Metastatic Squamous Non-small Cell Lung Research Articles

Bevacizumab en association à une première ligne de chimiothérapie chez des patients atteints d’un cancer bronchique non à petites cellules, non épidermoïde, à un stade avancé ou en rechute : résultats de l’étude non interventionnelle EOLE

The EOLE cohort aimed to describe, in routine clinical practice, the characteristics and management of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced metastatic or recurrent non squamous non-small cell lung cancer (nsNSCLC), as well as its efficacy and safety. A total of 423patients were enrolled in this prospective, national, multicenter study. Data were collected every 3months over an 18-month period. Amongst the 407patients analyzed (mean age 60±10years, male 68%, ECOG-PS≤1 88%, smokers or former smokers 87%, cardiovascular comorbidities 40%), all except for 2patients received bevacizumab (7.5 or 15mg/kg/3weeks in 99% of patients) in combination with doublet chemotherapy. A total of 160 (60%) patients who completed induction received bevacizumab maintenance therapy. Median progression-free survival was 6.9months (95% CI=[6.0-7.5]). Median overall survival (12.8 months [10.4-14.7]) was longer in patients with ECOG-PS≤1 (14.4 months [12.3-15.9] versus 4.9 months [3.4-8.3] if ECOG-PS=2). A total of 131 (32%) patients experienced at least one serious adverse event (SAE), and 51 (12%) at least one bevacizumab-related SAE. EOLE confirms the efficacy and safety of bevacizumab in aNSCLC patients, in current medical practice.

Abstract OT1-01-07: nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC)

Abstract Background: Nivo is an inhibitory antibody against programmed death receptor-1 (PD-1), a regulator of antitumor immunity. Nivo is approved for treatment of unresectable or metastatic melanoma and disease progression (PD) following ipilimumab or, in BRAF V600 mutation–positive melanoma, following a BRAF inhibitor, and for metastatic squamous non-small cell lung cancer (NSCLC) following PD during or after platinum-based chemotherapy. Nivo and other immune checkpoint inhibitors are also being investigated in other tumor-types. nab-P is a novel taxane formulation and does not require prophylaxis with immunosuppressive steroids. It has demonstrated superior efficacy over control regimens in phase III studies of MBC, pancreatic cancer, and NSCLC. This open-label, 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P in 3 cancer types (2 arms/disease): MBC, advanced NSCLC (+ carboplatin), and advanced pancreatic cancer (± gemcitabine). The study design for the MBC portion is described below. Methods: Eligibility criteria include histologically/cytologically confirmed HER2-negative MBC; 1 prior chemotherapy for MBC, including an anthracycline unless clinically contraindicated; no relapse < 12 months after taxane adjuvant therapy; measurable disease by RECIST v1.1; ECOG performance status 0-1; adequate organ function; and preexisting peripheral neuropathy grade < 2. Patients (pts) with MBC will be treated in 2 arms: nab-P 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus Nivo 3 mg/kg on days 1 and 15 starting at cycle 3 or nab-P 260 mg/m2 on day 1 of each 21-day cycle plus Nivo 5 mg/kg on day 15 starting at cycle 3. Pts will be treated until PD or allowed to continue treatment beyond RECIST v1.1–defined PD if they continue to meet study eligibility; do not have rapid PD or clinical deterioration or unacceptable toxicities; and can benefit from continuation of study treatment in the treating physician's opinion and will not delay an imminent intervention to prevent serious complications of PD. The primary endpoints of the study are the number of pts with dose-limiting toxicities (DLTs) in each treatment arm (part 1) and the percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to a TEAE (parts 1 and 2). Part 1 of the study will assess whether the starting dose of Nivo is deemed safe (≤ 1 DLT in 6 pts); otherwise, the Nivo dose will be de-escalated and assessed in a new cohort at the next lower dose level. The Nivo dose in combination with nab-P deemed safe in a treatment arm may be further assessed in part 2 of the study, with enrollment expanded to an additional ∼ 14 pts/arm (total of 20 Nivo-treated pts/arm). Secondary study endpoints include TEAEs leading to dose reduction, delay, interruption, or treatment discontinuation; progression-free survival; overall survival; disease control rate; overall response rate; and duration of response (per RECIST v1.1). Exploratory endpoints include tumor-associated PD-L1 expression, modulation of immune activation in the tumor and peripheral blood in response to Nivo treatment, Nivo serum levels, and development of anti-globulin antibodies. ClinicalTrials.gov identifier NCT02309177. Citation Format: Waterhouse D, Gutierrez M, Bekaii-Saab T, DeRosa W, Wainberg Z, George B, Duval Fraser C, Ko A, Pierce DW, Stergiopoulos S, Soliman H. nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-07.

