Metastatic Squamous Cell Carcinoma Of Lung Research Articles

Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) have significantly prolonged the survival of advanced/metastatic patients with lung cancer. However, only a small proportion of patients can benefit from ICIs, and clinical management of the treatment process remains challenging. Glycosylation has added a new dimension to advance our understanding of tumor immunity and immunotherapy. To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins, a series of serum samples from 12 patients with metastatic lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC), collected before and during ICIs treatment, are firstly analyzed with mass-spectrometry-based label-free quantification method. Second, a stratification analysis is performed among anti-PD-1/PD-L1 responders and non-responders, with serum levels of glycopeptides correlated with treatment response. In addition, in an independent validation cohort, a large-scale site-specific profiling strategy based on chemical labeling is employed to confirm the unusual characteristics of IgG N-glycosylation associated with anti-PD-1/PD-L1 treatment. Unbiased label-free quantitative glycoproteomics reveals serum levels' alterations related to anti-PD-1/PD-L1 treatment in 27 out of 337 quantified glycopeptides. The intact glycopeptide EEQFN 177STYR (H3N4) corresponding to IgG4 is significantly increased during anti-PD-1/PD-L1 treatment (FC=2.65, P=0.0083) and has the highest increase in anti-PD-1/PD-L1 responders (FC=5.84, P=0.0190). Quantitative glycoproteomics based on protein purification and chemical labeling confirms this observation. Furthermore, obvious associations between the two intact glycopeptides (EEQFN 177STYR (H3N4) of IgG4, EEQYN 227STFR (H3N4F1) of IgG3) and response to treatment are observed, which may play a guiding role in cancer immunotherapy. Our findings could benefit future clinical disease management.

Response Rate,Side Effect and Reduction in Tumor Size of Vinorelbine, Gemcitabine and Taxanes as First Line Setting of Advanced Squamous Cell Carcinoma of the Lung

Background: Squamous-cell carcinoma (SCC) of the lung is a kind of non-small-cell lung carcinoma. Cytotoxic chemotherapy has been found to deliver benefits to patients in advanced disease settings. Objective: To compare response rate and side effects between first-line chemotherapies vinorelbine, gemcitabine, and taxanes in patients with metastatic SCC of the lung. Patients and Methods: This is a retrospective study including 45 patients with metastatic lung SCC. All patients had received platinum-based doublet chemotherapy for 4-6 cycles. Patients were allocated into three groups based on the additional treatment protocol, with fifteen patients per group. A reduction in tumor size was assessed from tumor measurements for patients who had at least two evaluable assessments with computed tomography. The side effects of each drug were evaluated. Results: The reduction in tumor size in the gemcitabine, taxan, and vinorelbine arms was -5.59±35.62 cm3, 1.3±39.98 cm3 and -10.55±14.62 cm3, respectively, with no significant differences. The response rates in the taxan, gemcitabine, and vinorelbine arms were 73.33%, 80%, and 86.67%, respectively, with no significant differences. The side effects, including nausea, alopecia, diarrhea, arthralgia, and peripheral neuropathy, were, in particular, more common in patients in the taxan arm than in other arms, with significant differences. Conclusion: The three therapeutic arms, vinorelbine, gemcitabine, and taxanes, had similar efficiency based on response rate, with a mild preponderance of vinorelbine.

Response Rate, Side Effect and Reduction in Tumor Size of Vinorelbine, Gemcitabine and Taxanes as First Line Setting of Advanced Squamous Cell Carcinoma of the Lung

Background: Squamous-cell carcinoma (SCC) of the lung is a kind of non-small-cell lung carcinoma. Cytotoxic chemotherapy has been found to deliver benefits to patients in advanced disease settings. Objective: To compare response rate and side effects between first-line chemotherapies vinorelbine, gemcitabine, and taxanes in patients with metastatic SCC of the lung. Patients and Methods: This is a retrospective study including 45 patients with metastatic lung SCC. All patients had received platinum-based doublet chemotherapy for 4-6 cycles. Patients were allocated into three groups based on the additional treatment protocol, with fifteen patients per group. A reduction in tumor size was assessed from tumor measurements for patients who had at least two evaluable assessments with computed tomography. The side effects of each drug were evaluated. Results: The reduction in tumor size in the gemcitabine, taxan, and vinorelbine arms was -5.59±35.62 cm3, 1.3±39.98 cm3 and -10.55±14.62 cm3, respectively, with no significant differences. The response rates in the taxan, gemcitabine, and vinorelbine arms were 73.33%, 80%, and 86.67%, respectively, with no significant differences. The side effects, including nausea, alopecia, diarrhea, arthralgia, and peripheral neuropathy, were, in particular, more common in patients in the taxan arm than in other arms, with significant differences. Conclusion: The three therapeutic arms, vinorelbine, gemcitabine, and taxanes, had similar efficiency based on response rate, with a mild preponderance of vinorelbine. Keywords: Squamous-cell carcinoma,vinorelbine, gemcitabine,taxanes

