Treatment Of Advanced Lung Cancer Research Articles

Abstract 1671: Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small Cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets

Abstract Precision for Medicine (Precision) developed and qualified two 17 color flow immunophenotyping assays to be used as pharmacodynamic biomarkers for Advaxis clinical studies in patients with Metastatic Non-Small Cell Lung Cancer treated with ADXS-503 alone and in combination with Pembrolizumab (Pembro). ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T-cell responses against 22 tumor antigens commonly found in NSCLC. Pembrolizumab (Pembro) is a programmed death receptor-1 (PD-1)-blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Here, we qualified two multi-color flow cytometry assays to quantify total PD-1 expression in cryopreserved peripheral blood mononuclear cells (PBMCs) from individuals that were treated either with A503 only or with A503 in combination with Pembro. The detection of free PD-1 and Pembro-bound PD-1 was achieved by co-staining a partially competing αPD-1 antibody (clone PD1.3.1.3) with a biotinylated αHu-IgG4 antibody. The robustness of the assay was demonstrated using a nine-point half-log serial dilution of Pembro, where the highest concentration was 10µg/mL and the lowest concentration was 0.001µg/mL, including a no drug control. The assay conditions were optimized for sensitivity, optimal signal:noise ratio, detection of free and drug bound receptor by titrating and testing various commercial αPD-1 antibody clones and tertiary reagents to detect biotinylated αHu-IgG4. The Pembro bound receptor was detected using a biotinylated αHu-IgG4 antibody, while the free receptors were quantified using a commercial αPD-1 antibody. The assay was able to quantify free and drug bound PD-1 in the intended immune cell types without compromising the staining of other cell surface and intra-nuclear markers. Majority of the evaluable patients, 6 out of 8, had increased counts of NK, CD4+ and CD8+ T-cells, including TCM, TEM and memory stem cells after the administration of ADXS-503 ± Pembro. PD1 expression on circulating CD4+, CD8+ and NK T-cells was also increased while PD-L1 expression was elevated in on-therapy tumor biopsies in some of these patients. Measuring total PD-1 in T-cells can be more challenging in patients on Pembrolizumab therapy as no known commercial non-competing αPD-1 antibody clones are available. This novel assay will facilitate the evaluation of total PD-1 expression as a pharmacodynamic biomarker in T-cells when PD-1 blockade is being used. These results also support that combination of ADXS-503 with PD-1 blockade could lead to enhancement of efficacy of anti-tumor immunotherapy. Citation Format: Venkat Mohanram, Natalya Belkina, Angelina R. Bisconte, Jonathan W. Goldman, Gregory J. Gerstner, Missak Haigentz, Thomas Stinchcombe, Balazs Halmos, Surya Vangala, Victor Kabala, Dinesh Simkhada, Cristiane Metran, Darren Davis, Megan Parsi, Andres A. Gutierrez, Deborah Phippard, Suresh S. Ramalingam. Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small Cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1671.

A narrative review of hyperthermic intrathoracic chemotherapy for advanced lung cancer.

The traditional treatment of stage IV lung cancer is predominantly supportive or palliative. No current standardized guidelines promote the use of hyperthermic intrathoracic chemotherapy (HITHOC) in the treatment of advanced lung cancer with pleural involvement. Several small studies have examined the safety and utilization of HITHOC for this population, though the data is extremely limited. A review of the literature is presented in accordance with the Narrative Review checklist. The MEDLINE electronic database was searched for articles published in English from January 1999 – August 2020 using relevant keywords such as “hyperthermic intrathoracic chemotherapy”, “hyperthermic intrapleural chemotherapy” and “HITHOC”. This was supplemented by review and hand search of the reference lists. While data suggest a potential though controversial role for HITHOC for certain intrathoracic tumors such as malignant pleural mesothelioma and thymoma, there is insufficient evidence to confidently promote a role for hyperthermic intrathoracic chemotherapy in the treatment of advanced lung cancers. Existing studies are small, nonrandomized, and prone to bias. Hyperthermic intrathoracic chemotherapy is not a standardized treatment for advanced lung cancer, and is characterized by potentially serious side effects with little clinical benefit. Recent developments in targeted therapy and immunotherapy are unlikely to leave room for the development of large randomized controlled trials.

