Virtual Library

Abstract:
In recent years, we have seen a new practical distinction made in terms of management recommendations for the histologic subtypes of non-small cell lung cancer (NSCLC). There is now a growing recognition of the biological relevance of the differences between major histologic subtypes, as clinical trials and distinct management algorithms emerge for the advanced squamous (SQ) NSCLC population. Though differences in the clinical behavior of SQ vs. non-squamous (NSQ) NSCLC have been recognized for decades (1), the first functional distinction emerged with the recognition of different results for SQ and NSQ populations in multiple trials of pemetrexed that together demonstrated that the efficacy of this agent was limited to patients with NSQ histology (2), ultimately leading to a change in the label of pemetrexed, previously approved for all NSCLC patients as second line therapy, to being indicated for NSQ patients only (3). Development of the anti-angiogenic agent bevacizumab was also limited to patients with NSQ histology after a post-hoc analysis of results in a phase II trial of carboplatin/paclitaxel with either of two dose levels of bevacizumab or placebo demonstrated a high risk of life-threatening or fatal pulmonary hemorrhage among patients with SQ histology (4). Subsequent development and clinical use of bevaicizumab in advanced NSCLC has been limited to NSQ histology. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are another class of anticancer therapy that are more effective in NSQ than SQ NSCLC (5). Though patients with SQ NSCLC were included in early, pivotal trials in molecularly unselected populations that revealed a modest overall survival (OS) benefit with erlotinib, molecular selection of patients with an activating EGFR mutation has shown that high response rates (RR) and prolonged benefit with EGFR TKIs is overwhelmingly in patients with an activating EGFR mutation, so rare in SQ NSCLC that routine testing for it is not recommended. ALK and ROS-1 rearrangements are similarly rare in SQ NSCLC, with routine for these markers in SQ NSCLC not recommended. Patients with SQ NSCLC remain candidates for erlotinib in the maintenance or salvage setting, in which its value is so modest as to be debatable. SQ NSCLC patients are presumed to be ALK and ROS-1 wild type and rarely candidates for therapies against these targets. Until very recently, therefore, SQ NSCLC has been characterized by the NSCLC treatments that are considered ineffective, prohibitively toxic, or of relatively marginal benefit. Several new management options, however, have emerged that are more directed to the SQ NSCLC population. Though the randomized phase III trial that let to approval of nab-paclitaxel in advanced NSCLC (6) was not specifically directed to patients with SQ NSCLC, the trial of carboplatin with either paclitaxel or nab-paclitaxel demonstrated a higher response rate in the nab-paclitaxel arm of 41% vs. 24% in favor of nab-paclitaxel. In the absence of other therapies that have shown enhanced efficacy in SQ NSCLC, nab-paclitaxel has an arguable role as first line therapy for SQ NSCLC, though there are no confirmatory trials or biomarker correlates to corroborate a special utility for nab-paclitaxel here. Another chemotherapy-based approach directed to SQ NSCLC is nedaplatin, a second generation platinum compound tested in a Japanese trial of 350 patients with chemotherapy-naïve advanced SQ NSCLC in which subjects were randomized to cisplatin/docetaxel or nedaplatin/docetaxel (docetaxel on each arm administered at the standard Japanese dose of 60 mg/m2 d1 every 21 days) (7). Median OS was >2 months longer with nedaplatin (13.6 vs. 11.4 months, HR 0.81, p = 0.037), and toxicity was relatively comparable between the two arms. Nedaplatin/docetaxel combination may now be considered a new standard treatment for advanced SQ NSCLC in Japan, but the non-standard dosing of docetaxel for global populations and the recognition of potential differences in efficacy of regimens among different racial populations will likely limit broader use of nedaplatin until studies outside of Japan confirm superior efficacy. The SQUIRE trial of the monoclonal antibody against EGFR necitumumab trial in 1093 first line SQ NSCLC patients showed a modest OS benefit when this agent was added to cisplatin/gemcitabine, compared with chemotherapy alone (8). In absolute terms, however, the median OS benefit of only 1.6 months (11.5 vs. 9.9 months), counterbalanced by greater toxicities and costs with the addition of necitumumab, has led to little enthusiasm for favoring the broader incorporation of this agent. Afatinib has been studied in the LUX-Lung-8 trial as an alternative to erlotinib in previously treated patients with SQ NSCLC (9). While the 1.1 month OS benefit and HR 0.81 with afatanib reflect only marginal superiority to erlotinib, afatanib is now arguably the EGFR TKI of choice in this setting, pending FDA approval. However, with the value of erlotinib for SQ NSCLC considered so debatable in this setting, this may be interpreted as damning with faint praise. By far the greatest excitement for patients with advanced SQ NSCLC stemps from immune checkpoint inhibitor therapy, starting with the programmed cell death protein 1 (PD-1) inhibitor nivolumab, which was compared in the randomized Checkmate 017 trial to docetaxel as second line therapy in 272 chemotherapy-pretreated patients with advanced SQ NSCLC (10). Demonstrating a far superior median OS of 9.2 vs. 6.0 months, HR 0.59 (p = 000025), a median duration of response not yet reached, and a far more favorable tolerability than docetaxel, nivolumab is now the clear, FDA-approved second line standard of care for SQ NSCLC. This trial also demonstrated no correlation of efficacy with nivolumab as a function of tumor expression of programmed death protein ligand-1 (PD-L1), supporting its use in an unselected SQ NSCLC population. As genomic testing becomes more readily available and incorporated into clinical practice, molecular markers relevant for patients with SQ NSCLC are likely to provide new targeted therapy opportunities to accompany those of immunotherapies and conventional chemotherapy for this large population still greatly needing new advances. References 1) Hirsch, JTO 2008 2) Scagliotti, JTO 2011 3) Cohen, Oncologist 2010 4) Johnson, JCO 2004 5) Shepherd, NEJM 2005 6) Socinski, JCO 2012 7) Shukuya, Proc ASCO 2015, A#8004 8) Thatcher, Lancet Oncol 2015 9) Soria, Proc ASCO 2015, A#8002 10) Brahmer, NEJM 2015

