Targeted Therapy Plus Immune Checkpoint Inhibitors: Research Opportunities, But No Improvement in Activity to Date

By Ross Soo, MB BS, PhD, FRACP

The treatment of patients with advanced NSCLC harbouring an actionable oncogene with tyrosine kinase inhibitors (TKIs) directed at its oncogenic molecular alteration represents one of the most significant advances in lung cancer management. Another area of achievement in the treatment of advanced NSCLC has been the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1). Although EGFR and ALK TKIs can induce rapid responses in a large number of patients with advanced oncogene-driven NSCLC, the duration of response is generally modest. In contrast, immune checkpoint inhibitors have the potential for durable disease control; however, the response rates are lower. Given this situation, research must address whether molecular targeted agents and immune checkpoint inhibitors can be combined safely to improve antitumor activity.

Immune cell function can be modulated by targeted therapy (Table 1).1 In pre-clinical studies, oncogenic EGFR and ALK signaling was reported to induce immune escape via the PD-1/PD-L1 axis.2,3 Some retrospective studies suggested an association between EGFR-positive or ALK-positive NSCLC and PD-L1 expression.3 However, other studies have reported an inverse relationship between PD-L1 expression and EGFR mutations and no association between PD-L1 expression and ALK rearrangement, as well as an uninflamed tumor microenvironment.5-7

Existing Data
Early-phase studies of combination targeted therapy and immune checkpoint inhibitors in patients with pretreated or treatment-naive EGFR-positive or with EML4ALK–positive NSCLC have been reported (Table 2). Response rates for combination EGFR TKIs or ALK TKIs plus immune checkpoint inhibitors are, at best, similar to previously reported response rates with EGFR TKIs/ALK TKIs alone, suggesting no synergistic effect. This observation has also been seen in preclinical studies of EGFR TKIs and immune checkpoint inhibitors8 as well as ALK TKIs and immune checkpoint inhibitors.9 Unfortunately, in some studies of combination EGFR/ALK TKIs plus immune checkpoint inhibitors, grade 3 to 4 treatment-related adverse events were unexpectedly higher than previously reported with TKIs or immune checkpoint inhibitors alone (Table 2).10-12 For example, in a phase I study of osimertinib and durvalumab (TATTON), an unexpectedly increased frequency of treatment-related adverse toxicity was reported, with 38% of patients developing interstitial lung disease (ILD) with grade 3 to 4 toxicity seen in 16% of cases. To place this in context, the incidence of ILD with single-agent osimertinib and durvalumab is 2.9% and 2%, respectively.10 Because of the high frequency of ILD observed, this treatment arm has been discontinued. In a phase I/II study of crizotinib and nivolumab, severe hepatic toxicities leading to the discontinuation of the combination treatment were seen in 38% of patients. In contrast, the discontinuation rates due to hepatic toxicities from single-agent crizotinib and nivolumab are about 2.3% and 0.3% to 1.5%, respectively.12

Current studies of combination molecular targeted therapy and immune checkpoint inhibitors in EGFR-positive or EML4-ALK–positive NSCLC are often associated with increased toxicities but not with greater activity; these combinations should not be administered in routine clinical practice. These findings highlight the importance of conducting well-designed phase I studies and also provide an opportunity to evaluate for biomarkers of efficacy and safety. Further studies on safety and activity of immune checkpoint inhibitors plus targeted agents are required in other oncogene-driven lung tumors such as KRAS, BRAF, or ROS1 NSCLC. Other research avenues being pursued include the characterization of the tumor microenvironment in oncogene-driven NSCLC, use of preclinical models and clinical studies for optimal treatment dosing, and sequencing and development of biomarkers to identify immunotherapeutic activity in early-phase trials. ✦

About the Author: Dr. Soo is a senior consultant, Department of Haematology-Oncology, National University Cancer Institute, Singapore, and an adjunct senior research fellow, Cancer Science Institute, National University of Singapore.

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