Squamous carcinoma accounts for a decreasing proportion of non-small cell lung cancer (NSCLC), but still accounts for about 30% of new cases. Squamous carcinoma has unique epidemiologic, clinicopathologic, and molecular characteristics (e.g., strong association with smoking, low rate of EGFR and KRAS mutations, and low rate of ALK rearrangement). Meanwhile, the treatment options for squamous carcinoma patients are very selective, with platinum-containing double agents in the first line and docetaxel or erlotinib in the second line, after which there are no specific recommended treatment options. The ECOG1594 study showed that gemcitabine combined with cisplatin still provided the best PFS (4.3 months) and OS (9.4 months); pemetrexed showed poor efficacy in squamous carcinoma and therefore is not recommended; bevacizumab is contraindicated for squamous carcinoma due to safety considerations; and nano-paclitaxel combined with carboplatin was more efficacious than paclitaxel combined with carboplatin in first-line treatment. The first-line treatment of nanopaclitaxel and carboplatin is more effective than paclitaxel and carboplatin, with an objective response rate (ORR) of 41%, and a lower incidence of 3/4-degree neuropathy and osteoarthralgia; and the Japanese LETS study showed that the OS of S-1/carboplatin was better than that of paclitaxel/carboplatin. Although the exploration of driver genes for lung adenocarcinoma and the development and clinical application of corresponding targeted drugs have progressed considerably in recent years, very little is known about the driver genes for squamous lung cancer, and the studies are currently ongoing. Anti-angiogenic drugs There are several anti-angiogenic drugs for advanced NSCLC, which include monoclonal antibody anti-VEGF or VEGF receptor and multi-targeted anti-angiogenic drugs. 2014 Lancet Oncology published the results of the phase III study of REVEL, which enrolled a total of 1,253 patients with NSCLC who had failed cisplatin-based first-line chemotherapy regimens (both squamous and non-squamous). Patients were randomly assigned to either the docetaxel group or docetaxel in combination with ramucirumab. Compared with chemotherapy alone, the ramucirumab + chemotherapy combination group significantly improved patients’ PFS and OS, meeting the prespecified primary study endpoints; OS as well as PFS remained consistent with benefit in subgroup analyses of histologic types, including squamous versus non-squamous cancer populations. PFS and OS were prolonged in squamous cancer patients in the combination chemotherapy arm. Combining ramucirumab on a DOC basis did not increase the incidence of SAEs or lethal adverse events; REVEL is the first clinical study to show an overall survival benefit of a new drug in combination with standard chemotherapy in patients with stage IV NSCLC who have progressed on platinum-containing-based chemotherapy, and makes ramucirumab the first antiangiogenic agent that can be utilized in patients with squamous NSCLC. angiogenesis in patients with squamous NSCLC. EGFR Monoclonal Antibodies and EGFR-TKIs In order to find better therapeutic strategies for squamous lung cancer, researchers have not given up on exploring and validating the driver genes in squamous lung cancer. Squamous cancer patients have their unique genetics alterations, such as oxidative stress (KEAP1, NFE2L2, CUL3), squamous differentiation (SOX2, NOTCH1, TP63), and cell cycle control (CDKN2A, RB1). Mutations in genes can inactivate many oncogenes, and 69% of PI3K/RTK/RAS signaling pathways are altered, leading to aberrant cell proliferation, survival, and translation. Table 1 lists clinical studies of second-line treatment of squamous carcinoma using EGFR monoclonal antibodies and EGFR-TKI (ELCC, 2015), but the only study to obtain a significant difference was the SQUIRE study. The SQUIRE study compared necitumumab (a second-generation monoclonal antibody targeting EGFR, 800 mgD1, D8), Kenzey in combination with cisplatin against Kenzey in combination with cisplatin for the treatment of squamous carcinoma, and is the clinical study with the largest number of cases specifically targeting Stage IV squamous lung cancer. The results showed that necitumumab in combination with GP significantly prolonged PFS and OS compared with first-line treatment with GP. Previous FLEX studies have found that EGFR immunohistochemistry H-score > 200 predicted better efficacy of the combination of cetuximab with NP, but unfortunately H-score 200 as session value in this study did not predict necitumumab’s efficacy. Subgroup analyses suggested