Identification and prognostic analysis of ferroptosis‑related gene HSPA5 to predict the progression of lung squamous cell carcinoma.

Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, is implicated in the development and therapeutic responses of cancer. However, the role of ferroptosis-related gene profiles in lung squamous cell carcinoma (LSCC) remains largely unknown. The present study aimed to identify the prognostic roles of ferroptosis-related genes in LSCC. Sequencing data from the Cancer Genome Atlas were analyzed and ferroptosis-related gene expression between tumor and para-tumor tissue was identified. The prognostic role of these genes was also assessed using Kaplan-Meier analyses and univariate and multivariate Cox proportional hazards regression model analyses. Immunological correlation, tumor stemness, drug sensitivity and the transcriptional differences of heat shock protein (HSP)A5 in LSCC were also analyzed. Thereafter, the expression of HSPA5 in 100 patients with metastatic LSCC was evaluated using immunohistochemistry (IHC) and the clinical significance of these markers with different risk factors was assessed. Of the 22 ferroptosis-related genes, the expression of HSPA5, HSPB1, glutathione peroxidase 4, Fanconi anemia complementation group D2, CDGSH iron sulfur domain 1, farnesyl-diphosphate farnesyltransferase 1, nuclear factor erythroid 2 like 2, solute carrier (SLC)1A5, ribosomal protein L8, nuclear receptor coactivator 4, transferrin receptor and SLC7A11 was significantly increased in LSCC compared with adjacent tissues. However, only high expression of HSPA5 was able to predict progression-free survival (PFS) and disease-free survival in LSCC. Although HSPA5 was also significantly elevated in patients with lung adenocarcinoma, HSPA5 expression did not predict the prognosis of patients with lung adenocarcinoma. Of note, a higher expression of HSPA5 was related to higher responses to chemotherapy but not to immunotherapy. In addition, HSPA5 expression was positively correlated with 'ferroptosis', 'cellular responses to hypoxia', 'tumor proliferation signature', 'G2M checkpoint', 'MYC targets' and 'TGFB'. IHC analysis also demonstrated that a high expression of HSPA5 in patients with metastatic LSCC in the study cohort was associated with shorter PFS and overall survival. In conclusion, the present study demonstrated that the expression of the ferroptosis-related gene HSPA5 may be a negative prognostic marker for LSCC.

Long response to camrelizumab in metastatic lung squamous cell carcinoma with high PD-L1 expression despite EGFR G719S mutation: A case report

Immune checkpoint inhibitors (ICIs) have been widely used in non-small cell lung cancer with wildtype EGFR/ALK genes. However, the effect of ICIs on advanced NSCLC with EGFR genes sensitive mutations has been controversial. There are no reports on whether ICIs monotherapy can be used in the treatment of NSCLC with EGFR sensitive mutations. A patient with metastatic lung squamous cell carcinoma with EGFR G719s mutations, high PD-L1 score and a tuberculosis history was given first-line treatment of afatinib, camrelizumab monotherapy (200 mg, intravenous, once every three weeks) from February 24,2020 to January 2023. The patient achieved partial response (PR) after treatment with camrelizumab. The progress-free survival (PFS) due to camrelizumab monotherapy was more than 34 months.It is concluded that camrelizumab has promising potential effectiveness as a treatment option for lung squamous cell cancer with EGFR G719 mutations and high PD-L1 score.

Prognostic impact of metastatic patterns and treatment modalities on overall survival in lung squamous cell carcinoma: A population-based study.

