Oncology
Non-Small Cell Lung Cancer
Immune Checkpoint Inhibitors in Patients Carrying an Oncogenic Driver
Overview
For patients with non–small cell lung cancer (NSCLC) and a single oncogenic driver, it is recommended that the first-line therapy be a targeted agent for that driver. For instance, while some activity may be seen with immune checkpoint inhibitor monotherapy in patients with NSCLC who are EGFR mutated, response rates are generally lower.
Expert Commentary
Roy S. Herbst, MD, PhD
|
|
“We need to become more precise with our immunotherapies. We need to understand that some tumors have many infiltrating T cells while others do not, some tumors have a lot of PD-L1 expression while others do not, and some tumors have a lot of T-cell immunoglobulin-3 expression while others do not.”
I led the KEYNOTE-010 trial in which we examined the activity of single-agent pembrolizumab in patients with previously treated NSCLC, and, while you could see activity with monotherapy in those who were EGFR mutated, for the most part, we observed lower response rates with immunotherapy among those with single oncogenic drivers. Why is this? We think that it was related to the tumor mutational burden (TMB). If you have a single driver, you tend not to have many other mutations. Those with single drivers, many of whom are nonsmokers, are less likely to have other mutations as you move down the pathway. Patients with large numbers of mutations, or high TMBs, tend to respond the best with immunotherapy. If you have a single driver, by definition, you are going to have a lower TMB and be much less able to respond. Immune checkpoint inhibitors should be used when resistance emerges to the targeted agent. In the community, sometimes patients will be started on immunotherapy plus cytotoxic chemotherapy; this has not been our practice, as it may limit options when the patient progresses.
While targeted agents are more likely to produce a response compared with immunotherapy, I have never cured anyone with a kinase inhibitor, as the tumor always becomes resistant relatively quickly. With immunotherapy, response rates are lower, but durability can be much longer, lasting for several years in some patients with NSCLC. However, I think that we need to become more precise with our immunotherapies. We need to understand that some tumors have many infiltrating T cells while others do not, some tumors have a lot of PD-L1 expression while others do not, and some tumors have a lot of T-cell immunoglobulin-3 expression while others do not.
References
Bodor JN, Boumber Y, Borghaei H. Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC). Cancer. 2020;126(2):260-270. doi:10.1002/cncr.32468
Datar I, Sanmamed MF, Wang J, et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res. 2019;25(15):4663-4673. doi:10.1158/1078-0432.CCR-18-4142
Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7
Huerter MM, Ganti AK. Predictive biomarkers for immune checkpoint inhibitor therapy: we need to keep searching. J Thorac Dis. 2018;10(suppl 18):S2195-S2197. doi:10.21037/jtd.2018.06.144
Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):210-216. doi:10.1001/jamaoncol.2017.4427
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213(13):2835-2840. doi:10.1084/jem.20161462
VanderLaan PA, Rangachari D, Costa DB. Lung cancer with a high tumor mutational burden. N Engl J Med. 2018;379(11):1093. doi:10.1056/NEJMc1808566