Non-small Cell Lung Cancer Population Research Articles

89P Treatment patterns, overall survival (OS), and disease-free survival (DFS) in early stage non-small cell lung cancer (NSCLC) following complete resection

To understand adjuvant therapy use and clinical burden in patients (pts) with completely resected stage IB-IIIA NSCLC, this study described adjuvant therapy treatment pattern, OS, and DFS following surgery in the early-stage NSCLC population.

RUNX3/H3K27me3 Co-Expression Defines a Better Prognosis in Surgically Resected Stage I and Postoperative Chemotherapy-Naive Non-Small-Cell Lung Cancer.

The purpose of this study is to investigate the significance of RUNX3/H3K27me3 co-expression in surgically resected non-small-cell lung cancer (NSCLC) patients. Using tissue microarray (TMA), immunohistochemistry, fluorescent double immunostaining, and western blotting, 208 NSCLC and 5 benign pulmonary patients were studied of their expression of runt-related transcription factor 3 (RUNX3), trimethylated histone H3 at lysine 27 (H3K27me3), enhancer of zeste homolog 2 (EZH2), and Ki-67. Apoptotic index in cancerous tissue was evaluated via TdT-mediated dUTP-biotin nick end labeling (TUNEL). The correlation between clinicopathologic parameters and overall survival was determined by Cox regression and Kaplan–Meier survival estimates and log-rank test. GEPIA and KM plotter were used for validation of some survival analyses. As a result, together with other regular prognostic factors, RUNX3/H3K27me3 co-expression was found to be closely correlated with better prognosis in either pTNM-I or POCT-naive NSCLC patients, which might partially result from a higher cancerous apoptotic index. In conclusion, RUNX3/H3K27me3 co-expression defined some specific NSCLC population with better prognosis and longer OS and could probably be used as a biomarker in the prediction of better postoperative outcomes.

Clinical features affecting efficacy of immune checkpoint inhibitors in pretreated patients with advanced NSCLC: a Danish nationwide real-world study

Background Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population. Methods Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed. Results Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11–1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52–2.33; PS ≥2, HR = 4.15, 95% CI 3.13–5.5), liver metastases (HR = 1.72, 95% CI 1.34–2.22), and bone metastases (HR = 1.27, 95% CI 1.03–1.58) were significant poor prognostic OS factors. Conclusions Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer.

YAP (gene symbol YAP1) as a potential oncoprotein, is positively correlated with the malignancy of various tumors. However, overexpression of YAP alone in multiple normal tissue cells has failed to induce tumor formation and the underlying mechanism is poorly understood. Herein, we show that YAP activation directly induces transcription of its negative regulator, SAV1, to constitute a negative feedback loop, which plays a vital role in maintaining lung epithelial cell homeostasis and was dysregulated in non-small cell lung cancer (NSCLC). Notably, smoking promotes the hypermethylation of the SAV1 promoter region, which disrupts YAP negative feedback by inactivating the Hippo pathway. Besides, exogenous overexpression of SAV1 can act as a traffic protein, activating the Hippo signaling and concurrently inhibiting the WNT pathway to decrease cancer cell growth. Furthermore, using the lung cancer organoids, we found that lentivirus-mediated SAV1 gene transfer combined with methylation inhibitor and YAP-TEAD inhibitor is a potential feasible clinical medication regimen for the lung cancer patient, especially among the smoking population. Thus, this SAV1 mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP regulation and as a potential target of gene therapy for the smoking NSCLC population.

Abstract P05-02: A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC)

