Role of Immune Checkpoint Inhibitor Therapy in Advanced EGFR-Mutant Non-Small Cell Lung Cancer

Abstract

Over the last decade, the treatment of advanced non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed therapy and immune checkpoint inhibitors. In patients with epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience disease progression and thus an urgent need exists for improved subsequent lines of therapies. The concurrent revolution in immune checkpoint inhibitor (ICI) therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI therapy in the first line setting and inferiority to chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI therapies have demonstrated increased toxicities, and EGFR TKI therapy given after first-line ICI therapy has been correlated with severe adverse events. Nonetheless, combination therapies including dual-ICI blockade and ICI, chemotherapy, and angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the tumor biology and tumor microenvironment (TME) of EGFRm NSCLC tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.

Chemotherapy versus personalized therapy for EGFR mutant lung adenocarcinoma resistance to EGFR-Tyrosine Kinase Inhibitors: A Retrospective Dual-Center Study

“…The data from clinical trials have not shown substantial survival bene ts of single-agent ICI [17]. The combination therapy of chemotherapy and ICI or chemotherapy with anti-angiogenesis reported an e cacy with an ORR of 30-60% and a PFS of 5.0-7.0m [18][19][20]. ICIs combined with chemotherapy and anti-angiogenic drugs showed excellent bene ts for patients receiving prior EGFR-TKI treatment, with an ORR of 73.5% and a PFS of 10.2m in the IMpower150 subgroup, and an ORR of 43.9% and a PFS of 6.9m in the ORIENT-31 trail [21][22][23].…”

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer

“…The present study selected the combination of icotinib (or other EGFR-TKIs) and chemotherapy since it is the most studied combination in NSCLC, with apparent benefits in response and survival[ 9 , 18 , 24 , 34 - 36 , 49 ]. Still, the combination of EGFR-TKIs and immunotherapy could be a promising option for NSCLC[ 50 - 52 ], but some evidence suggests that immunotherapy is not effective in patients with EGFR -mutated NSCLC, probably because of the specific tumor microenvironment[ 52 , 53 ]. Indeed, early trials showed that immunotherapy monotherapy was inferior to EGFR-TKIs in EGFR -mutated NSCLC[ 52 , 53 ].…”

“…Still, the combination of EGFR-TKIs and immunotherapy could be a promising option for NSCLC[ 50 - 52 ], but some evidence suggests that immunotherapy is not effective in patients with EGFR -mutated NSCLC, probably because of the specific tumor microenvironment[ 52 , 53 ]. Indeed, early trials showed that immunotherapy monotherapy was inferior to EGFR-TKIs in EGFR -mutated NSCLC[ 52 , 53 ]. Subsequent studies showed that the combination of immunotherapy with EGFR-TKIs in EGFR -mutated NSCLC resulted in high rates of serious AEs (33.3%-71.4% of grade 3-4 AEs)[ 54 - 56 ].…”

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies

“…Preclinical studies in genetically engineered lung tumor models have suggested favorable changes to the immune TME in response to EGFR TKI treatment, such as early increased antigen presentation and CD8+ cytotoxic response, a reduction in Tregs, and the inhibition of M2 macrophages, though this was a dynamic process, with this phenotype disappearing with long-term treatment [ 89 ]. This unfavorable end result has been borne out clinically with tumors progressing after EGFR TKIs showing increased PD-L1 and decreased CD8 + TILs [ 90 ]. Theoretically, the addition of immunotherapy could present an opportunity to reverse this unfavorable long-term phenotype.…”

“…With the caveat that these studies have generally been conducted in EGFR-mutant disease (which is more likely to respond to EGFR monotherapy as a comparator), overall, EGFR TKI plus ICI trials in this population have shown disappointing results, with failure to achieve additive effects and concerning increased toxicity signals. These adverse effect profiles included elevated rates of hepatotoxicity with the combination of durvalumab or pembrolizumab with first-generation TKI gefitinib and interstitial lung disease with the combination of durvalumab with third-generation TKI osimertinib, leading to the early closure of both the TATTON and CAURAL trials [ 90 ]. While osimertinib, which has also shown toxicity when administered sequentially after ICI, is less relevant to BTCs as a mutation-specific EGFR TKI, these trials, together, unfortunately suggest a broader issue with the tolerability of EGFR plus ICI combination therapy.…”