine TMB using a noninvasive blood test. B-F1RST (ITT, n=152) is the first prospective trial to evaluate bTMB as a biomarker to predict benefit of 1L atezo monotherapy in advanced NSCLC. bTMB high (score of >=16; >= 14.5 mut/Mb) predicted better ORR with atezo vs bTMB low (< 16; 28.6% vs 4.4%) in the biomarker evaluable population (BEP) with >= 6 mo follow up in the primary analysis. Numerical benefit for bTMB high was seen in median (m)PFS and mOS. Here we report the B-F1RST final analysis.
Method(s): Eligibility criteria included untreated stage IIIB-IVB NSCLC and ECOG PS 0/1. Pts received atezo 1200 mg IV q3w until PD, intolerance or loss of benefit. Co-primary endpoints were investigator assessed ORR for efficacy (ITT) and PFS for biomarker analysis (BEP) at a prespecified bTMB cutoff of 16 for high (>= 16) vs low (< 16). PFS and OS, a secondary endpoint, were further evaluated at various bTMB cutoffs. Serum C-reactive protein (CRP), an inflammation marker in cancer, was evaluated as a surrogate biomarker, ratio of CRP at C3D1 to CRP at screening, to predict PFS and OS.
Result(s): With >= 18 mo follow up (data cutoff, 14 May 2019) in ITT pts, ORR was 17% (95% CI: 12, 24), mPFS was 4.1 mo (95% CI: 2.8, 4.9) and mOS was 14.8mo (95% CI: 12.7, 21.3). In bTMB >= 16 vs<16, mPFS was 5.0 vs 3.5 mo and mOS was 23.9 vs 13.4 mo (Table). For CRP ratio <0.5 vs >=0.5, mPFS was 14.1 vs 4.6 mo (HR, 0.43 [90% CI: 0.24, 0.77]), and mOS was NE vs 15.9 mo (HR, 0.30 [90% CI: 0.13, 0.72]). 14% of pts had treatment-related (TR) serious AEs, and 20% had Gr 3-4 TRAEs. 18% of pts had AEs that led to discontinuation.
Conclusion(s): B-F1RST shows the clinical utility of bTMB as a predictive biomarker for pts receiving 1L atezo monotherapy. The final analysis confirmed that pts with bTMB >= 16 had numerical benefit for PFS and OS. Decrease in serum CRP over 6 wk predicted PFS and OS benefit. No new safety signals were seen. (Table Presented)

OBJECTIVES/OBJECTIVE:Despite improved outcomes associated with immunotherapies for non-small cell lung cancer (NSCLC), many patients do not respond to treatment. Therefore, there is still an unmet need for molecularly targeted therapies in this patient population. Fusions of the RET oncogene have been identified as driver alterations in patients with NSCLC. Lenvatinib is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, and other targets. This study evaluated the safety and efficacy of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. MATERIALS AND METHODS/METHODS:In this phase 2, multicenter, open-label study (NCT01877083), patients with RET-positive lung adenocarcinoma received oral lenvatinib 24 mg/day. The primary end point was objective response rate (ORR) by investigator review per Response Evaluation Criteria In Solid Tumors v1.1 criteria. The secondary end points included safety and tolerability, progression-free survival (PFS), and overall survival (OS). RESULTS:Of 536 patients who screened for study inclusion and exclusion, 25 patients with RET translocations (KIF5B-RET [n = 13] and CCDC6-RET [n = 12]) were identified and received lenvatinib. The overall ORR was 16% (95% CI: 4.5%-36.1%). At data cutoff (February 3, 2016), the median PFS was 7.3 months (95% CI: 3.6-10.2) and the median OS was not reached. Duration of response was not estimable at the time of data cutoff. All patients experienced a treatment-emergent adverse event (TEAE); 23 (92%) patients experienced a TEAE of ≥ grade 3, and 6 (24%) patients discontinued lenvatinib due to a TEAE. The most common TEAEs were hypertension (68%), nausea (60%), decreased appetite (52%), diarrhea (52%), and proteinuria (48%). CONCLUSIONS:Lenvatinib demonstrated activity in patients with RET fusion-positive lung adenocarcinomas; although the response rate was relatively low, the median PFS supports the activity of lenvatinib in these patients.