Abstract Background: Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently FDA-approved for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received prior systemic therapy. The multi-arm phase 1b CodeBreaK101 master study is designed to evaluate the safety and tolerability of sotorasib in combination with both targeted and non-targeted therapies. Here we report the first safety and interim efficacy of sotorasib and afatinib, a pan-ErbB tyrosine kinase inhibitor, that had displayed synergistic antitumor activity in vitro. Methods: Patients with advanced KRAS p.G12C mutated NSCLC who had disease progression on prior therapies, including KRASG12C inhibitors, were enrolled in this dose exploration/expansion study. Patients were treated with 960 mg sotorasib QD and afatinib (20 mg or 30mg QD). Primary endpoint was safety/tolerability. Secondary endpoint was efficacy, including objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Results: Based on a July 12, 2021 snapshot, 33 pts with NSCLC (median age: 65.0 yrs) were enrolled. Ten pts received 20 mg afatinib/960 mg sotorasib QD (cohort 1) and 23 pts received 30 mg afatinib/960 mg sotorasib QD (cohort 2). Across both cohorts, the median number of prior therapies was 2 (range 0-7; 66.7% ≥ 2 prior lines) and 5 pts (15.2%) received prior sotorasib. The most common treatment-related adverse events (TRAEs) included diarrhea (23 pts [69.7%], 7 pts [21.2%] grade 3), nausea (7 pts [21.2%], all grade ≤ 2), and vomiting (6 pts [18.2%], all grade ≤ 2). Grade ≥ 3 TRAEs occurred in 30% pts within each dose cohort, with diarrhea being the most common. Eight pts (24.2%) discontinued sotorasib and/or afatinib due to an AE, with diarrhea leading to discontinuation in 5 pts. Median treatment duration of sotorasib/afatinib combination was 64.0 days (Q1, 29.0; Q3, 128.0). For cohort 1 (N=10 that includes 4 pts who received prior sotorasib), the ORR was 20.0% and DCR was 70.0% (2-confirmed partial response (PR), 5-stable disease (SD), 1-progressive disease (PD), 2-not available); among the KRASG12C inhibitor-naïve patients, the ORR was 33.3%. For cohort 2 (N=23 that includes 1 pt who received prior sotorasib), the ORR was 34.8% and DCR was 73.9% (8-confirmed PR, 9-SD, 4-PD, 2-not available). Among 5 pts receiving prior sotorasib, 3 had SD, 1 PD, and 1 withdrew from study due to an AE prior to any scan. EGFR co-mutation at baseline was detected in 4 of 24 pts; 2 of 4 pts responded to combination therapy. Conclusions: In this first report of a combination of sotorasib and a pan-ErbB inhibitor, combining sotorasib with afatinib was feasible in a heavily pre-treated KRAS p.G12C mutated NSCLC population that included 15% who progressed on prior sotorasib. The AEs observed are not new or novel to either agent, with diarrhea being the most common. Investigation is ongoing to further explore this combination in an expansion cohort of the CodeBreaK101 master protocol. Citation Format: David Gandara, Kristen Marrone, Ramaswamy Govindan, Ferdinandos Skoulidis, Gregory Durm, Jeffrey Clarke, Richard Frank, John Krauss, Wendy Snyder, Tian Dai, Omar Mather, Paul Cifuentes, Antreas Hindoyan, Abraham Anderson, Timothy Burns. A phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P05-02.

Patients harboring uncommon EGFR exon 19 deletion-insertion mutations respond well to first-generation EGFR inhibitors and osimeritinib upon acquisition of T790M

BackgroundIn the existing next generation sequencing (NGS) system, epidermal growth factor receptor (EGFR) exon 19 deletion-insertion (19delins) is still interpreted into the category of EGFR exon 19 deletion (19del). However, the controversy exists whether the two mutation types have the similar responses and resistant mechanisms to first-generation EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients.MethodsWe successively and retrospectively reviewed the NGS data of 3054 patients diagnosed as advanced NSCLC from November 2017 to September 2020. Finally, 41 patients with EGFR 19delins mutation and 41 patients with EGFR 19del mutation who received first-generation EGFR TKIs as first-line therapy were included in the study.ResultsA total of 17 genotypes were identified in this study, including L747_P753delinsS (10/41), L747_A750delinsP (9/41), L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, the population of EGFR 19delins respond well to first line EGFR TKIs as well as those of EGFR 19del, with little difference in median progression-free survival (mPFS): 10.4 months vs. 13.1 months, p = 0.1076). Interestingly, patients with L747_T751delinsP seem to have a better mPFS than others (18.7 months vs. 13.1 months, p = 0.035). After the disease progression, both EGFR 19delins and EGFR 19del had similar rates of developing EGFR T790M mutation resistance (45.8% vs. 57.8%), and those receiving osimeritinib as second-line treatment obtain the similar survival benefits (mPFS: 12.0 months vs. 12.2 months (p = 0.97).ConclusionsThis retrospective cohort study furnish the evidence that therapeutic responses and survival of untreated NSCLC population with EGFR 19delins mutation are equal to those with common EGFR 19del mutation after administration of EGFR TKIs therapy.

