Metastatic Squamous Non-small Cell Lung Cancer Research Articles

Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC).

e20546 Background: Anti-programmed death-1 antibodies (PD-1 Abs) have shown benefits in advanced NSCLC. The efficacy and safety of sintilimab, a PD-1 Ab, in combination with chemotherapy for 1L NSCLC is evaluated in this phase Ib study (NCT02937116). Methods: The study enrolled treatment-naïve unresectable locally advanced or metastatic non-squamous (nsq-) and squamous (sq-) NSCLC patients with neither EGFR mutations nor ALK rearrangements in cohort D and E respectively. Patients received sintilimab 200mg IV q3w in combination with pemetrexed 500mg/m2 and cisplatin 75mg/m2 IV q3w (4 cycles) in cohort D, or gemcitabine 1250mg/m2 D1,8 and cisplatin 75mg/m2 D1 IV q3W (6 cycles) in cohort E until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the efficacy and safety of the combination. Results: As data cutoff (15 Jan 2019), 21 and 20 patients were enrolled in cohort D and E respectively. ORR in nsq- and sq-NSCLC were 68.4% (95%CI, 43.4 to 87.4) and 64.7% (95%CI, 38.3 to 85.8) respectively based on data of 19 and 17 patients with at least one radiological assessment. Median PFS was 11.4 months (95%CI, 3.1 to NA) and 6.5 months (95%CI, 5.3 to 8.0) respectively (Table). Totally 38 (92.7%) patients experienced at least one treatment emergent adverse event (TEAE). Treatment-related AEs (TRAEs) occurred in 28 (68.3%) patients. TRAE ≥grade 3 occurred in 4 (9.8%) patients. Immune related AEs occurred in 10 patients (24.4%), the most common of which were skin rash (N = 5), pneumonitis (N = 3) and hypothyroidism (N = 2). There was no AEs leading to death. The biomarker analysis was ongoing. Conclusions: The combination of sintilimab and chemotherapy showed efficacy with an acceptable safety profile in 1L nsq- and sq-NSCLC. Two phase III trials are ongoing to evaluate the combination in 1L nsq- (NCT03607539) and sq-NSCLC (NCT03629925) respectively. Clinical trial information: NCT02937116. [Table: see text]

Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Cost-effectiveness of pembrolizumab in combination with chemotherapy versus chemotherapy and pembrolizumab monotherapy in the first-line treatment of squamous non-small-cell lung cancer in the US

Objective: To describe the cost-effectiveness of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel; P + C) in metastatic, squamous, non-small-cell lung cancer (NSCLC) patients in the US.Methods: A model comparing P + C versus C alone is developed utilizing partitioned survival analysis. Primary clinical efficacy, treatment utilization, health utility and safety data are derived from the KEYNOTE-407 trial and projected over 20 years. Costs for drugs and non-drug disease management are also incorporated. Additionally, the cost-effectiveness of P + C vs. pembrolizumab monotherapy (P) is evaluated via an indirect treatment comparison, for patient subgroups with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and 1–49%.Results: Overall, P + C is projected to increase life expectancy by 1.95 years vs. C (3.86 versus 1.91). The resultant ICER is $86,293/QALY. In patients with PD-L1 ≥ 50%, 1–49% and <1 the corresponding incremental cost-effectiveness ratios (ICERs) are $99,777/QALY, $85,986/QALY and $87,507/QALY, respectively. Versus P, in the PD-L1 ≥ 50% subgroup, P + C appears cost saving; however, this result should be interpreted with caution as there is considerable uncertainty in the relative efficacy of these comparators.Conclusions: Across all eligible patients, the addition of pembrolizumab to chemotherapy is projected to approximately double life expectancy, yielding an extension to a point not previously seen in metastatic squamous NSCLC. Overall, and within all relevant PD-L1 subgroups, use of P + C yields an ICER below $100,000/QALY, and can be a cost-effective first-line treatment for eligible metastatic squamous NSCLC patients for whom chemotherapy is currently administered. In the PD-L1 ≥ 50% subgroup, additional follow-up within trials of pembrolizumab plus chemotherapy and pembrolizumab monotherapy are needed to better define cost-effectiveness between these comparators.

