The Pharmacodynamic Experiment And Retrospective Study Of Pemetrexed Combined With EGFR-TKI In Lung Squamous Cell Cancer

Objective:(1) To investigate the in vitro inhibitory effect of pemetrexed combined with elortinib on breast and lung cancer cell lines, (2) and to identify the synergistic effect of pemetrexed combined with icotinib in lung squamous carcinoma by a retrospective analysis of the response rate and overall survival of pemetrexed combined with icotinib as the third line treatment in patients with advanced lung squamous carcinoma.Methods:(1) Evaluation of the synergistic, inhibitory effect of pemetrexed combined with elortinib on MCF-7 breast cancer cell line with MTT assay; (2) The synergistic, inhibitory effect of the combination treatment on human lung squamous cell lines NCI-H520, SK-MES-1, and CHLH-1 and human adenocarcinoma cell line A549 was evaluated; (3) Retrospective analysis of clinical efficacy and overall survival of the combination treatment as the third line therapy in patients with advanced lung squamous carcinoma.Results:(1) Although pemetrexed alone did not demonstrate dose-dependent inhibition to the proliferation of breast cancer cell MCF-7, elortinib suppressed the growth of MCF-7 in a dose-dependent manner. The combination of pemetrexed and elortinib showed significantly greater anti-proliferation effects than elortinib alone in a dose dependent manner, with the best inhibitory effects observed at low doses of elortinib.(2) In line with the findings mentioned above, elortinib markedly inhibited lung cancer cell lines (NCI-H520, SK-MES-1, CHLH-1 and A549) in a dose-dependent manner. Pemetrexed considerably inhibit the growth of NCI-H520, CHLH-1 and A549 lines and not SK-MES-1 cells, in a dose dependent manner, but the degree of inhibition is less than that induced by elortinib. Importantly, combined treatment with elortinib and pemetrexed at low concentrations still exhibited potent anti-proliferation effects against all these lung cancer cell lines.(3) ORR was 15.0% and DCR was 55.0% in pemetrexed alone group, while ORR was 16.7% and DCR was 66.7% in the combination group (P=1.0, P=0.522 respectively). Compared with pemetrexed alone group, PFS and OS were slightly increased in the combination group (3.2 months versus 3.1 months, P=0.637,8.2 months vs 7 months, P=0.231, respectively). Multivariate analysis using Cox’s regression model showed that sex, age, stage, smoking status, and PS were not significantly different in PFS between two groups (P>0.05). Moreover, there was no significant difference in the hematological toxicity between the two groups. But incidence of rash was 33.3% in the combination group compared with 5% in the pemetrexed group (P=0.038), and the incidence of diarrhea was 38.9% in the combination group compared with 5% in the pemetrexed group (P=0.016).Conclusion:(1) the combination treatment of pemetrexed and elortinib exhibited a significantly synergistic effect against tumor cells in vitro; (2) Retrospective analysis revealed that the combination of pemetrexed and icotinib was well tolerated and showed significant synergistic effects as evidenced by increased ORR, DCR, PFS, and OS in combination group. These results suggested pemetrexed combined with icotinib could be a promising strategy for lung squamous cancer patients. Prospective, controlled confirmatory trials are warranted.