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Wallace Akerley



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    FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP05.01 - Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Choice of Second-line Therapy   (ID 2718)

      00:00 - 00:00  |  Author(s): Wallace Akerley

      • Abstract
      • Slides

      Introduction

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor overall survival (OS). Disease biology, patient co-morbidities and performance status (PS), and a lack of biomarkers to guide therapeutic decision making all contribute to poor survival. There is limited data to guide choice of second-line therapy (2L) after progression of disease (POD) on first-line (1L) platinum-based combination chemotherapy. This study evaluates real-world survival outcomes of patients with MPM by physician’s choice of 2L single-agent chemotherapy versus immunotherapy.

      Methods

      The study included patients with MPM in the Flatiron Health nationwide electronic health record-derived de-identified database who initiated 2L therapy after POD on 1L platinum-based chemotherapy between May 2011 – July 2019, with follow-up through July 2019. Propensity weighting was performed to balance potential confounders, weight the Kaplan-Meier estimate of OS from initiation of 2L, and weight a Cox proportional hazard model on OS comparing immunotherapy versus single-agent chemotherapy. Propensity scores were constructed via logistic regression based on age, asbestos exposure, smoking history, region, race/ethnicity, PD-L1 status, histology, time to starting 2L therapy, serum creatinine, hemoglobin, absolute neutrophil, platelet, and white blood cell count, serum albumin, height, weight, 1L therapy, previous heart, kidney, neuropathy, and/or audiologic condition, and ECOG PS. An unweighted Cox proportional hazards model was fit adjusting for these baseline covariates and date of diagnosis.

      Results

      This study included 193 patients with MPM treated with single-agent chemotherapy (n=101) versus single-agent or combination immunotherapy (n=92) after POD on 1L platinum chemotherapy. Documented PD-L1 testing was limitedly available (n=38; 20%). Median age was similar between treatment groups. More patients with sarcomatoid histology and with ECOG PS 0 and 3 were treated with 2L immunotherapy than chemotherapy. Patients receiving single-agent chemotherapy were mostly diagnosed prior to 2016 (74%); only 15% of patients receiving immunotherapy were diagnosed by this time. The propensity score weighted analysis demonstrated an OS hazard ratio (HR) of 2L immunotherapy versus chemotherapy of 0.64 (p = 0.05; 95% CI: 0.41, 1.01). The unweighted analysis was consistent in estimating the HR to be 0.61 (p = 0.08, 95% CI = 0.35, 1.07).

      wclc figure 2 final 2l therapy.jpg

      Conclusion

      This is the largest real-world evidence assessment of 2L therapy following platinum chemotherapy in patients with MPM. While non-significant, single or combination immunotherapy had a suggestive benefit on OS compared to single-agent chemotherapy. The benefit had as much as a 59% HR reduction of death and had no worse than a 1% increased HR on OS.

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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.17 - The Impact of Blood Based Host Immune Profile to Identify Aggressive Early Stage NSCLC   (ID 3600)

      00:00 - 00:00  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Introduction

      Early detection of non-small cell lung cancer (NSCLC) provides the greatest opportunity for a cure. However, even when NSCLC is identified early, 30-60% of patients diagnosed with stage I-IIIA disease will experience local and/or distant recurrences, respectively. More precise tools are needed to refine lung cancer staging and identify patients that have a more aggressive disease who may benefit from additional treatment or enhanced disease surveillance following curative intent. The Host Immune Classifier (HIC) is a clinically validated, blood-based proteomic test designed to identify an inflammatory disease state associated with aggressive cancer. Here we report the results of a prospectively designed observational study evaluating the ability of the HIC to predict the survival outcomes of patients with early stage NSCLC.

      Methods

      The INSIGHT study (NCT03289780) has enrolled over 3,500 patients with NSCLC, regardless of stage, at 33 sites throughout the U.S. All subjects are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C) prior to treatment initiation. An interim analysis of secondary and exploratory endpoints was performed after 12-18 months (mo) follow-up with the first 2,000 enrolled patients. We report the overall survival (OS) of HIC-defined subgroups comprising patients with stage I through stage IIIA (defined by the AJCC seventh edition staging system) NSCLC treated according to standard of care practice.