First-line treatment of patients with advanced or metastatic squamous non-small cell lung cancer: systematic review and network meta-analysis.

The objectives of this systematic review and meta-analysis were to compare the survival, toxicity, and quality of life of patients treated with necitumumab in combination with gemcitabine and cisplatin. These agents were investigated in published randomized controlled trials (RCTs) of patients with squamous non-small cell lung cancer (NSCLC) in the first-line setting. The systematic review was executed on January 27, 2015, and updated on August 21, 2016, using a pre-specified search strategy. Searches were conducted using PubMed, Medline, and EMBASE, with supplemental searches using the Evidence Based Medicine Reviews and ClinicalTrials.gov to identify RCTs published in English from 1995-2016 and reporting at least one of the primary outcomes [overall survival (OS), progression-free survival (PFS), toxicity, or quality of life] in patients who received first-line treatment for advanced or metastatic squamous NSCLC. Study quality and risk of bias were assessed using the Physiotherapy Evidence Database (PEDro) scale and Cochrane risk of bias tool, respectively. A Baysian network meta-analysis was performed on the primary outcomes. Hazard ratios (HRs) were evaluated for the primary analysis; secondary analyses were conducted using median OS data. Planned sensitivity analyses were conducted including reanalysis using a Frequentist approach and limiting analyses to subsets based on clinical and demographic covariates. The systematic literature review resulted in identification of 4,016 unique publications; 40 publications (35 unique trials) were eligible for inclusion. Eight studies connected to a common network for the OS analysis using HR data. The majority of studies were not limited to squamous NSCLC, thus analyzable data were limited to a subset of data within the published trials. Carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin were associated with lower HRs for OS versus all other comparators. Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR. Data were not available to analyze toxicity or quality of life. Although the results suggest that carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin may have value in terms of OS versus other comparators, the results should be interpreted with caution due to the limited number of studies (with few focused exclusively on squamous NSCLC) and wide credible intervals.

Afatinib Therapy: Practical Management of Adverse Events With an Oral Agent for Non-Small Cell Lung Cancer Treatment.

Afatinib is an oral, irreversible ErbB family blocker indicated for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with non-resistant epidermal growth factor receptor (EGFR) mutations. Afatinib is also approved for the treatment of metastatic squamous NSCLC following progression on platinum-based chemotherapy. Common afatinib-associated toxicities include gastrointestinal and dermatologic events, which can be dose limiting. In this review, the authors describe clinical trial experiences with afatinib, as well as best practices and practical approaches to the management of afatinib-associated adverse events in EGFR mutation-positive NSCLC. Safety and tolerability data from phase 3 trials of afatinib were reviewed, together with real-life experiences from the authors' clinical practices. Patient education, combined with early assessment and effective management of afatinib-related adverse events as well as dose- reduction strategies, allows patients to continue treatment and maximize the clinical benefits of afatinib.

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non–Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group

BackgroundThe present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non–small-cell lung cancer (NSCLC). Patients and MethodsPatients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. ResultsA total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. ConclusionThe biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.

Estimated costs of managing treatment-related adverse events (TRAEs) of nivolumab (nivo) and docetaxel (doc) in the CheckMate 017 and CheckMate 057 phase III non-small cell lung cancer (NSCLC) trials.

6617Background: Nivo, a PD-1 antibody, received FDA approval based on superior overall survival in metastatic squamous (SQ) and non-squamous (NSQ) NSCLC patients who have progressed on or after platinum-based doublet chemotherapy. The purpose of this study was to assess the frequency and associated costs of grade 2–4 AEs in the CheckMate 017 (SQ) and CheckMate 057 (NSQ) phase III pivotal trials of nivo vs doc in stage IIIB/IV NSCLC. Methods: Patient-level data from these two trials were utilized to estimate the frequency of TRAEs requiring management in the nivo and doc arms, including serious and non-serious TRAEs. Minimum follow-up for AE reporting at database lock was 12 months. Grade 3–4 AE costs by event were identified from Healthcare Cost and Utilization Project (HCUP) data in 2010, which were adjusted to reflect 2012-equivalent US costs. Healthcare utilization associated with grade 2 AEs was based on clinical opinion and costs were based on HCUP or other sources as appropriate. Results: In both tr...