Identification of Stage IIIC/IV EGFR-Mutated Non-Small Cell Lung Cancer Populations Sensitive to Targeted Therapy Based on a PET/CT Radiomics Risk Model

ObjectivesThis project aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients with stage IIIC-IV epidermal growth factor receptor (EGFR)-mutated Non-small cell lung cancer (NSCLC) after first-line first and second generation EGFR- tyrosine kinase inhibitor (TKI) drug therapy and identify the first and second generation EGFR-TKI treatment-sensitive population.MethodsA total of 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line first and second generation EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images, respectively. A four-step feature selection method was performed to enable derivation of stable and effective signature in the training cohort. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared by Kaplan–Meier survival analysis.ResultsOur results shown that higher Rad-scores were significantly associated with worse PFS in the training (p < 0.0001), internal validation (p = 0.0153), and external validation (p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression. The Kaplan–Meier survival curves of the three cohorts present significant differences in PFS between the stratified slow and rapid progression subgroups.ConclusionThe PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line first and second generation EGFR-TKI drug therapy for NSCLC and identify EGFR-mutated NSCLC populations sensitive to targeted therapy, which might help to provide precise treatment options for NSCLC.

Cost-effectiveness analysis of first-line treatment with crizotinib in ROS1-rearranged advanced non-small cell lung cancer (NSCLC) in Canada

IntroductionWhile no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC.MethodsA Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations.ResultsIn the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib.ConclusionsAvailable data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

Integration of EGFR Inhibition With Radiation-Based Multimodality Treatment in Stage III EGFR Mutant NSCLC

<h3>Purpose/Objective(s)</h3> Patients with stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CRT) may not benefit from consolidation immune checkpoint inhibitors, and adjuvant EGFR tyrosine kinase inhibitor (TKI) treatment with osimertinib is now approved for stage IB-IIIA. Whether and how to integrate TKI into the treatment of unresectable or borderline resectable stage III disease is unclear. <h3>Materials/Methods</h3> Patients with stage III (AJCC 7th ed.) EGFR mutant NSCLC amenable to CRT ± surgery were enrolled onto an IRB-approved Phase II trial (clinicaltrials.gov registered) and received induction afatinib 40 mg QD x 2 months, either definitive or neoadjuvant CRT with cisplatin/pemetrexed, surgery if appropriate, and 2 years of adjuvant afatinib provided there was no primary progression during the induction phase. The trial was closed for slow accrual. The primary endpoint of objective response rate after induction TKI and early survival outcomes have been previously reported. This is a secondary analysis of recurrences and updated outcomes. <h3>Results</h3> Seventeen patients completed induction TKI and CRT ± surgery between 2012 and 2020. There were 74% females. Median age was 56 years (range, 34-75 years). Neoadjuvant and definitive median radiation doses were 54 Gy (range, 45-66 Gy) and 66.6 Gy (range, 63-72 Gy). Ten patients with biopsy confirmed N2 (n = 9) or N3 (n = 1) disease underwent surgery which showed a mediastinal sterilization rate of 60%. Adjuvant TKI was initiated in 14 patients including 1 case of off-protocol erlotinib. Three patients aborted TKI, 7 completed 2 years of TKI, 2 remained on TKI at last follow-up while 2 switched to other treatments after recurrence. Notably, of the 7 patients completing 2 years of TKI, 6 recurred after a median interval of only 3 months (range, 1-55 months) from the completion date. In total there were 11 recurrences. The dominant pattern of recurrence was distant with just 1 isolated local failure in a patient treated with definitive CRT. Five of 11 recurrences were CNS-only, all of which occurred after completion of adjuvant TKI at a median interval of 4 months. Four of these patients had intracranial disease control at last follow-up. No grade 3+ radiation treatment related toxic events were observed. With a median follow-up of 43.3 months for patients alive, median progression-free survival (PFS) and overall survival (OS) times were 32 months and not reached, respectively. 3-year PFS and OS rates were 31% (95% CI, 6-56%) and 69% (43-94%), respectively. <h3>Conclusion</h3> This trial highlights the efficacy of aggressive local therapy and the potential promise of TKI treatment for stage III EGFR mutant NSCLC though interpretations are limited by small sample size. One particular risk for patients was CNS-only recurrence suggesting that better CNS directed treatments and CNS surveillance strategies should be studied to increase cure rates in this unique, genotype-defined NSCLC population.