      Results

      At the time of database lock, 335 patients with newly diagnosed early stage NSCLC were included in the analysis. Disease stage at study entry was: 20% Stage IA (N=68, 3% HIC-C), 13% Stage IB (N=45, 11% HIC-C), 11% Stage IIA (N=37 (14% HIC-C), 13% Stage IIB (N=44, 21% HIC-C), 32% Stage IIIA (N=141, 34% HIC-C). Without biomarker stratification, landmark 15 mo OS was 85% (95% CI 78-90%) for patients with localized disease (Stage I-IIA) and 73% (95% CI 65-79%) for patients with regional disease (Stage IIB-IIIA), respectively. When patients with localized disease were evaluated with the HIC test, 15 mo landmark OS was significantly decreased for patients classified as HIC-C (HIC-C 55% (95% CI 23-78%) vs. HIC-H 87% (95% CI 80-92%), HR 3.68 (95% CI 1.38-9.87), p value 0.01). Similarly, 15 mo landmark OS for regionally advanced NSCLC was also significantly reduced for patients classified as HIC-C (HIC-C 60% (95% CI 45-72%) vs. HIC-H 79% (95% CI 70-85%), HR 1.77 (95% CI 1.02-3.06), p value 0.04). HIC remained prognostic for OS when adjusted for other covariates such as stage, ECOG performance status, histology, and treatment type in a multivariate analysis (HR of 1.89 (95% CI 1.15-3.12), p value 0.012).

      Conclusion

      The use of blood-based immune profiling may identify early stage lung cancer patients with aggressive disease that could potentially benefit from enhanced disease surveillance or additional treatment. Furthermore, the inclusion of blood-based biomarkers such as the HIC into the anatomic TNM staging system may help improve prognostication and aid in refining stage classification.

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    MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      MA08.03 - Immunotherapy Alone or with Chemotherapy in Advanced NSCLC? Utility of Clinical Factors and Blood-Based Host Immune Profiling (ID 1117)

      16:45 - 17:45  |  Presenting Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Introduction

      Immune checkpoint inhibitors (ICI) have revolutionized cancer care with greater overall survival (OS) in patients with advanced stage non-small cell lung cancer (aNSCLC). However, even for patients with good ECOG performance status (PS) 0-1 and high PD-L1 expression, the overall response rate to single-agent ICI in the treatment naïve population is only 45%. Combination treatments might increase efficacy but add toxicity and higher cost. Better predictors of response to treatment are needed to guide treatment decisions. A prospectively designed, observational study assessed the ability of clinical factors and a clinically validated, blood-based, host immune classifier (HIC) to predict ICI therapy outcomes.

      Methods

      Over 3,500 NSCLC patients at any stage and line of therapy across 33 US sites have been enrolled in the prospective observational study (NCT03289780) that assesses subject sera by the proteomic HIC test (HIC-Hot or HIC-Cold) prior to treatment initiation. An interim analysis was performed after 12-18 months follow-up with the first 2,000 enrolled subjects. The correlation of various factors, including PD-L1 expression, age, histology, PS, smoking history, gender and the HIC result, with OS of subjects receiving ICI alone (ICI, n=86) or in combination with platinum-doublet chemotherapy (ICI+PD, n=98) was assessed.

      Results

      In a real-world clinical setting, OS of subjects with newly diagnosed aNSCLC did not differ significantly between ICI and ICI+PD (median OS (mOS): 9.4 vs. 12.5 months, hazard ratio 0.80 [95% confidence interval: 0.54–1.19], P-value=0.28). Survival analysis for subjects receiving ICI indicated that HIC-Hot, better PS and younger age, but not high PD-L1 expression (either 50% or 90% cutoff) were significantly associated with longer OS according to univariate analyses (see table). When adjusted for covariates in a multi-variate analysis, HIC and age remained significant predictors of OS (p=0.0006 and p=0.005), while PS did not (p=0.40). For patients receiving ICI+PD, only high PD-L1 expression was significantly associated with increased OS. While HIC individually trended towards significance, its inclusion in a multi-variate analysis of gender, smoking history (ever vs. never) and PD-L1 expression (<50% vs. ≥50%) did not improve the fit, indicating that HIC is not independently associated with OS in subjects receiving ICI+PD (p=0.27).