B cells in lung cancer-not just a bystander cell: a literature review.

Metastatic lung cancer represents a significant global issue where it is responsible for the most cancer diagnoses and deaths worldwide. Treatment for advanced lung cancer has undergone a series of paradigm shifts from chemotherapy to targeted molecular agents to the most recent immunotherapy strategies. The most successful of the latter involves antibodies that block inhibitory receptors on tumor infiltrating T cells, thereby enhancing T cell activity against tumor cells. However, only a subset of patients demonstrate durable responses to these drugs and treatment resistance is common. Emerging evidence suggests that a critical role exists for B cells as more than a bystander immune cell in the tumor microenvironment (TME). However, this role is likely context-specific where B cells comprise distinct subtypes with unique effector functions that may result in anti- or pro-tumor effects. As such, the balance between various B cell subtypes affects the net B cell impact upon tumor immunity. To date, the factors needed to polarize B cell function toward anti-tumor activity are unclear. Understanding B cell biology in the lung cancer setting will help redefine and refine treatment strategies to augment anti-tumor immunity. This article presents a review of the literature describing the current knowledge of the development and function of B cells, and explores their role in lung cancer and potential as an immunotherapeutic strategy and as a predictive marker for response to immune checkpoint blockade.

A real-world study of camrelizumab in the treatment of advanced lung cancer patients.

e21056 Background: Camrelizumab, as a humanized antibody against PD-1, has shown high efficiency and survival benefits in clinical studies on lung cancer treatment. This study aims to observe the efficacy and safety of Camrelizumab in the treatment of advanced lung cancer in the real world. Methods: This is a prospective, open, multi-center observational study that includes patients with advanced lung cancer who are older than 18 years of age, regardless of gender, with an ECOG score of 0-2. Results: As of November 18, 2020, a total of 253 patients have been enrolled. Males accounted for 187 cases (74.2%). The ECOG PS score was 0 in 44 cases (17.3%), 1 in 162 cases (64.0%), and 2 in 47 cases (18.6%). There were 181 patients (71.5%) of stage IV, 96 patients (37.9%) of adenocarcinoma, and 98% of patients did not undergo PD-L1 testing. A history of radiotherapy accounted for 31.2%, and a history of surgery on the primary lesion accounted for 20.2%. Camrelizumab accounted for 29.6% of the first-line treatment, 27.2% of the second-line treatment, and 43.1% of the third-line and above. Camrelizumab monotherapy accounted for 20.1%, camrelizumab combined with chemotherapy accounted for 56.3%, combined anti-angiogenesis therapy accounted for 22.1%, and combined anti-angiogenesis + chemotherapy accounted for 1.5%. Among the 199 patients with evaluable efficacy, 4 were CR, 46 were PR, 116 were SD, and 33 were PD. The ORR reached 25.1% and the DCR reached 83.4%. The overall adverse event rate was 33.7%, the major adverse event RCCEP rate was 22.6%, appetite loss was 5%, and fatigue was 3.5%. There were 4 cases (2%) of RCCEP with adverse events greater than or equal to grade 3. Conclusions: In this real-world study of lung cancer, most of the patients enrolled were patients with poor PS score and late stage, but the efficacy and safety of camrelizumab in patients with advanced lung cancer were still confirmed. The dominant population and combination therapy are still under study. Clinical trial information: ChiCTR2000034595.

A phase 1 study of an off-the shelf, multi-neoantigen vector (ADXS-503) in subjects with metastatic non-small cell lung cancer (NSCLC) progressing on pembrolizumab as last therapy.