Characterization of the Entire Metastatic Spectrum for Non-Small Cell Lung Cancer in the Immunotherapy Era

Several randomized trials have demonstrated that metastasis-directed therapy for oligometastatic non-small cell lung cancer (NSCLC) improves outcomes. It is not clear what proportion of patients with metastatic disease fall into the oligometastatic category at presentation. Rational design of studies for patients beyond the oligometastatic range will require understanding the numerical and anatomic distributions of metastases in this population. To address this gap in knowledge, we comprehensively characterized the number and distribution of malignant lesions in a modern cohort of advanced NSCLC patients who were staged with FDG-PET/CT and treated with first-line immunotherapy.Advanced NSCLC patients with stage IV disease or recurrent incurable disease who underwent staging PET and were started on first-line immune checkpoint inhibitors targeting the PD-1/PD-L1 axis (with or without chemotherapy) at our institution between 2015 and 2019 were included in this analysis. A commercially available gradient-based segmentation tool was used to contour all visible hypermetabolic extracranial lesions on each staging PET. Counts and anatomic distributions of hypermetabolic lesions were recorded.One hundred twenty-four patients met inclusion criteria. Sixty-six patients (53%) received immunotherapy as monotherapy, and 58 (47%) received immunotherapy with chemotherapy. The median number of hypermetabolic lesions identified for each patient was 6 (range 0 to 53). The distribution of hypermetabolic lesion counts was as follows: 33 (27%) 0-3 lesions, 30 (24%) 4-6 lesions, 25 (20%) 7-10 lesions, 36 (29%) 11 or more lesions. The median number of lung tumors and regional lymph nodes per patient was 4 (range 0 to 33). Excluding parenchymal lung tumors and regional lymph nodes, the median number of distant metastases per patient was 2 (range 0 to 37). The distribution of distant metastasis counts was as follows: 60% 0-3 lesions, 21% 4-6 lesions, 11% 7-10 lesions, 8% 11 or more lesions. Distant metastases were most commonly located in bone (35%), distant lymph nodes (22%), and the liver (10%).To our knowledge, this is the first study to characterize the anatomic disease spectrum in a modern cohort of advanced NSCLC. Most patients had 3 or fewer metastatic lesions, meeting a conservative definition of oligometastatic disease. However, many patients had multifocal thoracic disease. Technological radiotherapy approaches that can efficiently ablate multiple lesions in diverse anatomic locations will enable investigation of aggressive local therapy in a broad NSCLC population.

OA01.03 Immune Checkpoint Inhibitor Dose Adaptation During the COVID-19 Pandemic in Non-Small Cell Lung Cancer– a Single-Center Experience

The COVID-19 pandemic forced all oncologists worldwide to reduce patient contacts to decrease risk of exposure to the virus, and to reallocate resources to provide necessary COVID-19 care. We realized such a reduction of site-visits in our center by adapting the dosing schedules of nivolumab and pembrolizumab monotherapy and consolidation therapy or adjuvant durvalumab for patients with stage III and IV non-small cell lung cancer (NSCLC). Here we report the toxicity of the adapted dose versus the standard dose schedule in a real-world NSCLC population.

P70.01 KRAS G12C Mutations Among NSCLC Patients Present With a High Intrerregional Variation, Indicating a Population Substructure

