Cell Lung Cancer Treatment Research Articles

Novel matrinic acid derivatives bearing 2-anilinothiazole structure for non-small cell lung cancer treatment with improved Hsp90 targeting effect.

Involved in mediating the folding and maturation of more than 300 client proteins, many of which are oncoproteins, Hsp90 has emerged as a promising drug target for cancer therapy. In particular, inhibiting Hsp90 plays a vital role in the treatment of non-small cell lung cancer. Owing to undesirable outcomes of Hsp90 inhibitors in clinical trials, a series of matrinic acid compounds bearing 2-anilinothiazole moiety were designed based on the structural features allocation shared among Hsp90 inhibitors within the ATP-binding pocket. Most of the compounds showed potent anticancer activities validated by MTT assay. Amongthem, the most potent compound C4 (IC50 < 10 μM against four cell lines) was chosen for further mechanism study. Notably, C4 showed a better safety profile than 17AAG with a higher SI value. Thermal shift assay data indicated C4 exhibited a strong binding affinity with Hsp90 (-18.85 ± 0.56°C) comparable to radicicol. Mechanism studies verified that C4 significantly inhibited proliferation and migration activities of A549 cells. Besides, C4 can induce a prolonged G1-phase and cell apoptosis. Western blot analysis results indicated C4 could moderately suppress Hsp90 and upregulate Hsp70 expression. Furthermore, the downregulated trend of the client proteins of Hsp90, such as β-Catenin and Bcl-2, were consistent with the cellular effect of C4, suggesting that C4 could exert anticancer activity via targeting Hsp90. In the xenograft model in vivo, C4 effectively inhibited lung cancer growth without obvious side effects. Collectively, C4 could be a promising therapeutic agent for lung cancer and the novel scaffold provided new insights into the design of Hsp90 inhibitors.

Abstract 5461: H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC

Abstract BACKGROUND: Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge in non-small cell lung cancer (NSCLC) treatment. EGFR activating mutations, such as exon 19 deletions (Del19) and L858R substitution, have been reported in 10-50% of patients with NSCLC. Although these patients respond well to early generations of TKIs, acquired resistance by mechanisms such as T790M mutation compromises their efficacy. Recently, the C797S mutation in combination with Del19 or L858R, and with T790M, has emerged as one of the most common mechanisms underlying on-target resistance to a third generation EGFR TKI, osimertinib. We are developing a fourth-generation EGFR inhibitor, H002, with a wide spectrum and high selectivity to address the growing unmet needs in NSCLC patients harboring C797S mutation. METHODS: H002’s selectivity was assessed by KINOMEscan against more than 400 human kinases. A panel of 44 kinases was further evaluated to enable early identification of off-target effect. In vitro and in vivo anti-tumor efficacy was determined in drug-resistant mutant cell lines, CDX and PDX models. Single mutants (Del or L858R), double mutants (Del/T790M or L858R/T790M) and triple mutants (Del/T790M/C797S or L858R/T790M/C797S) as well as wild type EGFR were assessed. Drug metabolism and pharmacokinetic (DMPK) properties were further assessed. H002’s safety profile was evaluated in rats and beagle dogs, and by hERG potassium channel assay. Acute toxicity, and repeated dose GLP toxicity studies were also conducted in IND-enabling studies. RESULTS: High kinase selectivity and very low off-target effects were demonstrated by kinome-wide profiling and safety screening. H002 was highly active against all forementioned single, double or triple EGFR mutants (IC50 &amp;lt; 5 nM), and highly selective against wild type EGFR. H002 also exhibited potent anti-tumor effects in a dose-dependent manner in various CDX and PDX models. Excellent PK properties were observed in rats and beagle dogs with bioavailability over 70%. H002 was shown to cross the blood-brain barrier post i.g. administration in rats. No adverse effects of respiratory, cardiovascular and central nervous system were observed in safety studies. Repeated-dose toxicity studies only showed EGFR-related adverse reactions, such as gastrointestinal and liver toxicity, with high safety margin over 10-folds. CONCLUSION: H002 has been demonstrated as a promising next generation EGFR inhibitor, with high selectivity, a wide spectrum and potent anti-tumor activity against various EGFR activating mutations, favorable DMPK and safety profiles. It will be further developed as a fourth-generation EGFR inhibitor to overcome drug resistance in NSCLC. Citation Format: Wei Huang, Lin Zhu, Xiaoe Yan, Xin Huang, Jia Hao, Shan Li, Xiangyu Li, Zhiming Chen, Yunchuan Jia, Haibo Li, Jianming Zhang, Xianming Deng, Caihong Yun. H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5461.