Nab-paclitaxel (nab-P) + nivolumab (Nivo) ± gemcitabine (Gem) in patients (pts) with advanced pancreatic cancer (PC).

TPS475 Background: Nivo, an antibody against PD-1, is approved for unresectable or metastatic melanoma and metastatic squamous non-small cell lung cancer (NSCLC) after initial standard therapies. nab-P does not require immunosuppressive steroid premedication and is approved for treatment of metastatic breast cancer (MBC) after initial chemotherapy (CT) including an anthracycline, and for advanced NSCLC (+ carboplatin), and metastatic PC (+ Gem). This 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P— based therapy in MBC, advanced NSCLC, and advanced PC. The study design for the pancreatic portion (arm A: nab-P + Nivo; arm B: nab-P + Gem + Nivo) is described below. Methods: This 2-part study will identify dose-limiting toxicities (DLTs) in Part 1 and assess safety and explore antitumor activity in Parts 1 and 2 (Table). If Arm A, Part 1, is deemed safe (≤ 1 DLT in up to 6 pts), then Arm B, Part 1, will initiate enrollment. Regimens in Part 1 may be expanded in Part 2. Enrollment in Arm A, Part 1, is ongoing. ClinicalTrials.gov: NCT02309177. Clinical trial information: NCT02309177. [Table: see text]

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.

Preclinical Advances in Combined-Modality Cancer Immunotherapy With Radiation Therapy

Cancer immunotherapy as a field seeks to exploit the pathways by which tumors and their microenvironment escape detection and elimination by the host immune system. Cancer cells have demonstrated a variety of ways of escaping immune detection, including decreased presentation of tumor-specific antigens, release of immunosuppressive cytokines, and activation of T-cell inhibitory pathways. Interventions against the latter mechanism have demonstrated the greatest potential of cancer immunotherapy to date. The cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 receptor (PD-1) are T-cell surface receptors that, when activated by their respective ligands, serve to suppress T-cell functions by separate pathways. Anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) have been developed as immune checkpoint inhibitors and approved by the US Food and Drug Administration for clinical use in the treatment of advanced melanoma (ipilimumab and nivolumab) and metastatic squamous non-small cell lung cancer (nivolumab). The finding that dual immune checkpoint blockade in patients with metastatic melanoma prolongs overall survival and induces greater responses over monotherapy advances the promise of immunotherapy as a treatment modality (1). Radiation therapy has long been used as a local treatment modality in cancer care. The cytotoxic effect of radiation results in release of tumor-associated antigens and damage-associated molecular patterns that can produce an immunogenic response, which in some cases can produce an abscopal effect. The earliest report of an abscopal effect, defined as an “effect of radiation that is manifested at a distance from the volume of tissue which is directly irradiated,” listed in PubMed.gov was authored by Law and Mole in 1961 (2). The earliest evidence that we are aware of that abscopal effects involved immune responses was by Mikuriya et al (3), who found that large doses of ionizing radiation could be leveraged into a systemic antitumor response. The initial report by Postow

