Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC)

Abstract

Treatment for advanced non-small cell lung cancer (NSCLC) has been significantly improved in recent years with the incorporation of drugs targeting antiangiogenesis and more specifically genomic alterations such as the EGFR mutations and ALK translocations. However, most patients invariably progress and die. The emergence of immune checkpoint inhibitors targeting the pathways involved in tumor-induced immunosuppression have redefined the management of the disease, achieving significant long-lasting responses with manageable safety profiles, regardless of histology. Still, response rates with immunotherapy are deemed suboptimal. Current efforts are focusing on new potential combination strategies with synergistic antitumor activity, using immune checkpoint blockade as a partner for targeted agents. Herein we discuss the available data on the combined use of immunotherapy, including PD-1/PD-L1 and CTLA-4 inhibitors, with EGFR and ALK inhibitors and comment on the current status of immunotherapy plus antiangiogenic drugs for molecularly unselected advanced NSCLC.

Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors

“…The role of immune checkpoint inhibitors is still not clear and merits further study, although the experience with immune monotherapy in NSCLC with other actionable oncogenic driver mutations has been disappointing to date. Current efforts include attempting to determine if there is synergistic antitumor activity with combined immunotherapy and targeted therapy (25). Additionally, high rates of CNS progression associated with crizotinib use and the inevitable development of crizotinib resistance mean that significant challenges exist as we try to transform the long-term outcomes of patients with this disease.…”

Monoclonal antibody therapy in cancer: When two is better (and considerably more expensive) than one

“…A subset of patients (approximately 20% or less) with advanced cancers (eg metastatic melanoma) can respond dramatically to single‐agent immune checkpoint blockade, but most patients do not respond to such therapy . This accounts for the enormous interest in combining immunological agents to improve the response rate and the duration of response.…”

“…18,22 A subset of patients (approximately 20% or less) with advanced cancers (eg metastatic melanoma) can respond dramatically to single-agent immune checkpoint blockade, but most patients do not respond to such therapy. 2,10,20,23 This accounts for the enormous interest in combining immunological agents to improve the response rate and the duration of response. The rationale for combining CTLA-4 and PD-1 blockers is strong, as CTLA-4 and PD-1 regulate distinct inhibitory pathways and have nonoverlapping mechanisms of actions, which appear to be complementary.…”

“…There is considerable interest in the use of combined anti-CTLA-4 and anti-PD-1/anti-PD-L1 therapy in non-small-cell lung cancer (NSCLC), where pembrolizumab is already first-line therapy in patients with tumours displaying strong PD-L1 expression. 23,30,32 In a Phase I study (CheckMate 012) of 78 patients with advanced NSCLC, the combination of nivolumab-plus-ipilimumab showed encouraging results by means of a relatively high response and tolerable safety profile. 33 Clinical activity was particularly enhanced in patients whose tumours expressed PD-L1 on at least 1% of their cancer cells (objective responses were achieved in 57%).…”

“…4 In the future, there will be a more individualized approach to combination therapy guided by patterns of expression of relevant biomarkers, to both predict and monitor clinical response, and improved knowledge of the mechanisms involved in the development of acquired tumour resistance, utilizing current existing approaches (eg mAbs, antibody-drug conjugates, chimeric antigen receptor (CAR)-T cells, natural killer (NK) cells, vaccines, oncolytic viruses, cytokines, regulatory T cells (Treg), tumour-associated macrophages), or with not-yet-discovered better immunotherapies. 18,20,21,23,[42][43][44] Individualization will extend to combination regimen dosing schedules and durations of therapy. There is likely to be an infinite grid of therapeutic possibilities, each of which needs to be considered carefully.…”