2616 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programmed death receptor-1 (PD-1)- blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: A phase 1 study of A503 ± Pembro has been conducted in patients (pts) with metastatic squamous or non-squamous NSCLC. In dose-escalation part B, A503 was added-on to Pembro within 12 weeks of the first scan showing disease progression per RECIST criteria v1.1. Both, A503 (1 x108 CFU) and Pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. The dose-escalation cohort has established safety, tolerability and immunogenicity of the combination therapy and it has been further expanded to evaluate efficacy (Goldman JW et.al., SITC 2020). Results: Nine pts have been treated and evaluated in Part B. Pembro + A503 combo has been well tolerated and without immune related AEs. Of the nine evaluable pts, one has achieved partial response (PR) and 3 stable disease (SD), yielding an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Two patients have had clinical benefit for over 12 months (i.e., one PR and one SD) and both of them had been on Pembro therapy for 2 years before enrollment. The two other pts with SD have sustained it for almost 6 months thus far. Seven pts have been evaluated for immunogenicity. In all pts there was a transient release of pro-inflammatory cytokines and proliferation of cytotoxic- and memory-CD8+ T cells. Seven evaluable pts had antigen-specific T cells within 1-2 weeks after starting therapy and 4/7 showed antigen spreading. Conclusions: ADXS-503 as an add-on therapy to Pembro at disease progression has been well tolerated and it has induced antigen specific-T cell responses and durable disease control in 44% of pts. Part B cohort is currently enrolling additional pts to further explore the potential reversal of Pembro resistance with ADXS-503. Clinical trial information: NCT03847519.

Impact of age and frailty markers on overall survival among hospitalized patients with lung cancer treated with immunotherapy.

e21151 Background: Although predictive of chemotherapy toxicity, geriatric assessment measures are not systematically collected in clinical practice and may or may not be predictive for immune-related adverse events. Furthermore, hospitalization during immune checkpoint inhibitor (ICI) treatment for advanced lung cancer has variable prognostic significance. This study aimed to evaluate whether age and documented patient characteristics mapped to geriatric assessment domains (frailty markers, FM) predict survival in this setting. Methods: A single-center retrospective cohort of advanced stage lung cancer patients who received >1 dose of an ICI from 6/1/18 to 2/1/20, were later hospitalized, and received ≥ 1 dose of systemic corticosteroids (n=97) was analyzed. Chart review ascertained documentation of any of the following FMs prior to ICI initiation: inability to walk one block, unintentional weight loss, decreased social activities, recent falls, need for assistance with medications, visual or hearing impairments, living alone, and concern regarding social support. Patients were stratified according to age and three FM categories (0 FM [low risk], ≥1 FMs [at risk], and ≥2 FMs [high risk]). Overall survival (OS) analysis was calculated from first dose of ICI to date of death or last follow-up. Cox’s proportional hazards models were used to assess the relationship between FMs and age on OS; hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results: Analysis of < 75 and ≥ 75 yo revealed a median OS of 15.1 and 5.4 months respectively (HR 2.76, CI 1.62-4.72). Controlled for performance status (PS), older age (≥75 yo) was associated with a higher risk of death (HR 2.39, CI 1.32-4.31). FMs were associated with higher mortality, adjusted for PS and age (at risk patients HR 1.81, CI 1.03-3.16; high risk patients HR 2.02, CI 1.07-3.78). PS prior to starting ICI was not associated with OS. Conclusions: Age ≥ 75 yo is associated with short survival among lung cancer patients hospitalized while receiving ICI. Pre-treatment FMs documented as part of usual care were associated with worse OS, even after controlling for PS and age. This study shows promise for use of machine learning algorithms to stratify risk in hospitalized patients undergoing treatment for lung cancer with ICIs. These data would allow providers to better target serious illness conversations and end-of-life resources.[Table: see text]

T‐cell response to phytohemagglutinin in the interferon‐γ release assay as a potential biomarker for the response to immune checkpoint inhibitors in patients with non‐small cell lung cancer

