Immunotherapy resistance of lung cancer

In recent years,immunotherapy has made remarkable breakthroughs and brought long-term survival benefits to lung cancer patients.However,a high percentage of patients do not respond to immunotherapy or their responses are transient,indicating the existence of immune resistance.Current studies show that the interactions between cancer cells and immune system are continuous and dynamic.A range of cancer cell-autonomous characteristics,tumor microenvironment factors,and host-related influences account for heterogenous responses.Furthermore,with the identification of new targets of immunotherapy and the development of immune-based combinations,we propose the response strategies to overcome resistance.

Favorable clinical outcomes of checkpoint inhibitorbased combinations after progression with immunotherapy in advanced non-small cell lung cancer

Aim:Immune checkpoint inhibitors(ICIs)have dramatically changed the treatment paradigm in patients with non-small-cell lung cancer(NSCLC).However,progression patterns with immunotherapy are currently unclear and therapeutic options beyond resistance remain challenging.Methods:We reviewed advanced NSCLC patients between January 2016 and December 2019 who were treated with anti-PD-1/PD-L1 inhibitors in our center and identified those who developed disease progression.Later-line treatment strategies were collected and objective response rate,progression-free survival(PFS),and overall survival(OS)were assessed.Results:Of the 118 patients,46(39.0%)showed oligoprogression and 72(61.0%)showed systemic progression.No difference in progression patterns was observed between monotherapy and combination therapy.Systemic progression was strongly associated with never-smokers(51.4%vs.21.7%,P=0.001)and ECOG PS=2(13.9%vs.2.2%,P=0.048)at baseline.The distribution of progression sites was roughly similar between oligoprogression and systemic progression,and the most commonly affected anatomic site was lung(66.9%),followed by bone(12.7%)and lymph nodes(11.0%).For patients beyond first disease progression,checkpoint inhibitor-based combinations could lead to a significantly longer PFS2 compared with ICIs monotherapy(9.63 months vs.4.23 months,P=0.004,HR=0.394,95%CI:0.174-0.893)and other therapy(9.63 months vs.4.07 months,P=0.046,HR=0.565,95%CI:0.326-0.980).Median OS of the ICIs combination group was not reached but was significantly longer than other therapy group(NR vs.14.37 months,P=0.010,HR=0.332,95%CI:0.167-0.661).Conclusion:Systemic progression occurs more frequently among NSCLC patients receiving ICIs.Checkpoint inhibitor-based combinations show favorable outcomes as subsequent treatment strategies after the failure of previous ICIs treatment.