Squamous cell carcinomas (SQCC) represent approximately 30 percent of all cases of non-small cell lung cancer (NSCLC). These tumors are strongly associated with cigarette smoking and are typically centrally located. Most of the recent progress in the treatment of NSCLC, including the remarkable benefit from epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with activating EGFR mutation and crizotinib for patients with ALK or ROS1 translocations has been restricted to patients with non-squamous histology, particularly adenocarcinomas. There are currently no clearly effective targeted therapies approved for the treatment of SQCC.
The standard therapy for metastatic SQCC is platinum-based combination chemotherapy. Since several randomized clinical trials reported between 2001 and 2003 showed no significant differences in outcomes among the chemotherapy regimens, the choice of therapy had been based mostly on personal preferences and toxicity profile. Histology did not play a role in the selection of chemotherapy regimen until the results of the JMDB trial, which compared cisplatin plus pemetrexed (CP) with cisplatin plus gemcitabine (CG). Although the median overall survival (OS) was identical for both arms at 10.3 months, CG was associated with a significant improvement in OS among patients with SQCC (10.8 vs. 9.4 months), whereas CP was associated with a significant benefit in non-squamous histology (11.8 vs. 10.4 months).
The decreased efficacy of pemetrexed in patients with SQCC has been attributed at least in part to the higher expression of thymidylate synthase. Therefore, pemetrexed is not indicated in patients with SQCC, with the treatment options restricted mainly to the combination of platinum plus gemcitabine, vinorelbine or a taxane.
In the initial randomized Phase II study comparing chemotherapy with or without bevacizumab, there were six life-threatening pulmonary hemorrhages among the 66 patients receiving bevacizumab, including four deaths. All six patients with severe hemorrhage had centrally located tumors close to the major blood vessels, five had tumor cavitation, and four had SQCC.
With four out of 13 SQCC patients treated with bevacizumab developing severe hemorrhagic events, this histology was excluded from the two subsequent randomized trials that led to the approval of bevacizumab in NSCLC with non-squamous histology. Although the BRIDGE study showed that delaying the use of bevacizumab until the third cycle of chemotherapy and excluding patients with intrathoracic cavitation or recent hemoptysis may be associated with decreased risk of severe pulmonary hemorrhage in SQCC, the use of bevacizumab in this population remains experimental and should not be pursued outside of a clinical trial.
Two randomized clinical trials comparing chemotherapy with or without cetuximab showed discordant results. While the FLEX study using cisplatin and vinorelbine showed a significant improvement in OS for patients in the cetuximab arm (11.3 vs. 10.1 months), this benefit was not observed in the BMS099 study using carboplatin plus paclitaxel, where the numerically higher OS in the cetuximab arm did not reach statistical significance (9.6 vs. 8.3 months).
A subsequent analysis of the FLEX study showed that patients with high EGFR expression, defined as immunohistochemistry score ≥ 200, had a significant benefit from the addition of cetuximab to the chemotherapy, whereas there were no benefits from the triplet in patients with low EGFR expression.
Although high-expression of EGFR was found in only 31 percent of patients, there were significant differences according to histology (25% in adenocarcinomas and 38% in SQCC). Furthermore, among all patients evaluated, the highest benefit from cetuximab was observed in patients with SQCC and high EGFR expression.
If the predictive value for EGFR expression is validated, the addition of cetuximab to chemotherapy may be considered during first-line therapy, particularly for SQCC, where the options remain limited. The ongoing SWOG 0819 trial, comparing chemotherapy with carboplatin plus carboplatin (and bevacizumab for eligible patients), with or without cetuximab, may validate high EGFR expression as one of the predictive factor for response to cetuximab and clarify whether the benefits can be also observed in a better tolerated carboplatin-based chemotherapy regimen.
Since the JMEN study showed improved survival for switch maintenance using pemetrexed after four cycles of a platinum-based regimen compared with no maintenance, several randomized clinical trials have been conducted, mainly to compare different maintenance strategies with pemetrexed and bevacizumab alone or in combination. However, these studies are not applicable for SQCC patients, since the benefits from JMEN were observed mainly in non-squamous, and neither pemetrexed nor bevacizumab are indicated in SQCC.
Therefore, the only recent maintenance study applicable for SQCC is SATURN, which compared erlotinib with placebo in patients without tumor progression after four cycles of chemotherapy. In patients with SQCC, maintenance erlotinib was associated with a significant improvement in progression-free survival (PFS) but not OS compared with placebo. However, when stratified by response to first-line chemotherapy, patients achieving stable disease had a significant improvement in OS with the use of maintenance erlotinib. In contrast, there was no OS benefit from maintenance erlotinib in patients who responded to prior therapy.
The current approved therapies for second-line therapy in NSCLC include docetaxel, pemetrexed, and erlotinib. Docetaxel was approved based on two randomized clinical trials, showing response rates between 5.5 and 10.8 percent and median PFS between 1.9 and 2.4 months. Since pemetrexed, which was shown to be equivalent to docetaxel, has no role in the treatment of SQCC, the current alternative to docetaxel is erlotinib.
Although earlier randomized studies comparing gefitinib with docetaxel showed no significant differences in outcome, patients were unselected by EGFR mutation status, preventing the comparison of the two therapies in wild type EGFR, which is less likely to benefit from EGFR TKIs. The TAILOR study, comparing docetaxel with erlotinib in patients with wild type EGFR, showed that docetaxel was associated with a significant improvement in response rates, median PFS, and OS compared with erlotinib.
Since reaching a plateau in efficacy with standard platinum-doublets, a growing percentage of patients with adenocarcinomas have achieved a significant improvement in survival with the use of new targeted therapies. Unfortunately, this improvement has not been shared with SQCC, where activating EGFR mutations and ALK translocations are either rare or absent.
Improving outcomes for patients with SQCC can only be achieved through a better understanding of the pathophysiology and molecular characterization of this heterogeneous group of malignancies. A significant step forward was The Cancer Genome Atlas (TCGA) research network study, which showed that approximately two thirds of patients with SQCC have somatic alterations of a potentially targetable gene, including EGFR, fibroblast growth factor receptors (FGFRs), and PI3K pathway. Furthermore, studies using monoclonal antibodies targeting the programmed cell death protein 1 (PD1) or its ligand (PDL1), have shown remarkable results regardless of the histology subtype.
Metastatic Squamous Cell Lung Cancer
My first treatment option for patients with metastatic SQCC is enrollment into a clinical trial. For patients who are not eligible for a trial, the first-line therapy is guided mostly by the performance status, co-morbidities, and patient preferences. For patients with good PS and no significant co-morbidities, my favored first-line treatment is the combination of carboplatin plus gemcitabine, with carboplatin plus paclitaxel as an alternative choice. Although cisplatin has been associated with a slight benefit compared with carboplatin in meta-analyses, individual trials have not shown significant differences, and carboplatin is usually better tolerated.
In case of poor performance status, I typically use single-agent docetaxel. Although the survival improvement from maintenance erlotinib is modest in patients with wild type EGFR, I often review the risks and benefits from maintenance erlotinib, particularly for patients with stable disease after chemotherapy.
My second-line therapy of choice is docetaxel. For patients with good performance status and progression after second-line docetaxel, I usually offer erlotinib. The replacement of a mostly empirical chemotherapy by the use of new drugs directed at specific driver mutations or abnormal pathways is expected to provide better treatment options in the near future, likely resulting in improved survival for patients with metastatic SQCC.