This study aimed to investigate the impact of distinct metastasis patterns on the overall survival (OS) of individuals diagnosed with organ metastatic lung squamous cell carcinoma (LUSC). OS was calculated using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were conducted to further assess prognostic factors. A total of 36,025 cases meeting the specified criteria were extracted from the Surveillance, Epidemiology, and End Results database. Among these patients, 30.60% (11,023/36,025) were initially diagnosed at stage IV, and 22.03% (7936/36,025) of these individuals exhibited metastasis in at least 1 organ, including the liver, bone, lung, and brain. Among the 4 types of single metastasis, patients with bone metastasis had the lowest mean OS, at 9.438 months (95% CI: 8.684-10.192). Furthermore, among patients with dual-organ metastases, those with both brain and liver metastases had the shortest mean OS, at 5.523 months (95% CI: 3.762-7.285). Multivariate Cox regression analysis revealed that metastatic site is an independent prognostic factor for OS in patients with single and dual-organ metastases. Chemotherapy was beneficial for patients with single and multiple-organ metastases; although surgery was advantageous for those with single and dual-organ metastases, it did not affect the long-term prognosis of patients with triple organ metastases. Radiotherapy only conferred benefits to patients with single-organ metastasis. LUSC patients exhibit a high incidence of metastasis at the time of initial diagnosis, with significant differences in long-term survival among patients with different patterns of metastasis. Among single-organ metastasis cases, lung metastasis is the most frequent and is associated with the longest mean OS. Regarding treatment options, patients with single-organ metastasis can benefit from chemotherapy, surgery, and radiotherapy, and those with metastasis in 2 organs can benefit from chemotherapy and surgery. Patients with metastasis in more than 2 organs, however, can only benefit from chemotherapy. Understanding the variations in metastasis patterns assists in guiding pretreatment assessments and in determining appropriate therapeutic interventions for LUSC.

Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis.

Metastatic lung squamous cell carcinoma (LUSC) is one of the most common causes of cancer death worldwide. As yet, however, the molecular mechanism underlying LUSC metastasis remains elusive. In this study, we report a novel mechanism involving signaling interactions between FGF19 and GLI2 that could drive the progression of LUSC. The expression of FGF19 in human LUSC samples was assessed by immunohistochemistry. The concentration of FGF19 in serum samples was assessed by ELISA. RNA sequencing, scratch wound-healing, trans-well, GO analysis, GSEA, luciferase reporter, Western blotting, immunofluorescence and immunohistochemistry assays, as well as an animal model were used to investigate the molecular mechanism underlying FGF19 driven LUSC progression. The therapeutic effect of a GLI2 inhibitor was determined using both in vitro cellular and in vivo animal experiments. We found that FGF19, a member of the fibroblast growth factor family, plays a crucial role in the invasion and metastasis of LUSC, and identified GLI2 as an important downstream effector of FGF19 involved in metastasis. Surprisingly, we found that FGF19 and GLI2 could reciprocally induce the expression of each other, and form a positive feedback loop to promote LUSC cell invasion and metastasis. These findings were corroborated by an association between a poor prognosis of LUSC patients and FGF19/GLI2 co-expression. In addition, we found that the GLI inhibitor GANT61 could effectively reduce FGF19-mediated LUSC invasion and metastasis. Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.