that all populations (gender, ethnicity, smoking status, PS score) could benefit from the combination therapy, except for patients >70 years old who could not benefit from the combination. Fibroblast Growth Factor Receptor (FGFR) Inhibitors 12% of patients with squamous carcinoma have amplification of FGFR, and preclinical studies have shown efficacy of its inhibitors, cediranib, nintedanib, pazopanib, and ponatinib. nintedanib targets FGFR, VEGFR, and PDGFR, and phase III The phase III LUME-lung 1 study evaluated the efficacy and safety of docetaxel in combination with nintedanib (n=206) versus docetaxel in combination with placebo (n=199) as a second-line treatment regimen for NSCLC, and demonstrated that, regardless of histologic type, the combination prolonged PFS, reduced the risk of tumor recurrence by 23%, and significantly prolonged adenocarcinoma patients’ overall survival OS. 42.1% of the enrolled population were patients with squamous carcinoma, which had a higher disease control rate than patients with adenocarcinoma, but poorer OS than patients with adenocarcinoma. Therefore, second-line treatment of squamous cancer patients with docetaxel in combination with nintedanib provided little benefit. Anti-PD-1 Nivolumab binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, therefore relieving the PD-1 pathway-mediated suppression of immune responses, including anti-tumor immune responses.In December 2014, the FDA granted accelerated approval for nivolumab for the treatment of patients with unresectable or metastatic melanoma patients who have not responded to other drugs. CheckMate 063 was a multicenter, single-arm Phase II clinical study that enrolled 117 cases of squamous NSCLC with IIIB/IV who had received at least 2 prior systemic therapies (65% had received 3 or more therapies) but had experienced progression of their disease and were given intravesical nivolumab at 3 mg/kg every 2 weeks, with the primary study endpoint of OS. results showed SD efficacy in 26% of patients with tolerable toxicities, a median OS of 8.2m (0-17), and a 1-year survival rate of 41%. results from the Phase III CA209-017 study showed that nivolumab treatment of patients with second-line squamous lung cancer improved the median OS by 3.2 months compared to standard docetaxel-based monotherapy. on March 4, 2015 the FDA approved nivolumab for the treatment of metastatic squamous NSCLC with disease progression during or after transplatinum-based chemotherapy, becoming the first PD-1 inhibitor to show survival efficacy in lung cancer. Currently, PD-L1 and PD-1 require more effective predictive biomarkers of immunotherapy efficacy, and several current assays are based on immunohistochemistry (IHC)-based detection of protein expression levels, with the heterogeneity of expression, which assay platforms, and the selection of cut-point values needing to be further confirmed. At the same time, the appropriate dose, sequence of treatment, and strategy of combination therapy (combination chemotherapy? other monitoring point inhibitors? TKI?), and exact predictive markers of efficacy all need to be clarified. There are many immunotherapy clinical studies for squamous carcinoma underway, such as ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), MED14736 (anti-PDL1), and MPDL3280a (anti-PDL1). Outlook The United States proposes the Lung Squamous Cell Carcinoma Major Protocol (LUNGMAP) for advanced squamous lung cancer, in which the tissues of nearly 1,000 patients with advanced squamous lung cancer will be sequenced annually to obtain multiple genetic alterations in squamous carcinoma, and this protocol will allow for the simultaneous conduct of many randomized phase II clinical studies of new targeted agents against squamous lung cancer in the framework of this clinical study.Lung-MAP, S1400 is given based on the results of the genetic tests second-line therapy: chemotherapy combined with a PIK3 inhibitor for PIK3CA mutations; CD4/6 inhibitor for CCND1 mutations; FGFR inhibitor for FGFR amplification; erlotinib combined with an HGF inhibitor for c-MET amplification; and MED14736 (anti-PD-1) for PDL1(+). It is the expectation of medical professionals and lung cancer patients worldwide that this study will lead to targeted therapies that correspond to the genetic alterations in their tumors and will enable other clinical studies to be conducted more efficiently and rapidly. Meanwhile, more unknown latent driver genes of squamous carcinoma may also be discovered, providing new targets for tumor drug development, and we look forward to encouraging results from these studies.