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Novel therapies for advanced squamous cell carcinoma of the lung
Konstantinos Koutsoukos1 & Giannis Mountzios*,2
Advanced squamous non-small-cell lung carcinoma (SqCC) has traditionally been considered the ‘neglected sibling’ compared with lung adenocarcinoma due to lack of effective targeted treatment options. Currently, limited progress has been made in the systemic treatment of advanced disease and combination chemotherapy remains the gold standard. However, the recent completion of the molecular characterization of SqCC revealed an interestingly complex genomic profile, comprising various genetic alterations that can potentially function as molecular targets for the development of novel targeted agents. Recent encouraging results of the use of immune checkpoint inhibitors in several neoplasms has emerged as a promising novel treatment option for advanced SqCC. Future personalized studies, enrolling SqCC patients according to specific driving mutations are underway. First draft submitted: 21 August 2015; Accepted for publication: 16 December 2015; Published online: 1 February 2016 Background Lung cancer, especially non-small-cell lung cancer (NSCLC) is one of the leading causes of cancerrelated deaths worldwide, with approximately 160,000 deaths annually in the USA [1] . Squamous non-small-cell lung carcinoma (SqCC) represents a distinct type of NSCLC. Although the prevalence of SqCC in developed countries is declining, it still accounts for 20–30% of new cases of NSCLC [2] constituting a major public health issue. Compared with other histologic types, SqCC exhibits distinct epidemiological, clinicopathological and molecular characteristics. In particular, SqCC lesions are usually located centrally in segmental, lobar or main bronchi, may show central cavitation and are associated with increased rates of hemorrhage compared with other lung cancer types; There is a clear association of SqCC incidence with smoking [3] ; Finally, driver oncogenic alterations that are found in lung adenocarcinoma, such as EGFR [4] and KRAS mutations, or even ALK [5] gene rearrangements, are rarely detected in SqCC. To date, SqCC treatment has seen little of the benefit from targeted therapies used in the treatment of lung adenocarcinoma. Therefore, current treatment options in stage IV disease are limited to conventional combination chemotherapy. Platinum-based chemotherapy regimens, combining third-generation agents – such as taxanes – and gemcitabine with cisplatin or carboplatin, remain the standard of care for first-line therapy of fit patients with favorable performance status [6] . Second- and third-line options include docetaxel monotherapy and/or the EGFR-tyrosine kinase inhibitor (TKI) erlotinib, with limited response rates and poor overall survival (OS). However, recently reported trials with novel immunotherapy agents have shown promising results in SqCC [7] . Medical Oncology Department, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece Department of Medical Oncology, 251 Airforce General Hospital, 115 25, Athens, Greece *Author for correspondence: [email protected]
Keywords
• non-small-cell lung cancer • novel therapies • NSCLC • review • squamous
1 2
10.2217/fon.15.358 © 2016 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694
Review Koutsoukos & Mountzios In this review, we emphasize on the latest advances in targeted therapies for SqCC and the emerging field of immunotherapy. Recent advances in chemotherapy Various combination doublets have been studied in first line treatment of SqCC with comparable efficacy. Therefore, selection of chemotherapy regimen should also take into account the different toxicity profile of agents and patient preference. To date, there is no clear survival advantage of a specific chemotherapy doublet [8] . The Cisplatin/gemcitabine combination is probably still offering the best efficacy results in terms of median progression-free survival (PFS) and median OS. According to a Phase III study, comparing this combination with cisplatin plus pemetrexed in chemotherapy-naive NSCLC patients, patients with SqCC assigned to cisplatin/gemcitabine (n = 229) had a superior median PFS and OS of 5.5 months and 10.8 months, respectively, compared with the cisplatin/pemetrexed arm (hazard ratio [HR] for the latter as compared with the former: 1.23; 95% CI: 1.00–1.51; p = 0.05). This noninferiority study reported better tolerability and efficacy (12.6 vs 10.9 months) of the pemetrexed/cisplatin in nonsquamous NSCLC and suggested a possible detrimental effect of the same combination in SqCC and therefore pemetrexed is not currently indicated for SqCC. Overexpression of thymidylate synthetase in squamous histology, compared with adenocarcinoma, may contribute to the resistance to pemetrexed observed in SqCC [9] . In another noninferiority Phase III trial conducted mainly in a Japanese population, the oral fluoropyrimidine derivative S-1 plus carboplatin was compared with paclitaxel/carboplatin in the first-line treatment of NSCLC [10] . A median OS of 15.2 months in the carboplatin plus S-1 arm was reported compared with 13.3 months in the control arm, with 1-year survival rates of 57.3 and 55.5%, respectively. In an updated efficacy analysis according to histology, median OS was 14.0 months in the carboplatin/S-1 arm and 10.6 months in the carboplatin/paclitaxel arm (HR: 0.713; 95% CI: 0.476–1.068) for patients with SqCC [11] . The most recently approved chemotherapy agent in Europe for advanced NSCLC and particularly SqCC is nab-paclitaxel, an albuminbound form of paclitaxel, in combination with carboplatin. In a Phase III study in first-line,
10.2217/fon.15.358
Future Oncol. (Epub ahead of print)
efficacy and safety of weekly nab-paclitaxel plus carboplatin was compared with solvent-based paclitaxel plus carboplatin in 1052 patients with advanced NSCLC [12] . Although no statistically significant PFS and OS differences were observed between the two groups, overall response rates (ORRs) in SqCC according to RECIST criteria were superior with the nabpaclitaxel/carboplatin combination, reaching the impressive 41 versus 24% (p