Abstract not provided

Abstract:
Management of patients with advanced Non-Small Cell Lung Cancer (NSCLC) in recent years has been approached based on defining the histologic subtype and identifying actionable genetic alterations in the tumor. Many of the recent developments in the management of advanced NSCLC are applicable only to non-squamous NSCLC patients. Cytotoxic chemotherapy has remained the primary systemic therapy for squamous cell lung cancer patients. Despite a decline in the incidence in some parts of the world, squamous cell lung cancer as a single entity remains one of the major causes of cancer related mortality worldwide. Therefore there is a need to advance therapy of squamous cell lung cancer patients beyond chemotherapy. Recently several new agents have been studied in squamous cell lung cancer patients and promising results have been observed, with some of the trial results leading to drug approval for NSCLC patients in general and squamous cell lung cancer patients in particular. The recent advances in drug therapy can be categorized according to drug type into cytotoxic chemotherapy agents, immune checkpoint inhibitors and molecularly targeted agents. Nab paclitaxel, an albumin bound formulation of paclitaxel combined with carboplatin was compared with the standard combination of the carboplatin and paclitaxel in advanced NSCLC patients (1). The nab paclitaxel combination showed a significant improvement in response rate in squamous cell patients (41% vs. 24%), p < 0.001). This improvement in response rate was associated with a modest but statistically non-significant improvement in progression free survival (PFS) and overall survival. These results, have led to the approval of this combination for the management of advanced NSCLC patients and this combination is preferentially considered in squamous cell patients. The immune check point inhibitors have generated most excitement in recent years. In a randomized trial, Checkmate 017, the anti-PD-1 drug nivolumab was compared with docetaxel in patients with progressive squamous cell lung cancer and demonstrated both PFS (HR-0.62) and survival (HR-0.59) improvement (2). Toxicities in general were less in patients who received nivolumab and immune related toxicities were not common. In this trial PD-L1 expression did not correlate with benefit from nivolumab. Ipilimumab, an anti-CTLA4 antibody, has also been evaluated in squamous cell lung cancer patients. In a randomized phase II trial phased in ipilimumab with chemotherapy demonstrated superior outcomes compared to advanced NSCLC patients receiving chemotherapy alone (3). Retrospective analysis suggested greater benefit in squamous cell patients. Based on these results, a randomized study evaluating ipilimumab with chemotherapy in advanced squamous cell patients as front line therapy was initiated and has completed accrual (NCT01285609). Drugs targeting EGFR (Epidermal Growth Factor Receptor) have been studied in squamous cell lung cancer patients. Though EGFR-tyrosine kinase mutations are extremely uncommon in squamous cell lung cancer patients EGFR amplification has been observed in 7-10% of the patients and EGFR is expressed in a high proportion of squamous cell lung cancers. Necitumumab, a recombinant human EGFR antibody combined with chemotherapy cisplatin and gemcitabine demonstrated a modest survival advantage (HR- 0.84, p = 0.01) compared to chemotherapy alone (4). Afatinib, an irreversible EGFR tyrosine kinase inhibitor demonstrated superior survival compared to erlotinib in patients with recurrent squamous cell lung cancer following front line therapy (HR-0.81, p = 0.007) (5). The modest benefit observed suggests that EGFR targeting drugs are useful only in a proportion of squamous cell lung cancer patients and a biomarker to identify patients that benefit from these drugs could be valuable in the future use of these drugs. Another drug that showed clinical benefit in squamous cell lung cancer patients, along with other NSCLC patients is ramucirumab, a VEGFR2 receptor directed monoclonal antibody. In the REVEL study NSCLC patients with progressive disease following front therapy were randomized to docetaxel with or without ramucirumab (6). The combination demonstrated a superior survival compared to single agent docetaxel (HR-0.86, p = 0.023). Benefits were seen across all histologies, including squamous cell lung cancer. Several drugs targeting other signaling pathways, specifically PI3K and FGFR, are currently undergoing evaluation. Results to date in patients with tumors that have these specific molecular alterations have shown only modest benefit or no benefit at all. The reasons for these results are unclear. Ongoing clinical trials will determine the potential benefit for targeting these pathways. A major effort in analyzing targeted drugs based on molecular alteration in the patient’s tumor is ongoing with the LUNG MAP study, led by Southwest Oncology Group (SWOG) with participation from all the US Oncology Cooperative Groups. In conclusion, after a period of no advances for the treatment of squamous cell lung cancer patients, several drugs recently have shown clinical benefit and several others are currently being evaluated. It is clear that therapy of advanced squamous cell lung cancer patients has evolved beyond cytotoxic chemotherapy and will provide greater clinical benefit. References 1. Socinski MA, Bondarenko I, Kasareva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first line therapy in patients with advanced non-small cell lung cancer: final results of a phase III trial. J Clin Oncol 2012;30:2055-62. 2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. 3. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first line treatment in stage IIIB/IV non-small-cell lung cancer: results of a randomized, double-blind, multicenter phase II study. 4. Thatcher N, Hirsch FR, Luft AV, 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, randomised, controlled phase 3 trial. Lancet Oncol 2015;16:763-74. 5. Soria JC, 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; epub ahead of print. 6. 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 multicenter, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73.