Molecular profiles of Non-small cell lung cancer (NSCLC) patients differ regarding sex, ethnic background, age, and exposure to tobacco smoke, among others. By extensively characterizing specific NSCLC populations, resource allocation and new molecular target exploration become more feasible. KRAS G12C mutations have become treatable in the last months, warranting a large-scale estimation of mutation prevalence and identifying possible interregional variability in its positivity, as observed in other molecular targets To determine geographical discrepancy with regards to KRAS G12C mutation status, patients with advanced/metastatic NSCLC, previously identified as EGFR (-) and ALK (-), were evaluated. Samples were collected from across the national territory of Colombia, warranting representation of several administrative regions. Mutational status was determined by ddPCR on formalin-fixed paraffin-embedded tissue. A total of 1,002 KRAS G12C evaluations were conducted across 26 of the 32 administrative regions, identifying 80 positive samples, yielding a national prevalence of 8%. (95%CI 6.3-9.7%) By excluding regions without a representative number of individuals, 979 samples across 18 administrative regions were included in the analyses. National positivity reached 7.97% (95%CI 6.27-9.66%). Three administrative regions presented with prevalence’s that differed from the national average. Bolivar (41 samples) had a 4.19% of positivity (95%CI 0-7.2%), similar to Bogota DC (Capital Region) with 259 samples and 5.4% of mutation prevalence (95%CI 2.7-8.2%). On the other hand, Antioquia (338 samples) debuted with 12.7% of KRAS G12C mutated samples (95%CI 9.1-16.3%) with a statistically significant difference among the first two and the last (p-value = 0.00262). Among NSCLC patients, interregional variability regarding KRAS G12C mutation frequencies indicates a distribution substructure, indicating that population composition and ethnicity could lead to varying prevalence in the same nation.

Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC-Real World Efficacy.

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6-20.0) and 6% (95% CI 5.1-7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

How to discriminate non-small cell lung cancer (NSCLC) cases from an Italian administrative database? A retrospective, secondary data use study for evaluating a novel algorithm performance

ObjectivesTo evaluate an algorithm developed for identifying non-small cell lung cancer (NSCLC) candidates among patients with lung cancer with a diagnosis International Classification of Diseases: ninth revision (ICD-9) 162.x code...

Safety and Clinical Activity of Atezolizumab Plus Ipilimumab in Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Results From a Phase 1b Trial

BackgroundThis phase 1b study investigated safety and activity of combined checkpoint inhibition (CPI) with programmed death-ligand 1 (PD-L1) antibody atezolizumab plus cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab in NSCLC. Patients and MethodsEligible patients had previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) or melanoma. A standard 3+3 dose escalation investigated atezolizumab (600-1200 mg IV every 3 weeks) plus ipilimumab starting at 1 mg/kg, administered as a single dose or 4 doses, administered every 3 weeks. The expansion stage included a cohort previously treated with atezolizumab. Patients were monitored for safety and tolerability; response was evaluated every 6 weeks. ResultsTwenty-seven patients were enrolled, 4 with melanoma and 23 with NSCLC; here, we focus on data for the NSCLC population. Three of 23 patients (13.0%) received prior CPI. No dose-limiting toxicities were reported during dose escalation; dose expansion occurred with atezolizumab 1200 mg plus 1 cycle of ipilimumab 1 mg/kg. Most common treatment-emergent adverse events were dyspnea (39%) and cough (35%); treatment-related Grade ≥3 adverse events occurred in 11 patients (48%), most frequently pneumonitis (17%) and amylase or lipase elevation (9% each). Six of 23 NSCLC patients (26%) achieved confirmed responses, 5 of whom (25%) were CPI naive. Median duration of response was 23.0 (95% CI, 3.2-36.9) months overall and 36.9 (95% CI, 2.9-36.9) months in CPI-naive patients. ConclusionPreliminary efficacy of atezolizumab plus ipilimumab was observed in metastatic NSCLC. The combination had manageable toxicity, with a safety profile consistent with those of the individual agents.

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer.

BackgroundThere is no standard procedure available to diagnose and treat with pregnancy-associated non-small cell lung cancer (NSCLC). The present study was to investigate the clinical and molecular features, and the proper intervention timing for this population.MethodsThis is a retrospective, pooled analysis. Cases from Guangdong Lung Cancer Institute and other published cases were collected and reviewed. The overall survival (OS) was analyzed according to the diagnosis timing, the treatment timing and the molecular character. The safety profile during pregnancy was also evaluated.ResultsSeventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00–0.22; HR =0.08, 95% CI: 0.01–0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy.ConclusionsThe pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated during pregnancy and patients treated after delivery.