Novel therapies for advanced squamous cell carcinoma of the lung
Konstantinos Koutsoukos1 & Giannis Mountzios*,2
Advanced squamous non-small-cell lung carcinoma (SqCC) has traditionally been considered the ‘neglected sibling’ compared with lung adenocarcinoma due to lack of effective targeted treatment options. Currently, limited progress has been made in the systemic treatment of advanced disease and combination chemotherapy remains the gold standard. However, the recent completion of the molecular characterization of SqCC revealed an interestingly complex genomic profile, comprising various genetic alterations that can potentially function as molecular targets for the development of novel targeted agents. Recent encouraging results of the use of immune checkpoint inhibitors in several neoplasms has emerged as a promising novel treatment option for advanced SqCC. Future personalized studies, enrolling SqCC patients according to specific driving mutations are underway. First draft submitted: 21 August 2015; Accepted for publication: 16 December 2015; Published online: 1 February 2016 Background Lung cancer, especially non-small-cell lung cancer (NSCLC) is one of the leading causes of cancerrelated deaths worldwide, with approximately 160,000 deaths annually in the USA [1] . Squamous non-small-cell lung carcinoma (SqCC) represents a distinct type of NSCLC. Although the prevalence of SqCC in developed countries is declining, it still accounts for 20–30% of new cases of NSCLC [2] constituting a major public health issue. Compared with other histologic types, SqCC exhibits distinct epidemiological, clinicopathological and molecular characteristics. In particular, SqCC lesions are usually located centrally in segmental, lobar or main bronchi, may show central cavitation and are associated with increased rates of hemorrhage compared with other lung cancer types; There is a clear association of SqCC incidence with smoking [3] ; Finally, driver oncogenic alterations that are found in lung adenocarcinoma, such as EGFR [4] and KRAS mutations, or even ALK [5] gene rearrangements, are rarely detected in SqCC. To date, SqCC treatment has seen little of the benefit from targeted therapies used in the treatment of lung adenocarcinoma. Therefore, current treatment options in stage IV disease are limited to conventional combination chemotherapy. Platinum-based chemotherapy regimens, combining third-generation agents – such as taxanes – and gemcitabine with cisplatin or carboplatin, remain the standard of care for first-line therapy of fit patients with favorable performance status [6] . Second- and third-line options include docetaxel monotherapy and/or the EGFR-tyrosine kinase inhibitor (TKI) erlotinib, with limited response rates and poor overall survival (OS). However, recently reported trials with novel immunotherapy agents have shown promising results in SqCC [7] . Medical Oncology Department, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece Department of Medical Oncology, 251 Airforce General Hospital, 115 25, Athens, Greece *Author for correspondence: [email protected]
Keywords
• non-small-cell lung cancer • novel therapies • NSCLC • review • squamous
1 2
10.2217/fon.15.358 © 2016 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694
Review Koutsoukos & Mountzios In this review, we emphasize on the latest advances in targeted therapies for SqCC and the emerging field of immunotherapy. Recent advances in chemotherapy Various combination doublets have been studied in first line treatment of SqCC with comparable efficacy. Therefore, selection of chemotherapy regimen should also take into account the different toxicity profile of agents and patient preference. To date, there is no clear survival advantage of a specific chemotherapy doublet [8] . The Cisplatin/gemcitabine combination is probably still offering the best efficacy results in terms of median progression-free survival (PFS) and median OS. According to a Phase III study, comparing this combination with cisplatin plus pemetrexed in chemotherapy-naive NSCLC patients, patients with SqCC assigned to cisplatin/gemcitabine (n = 229) had a superior median PFS and OS of 5.5 months and 10.8 months, respectively, compared with the cisplatin/pemetrexed arm (hazard ratio [HR] for the latter as compared with the former: 1.23; 95% CI: 1.00–1.51; p = 0.05). This noninferiority study reported better tolerability and efficacy (12.6 vs 10.9 months) of the pemetrexed/cisplatin in nonsquamous NSCLC and suggested a possible detrimental effect of the same combination in SqCC and therefore pemetrexed is not currently indicated for SqCC. Overexpression of thymidylate synthetase in squamous histology, compared with adenocarcinoma, may contribute to the resistance to pemetrexed observed in SqCC [9] . In another noninferiority Phase III trial conducted mainly in a Japanese population, the oral fluoropyrimidine derivative S-1 plus carboplatin was compared with paclitaxel/carboplatin in the first-line treatment of NSCLC [10] . A median OS of 15.2 months in the carboplatin plus S-1 arm was reported compared with 13.3 months in the control arm, with 1-year survival rates of 57.3 and 55.5%, respectively. In an updated efficacy analysis according to histology, median OS was 14.0 months in the carboplatin/S-1 arm and 10.6 months in the carboplatin/paclitaxel arm (HR: 0.713; 95% CI: 0.476–1.068) for patients with SqCC [11] . The most recently approved chemotherapy agent in Europe for advanced NSCLC and particularly SqCC is nab-paclitaxel, an albuminbound form of paclitaxel, in combination with carboplatin. In a Phase III study in first-line,
10.2217/fon.15.358
Future Oncol. (Epub ahead of print)
efficacy and safety of weekly nab-paclitaxel plus carboplatin was compared with solvent-based paclitaxel plus carboplatin in 1052 patients with advanced NSCLC [12] . Although no statistically significant PFS and OS differences were observed between the two groups, overall response rates (ORRs) in SqCC according to RECIST criteria were superior with the nabpaclitaxel/carboplatin combination, reaching the impressive 41 versus 24% (p
