Squamous lung cancer accounts for about 30% of new cases of non-small cell lung cancer (non-small cell lung cancer). Patients are mostly over 50 years of age, mostly men, and have a long history of heavy smoking. Most squamous carcinomas originate in the larger bronchi and are often of the central lung type. Many patients with squamous carcinoma will be prone to hemoptysis, either early or late in the course of the disease. The degree of differentiation of squamous carcinoma varies, but it is generally slow-growing. Squamous carcinoma has a long course and metastases later, and usually metastasizes first through the lymphatic tract and then bloodstream metastasis occurs in advanced stages. The surgical resection rate is high and the sensitivity to radiation and chemotherapy is low.
Typical squamous carcinoma cells are large, pleomorphic, with abundant cytoplasm, keratinization tendency, nuclear aberrations, deep staining, and intercellular bridges. Electron microscopy showed a large number of nucleoli and tense fiber bundles connected between the cancer cells. Squamous carcinoma invades the bronchial mucosa and is easily detached, and cancer cells can be easily found in sputum. Squamous carcinoma has a tendency to grow into the lumen, often causing bronchial narrowing or even blockage at an early stage, resulting in atelectasis or obstructive pneumonia.
Compared with lung adenocarcinoma, squamous lung cancer is less effective and has fewer treatment options. Squamous lung cancer has unique epidemiological, clinicopathological and molecular characteristics, such as close association with smoking, low EGFR mutation rate, low ALK rearrangement rate, etc., resulting in poor results of targeted therapy for squamous lung cancer. The treatment of squamous carcinoma is mainly focused on the field of chemotherapy and immunotherapy.
Chemotherapy
The ECOG1594 study was the first clinical study to compare the efficacy of third-generation chemotherapy drugs in combination with platinum in the first-line treatment of non-small cell lung cancer (NSCLC), and its results established gemcitabine, paclitaxel, and docetaxel in combination with platinum as the standard chemotherapy drugs for the first-line treatment of squamous lung cancer. The results of the study showed similar efficacy of gemcitabine, paclitaxel, and docetaxel combined with platinum in the first-line treatment of non-small cell lung cancer, but in the squamous cancer subgroup (288 cases), the gemcitabine combined with cisplatin (GP) regimen had the longest progression-free survival (PFS) and overall survival (OS) compared with the other regimens, at 4.4 months and 9.4 months, respectively, with a small survival benefit advantage.
The JMDB study, a large clinical study comparing gemcitabine + cisplatin and pemetrexed + cisplatin in the first-line treatment of non-small cell lung cancer, enrolled 1725 chemotherapy-naïve patients with advanced non-small cell lung cancer. The median PFS (5.5 months vs. 4.4 months) and OS (10.8 months vs. 9.4 months) were significantly longer in the squamous cancer subgroup. The findings suggest that pemetrexed is not suitable for patients with squamous lung cancer.
2. Targeted therapy
Although and patients with squamous lung cancer have only about 3% to 7% mutation rate of EGFR gene mutation. There are some individual reports in the literature that EGFR gene mutation in squamous lung cancer can be up to 17%. However, it is generally believed that the average chance of EGFR gene mutation in squamous lung cancer is around 5%. Note that the chance of EGFR gene mutation in squamous lung cancer is relatively low compared to adenocarcinoma, but not without the possibility of EGFR gene mutation. For lung squamous carcinoma with a confirmed EGFR gene mutation after genetic testing, there will be a wide variety of TKI drugs available in the first, second and third generation. For genetic mutations such as ALK/ROS1, the corresponding targeted drugs can be selected according to the type of mutation. The NCCN guidelines also recommend comprehensive genetic testing for patients with squamous lung cancer and mixed adenosquamous carcinoma diagnosed by small puncture specimens. Genetic testing of postoperative resection specimens for squamous carcinoma is also necessary.