BRAF mutation classes and co-occurring mutations in NSCLC.

9083 Background: Targeted therapy against unique molecular drivers has revolutionized non-small cell lung cancer (NSCLC) treatment. BRAF mutations, present in 2%-5%, have emerged as therapeutic targets, and can be divided into three classes: kinase-activating monomers (class I, V600) or dimers (class II), or kinase-inactivating dimers (class III). Most studies have focused on BRAF V600E NSCLC. Limited clinical data suggest classes II and III may not respond well to chemo- or targeted therapy and tend to have a poorer prognosis. Little is known about co-occurring mutations. This study examines BRAF classes and co-occurring mutations in NSCLC. Methods: Between October 2018 and October 2021, data from 3009 NSCLC Oncotype MAP test results were analyzed. This test utilizes tumor DNA to identify single nucleotide variants, indels, copy number alterations, and select structural variants/fusions by next generation sequencing with a 257 gene panel. Tumor mutational burden and microsatellite instability are also assessed. Pathogenic/likely pathogenic mutations were identified, BRAF mutations assigned to 3 different classes based on current understanding, and associations of other mutated genes with BRAF class examined. Results: Among samples, 133 (4.4%) had BRAF mutations: 30 class I (1%); 42 class II (1.4%); 36 class III (1.2%); and 25 unclassified (0.8%) (Table). Two genes showed associations with BRAF class: STK11 was significantly overrepresented in class II and III, and SETD2 in class I (p&lt;0.05 for both). BRAF class II mutations were further divided into subclasses, IIa (n= 5) and IIb (n= 35); two could not be assigned. The lack of a positive association between KRAS (and NF1) and BRAF class III was unexpected since class III is RAS-dependent while class I and II are RAS-independent. The overrepresentation of STK11 in classes II (with 11/12 events in IIb) and III might explain, at least in part, the poor prognosis relative to class I. By contrast, SETD2 is overrepresented in class I, which might help explain its better response to immunotherapy. Conclusions: For the first time we report the incidence of BRAF mutation classes and associated co-mutations in NSCLC. These associations may help to explain therapeutic outcomes. The impact of coexisting STK11 mutations in class II subclasses warrants further investigation.[Table: see text]

A real-world evidence of immunotherapy adoption in non-small cell lung cancer (NSCLC) treatment and its transition from platinum-refractory to the first line of therapy.

e18714 Background: over the past few years, multiple clinical trials have shown that immune checkpoint inhibitors (ICI) are active in NSCLC treatment. In 2015, survival improvement was demonstrated with second line immunotherapy. More recently, benefit was proven in the first line setting, both with ICI alone or in combination with chemotherapy. How fast the medical community has incorporated these advances into its clinical practice needs to be evaluated, as well as ICI efficacy in a real-world setting. Methods: retrospective analysis of the Oncoclinicas Data Lake was carried out to extract and curate information on the use of ICI in NSCLC patients from 2015 onwards, as well as survival outcomes from start of treatment to death or last follow-up. Patients with actionable driver alterations were excluded from this analysis. Results: 767 patients were identified. Median age was 72 years, 54% were male. The number of patients treated with ICI increased dramatically in the period, from 13 in 2015 to 243 in 2020. Most patients (86%) received ICI in the second line or beyond in 2015, while in 2019 and 2020 the preference was immunotherapy in the first-line setting (60%). The transition from platinum-refractory to the first line was observed for both ICI single agents and ICI combinations. As of 2021, 75% of ICI + chemotherapy treatments take place in the first line setting and 54% of ICI monotherapy treatments are given in first line setting. Overall, median overall survival was 15.7 months for first line setting use of ICI (CI 95% 12.2-19.6) and 11.6 months for second line and beyond (CI 95% 8.9-14.2). Survival rates at 12 and 24 months for first line ICI use were 56% and 48.5% and for second line and beyond 35% and 25.5%, respectively. Conclusions: ICI was promptly incorporated into the treatment of NSCLC and its use has shifted from platinum-refractory to treatment-naïve setting, mostly with combination regimens. Our cohort shows real-world overall survival rates comparable with published literature, despite a more elderly population than clinical trials.