Necitumumab: First Global Approval.

Eli Lilly is developing necitumumab (Portrazza™), an intravenously administered fully human IgG monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which is expressed in a variety of solid tumours and has been implicated in promoting oncogenesis and tumour progression. Necitumumab is approved as a part of combination therapy (with gemcitabine and cisplatin) in the USA for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), and regulatory submissions have been made in the EU for this same indication. Necitumumab was derived from the proprietary phage display library of Dyax Corp, and originated with ImClone Systems, which was acquired by Eli Lilly in November 2008. Necitumumab was also under phase II development for colorectal cancer in Belgium and Spain; however, no recent development has been reported for this indication. This article summarizes the milestones in the development of necitumumab leading to this first approval for the first-line treatment of metastatic squamous NSCLC, in combination with gemcitabine and cisplatin.

Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting the drug treatment paradigm with immunotherapies.

Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1) or its ligand (PD-L1) (nivolumab and pembrolizumab) have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided.

Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer.

Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody, developed by Bristol-Myers Squibb Inc., has activity across non-small cell lung cancer (NSCLC) histologies and is Food and Drug Administration approved for treatment of metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. PD-L1 has been investigated as a potential biomarker to predict clinical response to nivolumab in clinical settings. We report an automated PD-L1 immunohistochemistry (IHC) assay, which was developed to detect cell surface PD-L1 in formalin-fixed paraffin-embedded human tumor tissue specimens using Dako's Autostainer Link 48. The primary antibody for this assay is a rabbit monoclonal anti-human PD-L1 antibody, clone 28-8. The specificity of 28-8 for PD-L1 was demonstrated by antigen competition and genetic deletion of PD-L1 in tumor cell lines. The specificity of the PD-L1 IHC assay was further evaluated in a collection of 30 normal human tissues. The PD-L1 IHC assay was optimized for high sensitivity and precision in routine application. A pathology scoring and interpretation method specific to nivolumab clinical studies was adopted for the assay. The analytical performance of the assay was validated for application in the determination of PD-L1 status in human NSCLC specimens. The clinical application of the assay and scoring method was further validated in 3 Clinical Laboratory Improvement Amendments certified labs. The assay is currently being investigated in a variety of clinical studies for use as an in vitro diagnostic to select and stratify patients for treatment with the anti-PD-1 therapeutic antibody, nivolumab.

Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities.

Immune checkpoint blockade using inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has shown clinically significant antitumor response and has been approved for the treatment of malignant melanoma and squamous non-small cell lung cancer (NSCLC). These immunotherapies are associated with unique set of toxicities termed immune-related adverse events (irAEs) that are very different from toxicities observed with conventional cytotoxic chemotherapy. Prompt recognition and initiation of appropriate management, usually in the form of immunosuppression, usually results in complete reversibility, but failing to do so can lead to severe toxicity or even death. Clinical algorithms describing the management of common irAEs have been published based on clinical trial information and experience in metastatic melanoma with ipilimumab, a human IgG1 monoclonal antibody that binds to CTLA-4 and blocks T cell inhibition. The most common irAEs reported with ipilimumab are dermatologic toxicity, diarrhea/colitis, hepatotoxicity, and endocrinopathies, although other sites can also be affected. Similar irAEs have been observed with agents targeting PD-1. Nivolumab and pembrolizumab are humanized monoclonal antibodies that bind to PD-1 and prevent T cell inactivation. Ipilimumab, pembrolizumab, and nivolumab are approved by the Food and Drug Administration (FDA) for the treatment of advanced melanoma; nivolumab was also recently approved for metastatic squamous NSCLC. This review describes the optimal management of toxicities related to immune checkpoint inhibition from FDA-approved agents targeting CTLA-4 and PD-1.

BRIDGE: An open-label phase II trial evaluating the safety of bevacizumab (BV) plus paclitaxel/carboplatin (PC) as first-line treatment (tx) for patients (pts) with advanced, previously untreated, squamous non-small cell lung cancer (NSCLC).