Second-line targeted therapy
Afatinib, a second-generation oral inhibitor of EGFR small molecules, is indicated for patients with locally advanced or metastatic non-small cell lung cancer with EGFR gene-sensitive mutations who have not been previously treated with an EGFR tyrosine kinase inhibitor (EGFR-TKI), particularly in patients with rare mutations other than 19del and 21L858R.
The LUX-Lung8 study is a multicenter phase III clinical study randomized to compare afatinib with erlotinib in patients with advanced squamous lung cancer who have failed platinum-containing regimens in second-line therapy. The effectiveness and safety of afatinib and erlotinib were compared for patients with advanced squamous lung cancer. Patients with advanced squamous lung cancer who failed first-line therapy were assigned 1:1 to either the afatinib or erlotinib group in the study, and were followed for a mean of 18.4 months. The results suggested that the disease control rate, disease-free survival time, and overall survival time in the afatinib group versus the erlotinib group were 51% vs. 40%, 2.6 months vs. 1.9 months, and 7.9 months vs. 6.8 months, respectively. As for side effects, diarrhea and stomatitis were worse in the afatinib group, while rash was worse in the erlotinib group. It is because of the results of this study that the US FDA approved afatinib for second-line treatment of advanced squamous lung cancer, and our FDA also approved afatinib for second-line treatment of advanced squamous lung cancer
Immunotherapy
Immunotherapy has made great progress in the treatment of squamous lung cancer, with pabolizumab monotherapy currently used in first line (KEYNOTE-024 study), and in patients with PD-L1≧1% (KEYNOTE-042 study), and atelelizumab monotherapy also used in first line in patients with PD-L1≧50% or IC1≧10% (IMpower110 study).
In immune combination chemotherapy, pabrolizumab in combination with chemotherapy (KEYNOTE-407 study), carrilizumab in combination with chemotherapy (CameL-sq study), tirelizumab in combination with chemotherapy (RATIONALE307 study), sindilizumab in combination (gemcitabine + cisplatin) (ORIENT-12 study), nabritumomab + epirimizumab ( CheckMate227), and nabritumomab + epirimumab I + 2 cycles of chemotherapy (CheckMate9LA) were all used in first line in patients with advanced squamous cancer.
In second-line therapy, nabritumomab, pablizumab (PD-L1≧1%), atelelizumab, tirelizumab, and sindilizumab are approved for second-line use in patients who have progressed after chemotherapy.
Anti-angiogenic therapy
Because bevacizumab can cause lethal hemorrhage in central squamous lung cancer, bevacizumab should only be used in patients with non-squamous cancer.
The effectiveness of Endo monotherapy for advanced non-small cell lung cancer was only 3%, similar to the results of the US study (5%). However, in the phase III clinical study conducted by Wang Jinwan and Sun Yan et al, the combination of NP regimen for advanced non-small cell lung cancer improved the overall effective rate from 19.5% to 35.4% and the median time to tumor progression from 3.6 months to 6.3 months in the phase III clinical trial. For primary patients, the objective remission rates were 40.0% and 23.9% for the trial and control groups, respectively, and for relapsed patients, the objective remission rates were 23.9% and 8.5% for the trial and control groups, respectively, with clinical benefit rates of 65.2% and 61.7%, and median time to disease progression of 5.7 months and 3.2 months, respectively. Based on these results, China approved NP in combination with Endo for the first-line treatment of advanced non-small cell lung cancer. Encouragingly, NP+Endo still had an efficiency rate of 23.9% in relapsed patients with a median time to disease progression of more than 5 months.
Anlotinib (forcovir) is an orally administered novel small molecule multi-target TKI that potently inhibits multiple targets including VEGFR, PDGFR, FGFR and c-Kit, with dual effects of anti-tumor angiogenesis and tumor growth inhibition.