OBJECTIVE:The use of a neoadjuvant chemoradiation followed by surgery in patients with stage IIIA NSCLC is controversial and the benefit of surgery is limited. There are currently no clinically validated biomarkers to select patients for such an approach. In this study we evaluate computed tomography (CT) derived intratumoral and peritumoral texture and nodule shape features in their ability to predict major pathological response (MPR). MPR being defined as ≤10% of residual viable tumor, assessed at the time of surgery. MATERIAL AND METHODS/METHODS:Ninety patients with stage III NSCLC treated with chemoradiation prior to surgical resection were selected. The patients were divided randomly into two equal sets, one for training and one for independent testing. The radiomic texture and shape features were extracted from within the nodule (intra) and from the parenchymal regions immediately surrounding the nodule (peritumoral). A univariate regression analysis was performed on the image and clinicopathologic variables and then included into a multivariable logistic regression (MLR) for binary outcome prediction of MPR. The radiomic signature risk-score was generated by using a multivariate Cox regression model and association of the signature with OS and DFS was also evaluated. RESULTS:Thirteen stable and predictive intratumoral and peritumoral radiomic texture features were found to be predictive of MPR. The MLR classifier yielded an AUC of 0.90 ± 0.025 within the training set and a corresponding AUC = 0.86 in prediction of MPR within the test set. The radiomic signature was also significantly associated with OS (HR = 11.18, 95% CI = 3.17, 44.1; p-value = 0.008) and DFS (HR = 2.78, 95% CI = 1.11, 4.12; p-value = 0.0042) in the testing set. CONCLUSION/CONCLUSIONS:Texture features extracted within and around the lung tumor on CT images appears to be associated with the likelihood of MPR, OS and DFS to chemoradiation.

PURPOSE/OBJECTIVE:To determine the tumor tissue/cell distribution, functional associations and clinical significance of PD-1, LAG-3 and TIM-3 in human non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN/METHODS:Using multiplexed quantitative immunofluorescence (QIF) we measured CD3, PD-1, LAG-3 and TIM-3 in >800 NSCLCs from three tissuemicroarray-based cohorts. Associations between markers and tumor genomics were studied in TCGA-NSCLC dataset. Using mass-cytometry (CyTOF) analysis from 20 resected NSCLCs, we determined the levels, co-expression and functional profile of PD-1, LAG-3 and TIM-3 expressing immune cells. Finally, we measured the markers in 90 NSCLCs from patients treated with PD-1 axis blockers. RESULTS:PD-1, LAG-3 and TIM-3 were detected in TILs from 55%, 41.5% and 25.3% of cases, respectively. These markers showed association with each other, but not with clinicopathologic variables and survival in cases without immunotherapy. The markers were lower in EGFR-mutated adenocarcinomas and partially associated with tumor-mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T/NKT-cells; while TIM-3 was higher in NK-cells and macrophages. Co-expression of PD-1,LAG-3 and TIM-3 was associated with T-cell activation, effector function and proliferation, but also with pro-apoptotic markers. LAG-3 and TIM-3 were present in TILs lacking PD-1 and elevated baseline LAG-3 was associated with shorter progression-free survival after PD-1 axis blockade. CONCLUSIONS:PD-1, LAG-3 and TIM-3 have distinct tissue/cell distribution, functional implications and genomic correlates in NSCLC. Expression of these receptors is associated with activation, but also with pro-apoptotic T-cell phenotype. Elevated LAG-3 is associated with insensitivity to PD-1 blockade suggesting independence of these immune evasion pathways.