Exploring the immune-checkpoint inhibitors' efficacy/tolerability in special non-small cell lung cancer (NSCLC) populations: focus on steroids and autoimmune disease.

The advent of immune-checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis, both as monotherapy and in combination strategies, produced a paradigm change of the treatment algorithm for metastatic, non-oncogene addicted, non-small cell lung cancer (NSCLC) patients. Although the great efficacy and the optimal tolerability emerging from clinical studies has been confirmed for the majority of patients treated in the real-word scenario, however the potential activity and safety profile of these agents in uncommon NSCLC populations remains still controversial. Particularly, patients with previously diagnosed autoimmune disease or concomitant steroids treatment at the time of immunotherapy initiation represent two special subgroups of patients not unusual in the real-word practice, to whom the clinical implication of immune-checkpoint inhibitors administration is largely unknown. In this review we provided an updated literature overview, summarizing available evidence and reporting practical suggestions, which may guide physicians in their clinical management of these NSCLC sub-populations.

Association of low RKIP expression with poor prognosis in non-small cell lung cancer.

3068 Background: Raf1 kinase inhibitor protein (RKIP) is able to bind Raf1 to inhibit Ras-Raf-MEK-ERK signaling, a major oncogenic pathway. It has been reported that reduced RKIP expression associates with poor prognosis in many cancers, including gastric adenocarcinoma, gliomas and bladder cancer. However, there are only several studies on its role in non-small cell lung cancer (NSCLC) and the conclusion is still controversial. Hence, we performed this study to assess the prognostic significance of RKIP in our NSCLC population. Methods: Between June 2017 and June 2020, 156 NSCLC patients treated at our hospital were included for the present study. None of the patients had received chemotherapy, radiotherapy or surgery before. Their tumor tissues and surrounding normal lung tissues were collected for immunostain and western blot analysis of RKIP expression and ERK signaling. We collected information about gender, age, histological differentiation, tumor size, TNM stage, and lymph node status. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of various variables in a univariate and multivariate setting. Results: Immunostain and western blot results showed a lower RKIP expression and a higher p-ERK level in cancer tissues compared with the surrounding normal tissues. A reduced RKIP expression with high level of p-ERK was also observed in TNM stages III and IV as compared with I and II. Pearson's chi-squared test confirmed low RKIP expression associated with poorer TNM stage ( p&lt; 0.001) and N-stage ( p&lt; 0.05). No significant correlation was observed between RKIP expression level and gender, age, histological type or tumor size. Kaplan-Meier survival analysis revealed that patients with low RKIP expression had significantly worse overall survival than patients with high RKIP expression ( p= 0.019, log-rank). This conclusion was consistent in the stage I&amp;II patients ( p= 0.011, log-rank) but not in the stage III&amp;IV patients ( p= 0.711, log-rank). Univariate Cox proportional hazards regression analysis indicated Tumor size, TNM stage and RKIP expression significantly affected overall survival of the NSCLC patients. Multivariate Cox proportional hazards regression analysis confirmed RKIP expression remained a significant predictor of survival after correcting for the effects of Tumor size and TNM stage (hazard ratio = 1.730, 95% confidence interval = 1.017 – 2.942, p = 0.043). Conclusions: In this study, low RKIP expression was a poor prognostic indicator in NSCLC as it significantly correlated with poorer TNM stage, N-status, and overall survival. Our findings suggest that by inhibiting Ras-Raf-MEK-ERK pathway RKIP may play an anti-tumor role in NSCLC.

Does prior treatment with anti-PD 1 immune check point inhibitors (ICIs) mitigate infection with herpes and SARS-CoV-2 viruses: Clinical evidence supporting basic hypotheses.