PSAT042 Adrenal Insufficiency Associated to Immune Checkpoint Inhibitors

Abstract Background Innovations in management of multiple malignancies have developed throughout the years. Despite benefits in immune checkpoint inhibitors there is an incidence of approximately 9.4% to 10.4% in endocrine immune related disorders. The challenge advocates to promptly recognize the clinical manifestations related to adverse effects. Clinical Case We report a case of a 61-year-old caucasian woman with Metastatic Lung Squamous Cell Carcinoma Stage IV on immunotherapy and radiotherapy who presented to ED with nausea and vomiting for the last 2 weeks. The review of the system pertinent for weight loss 18 pounds in the last 2 months, fatigue and decreased appetite. Medication history pertinent for active Pembrolizumab (started 6 months prior to presentation; cycle every 3 weeks); Radiotherapy (3 cycles) and steroid injections (last dose 1 month prior for bilateral knee pain). Upon arrival vital signs T 36.9C, HR 110/min, RR 18/min, BP 80/60mmHg, and StO2 98%. The physical examination pertinent for an acutely ill patient with tachycardia. Initial laboratory studies showed peripheral eosinophilia 14% (n <6%); high anion gap metabolic acidosis (AG 18), hypokalemia 2.8 mmol/L (n 3.5-5.0mmol/L). The patient was hospitalized with sepsis and intractable vomiting. Gastroenterology evaluated with EGD showed erosive gastritis and reflux esophagitis. CT abdomen with IV contrast showed numerous sclerotic bone lesions and single hepatic lesion suggestive of metastatic disease; unremarkable adrenal glands. Poor response to initial hydration and antibiotics as blood pressure remained fluctuant borderline low prompted evaluation. Random cortisol at 6: 50am showed hypocortisolism (1.6mcg/dl) and TSH 1.290 mcIU/mL (n 0.358- 3.74mcIU/mL); patient was started on stress dose steroids and endocrinology was consulted for suspected adrenal insufficiency. Cosyntropin stimulation test (n >18 mcg/dL) with baseline cortisol levels 1.6mcg/dl and ACTH less than 5mcg/dl; cortisol levels at 30 minutes after 250 mcg of Cosyntropin was 4.3mcg/dl and at 1 hour 6.8mcg/dl, confirming most likely secondary vs primary adrenal insufficiency. Within 24-48 hour stress dose steroids were weaned and the patient was then discharged home with hydrocortisone 20 mg am and 10mg pm for further outpatient management. Conclusion Pembrolizumab is a human programmed death receptor-1-blocking antibody that on October 2015 was FDA approved for treatment of non-small cell lung cancer. Adrenal Insufficiency can cause a broad nonspecific clinical scenario with reported incidence of 0.6-0.7% pembrolizumab-induced AI. This rare clinical entity adrenal insufficiency immune mediated endocrinopathy by pembrolizumab constitutes an emergency that prompts attention for early identification and initial management. Nevertheless increased morbidity and mortality is associated with acute adrenal crisis encouraging physicians to be aware of this particular risk. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

A TNFR1–UBCH10 axis drives lung squamous cell carcinoma dedifferentiation and metastasis through a cell-autonomous signaling loop

Tumor necrosis factor receptor 1 (TNFR1), encoded by TNFRSF1A, is a critical transducer of inflammatory pathways, but its physiological role in human cancer is not completely understood. Here, we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-dead Ikkα knock-in (KA/KA) mice. Knocking out Tnfrf1a in KA/KA mice blocked lung SCC formation. When injected via tail vein, KALLU+ lung SCC cells that highly expressed TNFR1/TNF, Sox2, c-Myc, Twist1, Bcl2, and UBCH10, generated dedifferentiated spindle cell carcinomas with epithelial–mesenchymal transition markers in mouse lungs. In contrast, KALLU+ cells with silenced TNFR1 and KALLU- cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10, an E2 ubiquitin-conjugating enzyme with targets including Twist1, c-Myc, and Sox2, which enhanced SCC cell dedifferentiation. Furthermore, Tg-K5.TNFR1;KA/KA mice, which expressed transgenic TNFR1 in keratin 5-positve epithelial cells, developed more poorly differentiated and metastatic lung SCCs than those found in KA/KA mice. These findings demonstrate that an overexpressed TNFR1–UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may contribute to the development of differentiation-related therapies for lung SCC.

Determination of EGFR Mutation Prevalence in Advanced and Metastatic Lung Squamous Cell Carcinoma in Vietnam

Abstract: This paper aims to determine the rate of epidermal growth factor receptor (EGFR) gene mutations in advanced and metastatic squamous cell lung cancer in Vietnamese patients. EGFR mutation testing was performed on 559 formalin-fixed paraffin-embedded tissue samples from advanced and metastatic squamous cell lung cancer patients by real-time PCR. The results showed that EGFR mutations were found in 8.4%. Most of them were exon 19 deletions, approximately 51.1%. Multivariate analysis showed that EGFR mutations were more prevalent in gender (p<0.0001). In conclusion, EGFR mutation testing should be performed in patients with squamous cell lung cancer.
 Keywords: Lung squamous cell carcinoma, EGFR gene. 
 

Multiomics profiling and association with molecular and immune features in association with benefits from immunotherapy for patients with previously treated stage IV or recurrent squamous cell lung cancer from the phase III SWOG LungMAP S1400I trial.