Blood monocyte and lymphocyte counts patient outcomes in non-small cell lung cancer after immune checkpoint inhibitor therapy: Real-world data of 12,416 patients.

e21023 Background: Immune checkpoint inhibitors (ICPi) are now commonly used in non-small cell lung cancer (NSCLC) treatment. Beyond PD-L1 status, no clinically validated predictive biomarkers guide therapeutic decision making regarding their use. Blood monocyte, lymphocyte counts, or their ratio might inform clinical utility of these expensive, potentially toxic agents. Methods: Adults with advanced/metastatic NSCLC receiving any ICPi after diagnosis from January 2015 to November 2020 were included. Treatment outcomes were followed until 31 May 2021. Data were sourced from structured fields of electronic health records from The US Oncology Network and non-Network practices. The primary end point was overall survival (OS), and time to treatment discontinuation (TTD) was secondary. Baseline absolute monocyte count (AMC), absolute lymphocyte count (ALC), and monocyte-to-lymphocyte ratio (MLR) were subdivided into quintiles (Q) with Q1 lowest and Q5 highest. Patient (pt) and treatment characteristics were described. Time-to-event outcomes were assessed by Kaplan-Meier methods. Univariate and multivariate Cox regression analyses described associations among baseline biomarkers, OS, and TTD. Results: For 12,416 pts with NSCLC, median OS and TTD were 13.6 months (mos) and 4.5 mos, respectively. For AMC, patients in Q2 and Q3 had the longest median OS of 15.9 mos. Median TTD by AMC was longest for Q1 and Q2 (5.1 mos), declining sequentially to 3.3 mos for Q5. For ALC, Q5 had longest median OS of 19.2 mos, as well as longest median TTD of 5.8 mos. For MLR, Q1 had the longest median OS and TTD of 22.3 and 6.2 mos., respectively. In univariate Cox regression, AMC, ALC, and MLR each associated with OS and TTD (p &lt; 0.0001). Pts in AMC Q5, compared with AMC Q1, had an OS hazard ratio (HR) of 1.48 (95% CI 1.38-1.60). For ALC, each successive increasing quintile, compared to ALC Q1, demonstrated a lower risk of death (p &lt; 0.0001). Pts in MLR Q5, compared with MLR Q1, had an OS HR of 2.21 (95% CI 2.04-2.39). Conclusions: This data set is the largest to date to examine interactions among baseline immune cell counts, ICPi use, and pt outcome in NSCLC. These data inform efforts to describe immune-based prognostic risk groups among NSCLC pts receiving immunotherapy.[Table: see text]

Comparison of surgical outcomes and prognosis between wedge resection and simple Segmentectomy for GGO diameter between 2\u2009cm and 3\u2009cm in non-small cell lung cancer: a multicenter and propensity score matching analysis

BackgroundAs segmentectomy had become commonly used for Non-Small Cell Lung Cancer (NSCLC) treatment, which had the advantages of radical operation, however, it remains controversial owing to procedural complexity and risk of increased complications compared with wedge resection. We evaluated operative and postoperative outcomes of simple segmentectomy compared to wedge resection in ground-glass opacity (GGO) diameter between 2 cm and 3 cm NSCLC.MethodsWe retrospectively reviewed 1600 clinical GGO diameter between 2 cm and 3 cm NSCLC patients who received simple segmentectomy and wedge resection between Jan 2011 and Jan 2015. Participants were matched 1:1 on their propensity score for two groups. Clinic-pathologic, operative, and postoperative results of two groups were compared.ResultsAfter using propensity score methods to create a matched cohort of participants with simple segmentectomy group similar to that wedge resection, there were no significant differences detected in tumor size, margin distance, histology, age, sex, preoperative comorbidities and preoperative pulmonary function. Overall complications in simple segmentectomy group were more than wedge resection group (21% vs 3%, p = 0.03). Median operative time (110.6 vs. 71.2 min; p = 0.01) and prolonged air leakage (12% vs. 3%; p = 0.02) was significantly longer in the simple segmentectomy group. There was no difference in recurrence free survival (RFS) and overall survival (OS) of 5-years between simple segmentectomy group and wedge resection group. Postoperative pulmonary function in simple segmentectomy group recovered more slowly than wedge resection group.ConclusionWedge resection may have comparable efficacy as simple segmentectomy for GGO diameter between 2 cm and 3 cm NSCLC, but lead to less complications, less surgical procedure and faster recovery of pulmonary function.

Implementation of an EHR-embedded decision support tool in community oncology practices.

