Non-Small Cell Lung Cancer
Immunotherapy and Targeted Therapies in Non–Small Cell Lung Cancer
Immunotherapies and targeted agents for non–small cell lung cancer (NSCLC) have significantly improved overall survival. Efforts to further improve outcomes include investigations of immune checkpoint inhibitor (ICI) therapy in combination with tyrosine kinase inhibitor (TKI) therapy for select tumors with high tumor mutational burden (TMB).
What does the future hold for combined immunotherapy and targeted therapy to optimize treatment for select patients with NSCLC?
“Patients with BRAF mutations, who tend to have a higher TMB than those with EGFR mutations, represent an important subset when exploring whether ICI and TKI combinations might be of benefit. Higher TMB is a predictor of response to ICI therapy, so these are the people who may be more likely to respond to combination therapy.”
The ongenetic alterations such as the EGFR and MET exon 14 skipping mutations almost exclusively arise in never smokers or in those who have smoked very little. In contrast, the majority of people with BRAF mutations are those who are current or former smokers who have many other mutations. So, patients with BRAF mutations, who tend to have a higher TMB than those with EGFR mutations, represent an important subset when exploring whether ICI and TKI combinations might be of benefit. Higher TMB is a predictor of response to ICI therapy, so these are the people who may be more likely to respond to combination therapy. The use of BRAF-targeted agents with anti–PD-1 checkpoint inhibition has already been studied in advanced melanoma, and there were not really any unexpected toxicities with this regimen.
Patients with EGFR mutations and ALK rearrangements have largely been excluded from trials of ICIs, so there is not much information on these combinations. One of the reasons for this is that patients with those oncogenic drivers commonly have low predictive biomarkers, PD-L1 expression and TMB, both biomarkers that are associated with a poor response to immunotherapy. Adding a second ICI to the PD-1 blockade, such as a T-cell immunoglobulin-3 (TIM-3)– or lymphocyte-activation gene 3 (LAG-3)–directed therapy, has not yet yielded encouraging results. Just adding a second ICI that works at a different receptor is unlikely to work for every patient. We will likely have to do something similar to what we have done with precision targeted therapies (ie, come up with a more tailored approach based on the mechanisms of suppression of the immune systems in different individuals).
Vice Chair, Clinical Research
“Right now, we only have US Food and Drug Administration–approved ICIs that target the PD-1/PD-L1 axis. To forge ahead with immunotherapy, we need additional ICIs beyond the anti–PD-1 agents, just as 15 years ago we needed additional targeted therapies to move beyond EGFR.”
A fair number of studies have been conducted exploring the combination of TKIs with ICIs in patients with EGFR mutations or ALK gene rearrangements. Overall, we have never seen any real benefit to this approach. In fact, when we have combined some EGFR TKIs with ICIs, we have seen excess pulmonary toxicity. It is important for clinicians to be aware so that they do not combine EGFR TKIs, for instance, osimertinib, with ICIs.
The key next step in this, of course, is actually identifying more active ICIs. Right now, we only have US Food and Drug Administration–approved ICIs that target the PD-1/PD-L1 axis. To forge ahead with immunotherapy, we need additional ICIs beyond the anti–PD-1 agents, just as 15 years ago we needed additional targeted therapies to move beyond EGFR. Although we have a long way to go with optimizing the use of ICIs, it is heartening to see, from the phase I KEYNOTE-001 study, that between 10% and 20% of patients who have been previously treated and then receive ICIs will still be alive in 5 years. And in patients with a PD-L1 tumor proportion score of 50% or greater, that survival rate went up to 25% in previously treated patients. So, although there are limitations to how effective these agents are, they can, for reasons that we do not completely understand, help some of our patients achieve a 5-year survival.
“I agree that many patients who express high levels of PD-L1 will respond to PD-1 and PD-L1 inhibitors with amazing results. However, an even larger number of patients will not respond, highlighting the need to personalize immunotherapy to increase the efficacy.”
I agree that patients who are smokers and have many mutations tend to have inflammation in the tumor microenvironment and that many patients who express high levels of PD-L1 will respond to PD-1 and PD-L1 inhibitors with amazing results. However, an even larger number of patients will not respond, highlighting the need to personalize immunotherapy to increase the efficacy. The potential reason for this nonresponse may be that the tumor is not driven as much by PD-L1, with adaptive responses driven by other immune checkpoints such as TIM-3 or LAG-3. Many companies are exploring these other agents. Analogous to the use of PD-1/PDL-1 inhibitors, targeting one of these newer inhibitory receptors may be a useful therapeutic approach. To date, I have not seen any notable positive results evaluating the blockade of these newer checkpoints. It is not known whether this is because the targets are not useful or whether the antibodies directed against these targets are not effective. It will be important to understand whether these checkpoints are found in large quantities in these tumors, so the development of assays to test for their presence is important in the ongoing development.
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