PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions.

The use of immune checkpoint inhibitors (ICIs) has become one of the most promising approaches in the field of cancer therapy. Unlike the current therapies that target tumor cells, such as chemotherapy, radiotherapy, or targeted therapy, ICIs directly restore the exhausted host antitumor immune responses mediated by the tumors. Among multiple immune modulators identified, the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis leading to the exhaustion of T-cell immunity in chronic infections and tumors has been widely investigated. Therefore, blocking antibodies targeting PD-1 or PD-L1 have been developed and approved for the treatment of various advanced cancers, including non-small-cell lung cancer (NSCLC), making them the most successful ICIs. Compared with chemotherapy or radiotherapy, PD-1/PD-L1 blockade therapy significantly improves the durable response rate and prolongs long-term survival with limited adverse effects in both monotherapy and combination therapy for advanced NSCLC. However, extensive challenges exist for further clinical applications, such as a small fraction of benefit population, primary and acquired resistance, the lack of predictive and prognostic biomarkers, and treatment-related adverse effects. In this article, we summarize the latest clinical applications of PD-1/PD-L1 blockade therapy in advanced NSCLC worldwide, as well as in China, and discuss the bottlenecks related to the use of this therapy in clinical practice. An exploration of the underlying mechanism of PD-1/PD-L1 blockade therapy and biomarker identification will maximize the application of ICIs in advanced NSCLC and facilitate bedside-to-bench studies in cancer immunotherapy as well. IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) display apparent benefits for the treatment of advanced non-small-cell lung cancer (NSCLC). However, the clinical applications of these therapies are challenged by the limited benefit population with additional high economic burden and adverse events. This review discusses the bottlenecks of ICI therapy in clinical practice and provides appropriate guidance in the development of predictive biomarkers, the establishment of the criteria for combining PD-1/PD-L1 blockade therapy with the existing therapies, and the management of adverse events observed both in monotherapy and combination therapy, which will help maximize the applications of ICIs in advanced NSCLC.

Xia L ，Liu Y ，Wang Y 《-》

Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC).

Yoneda K ，Imanishi N ，Ichiki Y ，Tanaka F ... -  《-》

Switching administration of anti-PD-1 and anti-PD-L1 antibodies as immune checkpoint inhibitor rechallenge in individuals with advanced non-small cell lung cancer: Case series and literature review.

Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti-programmed death-1 (PD-1) antibodies (e.g. nivolumab, pembrolizumab) and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients. We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti-PD-1 and anti-PD-L1 antibodies during their clinical courses. Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression-free survival of ICI rechallenge in these patients was 4.0 (range: 0.4-8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6-46.8) months. Of the 10 patients who developed immune-related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable. Switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients. • Significant findings of the study In this study, switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC. • What this study adds Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.

Kitagawa S ，Hakozaki T ，Kitadai R ，Hosomi Y ... -  《-》

Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC).

KRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC. In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available. A total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti-programmed death 1, anti-PD-L1, or anti-cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non-KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%). For patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.

Jeanson A ，Tomasini P ，Souquet-Bressand M ，Brandone N ，Boucekine M ，Grangeon M ，Chaleat S ，Khobta N ，Milia J ，Mhanna L ，Greillier L ，Biemar J ，Nanni I ，Ouafik L ，Garcia S ，Mazières J ，Barlesi F ，Mascaux C ... -  《-》

Combination therapy with PD-1 or PD-L1 inhibitors for cancer.

Hayashi H ，Nakagawa K 《-》