      Association of selected clinical factors and HIC individually with OS of patients receiving ICI or ICI+PD.
      Treatment Type Univariates mOS Hazard Ratio
      (95% confidence interval)
      P-value
      ICI HIC-Cold (N=30)
      vs.
      HIC-Hot (N=56)
      2.2 months
      vs.
      16.3 months
      2.61
      (1.49-4.56)
      0.0008
      ICI PS 2+ (N=24)
      vs.
      PS 0-1 (N=62)
      4.2 months
      vs.
      16.3 months
      2.10
      (1.19-3.73)
      0.011
      ICI Age >65 years (N=48)
      vs.
      Age <65 years (N=38)
      6.7 months
      vs.
      not reached
      1.80
      (1.01-3.20)
      0.046
      ICI PD-L1 <50% (N=12)
      vs.
      PD-L1 ≥50% (N=74)
      10.1 months
      vs.
      9.3 months
      1.32
      (0.64-2.72)
      Not significant
      (0.45)
      ICI PD-L1 <90% (N=57)
      vs.
      PD-L1 ≥90% (N=29)
      8.0 months
      vs.
      9.4 months
      1.43
      (0.77-2.65)
      Not significant
      (0.25)
      ICI+PD PD-L1 <50% (N=59)
      vs.
      PD-L1 ≥50% (N=39)
      8.5 months
      vs.
      not reached
      2.02
      (1.08-3.77)
      0.028
      ICI+PD HIC-Cold (N=33)
      vs.
      HIC-Hot (N=65)
      7.0 months
      vs.
      17.3 months
      1.76
      (0.99-3.11)
      Not significant
      (0.053)
      ICI+PD PS 2+ (N=17)
      vs.
      PS 0-1 (N=81)
      8.5 months
      vs.
      16.0 months
      1.42
      (0.74-2.85)
      Not significant
      (0.33)

      Conclusion

      The HIC test provides clinically meaningful information in addition to currently utilized clinical factors to potentially help guide immunotherapy treatment decisions for patients with newly diagnosed aNSCLC. HIC stratified survival for patients receiving ICI but not ICI+PD, suggesting that patients classified HIC-Cold may benefit from addition of chemotherapy to ICI.

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    OA09 - Mesothelioma from Pathogenesis to Therapy (ID 132)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
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      OA09.05 - Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Physician’s Choice of First-line Platinum Chemotherapy (ID 2717)

      15:30 - 16:30  |  Author(s): Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Introduction

      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor overall survival (OS). Cisplatin is the preferred platinum chemotherapy backbone in national guidelines, and the only FDA-approved agent in combination with pemetrexed, due to observed survival benefits in clinical trials. Unfortunately, most patients with MPM are elderly, and many suffer from comorbidities or poor ECOG performance status (PS) which preclude cisplatin use. Carboplatin is routinely prescribed in practice given its tolerability. This study evaluates real-world survival outcomes of patients with MPM by first-line (1L) cisplatin versus carboplatin combination chemotherapy.

      Methods

      This study included patients with MPM in the Flatiron Health nationwide electronic health record-derived de-identified database who initiated therapy between January 2011 through July 2019 with follow-up through July 2019. OS was summarized by 1L platinum choice via Kaplan-Meier, and was compared in the context of a propensity weighted Cox proportional hazards model. Propensity scores were constructed via logistic regression based on age, asbestos exposure, smoking history, region, race/ethnicity, PD-L1-status, histology, weight, height, neuropathy, previous heart, kidney, and/or audiology condition, ECOG PS, diagnosis year, hemoglobin, neutrophil count, serum creatinine, and practice type (academic/community).

      Results

      This study included 735 patients with MPM, 68% had asbestos exposure, and 59% had epithelioid histology. More patients were treated with carboplatin (n=434) than cisplatin (n=301). Carboplatin treated patients were older (median age 77 versus 70 years) and had worse ECOG PS. Propensity weighting was performed to achieve balance of potential confounders (all SMDs < 0.1). The propensity weighted median OS for patients treated with 1L carboplatin was 12.45 months and cisplatin was 12.88 months, respectively. A propensity score weighted analysis demonstrated a hazard ratio (HR) of cisplatin relative to carboplatin of 1.09 (95% CI: 0.89 - 1.34) which is not statistically significant but places upper and lower bounds on the relative effect of the two therapies on OS.

      wclc figure abstract 1 platinum therapy final (1).jpg

      Conclusion

      To-date, this is the largest real-world cohort of patients with MPM. We found no statistically significant difference in OS by choice of 1L platinum chemotherapy. While more observations are required to determine which of the two treatments is superior for extending survival, we provide bounds in this cohort that cisplatin provides at most an 11% reduction on OS HR and up to a 34% increase on OS HR. This provides added context when choosing between the two agents, given what is known regarding carboplatin’s favorable tolerability and toxicity profile.