9046 Background: Immune checkpoint blockade (ICB) has become a standard pillar of treatment for lung cancer. However, only ̃20% of unselected patients can achieve durable clinical benefits. We performed immunogenomic profiling of tissue specimens from a randomized Phase III trial S1400I on metastatic lung squamous cell carcinoma (SCC) to evaluate if there were factors associated with better prognoses with ICB from single-agent versus combined targeting PD-1/CTLA-4 and evaluate if any differentiated between the treatments. Methods: We utilized FFPE tumor tissue submitted for Lung-MAP screening provided by the SWOG bank. SCC samples from 82 eligible patients treated with combined nivolumab+ipilimumab (N+I) or single agent nivolumab (N) were subjected to multiplex immunofluorescence (mIF, n = 82) and NanoString (ncounter PanCancer Immune Profiling Panel, n = 32). Cell density phenotypes (cells/mm2) were defined using image analysis of staining for cytokeratin, CD3, CD8, granzyme B, CD45RO, FOXP3, PD1, PD-L1, and CD68. Immunogenomic features were associated with response, PFS, and OS derived from data provided by the LungMap team to the CIDC portal. For statistical analyses, non-parametric tests were utilized to assess associations of cell phenotypes versus continuous or categorical variables, and log-rank test analysis was performed to identify cell phenotypes or genes correlated with survival. Results: In both arms higher densities of total CD3+CD45RO+ T cells ( P= 0.041), CD3+PD-1+ T cells ( P= 0.024) and CD3+CD8+PD-1 T cells in stroma ( P= 0.042) and CD3+CD8+GZMB+ T cells in the tumor compartment ( P= 0.011) were positively associated with PFS. In the N+I arm but not in the N arm, higher densities of CD3+CD8+GZMB+ T cells in the tumor compartment were associated with better PFS ( P= 0.015) and higher densities of stroma CD3+CD8-FOXP3+ T cells with worse OS. Spatial analysis showed that the presence of CD8+GZMB+ T cells close to malignant cells (median, ≤19.27 µm) was associated with better PFS ( P= 0.037) in N+I arm and cluster analysis showed low clustering of cells in TMB-high vs. TMB-low tumors (P < 0.01). Gene expression profiling demonstrated that myeloid infiltration, immune recruitment, and inflammation genes were associated with a positive clinical outcome ( P< 0.05). In both arms, BLNK, CD163, FCGR2A were associated with better OS ( P< 0.01), IRF1 and BLNK were associated with increased PFS ( P< 0.01). In the N+I arm but not in the N arm, we observed significantly higher CD45 immune cell scores, including CD8 T cells and neutrophils, in responders versus non-responders. Conclusions: Our findings suggest a potential advantage in PFS and OS with an increased presence of cytotoxic immune cells and genes associated with the recruitment and proliferation of these cell types before therapy.

Bullous pemphigoid associated with squamous cell lung carcinoma showing remarkable response to carboplatin-based chemotherapy: a case report

BackgroundBullous pemphigoid is an uncommon dermatologic manifestation seen in squamous cell lung cancer, and evidence guiding optimal treatment, especially in the elderly population, is limited. We report herein a case of squamous cell lung cancer diagnosed after being investigated for refractory bullous pemphigoid showing marked response to carboplatin-based chemotherapy. This is the first case report that shows carboplatin can be used as an effective alternative in treatment of malignancy-associated bullous pemphigoid.Case reportAn 80-year-old caucasian man developed extensive vesiculobullous rashes on his trunk, chest, abdomen, and inguinal region associated with significant pruritus causing sleep disturbance. The diagnosis of bullous pemphigoid was confirmed on skin biopsy. The skin lesions continued to worsen even after use of oral and topical steroid in addition to oral doxycycline. Chest computed tomography revealed a spiculated left lung lesion along with mediastinal lymphadenopathy. Fine-needle aspiration from the mediastinal lymph node confirmed metastatic squamous cell lung carcinoma. Carboplatin with gemcitabine was initiated, and significant response was seen within 3 days of chemotherapy. The skin lesions continued to remain in remission even after stopping the chemotherapy.ConclusionAlthough there are still controversies regarding paraneoplastic etiology of bullous pemphigoid, this case presents a temporal association. It is the first case report showing a remarkable response with the use of a carboplatin-based regimen.

Construction and Validation of Prognosis Nomogram for Metastatic Lung Squamous Cell Carcinoma: A Population-Based Study.