274 Background: Clinical decision support (CDS) tools facilitate value based cancer care delivery and can enable measurement of guideline concordance, but can be challenging to implement. Flatiron Assist is an EHR-embedded and customizable CDS tool which facilitates selection and documentation of NCCN Guideline concordant and NCCN Preferred treatment regimens. We assessed performance metrics after the first year of use of this tool at eleven sites of care. Methods: We reviewed all non-small cell lung cancer (NSCLC) treatment orders as entered at 11 community practice sites of care in the northeast and southeast US from launch May 15, 2020, through May 23, 2021. Use of the CDS tool is not mandatory at these practices, and is deployed via prescriber choice. The tool documents and reports various quality metrics. We describe monthly prevalence of the CDS tool use, proportion of orders documented as guideline concordant, and prescriber-reported reasons for non-concordance. Results: All 954 NSCLC treatment regimen orders by the 89 prescribers who had the option to use the CDS tool were analyzed during the 1 year observation period. 658 regimens (69%) were ordered via the tool. Table describes prescriber users and non-users over time. The tool was deployed for 60% of NSCLC orders at 2 months, 69% at 6 months and 78% at 1 year post launch. Over the observed time period, 92% of treatment regimens ordered via the tool were documented as guideline concordant (94% at 2 months, 96% at 6 months and 85% at 1 year post-launch). Prescriber-reported reasons for ordering non-concordant regimens were “physician choice” (59%), “patient status” (12%), “newly published evidence” (10%), “second opinion from outside institution” (9%), “financial burden on patient/insurance doesn’t cover” (5%), “patient choice” (2%) and “other (allergy, disease progression, atypical disease)” (3%). Conclusions: At the study sites, this EHR-embedded CDS tool was rapidly adopted by most prescribers (approximately two thirds within 6 months of launch), and used for the majority of NSCLC candidate order sets during the 1 year observation period. NCCN concordance among users was empirically high overall and declined slightly over time, perhaps due to increased usage and/or greater comfort with the optional tool with ongoing use. Prescribers most commonly self-attributed the selection of non-concordant therapy to “physician choice” as opposed to factors such as financial hardship or patient choice. Further research will characterize workflow time, predictors of non-use and non-concordant orders, and evaluate whether Flatiron Assist improves clinical outcomes.[Table: see text]

Innovative immunotherapy targeting at PD-1/PD-L1 signaling pathway: mechanism, efficacy and safety analysis of monotherapy and combination therapies in non-small cell lung cancer (NSCLC) treatment

Lung cancer remains a leading cause of cancer-related mortality worldwide with a poor prognosis. Conventional therapies are most commonly used in all kinds of treatment because of their relatively high efficacy in killing tumor cells at first. However, as treatment time increases, this efficacy would gradually decrease, along with unavoidable and growing resistance and multiple and serious side effects. At this point, immunotherapy, including anti-PD-1 and anti-PD-L1 antibodies, renders an innovative and more effective way to take advantage of our own immune response to kill cancer cells. It is confirmed to have greater efficacy and safety of immunotherapy over conventional therapies in various cancer treatments, including non-small cell cancer. Combining conventional therapies can also lead to synergistic effects in controlling and killing cancer cells. The purpose of this summary is to verify the efficacy and safety of immune checkpoint inhibitor monotherapy and the synergistic effects of combination therapy with chemotherapy and radiotherapy. This review will introduce the mechanism, efficacy, and safety of immune checkpoint inhibitor monotherapy and combination therapies with chemotherapy and radiotherapy via a summary and interpretation of related preclinical and clinical trials.

Real world efficacy of immunotherapy in nonsmall cell lung cancer

The evolution of drug therapy in solid tumors primarily leads to the increase in cancer specific survival, but inevitably raises financial burden. So far, none of the countries can venture total reimbursement with all necessary contemporary drugs for all patients. Doubling of expenses for cancer drug therapy in Russia in 2019 allowed oncologists using the most expensive treatments in more than 70 % of patients.Purpose: To evaluate efficacy of various treatment types of non‑small cell lung cancer in real clinical setting.Material and methods. We included patients with histologically verified metastatic non‑small cell lung cancer without activating mutations treated with first or second line therapy in 2018 – 2019. In total 287 patients were included: 230 — for the first line efficacy analysis, 100 — for the second. Time to disease progression, overall survival and objective response rate were evaluated.Results. The use of checkpoint inhibitors in accordance with all actual recommendations (first line pembrolizumab monotherapy in PD-L1 &gt; 50 %, chemoimmunotherapy in first line or monotherapy in the second line irrespectively to PD-L1 status) decreased one‑year mortality from 61 % in 2018 to 33 % in 2019, but significantly increased financial cost (p &lt; 0.000). Moreover, checkpoint inhibitors in combination with chemotherapy irrespectively of PD-L1 expression increased response rate (from 10 % and 21 % for monotherapy and platinum doublet, respectively, to 33,2 % for chemoimmunotherapy). PD‑1 inhibitors as monotherapy increased median time to disease progression (4,1 and 6,2 months for monotherapy with chemotherapy and platinum doublet, respectively, to 6,5 months and not achieved for chemoimmunotherapy and monotherapy with checkpoint inhibitors).Conclusion. More than doubling of financial costs spent for non‑small cell lung cancer treatment allowed access to contemporary treatment for all patients. Such unprecedented measures significantly improved efficacy, including double decrease of one‑year mortality. Nevertheless, rational design of regional clinical guidelines interpretation is of great importance in accurate and effective use of the healthcare budget.