BackgroundImmune checkpoint inhibitors are a standard treatment for advanced lung cancer, although it remains important to identify biomarkers that can accurately predict treatment response. Immune checkpoint inhibitors enhance the antitumor T‐cell response, and interferon‐γ plays an important role in this process. Therefore, this study evaluated whether the number of interferon‐γ‐releasing peripheral T cells after phytohemagglutinin stimulation in the interferon‐γ release assay might act as a biomarker for the response of non‐small cell lung cancer to immune checkpoint inhibitor treatment.MethodsData were retrospectively collected regarding 74 patients with non‐small cell lung cancer who had received immune checkpoint inhibitors. Pretreatment screening tests had been performed using the T‐SPOT.TB assay, which quantifies the number of interferon‐γ‐releasing T cells (as immunospots) in response to phytohemagglutinin and tuberculosis‐specific antigen stimulation. Clinical factors and the number of spots in the T‐SPOT fields were evaluated for associations with patient outcomes. The median number of spots was used to categorize patients as having high or low values, and the two groups were compared.ResultsRelative to patients with a low ratio, patients with a high ratio of phytohemagglutinin/tuberculosis‐specific antigen spots (i.e. more responsive T cells) had significantly better progression‐free survival after immune checkpoint inhibitor treatment. When we only considered patients with negative T‐SPOT results, a high number of phytohemagglutinin‐stimulated spots corresponded to significantly longer progression‐free survival.ConclusionThe T‐SPOT.TB assay can be used to quantify the number of immunospots in response to antigen stimulation, which may predict the response to immune checkpoint inhibitors in patients with non‐small cell lung cancer.

Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions.

Simple SummaryLung cancer is the leading cause of cancer-related death worldwide, accounting for nearly one-fifth of all cancer-related deaths. Immunotherapy with immune checkpoint inhibitors has become one of the most promising approaches in the treatment of advanced lung cancer, although beneficial responses are seen only in a proportion of patients. To improve immunotherapy treatment responses in lung cancer, we need to identify which immunosuppression mechanisms are activated in the tumor microenvironment. In this study, we investigated gene expression profiles in intra-tumoral immune cells in lung cancer, focusing on tumor-associated macrophages, and interactions with CD4+ and CD8+ T cells. Our data highlight two newly described immunosuppressive pathways, which may represent novel innate immune checkpoints dampening the anti-tumor T cell immune response in lung cancer. Our results substantiate the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.

Implementing 'Goals of Care' discussion and palliative care referral for patients with advanced lung cancer: an outpatient-based pilot project.

Early involvement of palliative care and advance care planning improves quality-of-life outcomes and survival for patients with advanced lung cancer; however, there are barriers to implementation. A single-centre prospective audit reviewing 'Goals of Care' (GOC) form completion and palliative care referrals in an oncology clinic was undertaken with the aim of increasing GOC completion and palliative care referrals for patients with advanced lung cancer. Involved physicians attended a communication skills course and then received a communication-priming intervention. Clinicopathological factors associated with GOC completion and palliative care referral were explored. A total of 84 patients receiving palliative treatment for advanced lung cancer was enrolled. Clinicopathological factors, such as poorer performance status, were associated with higher likelihood of GOC completion (P = 0.018) prior to the intervention. Male sex (P = 0.023), absence of sensitising epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangement (P = 0.017), type of systemic therapy (P = 0.031) and poorer performance status (P < 0.001) were associated with higher likelihood of palliative care referral. The intervention improved GOC completion (relative risk (RR) 1.29, P = 0.004); however, this was not sustained in a follow-up audit (RR 0.98, P = 0.92) and there was no change in palliative care referral rate (RR 2.5, P = 0.16). Predictors of palliative referral following clinical review included age (RR 1.16, P = 0.001), male sex (RR 14.2, P = 0.02) and poorer performance status (RR 1.76, P < 0.001). Communication-priming interventions can improve GOC completion for patients with advanced lung cancer. Further investigation is needed to pursue sustainable options for managing this complex patient group and improve guideline-adherence and patient care.

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer.

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.

P84.20 VATS Right Upper Lobectomy for Advanced Non-Small Cell Lung Cancer After ALK-Tyrosine Kinase Inhibitor Administration.