Treatment of Advanced and Metastatic Squamous Non-small Cell Lung Cancer

Lung cancer is a disease with a poor prognosis, and is the leading cause of cancer-related death in Korea as well as the USA. Unlike non-squamous non-small cell lung cancer (NSCLC), squamous NSCLC rarely harbors epidermal growth factor receptor and anaplastic lymphoma kinase mutations for which directed molecular targeted therapies are available. Traditional cytotoxic chemotherapy drugs, including cisplatin, have been approved for use in the treatment of advanced and metastatic squamous NSCLC. The second-generation regimens—gemcitabine, paclitaxel, docetaxel, and vinorelbine with cisplatin—are standard first-line treatments for advanced and metastatic squamous NSCLC. Docetaxel was approved for second-line treatment in 1999. Addition of the anti-angiogenic agent, ramucirumab, to docetaxel showed improved survival in squamous cell NSCLC patients in the second-line setting compared with single-agent docetaxel. The immune checkpoint inhibitor-programmed cell death-1 inhibitor, nivolumab, is currently approved for squamous cell NSCLC. Pembrolizumab also received FDA approval for treatment of NSCLC cases in which tumor tissue is positive for programmed cell death-ligand 1 expression. Keywords: Neoplasm, Squamous cell; Lung neoplasms; Drug therapy; Angiogenesis inhibitors; Immunotherapy 중심 단어: 편평상피세포암; 폐암; 약물 치료; í˜ˆê´€í˜•ì„±ì–µì œì œ; 면역 치료

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer

The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

Abstract B94: Efficacy of PD-1 - PD-L1 pathway disruptors in syngeneic models

Abstract Immune checkpoint modulators, such as antibodies targeting CTLA-4 or PD-1, are now being approved for treatment of patients with unresectable or metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC) who have progressed on or after platinum-based chemotherapy. Efficacy was also evidenced on other tumor types (renal cell carcinoma, bladder, Hodgkin lymphoma, colorectal carcinoma (CRC) ⋯). However, there is still needs to identify predictive biomarkers of response in order to select patients who will benefit from treatments. PD-L1 expression was proposed to be a good candidate for NSCLC, even if PD-L1 expression is a difficult parameter due to its expression on both tumor cells and immune cells as well as technical challenges to use immunohistochemical detection. The dynamic of the immune system as well as the site and time where interactions between tumor cells and immune cells take place, increase the complexity of having a solid biomarker identified. In addition, for other pathologies like colorectal carcinoma, genomic biomarkers were evidenced. For example, CRC patients with mismatch repair (MMR) deficiencies have an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors. We propose here the use of syngeneic models to address mechanism of action and biomarker related questions for agent targeting PD-1 / PD-L1 axis. Syngeneic model systems remain one of the only options to analyse physiologically relevant interactions between tumor and immune cells. Up to now, eight models were characterized for response to either PD-1 and/or PD-L1 targeting antibodies. Among them, 4T1, LLC and Renca were identified as non-responders and B16-F10, CT-26, EMT-6, MBT-2 identified as partial responders. Most of the time, targeting PD-1 is more effective than targeting PD-L1, even if there is exception (e.g. B16-F10). Attempting to identify key parameters that could help us understand efficacy of PD-1 /PD-L1 axis disruptors, intratumoral immune infiltrate was analyzed in depth using flow cytometry: regulatory T cells (Treg), effector T cells (Teff), M-MDSCs, G-MDSCs, TAMs were phenotyped and quantified. In contrast to CTLA-4 targeting therapy, where Teff/Treg ratio was correlated to treatment efficacy, this is not the case for PD-1 or PD-L1 targeting therapies. It is now hypothesized that a more complex signature (e.g. detailed phenotype of CD8 positive T cells, tumor neoantigen expression⋯) will be needed to identify valuable biomarkers of response. Preliminary results using syngeneic models, both subcutaneously or orthotopically engrafted with tumors, will be presented. Citation Format: MARC HILLAIRET DE BOISFERON, Francis Bichat, CAROLINE MIGNARD, XAVIER TIZON, DAMIEN FRANCE, SYLVIE MAUBANT, Jean-Francois Mirjolet. Efficacy of PD-1 - PD-L1 pathway disruptors in syngeneic models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B94.