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    P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P01.07 - Real World Outcomes of Advanced Non-Small Cell Lung Cancer (NSCLC) With Attention to Carboplatin Area Under the Curve (AUC) = 5 Versus 6 (ID 3016)

      00:00 - 00:00  |  Author(s): Wallace Akerley

      • Abstract
      • Slides

      Introduction

      Carboplatin remains the backbone for combination therapy of patients with many cancers including NSCLC. Dosing ranges from AUC 5-7.5, but the optimal AUC dosing of carboplatin is unclear. Doses of AUC equal to 5 or 6 are commonly administered in NSCLC based on sentinel studies leading to the approval of carboplatin-based regimens. Therefore, we sought to evaluate if there is a difference in efficacy and/or toxicity between the two doses.

      Methods

      We conducted a single-institution retrospective analysis of patients with advanced NSCLC who were treated with carboplatin/pemetrexed from 2011-2016. During this period, an institutional chemotherapy template adjustment from AUC 5 to 6 occurred with change in electronic medical record in 2014. In addition, the advent of commercial PD-1 therapy occurred in October 2015. Patients were divided into two groups based on treatment dose received: Carboplatin AUC 5 and Carboplatin AUC 6. Progression Free Survival (PFS) and Overall Survival (OS) were calculated using the Kaplan-Meier method and Cox proportional hazards [PH] models adjusted for confounding factors. Grade 3/4 events, dose reductions, and likelihood to receive 2nd line or greater immunotherapy or targeted therapy were examined using logistic regression.

      Results

      A total of 133 patients were analyzed, with 59 (44%) treated with Carboplatin AUC 5 and 74 (56%) with Carboplatin AUC 6. Most patients treated with AUC 5 were treated prior to 2014 (83.4%) and the majority of patients treated with AUC 6 were treated in 2014 or later (96%). PFS was similar between both groups (HR = 0.99, CI 0.68-1.43, p = 0.548), but AUC 6 was associated with significantly superior OS (HR = 0.67, CI 0.46-0.99, p=0.045). Treatment with AUC 6 was more likely to lead to dose reduction (OR = 3.6, CI 1.11-10.17, p=0.032) and a trend towards more Grade 3/4 adverse events in the AUC 6 group was observed (OR = 2.43, CI 0.78-7.52, p=0.124). Patients in the AUC 6 group were more likely to receive 2nd line or greater immunotherapy (OR= 3.73, CI 1.35-10.26, p=0.011).

      Conclusion

      Patients treated with Carboplatin AUC 6 had better OS as compared to AUC 5. However, they were also more likely to receive post-platinum immunotherapy, which may explain their survival advantage. In this real-world analysis of Carboplatin AUC 5 vs 6, there appears to be no clinically significant difference in survival and toxicity outcomes between the two dosing strategies in patients with advanced NSCLC.

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    P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P15.02 - Phase Ib Study to Evaluate the Safety and Efficacy of Osimertinib in Combination with Ipilimumab in EGFR Mutated NSCLC (ID 1352)

      00:00 - 00:00  |  Author(s): Wallace Akerley

      • Abstract
      • Slides

      Introduction

      Mutations in epidermal growth factor receptor (EGFR) occur in approximately 15% of patients with metastatic non-small cell lung cancer (mNSCLC). Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) approved as first-line therapy for NSCLC with EGFR TKI sensitizing mutations and is associated with a median progression-free survival (PFS) of 18.9 months. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of mNSCLC lacking driver mutations. However, an attempt at combining osimertinib with ICI durvalumab (anti-PD-1) was associated with excessive pulmonary toxicity in EFGR mutant(m) patients in the TATTON trial. While immunotherapy with PD1/PD-L1 inhibitors has shown to be relatively ineffective as monotherapy in EGFRm NSCLC, other ICIs, either alone or in combination, remain largely unstudied. In a small phase I trial, we evaluated the combination of CTLA-4 inhibitor ipilimumab and first-generation EGFR TKI erlotinib in 11 patients with EGFRm NSCLC; the combination was associated with dose-limiting gastrointestinal toxicity leading to an early closure of the study. However, long term follow-up revealed unexpected prolongation of patient survival with a median PFS of 27.8 months and median overall survival (OS) of 42.3 months. Based on these observations, we designed a phase I trial to evaluate the combination of ipilimumab and osimertinib in EGFRm NSCLC. This trial in progress aims to build upon the possible efficacy seen in the prior study while decreasing the toxicity of combination therapy by replacing erlotinib with osimertinib, an EGFR TKI with a more tolerable safety profile. We hypothesize that ipilimumab in combination with osimertinib will be safe and tolerable in EGFRm NSCLC.