7583 Background: In a phase II study of first-line tx with BV + PC for NSCLC, squamous histology was found to be a risk factor for severe (Gr ≥ 3) pulmonary hemorrhage (PH). Subsequently, pts with predominantly squamous histology were generally excluded from phase III studies. This final analysis from the BRIDGE study assesses safety of delayed BV administration in pts with locally advanced or metastatic squamous NSCLC. Methods: BRIDGE was an open-label, single-arm, multicenter pilot study of PC alone in cycles 1 and 2, and PC + BV in cycles 3 to 6, followed by BV until progressive disease (PD) or unacceptable toxicity. Eligible pts had stage IIIb (with pleural effusion), stage IV, or recurrent squamous NSCLC. Pts with recent arterial thromboembolic events, gastrointestinal perforation, hemoptysis, untreated brain metastases, intrathoracic lesion(s) with cavitation, or anticoagulation therapy were not eligible. The primary endpoint was incidence of Gr ≥ 3 PH. Results: Forty- seven pts received 2 initial cycles of PC, and 31 continued on study to receive ≥ 1 dose of BV. Median age was 65 (range: 48-80); 96.3% had Stage IV disease. Pts received a median of 6.0 (range, 1-18) doses of BV, and 2 pts (6.5%) completed 12 mos of tx. Among the 31 pts who received BV, there were 3 reports of PH of any grade in 2 pts. One pt had Gr 1 PH during cycle 3, withdrew due to PD on the same day, and recovered from PH. A second pt developed Gr 3 PH after post-progression treatment, 44 days after the last BV dose; PH resolved 2 d later, but after another 55 d the pt developed Gr 4 PH, and subsequently died due to PD. Incidence of Gr ≥ 3 PH (1 pt) was 3.2% (90% CI: 0.3-13.5%). Nine pts (29.0%) experienced Gr 3 events, including 5 (16.1%) with hypertension; 5 experienced Gr 4 events (dyspnea, PH, basal ganglia infarction, cerebral ischemia and pain). Median progression-free survival (PFS) was 6.2 mos (95% CI: 5.32-7.62 mos); 57% of pts had PFS of ≥ 6 mos. Conclusions: The incidence of Gr ≥ 3 PH in this study was 3.2% (1 pt). No new safety signals were identified. Until further trials are conducted, tx of squamous NSCLC with BV should be considered experimental. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche

Expression of gemcitabine and cisplatin-related genes according to histology and stage in non-small-cell lung cancer (NSCLC)

14644 Background: A number of pharmacogenomic studies have been recently carried out to find out a possible relationship between gene expression and treatment outcome in NSCLC; however, to our knowledge, no data are available on the possible influence of tumor histology and tumor stage on gene expression profile. The aim of this study was the characterization of the expression pattern of genes involved in gemcitabine and cisplatin activity in primary or metastatic adenocarcinoma or squamous carcinoma NSCLC specimens. Methods: Excision repair cross-complementing 1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5’-nucleotidase (5’-NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) were analyzed by quantitative RT-PCR in 89 laser microdissected lung tissues (52 primary tumors, 23 metastatic lymph nodes and 14 normal lung tissues), from 69 patients. β-actin was used as housekeeping gene. Results: The quantitative expression analysis in patients’ samples demonstrated that these target genes were detectable in most surgical specimens. hENT1, CDA and dCK expression was significantly lower in normal than in tumor tissues (p<0.05). A difference in mean CDA expression was also found between tumor (1.015±0.015) and node metastasis (0.965±0.019). Furthermore, a significant (p<0.05) variability of mean gene expression was observed between adenocarcinoma and squamous cell carcinoma with respect to 5’-NT, RRM1 and RRM2. In particular, the mean gene expression values of both RRM1 and RRM2 were significantly higher in squamous cell carcinomas with respect to adenocarcinomas, while 5’-NT expression values were significantly higher in adenocarcinomas. Conclusions: We have identified the differences in expression of gemcitabine and cisplatin-related genes due to tumor stage and histology. The knowledge of these variations in gene profiles should be be taken into account for pharmacogenomic data interpretation and must be considered in predicting gemcitabine/cisplatin efficacy and in personalizing treatment for lung cancer patients. No significant financial relationships to disclose.