Surgical resection is not generally indicated, but systemic chemotherapy or several molecular-targeted agents are selected as main treatments for advanced lung cancer. But as for the molecular-targeted agents, most patients eventually experience tumor progression due to acquired resistance. The role of residual or recurrent tumor resection after the treatment is unclear. A 65 year-old man was referred to our hospital due to abnormal radiographic image. Chest CT revealed a 50mm solid mass in the right upper lobe. The tumor involved hilar lymph node and extended to the junction of upper lobar bronchus. MRI revealed a 20mm brain metastasis in the left parietal lobe. He was initially diagnosed with cT2bN1M1b StageIVA EGFR(-) adenocarcinoma by transbronchial lung biopsy. Then, brain metastasis was removed surgically. He was finally diagnosed with ALK-rearranged adenocarcinoma from tissue of brain metastasis. Alectinib (600mg/day) was started as the first-line therapy. After 14 months of alectinib therapy, chest CT revealed remarkable reduction of the tumor and other two new lesions in the right upper lobe. One was a 10mm nodule close to the scar of primary tumor, which had not found at chest CT from three months ago. The other was a 15mm nodule apart from the scar, which existed before the alectinib treatment and had got larger gradually. PET-CT revealed the high fluorodeoxyglucose (FDG) uptake of only two new lesions. We performed complete VATS right upper lobectomy and mediastinal lymph node dissection for treatment and diagnosis. Histopathlogical diagnoses: No residual viable cell was found in the primary lesion. The lesion close to the scar of the primary lesion was adenocarcinoma (ALK-rearranged), which was thought to be a recurrent lesion because of resemblance to brain metastasis in pathological tissue. The lesion apart from the main lesion was pT1bN0M0 StageIB squamous cell carcinoma, which was thought to be primary lung cancer. Alectinib was continued after the operation, and chest CT shows no sign of recurrence so far. We experienced a VATS right upper lobectomy for advanced non-small cell lung cancer after ALK-tyrosine kinase inhibitor administration.

P31.01 A False Alarm of COVID-19 Pneumonia in Lung Cancer: A Case Report of Anti-PD-1 Related Pneumonitis

The inhibition of immune checkpoint therapy emerged as the novel treatment in advanced lung cancer, including anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies. The fatal toxicity of anti-PD-1/PD-L1 agents is pneumonitis, which is defined as a noninfectious inflammation to the lung parenchyma. The diagnosis of pneumonitis consists of the history of immunotherapy, clinical symptoms and presentation of computed tomography (CT) imaging. The typical CT findings include ground-glass opacities.

P78.12 A Rare Case of Dermatomyositis as Late Immune-Related Toxicity During Anti-PD1 Treatment for Advanced Lung Cancer

P78.12 A Rare Case of Dermatomyositis as Late Immune-Related Toxicity During Anti-PD1 Treatment for Advanced Lung Cancer

Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan.

BackgroundAlthough immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities—including diabetes—with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer.MethodsPatients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan–Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival.ResultsAmong the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score–matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan–Meier estimates, p=0·04 and 0·03, respectively). In propensity score–matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0·36; 95% CI, 0·13–0·98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan–Meier estimate, p=0·04).ConclusionPre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.

First-Line EGFR-TKIs Treatment in Stage I Non-Small-Cell Lung Cancer Patients Harboring EGFR Gene Mutations with Postoperative Intrapulmonary Recurrence.

BackgroundThe epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is an effective treatment for advanced lung cancer harboring EGFR gene mutations, and has improved progression-free survival in several clinical trials.MethodsWe investigated 30 stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence. Progression-free survival and response rate were analyzed.ResultsPartial response was achieved in 23 patients and stable disease was found in 7 patients. The objective response rate was 76.7% and disease control rate was 100%. The median progression-free survival (PFS) time was 24.5 months. The median PFS in patients with only intrapulmonary recurrence was significantly superior to patients with both intrapulmonary recurrence and metastasis (32.0 months vs 14.0 months, P = 0.003). The median PFS observed in patients who underwent icotinib treatment was significantly longer than in patients who underwent gefitinib treatment (30.5 months vs 12.0 months, p = 0.005). There were no statistical differences in median PFS between patients with tumors harboring exon 21 mutation and exon 19 deletion, age <65 and ≥65, male and female, smoker and non-smoker.ConclusionOur result reveals that first-line EGFR-TKIs treatment for stage I non-small-cell lung cancer patients harboring EGFR gene mutations with postoperative intrapulmonary recurrence is effective and could be a useful option in practical setting.