Purpose: This study aimed to establish a nomogram to predict overall survival in lung squamous cell carcinoma patients with metastasis for clinical decision-making. Methods: We investigated lung squamous cell carcinoma patients diagnosed with stage M1 in the Surveillance, Epidemiology, and Final Results database between 2010 and 2015. They were divided into training cohort and validation cohort. In the training cohort, statistically significant prognostic factors were identified using univariate and multivariate Cox regression analysis, and an individualized nomogram model was developed. The model was evaluated by C-index, area under the curve, calibration plot, decision curve analysis, and risk group stratification. Results: In total, 9910 patients were included in our study, including 6937 in the training cohort and 2937 in the validation cohort. Factors containing age, T stage, N stage, bone metastasis, brain metastasis, liver metastasis, surgery, chemotherapy, and radiotherapy were independent prognostic factors for overall survival and were used in the construction of the nomogram. The C-index in the training cohort and validation cohort were 0.711 (95% confidenc interval: 0.705-0.717) and 0.707 (95% confidenc interval: 0.697-0.717), respectively. The time-dependent area under the curve of both groups was higher than 0.7 within 5 years. Calibration plots indicated that the nomogram-predicted survival was consistent with the recorded 6-month, 1-year, and 2-year prognoses. Furthermore, decision curve analysis revealed that the nomogram was clinically useful and had a better discriminative ability to recognize patients at high risk than the TNM criteria-based tumor staging. And then we developed an overall survival risk classification system based on the nomogram total points for each patient, which divided all patients into a high-risk group and a low-risk group. Finally, we implemented this nomogram in a free online tool. Conclusion: We constructed a nomogram and a corresponding risk classification system predicting the overall survival of lung squamous cell carcinoma patients with metastasis. These tools can assist in patients’ counseling and guide treatment decision-making.

Real-world effectiveness of second-line Afatinib versus chemotherapy for the treatment of advanced lung squamous cell carcinoma in immunotherapy-na\xefve patients

BackgroundLimited treatment options exist for relapsed advanced lung squamous cell carcinoma (SCC), leading to poor outcomes compared with adenocarcinoma. This study aimed to investigate the efficacy of second-line afatinib versus chemotherapy in patients with advanced lung SCC who progressed after first-line chemotherapy.MethodsIn this retrospective, multisite cohort study, we recruited patients with initial locally advanced or metastatic lung SCC from four institutes in Taiwan between June 2014 and October 2020. The primary endpoint of this study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsThe present study enrolled 108 patients: 19 received second-line afatinib, and 89 received second-line chemotherapy. The median ages were 71 and 67 years, respectively. PFS was significantly longer among patients who received afatinib than among those who received chemotherapy (median 4.7 months [95% confidence interval (CI), 0.1–7.5] vs. 2.6 months [95% CI, 0.9–6.7]; hazard ratio (HR) 0.53 [95% CI 0.32–0.88], p = 0.013). Compared with the chemotherapy group, OS was longer in the afatinib group but did not reach significance (median 16.0 months [95% CI, 6.1–22.0] vs. 12.3 months [6.2–33.9]; HR 0.65 [95% CI 0.38–1.11], p = 0.112).ConclusionsAfatinib offered a longer PFS and comparable OS to chemotherapy in advanced lung SCC patients in a real-world setting, it may be considered as a 2nd line alternative treatment choice for immunotherapy unfit advanced lung SCC patients.

CTNI-46. PHASE I OPEN-LABEL, SINGLE-CENTER, DOSE ESCALATION STUDY (NCT02423525) OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER

Abstract Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patients were screened and 24 were enrolled (median age 60, 78% male, 87.5% Caucasian, glioblastoma N=16, chordoma N=3, brain metastases N=2, meningioma N=1, anaplastic mixed oligoastrocytoma N=1). Patients had received a median of 2.5 prior treatments. The study proceeded through the 4 dosing cohorts without reaching dose-limiting toxicity: Cohort 1 (80mg every 4 days) N=3; Cohort 2 (120mg every 4 days) N=3; Cohort 3 (180mg every 4 days) N=7, including replacement patients; Cohort 4 (280mg every 7 days) N=11. Diarrhea (75%), rash (75%), nausea/vomiting (37.5%), fatigue (29.2%), anorexia (25%), and limb edema (16.7%) were the most common side effects. There were no CTCAE defined grade 4 toxicities. Grade 3 side effects infrequently occurred in the highest dosing cohort and once in each cohort 2 and 3. These results demonstrate that pulsatile Afatinib at a dose of 280mg every 7 days is safe and tolerable for patients with brain involving cancers.