Abstract 2412: Pemetrexed induces calreticulin expression most robustly in parallel with apoptosis among chemotherapeutic agents used in non-small cell lung cancer (NSCLC) treatment

Abstract Recent clinical trials have shown that the addition of immune checkpoint inhibitors (ICIs)–such as antibodies to PD-1 or to PD-L1–to platinum-based combination chemotherapy resulted in a significant extension of overall survival in patients with advanced non-small cell lung cancer (NSCLC). This synergistic effect is possibly attributable in part to the phenomenon of immunogenic cell death (ICD), which is characterized by the release of danger-associated molecular patterns (DAMPs) from dying tumor cells. Calreticulin (CRT) is one of the most potent DAMPs and its cell surface translocation (ecto-CRT) serves as an “eat me” signal to antigen-presenting cells (APCs), which plays a pivotal role in activating anti-tumor immunity. However, there is limited information which chemotherapeutic agents used in the treatment of NSCLC can induce the expression of ecto-CRT most robustly on the surface of dying lung cancer cells. In current study, to identify the most effective inducer of ecto-CRT, using flow cytometry, we compared the expression levels of ecto-CRT on different 3 NSCLC cell lines treated with 9 chemotherapeutic agents including oxaliplatin (as positive control), cisplatin, carboplatin, pemetrexed, gemcitabine, 5-fluorouracil, docetaxel, paclitaxel and vinorelbine under each value of IC50 (0.0023 μM~25.2 μM) determined by MTS assay after 72 hours exposure to each chemotherapeutic agent. We found that pemetrexed induced the highest expression of ecto-CRT compared with other chemotherapeutic agents in all NSCLC cell lines examined. There are significant positive correlations between positive rates of ecto-CRT and annexin V, commonly used to detect apoptotic cells, in all NSCLC cell lines (r=0.79~0.95, p=0.0001~0.0088). In addition, pemetrexed-inducible expression of ecto-CRT on A549 cells was remarkably reduced when pan-caspase inhibitor z-VAD-fmk was added, illustrating its dependency on the caspase activity associated with apoptosis. Furthermore, using a syngeneic mouse tumor model that is moderately sensitive to anti-PD-1 therapy, we confirmed that combination treatment with pemetrexed enhanced the in vivo antitumor effect compared with anti-PD-1 or pemetrexed monotherapy. Notably, in clinical settings, we found that the plasma concentrations of soluble CRT collected from 3 NSCLC patients treated with pemetrexed alone were increased during the first cycle of treatment in all patents examined. Collectively, our findings showed that pemetrexed is the most effective inducer of ecto-CRT in NSCLC cell lines among numerous chemotherapeutic agents, suggesting that the combinational use of pemetrexed on ICIs therapy might exert synergistic antitumor immunity by triggering abundant expression of ecto-CRT in parallel to apoptosis induction in local tumor tissues of patients with advanced NSCLC. Citation Format: Rie Furukawa, Hiroyuki Inoue, Hirono Tsutsumi, Ando Nobuhisa, Yuki Ikematsu, Keiichi Oota, Eiji Iwama, Yasuto Yoneshima, Kentaro Tanaka, Yoichi Nakanishi, Isamu Okamoto. Pemetrexed induces calreticulin expression most robustly in parallel with apoptosis among chemotherapeutic agents used in non-small cell lung cancer (NSCLC) treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2412.

Survival impact of multidisciplinary thoracic oncology care in a regional healthcare system.