Necitumumab in metastatic squamous non-small cell lung cancer (mSqNSCLC): Establishing a value-based cost.

6505 Background: The SQUIRE trial demonstrated that adding necitumumab to chemotherapy for patients with mSqNSCLC produces a median overall survival benefit of 1.6 months (hazard ratio 0.84). The objective of this study was to evaluate the range of drug costs for which adding necitumumab to chemotherapy could be considered cost-effective. Methods: We developed a Markov model to compare the incremental cost-effectiveness of standard chemotherapy with or without necitumumab in the first-line treatment of mSqNSCLC. In the model, patients received gemcitabine and cisplatin for 6 cycles or gemcitabine, cisplatin, and necitumumab for 6 cycles followed by maintenance necitumumab. The clinical inputs were the survival benefits and frequency of adverse events (AEs) described in the SQUIRE trial. Weibull models were fitted to the survival curves in the SQUIRE trial. The cost inputs included drug costs based on the Medicare average sale prices, and costs for drug administration and the management of AEs based on Med...

A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC).

8009 Background: Treatment options are limited for patients (pts) with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC). We report results of a randomized, open-label, global ...

Real-world treatment patterns and costs in a US Medicare population with metastatic squamous non-small cell lung cancer.

Despite advances in the treatment of nonsquamous non-small cell lung cancer (NSCLC), therapeutic choices and overall disease course for squamous NSCLC have remained relatively unchanged over the past several years. We provide a detailed account of current treatment patterns, healthcare use, and survival in real-world clinical settings for metastatic squamous NSCLC. Patients aged ≥65 years with metastatic squamous NSCLC diagnosed 2001-2009 were identified and followed through 2010 using the Surveillance, Epidemiology and End Results-Medicare database. Treatment patterns were descriptively analyzed. Multivariate logistic regressions were estimated to identify predictors of treatment pattern events; generalized linear models were estimated for total all-cause and NSCLC-related costs to assess cost drivers. Of 17,133 patients, 72% received cancer-directed therapy (surgery, radiation, chemotherapy, or biologic therapy), whereas 28% received only supportive care. Median survival was significantly longer in patients receiving cancer-directed therapy (8 months) than in patients receiving supportive care only (2 months) (P<0.0001). An agent-specific first-line chemotherapy regimen was identified for 91% of the 7700 patients who received chemotherapy. Among these, the most common first-line regimen was carboplatin-paclitaxel combination therapy (46%). Common second-line regimens were gemcitabine monotherapy (16%) and pemetrexed monotherapy (11%). Factors associated with decreased odds of receiving cancer-directed treatment were black versus white race (OR, 0.72; 95% CI, 0.64-0.82), residence in the West versus South (OR, 0.73; 95% CI, 0.66-0.81), and metastatic disease at initial diagnosis versus progression to metastatic disease (OR, 0.77; 95% CI, 0.70-0.84). Our study shows that prognosis remains poor for patients with metastatic squamous NSCLC, even among those receiving treatment, but particularly for patients limited to supportive care only, highlighting the continuing unmet medical need in this population. Additionally, our analysis indicates that selections for second-line and third-line chemotherapies are not necessarily consistent with National Comprehensive Cancer Network guidelines.