Structure-Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors.

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.

Plasma cytokines interleukin-18 and C-X-C motif chemokine ligand 10 are indicative of the anti-programmed cell death protein-1 treatment response in lung cancer patients.

BackgroundAlthough programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment.MethodsWe prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition.ResultsThe baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs.ConclusionsPlasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

The Effect of Dezocine Combined with Oxycodone in the Treatment of Advanced Lung Cancer with Bone Metastasis and Severe Cancer Pain on the Numerical Rating Scale Score of Patients

The effect of dezocine combined with oxycodone on the pain score (numerical rating scale score) of patients with severe cancer pain caused by bone metastasis of advanced lung cancer was analyzed. The patients were divided into two groups with 50 cases in each group. The control group was given intramuscular injection of dezocine for analgesia and the observation group was given oral oxycodone hydrochloride controlled release tablets on the basis of intramuscular injection of dezocine for analgesia. The pain relief rate and analgesic efficiency of the observation group were better than those of the control group and the numerical rating scale score was lower than that of the control group. The number of burst pain in the observation group was less than that in the control group, the stable time of first pain control was shorter than that in the control group and the increase time of 24 h sleep was longer than that in the control group, with statistical significance. After treatment, the overall health status score, functional score and symptomatic score of the two groups were significantly higher than those before treatment. Dezocine combined with oxycodone in the treatment of severe cancer pain in advanced lung cancer with bone metastasis can effectively relieve pain, regulate the expression of pain factors and improve the quality of life.

The cutting edge of advanced lung cancer treatment

The cutting edge of advanced lung cancer treatment

59P Real-world data of immunotherapy in patients over 65 years old with lung cancer

Immunotherapy (IO) has become one of the leading treatments for advanced lung cancer. The number of elderly patients treated in routine clinical practice contrasts with the low representation of these in clinical trials. The aim of the study is to establish clinical differences between patients older and younger than 65 years treated with IO. We conducted a single centre retrospective review including 137 patients treated with IO in Puerta de Hierro University Hospital (Madrid) between 2014 and 2019. We collected information regarding epidemiology, treatments, response and survival patterns and we performed a comparative analysis between patients <65 and ≥ 65 years. Clinical data, toxicities, treatments and survival are shown in the table. There were no differences in high grade toxicities (9.1% vs 10.4%) or treatment interruption (20.3% vs 17.6%, p=0.576). We didn´t find difference in OS (16.0 vs 17.0) between both groups. Table: 59P<65 (69)>65 (68)Long rank (p)Sex M F54.5% 45.6%74.6% 25.4%Age5872ECOG 0-1 ≥293.2% 4.5%97.0% 3.0%Histology Adenocarcinoma Squamous Small cell Others59.1% 27.3% 2.3% 11.4%56.7% 25.4% 4.5% 13.4%Toxicity type Asthenia Pneumonitis Thyroid disorders Skin Others11.4% 14.8% 10.2% 9.1% 24.9%13.4% 11.9% 11.9% 9.0% 19.5%Grade 1-2 ≥323.8% 9.1%28.3% 10.4%0.99Treatments (CI, 95%)Median OS16.0 (9.1-22.9)17.0 (7.5-26.5)0.8251° lineMedian PFS3.0 (0-6.8)7.0 (1.2-12.8)0.164Duration (median)3.03.02° lineMedian PFS11.0 (9.6-12.4)11.0 (5.1-16.9)0.837Duration (median)9.54.03° lineMedian PFS2.0 (1.2-2.8)2.0 (0.1-3.9)0.338Duration (median)2.02.0 Open table in a new tab Our results show that IO has an adequate safety profile in patients ≥65 years and survival results are similar to young patients. Therefore, in our opinion, IO represents a valid and safe option for advanced lung cancer treatment in patients ≥65 years.