Paclitaxel liposome for injection (Lipusu) plus cisplatin versus gemcitabine plus cisplatin in the first-line treatment of locally advanced or metastatic lung squamous cell carcinoma: A multicenter, randomized, open-label, parallel controlled clinical study.

BackgroundLipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC.MethodsPatients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.ResultsThe median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend.ConclusionThe LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations

IntroductionThe efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. MethodsWe reviewed the database of the MD Anderson Cancer Center and identified metastatic LUSC with classic EGFR or ALK alterations. ResultsThere were eight patients with EGFR-mutant LUSC (median age = 58 y) and six patients with EML4-ALK LUSC (median age = 50 y) who received tyrosine kinase inhibitors (TKIs) that were identified. Of the 14 patients, 11 (79%) were females and 12 (86%) were never smokers, similar to the demographics of EGFR or ALK LUAD. With TKI treatment, seven of eight cases of EGFR LUSC and four of six cases of ALK LUSC achieved partial response or stable disease, but the progression-free survival was 4.9 months and 2.9 months for EGFR-mutant and ALK-rearranged LUSC, respectively. In addition, we compared comutation profile of EGFR-mutant LUAD (The Cancer Genome Atlas, n = 46) versus LUSC (n = 19) and found that the comutation patterns are more consistent with squamous disease with a higher incidence of PIK3CA (p = 0.02) and KRAS or BRAF (p = 0.04) alterations. ConclusionsEGFR or ALK alterations occur in patients with LUSC, especially never-smoker females. TKI treatments render clinical benefit in disease control, but the duration was considerably truncated compared with those historically observed in LUAD.

S2724 Clinical Presentation, Treatment Strategies, and Chronic Sequelae of Immune Checkpoint Inhibitor-Mediated Cholangiopathy: A Case Study

Introduction: Immunotherapy-mediated cholangiopathy (IMCp) is an under-recognized phenotype of immunotherapy-mediated hepatobiliary toxicity (IMH) with specific consequences. IMCp cases bear a risk of the need for treatment escalation beyond corticosteroids alone, and the long-term sequelae are not well documented. We describe a case of steroid-refractory IMCp successfully treated with tocilizumab and ursodiol. Case Description/Methods: A 56-year-old man, treated with ipilimumab and nivolumab for metastatic lung squamous cell carcinoma, presented with abnormal liver enzymes attributed to toxicity secondary to immune checkpoint inhibitors. The initial peak ALT was 273 U/L, with AST 128 U/L, alkaline phosphatase (ALP) 590 U/L, GGT 938 U/L, and total bilirubin 2.0 mg/dL; R factor was < 2, suggesting a cholestatic-predominant pattern of injury. Oral prednisone 60 mg/d and ursodiol yielded only partial improvement; prednisone dose was increased to 80 mg/d, and azathioprine (AZA) 50 mg/d was added. Liver biopsy confirmed histologic bile duct injury; abdominal MRI showed enhancement of the left, right, and common hepatic ducts. ALT increased to >350 U/L with total bilirubin to 2.4 mg/dL despite intravenous (IV) methylprednisolone 160 mg/d. IV tocilizumab (TCZ) 8 mg/kg was administered, allowing for tapering off of prednisone, while continuing ursodiol and AZA. ALT improved from 519 to 82 after 44 days, and another infusion of IV TCZ at 4 mg/kg was given. The ALT improved and remained stable in 40-50 range for another 5 months. The ALP approached a nadir of 160 and eventually settled between 300-400. After ursodiol and AZA were discontinued, brief increases were seen of ALT to 106, AST to 82, ALP to 574, and GGT to 1283, which improved to baseline after ursodiol was resumed. Nine months after initial diagnosis, MRI showed persistent intrahepatic biliary ductal dilation with normal common hepatic duct and common bile duct. Patient was doing clinically well. Discussion: In this case of relapsing and steroid-refractory IMCp, with intrahepatic sclerosing cholangitis, tocilizumab, an IL-6 receptor antagonist, yielded successful biochemical and clinical remission, allowing discontinuation of prednisone, despite persistent intrahepatic biliary dilatation. Ursodiol as an adjunct may also play a crucial role in treating IMCp to manage cholestasis and as maintenance therapy. Longitudinal studies are needed to determine if permanent biliary sequelae may occur and whether these features pose practical clinical consequences.Figure 1.: (A) Liver biopsy (H&E, 200x) histology demonstrating expansion of the portal tracts by inflammation which is centered on the damaged bile duct. (B) Abdominal MRI/MRCP showing enhancement of the intrahepatic biliary tree; some of the right intrahepatic ducts demonstrate new beaded appearance; related findings were interpreted as progressive when compared to a prior MRI/MRCP. (C) Chronological clinical course trending liver biochemistries in relation to treatments employed before and after development of immune checkpoint inhibitor-mediated cholangiopathy. (Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; Nivo, nivolumab; Pred, prednisone; UDCA, ursodeoxycholic acid or ursodiol; AZA, azathioprine; IV, intravenous; methylpred, methylprednisolone).