2004 Background: Much-advocated, the value and impact of multidisciplinary care and planning (MDC) needs greater evidence. We compared non-small cell lung cancer (NSCLC) patient characteristics, treatment patterns and survival in a large community healthcare system spanning 3 US states with some of the highest lung cancer incidence and mortality rates. Methods: We identified MDC patients in the Tumor Registry NSCLC data from 2011-2017. Because the MDC program was located in metropolitan Memphis, we separated non-MDC patients by location of care resulting in 3 cohorts: MDC, non-MDC metropolitan care and non-MDC regional care. Using National Comprehensive Cancer Network guidelines, we categorized treatment by stage as ‘preferred’, ‘appropriate’ (allowable under certain circumstances). We compared demographic and clinical characteristics across cohorts using chi-squared tests and compared survival using Cox regression with Bonferroni adjustment. We repeated survival analysis with propensity matched cohorts. Results: Of 6259 patients, 14% received MDC, 56% metro care and 30% regional care; MDC had the highest rates of African Americans (34% v 28% v 22%), stage I-IIIB (63 v 40 v 50), urban residents (81 v 78 v 20), stage-preferred treatment rates (66 v 57 v 48), stage-appropriate treatment rates (78 v 70 v 63;), and lowest non-treatment rates (6 v 21 v 28). All p&lt;0.001. Compared to MDC, the hazard for death was higher in metro (1.4, 95% confidence interval 1.3-1.6) and regional (1.7, 1.5-1.9); hazards were higher in regional care v metro (1.2, 1.1-1.3); all p&lt;0.001 after adjustment. Results were similar for MDC comparisons after propensity matching with and without adjusting for preferred treatment. No differences in regional and metro cohorts. Conclusions: In this large community-based healthcare system, receipt of MDC for NSCLC was associated with significantly higher rates of guideline-concordant care and survival, providing strong evidence for recommending rigorous implementation of MDC. [Table: see text]

Predictors of and longitudinal assessment of health utility scores in patients with small cell lung cancer using real-world data.

e19306 Background: Recent advances in small cell lung cancer (SCLC) treatments necessitate a better understanding of health utility scores (HUS) of patients treated under standard regimens to facilitate robust pharmaco-economic assessments. HUS collected in clinical trials may be inherently skewed due to restrictive eligibility criteria, highlighting the need for real-world data. Methods: In this cohort observational study, HUS were evaluated in SCLC patients through EQ-5D surveys. We also evaluated patient reported (pr) ECOG performance status (PS)), treatment toxicities (modified patient reported (mpr) CTCAE) and symptoms (Edmonton Symptom Assessment System, ESAS). Clinical data were abstracted from electronic medical records. The impact of these variables on HUS was explored using regression. Results: Of 282 clinical encounters (12% newly diagnosed; 37% stable on treatment; 22% progressing; 29% stable off therapy/other) in 111 SCLC patients (58% male; 64% extensive stage), 29% had pr-ECOG PS ≥ 2 at the first encounter. Mean HUS in treatment naïve patients with limited disease was 0.848 (SEM = 0.028); for extensive stage, mean HUS = 0.715 (SEM = 0.046). Extensive stage (β = -0.12; p = 0.03), bone metastases (β = -0.10; p = 0.04), females (β = -0.07; p = 0.006), and pr-ECOG PS ≥ 2 (β = -0.21; p &lt; 0.001) were each associated with decreased HUS in multivariable analyses. When excluding pr-ECOG PS from the model (highly correlated with HUS), progressive disease (β = -0.07; p = 0.02) was also associated with decreased HUS. Longitudinally, in patients with disease stability, HUS were unchanged in limited disease, but slowly decreased for extensive stage over time. HUS were inversely associated with increasing severity of most measured toxicities (mpr-CTCAE rho values ranged from -0.34 to -0.47) and symptoms (rho values -0.27 to -0.54). Conclusions: HUS in SCLC is impacted by the presence of extensive stage and bone metastases, in addition to cancer symptoms and treatment toxicities. The values reported from this real-world sample provides a basis in which to compare with new SCLC therapies in health technology assessments. [Table: see text]

Differences in real-world (RW) non-small cell lung cancer (NSCLC) treatment patterns among people living with HIV/AIDS (PLWHA) compared to those without HIV/AIDS (PWoHA).