e24045 Background: We present the initial clinical evidence of likely mitigation of viral infections in patients with non-small cell lung cancer (NSCLC) who previously responded to pembrolizumab. This may constitute a late beneficial effect of ICI treatment, and may identify patients with decreased risk for poor outcomes from major viral infections.While prior clinical reports are lacking, there is abundant laboratory evidence that: 1) immune checkpoint inhibition of the PD-1-mediated signaling pathway augments the response of antigen-specific T cells which likely leads to enhanced viral clearance (Dyke, Eur J Clin Immunol 2017); and 2) high levels of PD-1 positive CD-8 T cells have been demonstrated in HIV, Hepatitis B &amp; C infections, akin to the PD-1 positive tumor-reactive tumor infiltrating cells described in host directed mechanisms against cancer (Rao, Int J Inf Dis 2017). Methods: We report the limited pattern and shortened course of three instances of herpetic infection, and one occurrence of SARS-CoV-2, which suggest enhanced mitigation of viral infection in patients previously treated with ICIs. We have seen no other cases of such limited and rapidly clearing herpes in our thoracic oncology practice. Results: Patient characteristics: ages 38 – 78; 1 female; all stage IV extent; 1 with squamous cell carcinoma and the others had adenocarcinoma/sarcomatoid carcinoma NSCLC; PDL-1 tumor proportion scores &gt; 90% except for the 1 patient with squamous cell carcinoma who had a PDL-1 score &lt; 1%. One patient received only pembrolizumab; the others also received cisplatin-based combination chemotherapy. All responded well to anticancer treatment, were off all treatment for &gt; 1 year, and continue to do well 2 – 5 years after diagnosis. Three infections diagnosed as Herpes zoster presented in each case with only one or two vesicles within a single dermatome. Each infection was diagnosed 48 – 72 hours after eruption, was only minimally symptomatic, and cleared within one or two days. The case of documented SARS-CoV-2 occurred in a 60 year old woman with NSCLC and COPD who was off ICI therapy for 3 years with a complete response. She had minimal COVID-19 symptoms which cleared within 3 days. Conclusions: We conclude that: 1) these cases suggest mitigation of viral infections in patients with NSCLC who had prior anticancer benefit with pembrolizumab, and constitute a long term positive effect of ICIs; 2) these results support the pre-clinical findings and hypotheses of enhanced antiviral immune response with ICI agents; and 3) prospective evaluation of large populations of patients with cancer receiving ICIs is warranted to determine if this benefit is reproducible, what proportion of patients benefit, the magnitude of benefit, and to guide in prospective antiviral treatment in the highly vulnerable NSCLC population.

Impact of a regimen-level prior authorization tool on provider adherence to clinical guidelines’ and cost savings in a Medicare advantage population.

1522 Background: In 2019, a large national health system developed a comprehensive approach to improve the quality and cost of cancer care; this solution included a Web-based clinical decision support prior authorization (PA) tool, Novologix (NLX), which approves at the regimen rather than drug level to reduce administrative burden and elevate the quality of care. Evidence-based guidelines in NLX are updated in real-time via a partnership with the National Comprehensive Cancer Network (NCCN). The purpose of this study is to evaluate the NCCNconcordance of PAs submitted via NLX and total cost of care for Medicare Advantage (MA) patients with non-small cell lung cancer (NSCLC) who received NCCNconcordant versus non-concordant therapies. Methods: Eligible patients included MA patients diagnosed with NSCLC; our initial analysis included only the NSCLC subset of patients. NCCN regimen concordance was identified from pharmacy and medical claims and defined as concordant if the entire prescribed treatment regimen matched an NCCNregimen; patients not receiving an NCCN recommended regimen were deemed to be non-concordant. Total cost of care for MA patients with NSCLC were calculated. Results: From April-December 2020, 279 PAs were submitted via NLX and 83% were automatically approved in real-time. PAs not automatically approved were deemed concordant after peer-to-peer consultations that led to NCCN concordance; no PA denials were made. In the first half of 2020, 2,690 MA patients with NSCLC were identified; 2,166 (81%) patients were defined as NCCN concordant. Beginning with and including the first treatment and for 30-days thereafter, total cost of care for concordant patients averaged $19,321 while non-concordant patients averaged $26,405, a statistically significant savings of $7,084 (p &lt; 0.001). Conclusions: Preliminary findings with a MA NSCLC population suggest engaging oncology practices through an enhanced payer-provider collaboration and implementing an automated regimen-level precertification process with real-time NCCNupdates can facilitate lower cost, and more efficient oncology care. Financial savings by encouraging providers to follow NCCN guidelines may lead to a 27% reduction in total cost of care with further proper adjustment on population bias; this may lead to similar findings in other cancer types. Future studies are needed to measure the long-term impact of this program on total cost of care for other care models and cancer types.