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J. Spaans

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    ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)

    • Event: WCLC 2015
    • Type: Education Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ED07.02 - Current State of the Art (ID 1799)

      14:15 - 15:45  |  Author(s): J. Spaans

      • Abstract
      • Presentation

      Squamous cell carcinoma of the lung accounts for 20-30% of all non-small cell lung cancer (NSCLC). Until recently, treatment options for advanced squamous NSCLC (sqNSCLC) were limited. Compared to non-squamous NSCLC, standard care of sqNSCLC was restricted to first-line platinum-based doublet chemotherapy and second-line docetaxel or the epidermal-growth factor receptor (EGFR) inhibitor, erlotinib, and did not include pemetrexed because of inferior efficacy[1], bevacizumab because of increased risk of pulmonary hemorrhage[2] or agents active against known oncogenic driver mutations. Prompted by the high levels of EGFR overexpression in sqNSCLC and encouraging activity of EGFR-targeted therapies in patients with squamous histology [3,4] EGFR-inhibition trials limited to patients with sqNSCLC were initiated, the results of which are redefining the treatment of sqNSCLC. In the first-line setting, the addition of the second-generation recombinant human IgG1 EGFR monoclonal antibody (Mab), necitumumab, to gemcitabine and cisplatin has been shown to improve overall survival (OS) 11.5m vs 9.9 m (HR: 0.84, 95%CI: 0.74-0.96) in the phase III open-label SQUIRE trial, with comparable adverse events (AE) leading to treatment discontinuation in both treatment arms.[5] The better tolerability of necitumumab over the first-generation chimeric EGFR Mab, cetuximab, is supported by the similar OS efficacy in patients with good (PS: 0-1) (HR: 0.85, 95%CI: 0.74-0.98) and poor performance status (PS=2) (HR: 0.78, 95%CI: 0.51-1.21), in the absence of additional safety risk.[6] In fact, in SQUIRE, necitumumab was notably more effective at higher levels of baseline symptom severity[7] , which is contrary to the belief that patients with sqNSCLC deteriorate too quickly to benefit from combination approaches. In the second-line setting, the newer second-generation EGFR small molecule inhibitor, afatinib, has also been shown to improve OS. Most recently, the results of the phase III LUX-Lung 8 trial of afatinib vs erlotinib in patients with sqNSCLC progressing after four cycles of platinum-based chemotherapy have been published, demonstrating improved OS with afatinib 7.9m vs 6.8m (HR: 0.81, 95%CI: 0.69-0.95), with similar adverse events profiles noted between groups.[8 ]Based on these results, afatinib is clearly a treatment option for patients in the second-line management of sqNSCLC. Together, the recent results of these small molecule and MAb anti-EGFR studies support the continued relevance of EGFR as a target in the treatment of sqNSCLC and are shaping management strategies. Despite being a hallmark of cancer, the inhibition of angiogenesis has historically proven challenging in the treatment of patients with sqNSCLC due to the central location of these tumors and their close proximity to large blood vessels in the chest wall, and has been associated with an increased risk of bleeding. Findings from newer second-generation angiogenesis inhibitors, however, show comparable levels of gastrointestinal and respiratory tract bleeding events across all NSCLC histologies. [9 ] Compared to placebo, the anti-VEGFR-2 IgG MAb, ramucirumab, has recently been shown to improve progression-free survival (PFS) 4.5m vs 3.0 m (HR: 0.76, 95%CI: 0.68-0.86) and OS 10.5m vs 9.1m (HR: 0.86, 95%CI:0.75-0.98) in patients with advanced NSCLC progressing after first-line platinum-based chemotherapy, with significant improvements in patients with squamous histology in terms of overall objective response (ORR) (26.8% vs 10.5%, p=0.001), disease control rate (59.9% vs 45%, p=0.015) and PFS 4.2m vs 2.7m (HR 0.78, 95%CI0.61-0.96) and a numerically superior OS benefit 9.5m vs 8.2m (HR: 0.88, 95%CI: 0.69-1.13). [9 ] In Dec 2014, ramucirumab received FDA approval for use with docetaxel in the second-line management of advanced NSCLC, including patients with squamous histology. Finally, the inhibition of T-cell activation through programmed death (PD-1) receptor interaction with the tumor expressing PD-L1 ligand (immune checkpoint) is a noted mechanism of tumor immune surveillance escape in NSCLC. From early clinical trials immune checkpoint blockade is an attractive therapeutic strategy in NSCLC, given its ability to activate the immune system and produce long-term response. In the management of sqNSCLC, the fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has recently replaced docetaxel as the preferred second-line therapy based on the results of CHECKMATE 017 [10], a phase III study of nivolumab versus docetaxel. Findings in CHECKMATE 017 demonstrated improved median OS 9.2m vs 6.0m (HR: 0.59, 95%CI: 0.44-0.79) and improved 1-year survival over docetaxel (42% vs 24%), with a more favorable safety profile and fewer treatment related grade 3/4 AE (7% vs 55%).[10] With the recent FDA approval of nivolumab in the second-line setting in March 2015, docetaxel will likely be relegated to third-line therapy in the management of sqNSCLC. However, additional studies are required to confirm the results of CHECKMATE 017 given the lower than expected median survival observed in the docetaxel arm, to identify biomarkers of response, and to better define the unique toxicities associated with these immune-modulating agents. The last year has seen an unprecedented evolution in the management of sqNSCLC, with survival gains noted in both the first and second-line setting in randomized clinical trials. Unfortunately, to date the identification of oncogenic driver mutations in sqNSCLC have yet to yield the significant improvements seen in non-squamous histology, however it is likely that the relevant biomarkers of efficacy will soon be identified. Regardless, with the current regulatory approvals and the numerous novel agents in development, improved outcomes in patients with squamous cell carcinoma of the lung are anticipated. The immediate task, with the expanded treatment options now available for sqNSCLC, is the interrogation of new combinations and the sequencing of available therapies to maximize the benefit for this historically underserved subgroup of patients with NSCLC. References 1. Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in non-squamous non-small cell lung cancer. J Thorac Oncol 2011; 6: 64-70. 2. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2004; 22: 2184-91. 3. Pujol JL, Pirker R, Lynch TJ et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 2014; 83: 211-218. 4. Kim JH, Grossi F, De Marinis F et al. Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy : interim subset analysis from a phase III trial. Proc Am Soc Clin Oncol 2012; 30 (suppl 15): abstr 7558. 5. Thatcher N, Hirsch F, Luft A et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol 2015; 16(7): 763-774. 6. Socinski M, Luft A, Szczesna A et al. Subgroup analyses by performance status (PS) in the phase III SQUIRE study: First-line necitumumab (N) plus gemcitabine-cisplatin (GC) vs. GC in squamous non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33:suppl; abstr e19023. 7. Reck M, Gralla RJ, Bonomi P et al. Maximum severity score (MSS) of baseline patient-reported Lung Cancer Symptom Scale (LCSS) as a prognostic and predictive factor for overall survival (OS) in the Phase III SQUIRE study. ASCO Meeting 2015 abst; 33: 8099. 8. Soria J-C, Felip E, Cobo M et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet 2014; 384: 665-73. 10. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in advanced squamous-cell non small cell lung cancer. NEJM 2015; doi: 10.1056/NEJMoa1504627.

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