7070 Background: NSCLC is the most common non-AIDS-defining cancer in PLWHA with an estimated prevalence 2-5 times that of PWoHA. Guidelines now support treatment of NSCLC among PLWHA to follow those for PWoHA. However, PLWHA have been often excluded from cancer clinical trials that test novel agents including immunotherapy (IO). This study aimed to assess differences in systemic therapy patterns for advanced NSCLC among PLWHA and PWoHA in the RW. Methods: Adult patients with ≥2 claims for NSCLC between 1/1/13-12/31/18 (earliest claim = index date), ≥3 months data pre/post index date, and no evidence of clinical trial participation, pregnancy or other malignancy prior to index date were identified from Symphony Health longitudinal prescription and medical claims. Patient characteristics and treatment patterns were summarized by descriptive statistics and comparisons by HIV status made on univariate analyses. Times to discontinuation were estimated by Kaplan-Meier method and compared by log-rank tests. Results: There were 60,278 NSCLC PWoHA who received systemic therapy. Of 1,344 PLWHA with NSCLC, 239 (18%) received systemic therapy. PLWHA differed significantly from PWoHA: median age at diagnosis (58 v 68 years), male preponderance (66% v 47%), payer mix (Medicare 26% v 42%; Medicaid 21% v 7%), Charlson Comorbidity Score (median 6 v 1), depression (13% v 5%) and liver disease (8% v 2%), respectively (all P&lt; 0.01). Differences in common systemic therapies among PLWHA v PWoHA include use of first line (1L) carboplatin + paclitaxel (28% v 19%; P&lt; 0.01), 1L erlotinib (6% v 11%, P= 0.02) and 2L gemcitabine (10% v 4%, P&lt; 0.01). IOs were used in 1L among 43 (18%) and 7,149 (12%) of PLWHA v PWoHA, respectively ( P&lt; 0.01). RW surrogates for PFS: median duration of 1L therapy was shorter among PLWHA (1.8 v 2.3 months, P&lt; 0.01); median times from 1L initiation to 2L were similar (5.4 v 4.9 months; P= 0.48). Similar proportion of patients continued onto 2L (32% and 30%) and 3L (10% and 9%) among PLWHA and PWoHA, respectively (all P&gt; 0.05). Total time from diagnosis to last follow-up (RW surrogate for overall survival) was 12.8 v 15.5 months in PLWHA and PWoHA ( P= 0 .07). Conclusions: PLWHA are younger at diagnosis of NSCLC and have higher comorbidity. Important differences in regimen selection and IO utilization exist across PLWHA and PWoHA. PLWHA have shorter 1L than PWoHA. Given higher risk and younger age at diagnosis, additional research is needed to establish screening and treatment guidelines for NSCLC in PLWHA.

Abstract B79: PET CT might be better than CT scan when evaluating immune checkpoint inhibitor response

Abstract Background: Immune checkpoint inhibitors (ICIs) are changing the paradigm of non-small cell lung cancer (NSCLC) treatment. However, in assessing tumor response, hyperprogression or pseudoprogression can cause difficulties in accurately identifying therapeutic response. We analyzed the usefulness of positron emission tomography-computed tomography (PET-CT) in treatment response assessment of ICI. Methods: We retrospectively analyzed 12 advanced NSCLC patients who used ICI (pembrolizumab) as the first-line treatment. Chest CT was taken at two cycle intervals, and PET-CT was taken before ICI treatment and after the 2nd cycle. Comparison of response evaluation of tumor size was analyzed using chest CT, and the standardized uptake value (SUV) max was compared using PET-CT. Results: Among 13 patients, eleven cases were male and one case was female. The mean age was 66.2 ± 6.7 years. Seven patients were treated with pembrolizumab monotherapy, and five patients were treated with pembrolizumab plus cytotoxic chemotherapy. 8 of the 12 patients received more than four cycles of treatment. The mean tumor size before treatment was 7.3 ± 3.3 cm and after treatment was 6.2 ± 3.7 cm, which was not statistically significant (P-value = 0.099). The mean SUV maximum value before treatment was 10.1 ± 3.3 and after treatment was 5.8 ± 2.6 cm, which was statistically significant (P-value = 0.004). SUV max showed a more pronounced trend than tumor size. Two of the five patients who showed stable disease in the first response assessment showed a partial response in the second response assessment. The mean SUV max value was decreased at 58.2% in these two patients. Conclusion: In evaluating the response of ICIs, PET-CT showed more predictive change compared to CT scan. In predicting the therapeutic response of an ICIs, measuring the metabolic activity of a tumor may be more important than comparing tumor size. PET CT may be a useful tool in evaluating the treatment response of ICI. Citation Format: JuWhan Choi, Hyun Seock Shin, Jee Youn Oh, Young Seok Lee, Kyung Hoon Min, Jae Jeong Shim, Sung Yong Lee. PET CT might be better than CT scan when evaluating immune checkpoint inhibitor response [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B79.

Rare GCC2-ALK fusion G13:A20 detected by next generation sequencing in non-small cell lung cancer patients and treatment response

Two patients with rare GCC2-ALK fusion G13:A20 which were found in Chinese population by next generation sequencing (NGS) developed resistant to crizotinib with a prolonged progression-free survival (PFS). Both patients showed unfavorable response to subsequent second or third generation tyrosine kinase inhibitors (TKIs) treatment with shorten PFS. In conclusion, non-small cell lung cancer (NSCLC) patients with rare GCC2-ALK fusion G13:A20 may be optimal candidates for crizotinib as front-line therapy and may have a high possibility to exhibit unsatisfactory response to subsequent second or third generation TKIs target therapy after acquiring resistance to crizotinib.