      Methods

      This is a single institution, investigational, open-label, phase IB trial of patients with locally advanced or mNSCLC harboring EGFR TKI sensitizing mutations. Eligible patients should be on a stable dose of first-line osimertinib (40 mg or 80 mg daily) ≥ 28 days without clinical disease progression. The trial will begin with dosing in cohort 1 (osimertinib 40 mg or 80 mg daily plus ipilimumab 3mg/kg every 3 weeks) with a safety run of 6 patients. If </= 1/6 patients experience dose-limiting toxicity (DLT), the trial will be expanded at cohort 1 dose to accrue 14 additional patients. If >/= 2/6 patients experience DLTs, six patients will be accrued to cohort 2 (osimertinib 40 mg or 80 mg daily plus ipilimumab 1mg/kg every three weeks), and this cohort will be expanded to accrue 14 additional patients if </=1/6 patients experienced DLTs. The trial will be closed if >/= 2/6 patients experience DLT in cohort 2. The primary objective of the study is to determine the tolerability (NCI CTCAEv5) of ipilimumab in combination with osimertinib. Key secondary endpoints are overall response rate, PFS, OS, and time to initiation of next-line therapy. The sample size calculation of around 20 patients assumes 18 months for accrual and patients will be followed for 5 years for survival from the end of treatment. Serial blood samples will be obtained to evaluate for potential predictive biomarkers and mechanisms of resistance (NCT04141644). The trial was open to accrual on 17th July 2020.

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    P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P89.05 - Management of Patients with EGFR and ALK-Mutated Advanced Non-Small Cell Lung Cancer Post-TKI Therapy – A Real-World Survival Analysis (ID 2719)

      00:00 - 00:00  |  Author(s): Wallace Akerley

      • Abstract
      • Slides

      Introduction

      Targeted therapy with tyrosine kinase inhibitors (TKIs) is the preferred first-line therapy for advanced non-small cell lung cancer (NSCLC) with actionable mutations. It is unknown which treatment strategy is most efficacious post-TKI progression. Studies have demonstrated minimal activity with single-agent immune checkpoint inhibitors (ICIs) and most combination chemoimmunotherapy (CIO) trials have excluded EGFR and ALK-mutated patients. We performed a real-world analysis to evaluate time to next treatment (TTNT) and overall survival (OS) for patients with EGFR and ALK-mutated NSCLC post-TKI progression.

      Methods

      The study included patients with EGFR and ALK-mutated NSCLC in the Flatiron Health nationwide electronic health record-derived de-identified database who initiated chemotherapy (C), CIO, immunotherapy (IO), or C with VEGF inhibition (CV) post-progression after initial treatment with one or more TKIs between 2011-2018, with follow-up through June 2019. We excluded patients with over 90 days between advanced diagnosis date and next visit to ensure patients were actively involved in care, and required initiation of post-TKI therapy at least 6 months before end of follow-up. TTNT and OS were compared for the four post-TKI therapy categories using Kaplan-Meier curves and multivariable Cox proportional hazards models. Models were adjusted for smoking (history/none), gender, age at post-TKI therapy, year of post-TKI therapy, time on TKI therapy, number of initial TKI therapies, and ECOG PS at time of TKI failure.

      Results

      This study included 480 patients with EGFR and 86 patients with ALK-mutated NSCLC. In adjusted analyses for TTNT, patients with EGFR-mutated tumors who received CIO and CV demonstrated improvements in TTNT with HRs of 0.46 (95% CI 0.30-0.70, p<0.001) and 0.74 (95% CI 0.57-0.96, p=0.02) relative to C, respectively. No statistically significant difference in TTNT between IO and C was detected. Results were similar among ALK-mutated patients, although not statistically significant. In adjusted analyses for TTNT, patients receiving CIO and CV had HRs of 0.40 (95% CI 0.15-1.06, p=0.06) and 0.52 (95% CI 0.25-1.06, p=0.07) relative to C, respectively. In adjusted analyses for OS, the only statistically significant finding was for CIO vs. C (HR 0.55, 95% CI 0.31-0.98, p=0.04) among patients with EGFR-mutated tumors. wclc figure 3 final ttnt.jpg

      Conclusion

      Patients with EGFR and ALK-mutated advanced NSCLC demonstrate a TTNT benefit from combined CIO and C with VEGF inhibition post-TKI progression in the real-world. Ongoing and future clinical trials are needed to provide prospective evidence for the management of combination therapies in EGFR and ALK-mutated NSCLC patients who have exhausted TKI options.

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