Prognostic factor analysis of patients with unresectablelung squamous cell carcinoma

Objective: To investigate the prognostic factors associated with unresectable (stage Ⅲa-Ⅳ, according to the 7th edition of the AJCC cancer staging manual) lung squamous cell carcinoma. Methods: We retrospectively analyzed 350 patients with inoperable locally advanced, recurrent or metastatic lung squamous cell carcinoma who were admitted to the First Affiliated Hospital of Chinese Medical University from January 2005 to June 2018. The clinical pathological data, treatment and survival follow-up information of the patients were collected. Kaplan-Meier survival was used to compare the overall survival rate of different risk groups. Univariate analysis and multivariate Cox regression analysis were used to determine the independent prognostic factors. Results: A total of 350 patients were enrolled. The median overall survival (OS) of these patients was 16.7 months. Univariate analysis showed the stage, Eastern Cooperative Oncology Group(ECOG), first-line chemotherapy evaluation (RECIST version 1.1), radiation therapy, number of systemic chemotherapy lines, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), C reactive protein (CRP), lactate dehydrogenase (LDH), whether liver, brain, boneor metastasis were associated with the OS of patients with advanced lung squamous cell carcinoma (all P<0.05). Multivariate analysis showed that ECOG score (HR=1.855, 95% CI: 1.063-3.239, P=0.030), whether underwent lung resection (HR=0.476, 95%CI: 0.302-0.751, P=0.001), first-line chemotherapy evaluation [stable disease (SD): HR=0.293, 95%CI: 0.159-0.540, P<0.001; complete response (CR)+ partial response (PR): HR=0.223, 95%CI: 0.120-0.413, P<0.001], CRP (HR=1.715, 95% CI: 1.080-2.723, P=0.042), LDH (HR=1.116, 95%CI: 0.780-1.596, P=0.002) and CEA (HR=1.855, 95%CI: 1.361-2.528, P<0.001) before chemotherapy, liver metastasis (HR=2.453, 95%CI: 1.461-4.120, P=0.001) are independent prognostic factors for patients with unresectable lung squamous cell carcinoma. Conclusion: The ECOG score, surgical treatment history, first-line chemotherapy, LDH, CEA and CRP before chemotherapy, liver metastasis are independent prognostic factors for patients with advanced lung squamous cell carcinoma.

The Current Landscape of Immune Checkpoint Blockade in Metastatic Lung Squamous Cell Carcinoma.

In addition to surgery, chemotherapy, radiotherapy, and targeted therapy, immunotherapy has emerged as a standard pillar of cancer treatment. Immune checkpoint inhibitors (ICIs) such as targeting programmed death-1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have been integrated into standard-of-care regimens for patients with advanced lung squamous cell carcinoma (LUSC), who were previously limited by the lack of treatment options. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Recent successes and failures of immune checkpoint blockade-based combination therapies have provided significant insights into implementing combination strategies in LUSC. Therefore, there is an urgent need to correctly select patients who are more likely to respond to immunotherapy and understand the mechanisms of primary or acquired resistance. In this review, we aim at summarizing the emerging clinical data on the promise and challenge of ICIs, discussing the unmet need of potential biomarkers for predicting response or resistance to immunotherapy, and providing an overview of the current immune landscape and future directions in advanced LUSC.