The ALTER0303 study is a phase III clinical study of anlotinib in third-line and beyond for advanced non-small cell lung cancer, enrolling 437 patients with stage IIIB/IV non-small cell lung cancer who had received at least two prior systemic chemotherapy regimens and were randomized to anlotinib (n=294) or placebo (n=143) until disease progression or intolerable toxicity .
The results showed that anlotinib alone significantly prolonged median overall survival (9.6 vs 6.3 months; HR=0.68; 95% CI,0.54-0.87; p=0.0018) and progression-free survival (5.4 vs 1.4 months; HR=0.25; 95% CI,0.19-0.31; p<0.0001). EGFR subgroup analysis showed that patients with either positive or negative EGFR-sensitivity mutations benefited from both overall and progression-free survival from treatment with anlotinib. Anlotinib demonstrated a favorable safety profile with an adverse event rate similar to that of the control group.
Therefore, anlotinib is approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have progressed or relapsed after receiving at least 2 prior systemic chemotherapies. For patients with EGFR mutations or ALK positivity, progression or recurrence should have occurred after treatment with the appropriate targeted agent and after at least 2 prior systemic chemotherapies prior to initiating therapy with this product. However, it is contraindicated in patients with central squamous cell carcinoma of the lung or at risk of massive hemoptysis, or in patients with severe hepatic or renal impairment.
Drugs approved abroad but not approved in China
Nexituzumab, a monoclonal antibody against EGFR mutations, was approved by the US FDA in November 2015 in combination with chemotherapy (cisplatin + gemcitabine) as a first-line treatment option for squamous lung cancer. The SQUIRE study, published in The Lancet Oncology, is an ultra-large clinical study including 1093 patients with initially treated advanced squamous lung cancer. Patients were assigned 1:1 to two groups: cixotuzumab-resistant combined with chemotherapy vs. chemotherapy alone. The results showed that cixotuzumab-resistant combination chemotherapy improved overall survival from 9.9 months to 11.5 months and reduced the risk of death by 16%.
Remolimumab is a recombinant humanized monoclonal antibody against VEGFR2. The REVEL study was a randomized controlled phase III study that enrolled 1253 patients with non-small cell lung cancer who had received platinum-based chemotherapy (in combination with or without bevacizumab, or bevacizumab maintenance therapy followed by disease progression) and were randomly assigned to receive remolimumab (10 mg, 628 patients) in combination with docetaxel (75 mg/m2) or placebo combined with docetaxel (625 cases), with the aim of clarifying the efficacy and safety of single-agent docetaxel compared with docetaxel combined with ramolutumab. The results showed that among patients with lung adenocarcinoma, the median overall survival was 11.2 months and 9.8 months (HR=0.83, 95% CI 0.69-0.99) in the ramolutumab combined with docetaxel group (?377 patients) and placebo combined with docetaxel group (348 patients), respectively. Among patients with squamous carcinoma, the median overall survival was 9.5 months and 8.2 months (HR=0.88, 95% CI0.69 to 1.13) in the ramolutumab combined with docetaxel group (157 patients) and placebo combined with docetaxel group (171 patients), respectively. For patients with other types of non-squamous cancer, the median overall survival was 10.8 months and 9.3 months (HR=0.86, 95% CI0.59-1.26) in the ramolutumab combined with docetaxel group (74 patients) and placebo combined with docetaxel group (78 patients), respectively. The incidence of treatment-related adverse events was similar in patients in the two regimen treatment groups in different pathology type subgroups. results from the REVEL study showed that ramolutumab in combination with docetaxel improved efficiency in patients with non-squamous non-small cell lung cancer (non-small cell lung cancer) and squamous lung cancer.
Compared to lung adenocarcinoma, lung squamous carcinoma has a low incidence of sense gene mutations and relatively poorer efficacy. However, there are still significant advances in immunotherapy and small molecule anti-vascular drugs for lung squamous carcinoma. The rational and good use of these drugs is still important to improve the life treatment of patients with squamous carcinoma and improve the survival prognosis.