Human serum albumin nanoparticulate system with encapsulation of gefitinib for enhanced anti-tumor effects in non-small cell lung cancer

Gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has showed remarkable activity in non-small cell lung cancer patients with tumors carrying sensitive EGFR mutation. However, Iressa® tablets present problems, including insolubility, large absorption disparity, low oral bioavailability, gastrointestinal side effects and drug resistance, which limit their application. In present study, we developed gefitinib-loaded human serum albumin nanoparticles (GFNPs) by Nab™ technology for intravenous administration. By utilizing oleic acid as a co-emulsifier, which could increase the binding of gefitinib to human serum albumin, GFNPs were successfully fabricated with an amorphous state in GFNPs and its release from the nanoparticles conformed to the Ritger-Peppas process. The albumin nanoparticles could rapidly disassociate in the bloodstream and were effectively uptaken by the NCI–H358 cells via the mechanisms of secreted protein acidic and rich in cysteine (SPARC)-mediated transport, resulting in higher growth inhibition and apoptosis induction compared to free gefitinib. In tumor-bearing mice, the albumin nanoparticles demonstrated an increased, lasting tumor distribution. Compared with the commercial Iressa, GFNPs at only 10% of Iressa dose showed superior antitumor efficacy, with little effect on body weight of mice, suggesting that GFNPs might serve as a clinical candidate for a safe and effective anti-non-small cell lung cancer treatment.

The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations.

e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P&lt; 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( &lt; 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.

Radiologic imaging utilization of small cell lung cancer staging and treatment.

e20079 Background: Over the past several decades, first line therapy recommendations for small cell lung cancer (SCLC) have remained relatively unchanged. Additionally, the National Comprehensive Cancer Network (NCCN) guidelines regarding initial evaluation, staging, response assessment, and surveillance of SCLC have also remained relatively static. To evaluate radiologic imaging utilization for SCLC, we reviewed patients imaging data and assessed their association with staging, metastatic sites at presentation, overall survival, and other clinical factors. Methods: Retrospective analysis of patients with a diagnosis of SCLC that received treatment and follow up from 2003 through 2018 was completed. Cross-sectional radiology imaging data including computed tomography of the chest abdomen and pelvis (CT CAP), magnetic resonance imaging (MRI), and positron-emission tomography (PET) was obtained from the picture archiving and communication system (PACS) and clinical data including age, sex, race, smoking history, extensive/limited stage, and metastatic sites at presentation was obtained from the electronic medical record. Results: The average age at diagnosis for all SCLC patients (n = 518) from 2003 to 2018 was 66 with a male to female ratio of 0.89. The mean overall survival of all SCLC patients was 410.2 days with extensive (n = 371) stage = 312.5 days and limited (n = 147) stage = 718.8 days. We found a significantly increased number of patients less than age 66 presented with brain metastasis compared to those greater than age 66 ( P&lt; 0.01). The absolute total number of CT CAP and PET studies was significantly increased in limited stage patients compared to extensive stage ( P&lt; 0.001). However, when accounting for mean overall survival, extensive stage patients received a significantly increased number of CT Brain ( P&lt; 0.05), PET ( P&lt; 0.01), CT CAP, and MRI Brain ( P&lt; 0.001) studies compared to limited stage per year. Conclusions: Overall radiology imaging utilization is significantly different between limited and extensive stage SCLC patients over the past 15 years.

Enhancing sensitivity to platinum-based therapy by suppressing the novel prognostic factor CDCA3 in non- small cell lung cancer

Introduction: Lung cancer is the leading cause of cancer-related mortality worldwide a survival rate of 14%. While platinum-based chemotherapy remains the most effective non-small cell lung cancer (NSCLC) treatment, less than 35% of patients have an objective partial response. Novel approaches are needed to best identify the patients who will derive the most benefit and prevent unnecessary treatment and toxicity. Herein we describe cell division cycle associated protein-3 (CDCA3) as a novel prognostic factor to delay or prevent platinum resistance in NSCLC.

Therapy for elderly patients with advanced non-small cell lung cancer

Chemotherapy is recommended for stage ⅢB/Ⅳ non-small cell lung cancer (NSCLC) treatment. The treatments for elderly patients with advanced NSCLC are mainly single-agent chemotherapy and platinum-based combination chemotherapy. However, elderly patients tolerate chemotherapy poorly because of age-related comorbidities. Therefore, the curative effect of elderly patients is relatively poorer as compared to their younger counterparts. Targeted therapy and immune therapy have become new research directions. It is important to select an appropriate program for elderly patients according to geriatric assessments. Key words: Carcinoma, non-small-cell lung; Aged; Antineoplastic protocols