Abstract LB-215: The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab

Abstract Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that has shown efficacy in metastatic colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Clinical data suggests that patients whom initially respond to cetuximab eventually acquire resistance, highlighting the importance of understanding resistant mechanisms for the development of better treatment regimes for cancer patients. Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, and more specifically the Axl receptor as playing a key role in promoting tumor growth and metastasis. In the current study, we utilized NSCLC and HNSCC models of acquired resistance to cetuximab and found that Axl was overexpressed, activated, and highly associated with EGFR as compared parental controls. Further, using siRNA technology and novel Axl targeting agents (antibody and tyrosine kinase inhibitor), Axl was found to regulate proliferation, EGFR activation, and MAPK signaling in cetuximab resistant clones (CtxR). Additionally, Axl mRNA expression was regulated by EGFR induced MAPK activation in resistant cells. To investigate the role of Axl in in vivo models of acquired resistance to cetuximab, de novo acquired resistance was created by prolonged treatment of cetuximab sensitive (CtxS) tumor xenografts with cetuximab. Analysis of resultant CtxR tumors demonstrated that Axl was hyperactivated and highly associated with EGFR as compared to vehicle treated tumors. In addition, CtxR tumors expressing the highest levels of phosphorylated Axl also expressed hyperactivated EGFR, supporting the role of Axl in EGFR activation. Finally, to expand these findings to other members of the TAM family, Tyro, Axl, or Mer were stably overexpressed in CtxS parental NSCLC cells and tested for cetuximab response. The results of this experimentation indicated that stable overexpression of each TAM receptor rendered CtxS cells resistant to cetuximab therapy. Collectively, the studies presented herein identify the TAM family of receptors as key players in acquired resistance to cetuximab and provide rationale for the clinical evaluation of anti-TAM receptor therapeutics in the resistant setting. Citation Format: Toni Michel Brand, Mari Iida, Kelsey L. Corrigan, Neha Luthar, Megan Hornung, Mahmoud Toulany, Parkash Gill, Ravi Salgia, Deric L. Wheeler. The TAM family of receptor tyrosine kinases play a role in acquired resistance to cetuximab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2014-LB-215

32 Review of pemetrexed with platinum chemotherapy for locally advanced or metastatic non squamous non-small cell lung cancer (NSCLC) in Northern Ireland

32 Review of pemetrexed with platinum chemotherapy for locally advanced or metastatic non squamous non-small cell lung cancer (NSCLC) in Northern Ireland

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus docetaxel in patients with previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC).

TPS8122 Background: NSCLC is the leading cause of cancer death worldwide, exceeding breast, colon and prostate cancer combined. Most patients (pts) are diagnosed with advanced/recurrent disease. NSCLC therapies have incrementally improved overall survival (OS), but benefit has reached a plateau (median OS for late stage pts is just 1 yr). Squamous cell carcinoma (SCC) represents one quarter of NSCLC cases and has limited treatment options. Pemetrexed and bevacizumab are not approved in SCC, and molecularly targeted therapies have limited application. Single-agent chemotherapy is standard of care following progression with platinum-based doublet chemotherapy (Pt-doublet), resulting in median OS of approximately 7 months. Immune checkpoint blockade in NSCLC may promote tumor regression by reversing tumor-induced immunosuppression and restoring the antitumor immune response. Programmed death-1 (PD-1), an immune checkpoint receptor that negatively regulates T-cell activation, is upregulated in tumor infiltrating lymphocytes; expression of its ligand PD-L1 has been associated with poor prognosis in NSCLC. Nivolumab, a PD-1 receptor blocking antibody, showed encouraging antitumor activity in SCC pts in a phase 1 study, with objective responses (ORs) in 4 pts (27%) and stable disease ≥24 weeks in 1 pt (7%) (3 mg/kg; n=15) (Gettinger S et al; ESMO 2012 [Abstr 1237PD]). We describe an ongoing open-label phase 3 study to compare the clinical benefit of nivolumab vs docetaxel in advanced/metastatic SCC pts following failure of Pt-doublet. Methods: A total of 264 pts will be randomized 1:1 to nivolumab monotherapy 3 mg/kg IV every 2 weeks or docetaxel 75 mg/m2 every 3 weeks until disease progression or unacceptable toxicity. Pts will be stratified by prior paclitaxel use and geographic region. Tumor response will be assessed using modified RECIST 1.1. The co-primary objectives are OR rate and OS. Secondary objectives include progression free survival, clinical benefit in PD ligand 1 (PD-L1+) and PD-L1– subgroups (archived tissue required for entry), durability of and time to OR, and pt proportion with symptom improvement. Clinical trial information: NCT01642004.