Tumor PD-L1 expression and molecular profiling are not associated with immune checkpoint inhibitor-induced thyroid dysfunction in advanced NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.

Horesh A ，Pollack R ，Nechushtan H ，Dresner-Pollak R ，Neuman T ... -  《-》

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 ... -  《-》

Effectivity and safety of PD-1/PD-L1 inhibitors for different level of PD-L1-positive, advanced NSCLC: A meta-analysis of 4939 patients from randomized controlled trials.

Effective improvement for the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors had been shown in advanced non-small cell lung cancer (NSCLC) patients compared with traditional therapy. However, we do not have ample evidences to demonstrate the safety and effectivity in the treatment of PD-L1-positive, advanced NSCLC. The relation was controversial about the expression of PD-L1 and survival outcomes of PD-1/PD-L1 inhibitors. Electronic databases (PubMed, EMBASE, and the Cochrane library) and major conference proceedings were systematically searched for all clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Randomized controlled trials (RCTs) were included to compare PD-1/PD-L1 inhibitors with chemotherapy in advanced NSCLC patients reporting adverse events (AEs) and immune-related AEs (irAEs). The incidence, Hazard Ratio (HR), Odds Ratio (OR), and corresponding 95% confidence interval (CI) of outcomes were calculated. A total of 4939 patients from 10RCTs were included. In the group of PD-L1 ≥ 1%, PD-L1 ≥ 5%, PD-L1 ≥ 10%, PD-L1 ≥ 50%, the HR of OS is 0.31(95%CI 0.38-0.23; p < 0.0001), 0.47(95%CI 0.82-0.12; p = 0.008), 0.85(95%CI 1.17-0.53; p < 0.0001), 0.47(95%CI 0.59-0.36; p < 0.0001) respectively. The HR of PFS is 0.13(95%CI 0.01-0.24; p = 0.027), 0.31(95%CI 0.00-0.62; p < 0.0001), 0.62(95%CI 0.30-0.93; p < 0.0001), 0.40(95% CI 0.20-0.59; p < 0.0001) respectively. In terms of summary adverse events, PD-1/PD-L1 inhibitors groups had a significant lower risks in any treat-realated AEs than chemotherapy. About irAEs, PD-1/PD-L1 inhibitors groups had a significant higher risks in irAEs than chemotherapy. PD-1/PD-L1 inhibitors are generally effected and safer than chemotherapy for patients with PD-L1-positive, advanced NSCLC. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and even life-threatening.

Shi Y ，Duan J ，Guan Q ，Xue P ，Zheng Y ... -  《-》

Immune Checkpoint Inhibitor-induced Thyroid Dysfunction Is Associated with Higher Body Mass Index.

Obesity is a proinflammatory metabolic state that may play a role in the development of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. To characterize the association between body mass index (BMI) and thyroid irAEs. We performed a single-center, retrospective analysis of 185 cancer patients treated with anti-PD-1/L1 from January 2014 to December 2018. Patients with normal thyroid function at baseline and available BMI were included. The primary endpoint was difference in BMI in patients who developed overt thyroid dysfunction versus those who remained euthyroid following anti-PD-1/L1 initiation. Additional endpoints included any (overt or subclinical) thyroid dysfunction, overt thyrotoxicosis or overt hypothyroidism, and time to development of dysfunction according to BMI. Any thyroid dysfunction developed in 72 (38.9%) patients and 41 (22.1%) developed overt thyroid dysfunction. Mean BMI was higher in those with overt thyroid dysfunction versus euthyroid (27.3 ± 6.0 vs 24.9 ± 4.5, P = .03). Development of overt thyrotoxicosis versus remaining euthyroid was associated with higher BMI (28.9 ± 5.9 vs 24.9 ± 4.5; P < .01), whereas overt hypothyroidism was not (26.7 ± 5.5 vs 24.9 ± 4.5, P = .10). Overt thyrotoxicosis developed within 57.5 (interquartile range [IQR] 31.8-78.8) days of treatment in the low-normal BMI group, 38.0 (IQR 26.8-40.5) days in the overweight group, and 23.0 (IQR 21.0-28.0) days in the obese group (P = .02). Patients treated with PD-1/L1 inhibitors were more likely to develop thyroid irAEs, specifically overt thyrotoxicosis, with increasing BMI. Overt thyrotoxicosis occurred earlier in obese versus leaner patients. These data highlight the complex interplay between obesity and immune response in immune checkpoint inhibitor-treated patients.

Pollack R ，Ashash A ，Cahn A ，Rottenberg Y ，Stern H ，Dresner-Pollak R ... -  《-》

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Kim HI ，Kim WG ，Kim M ，Ko NG ，Jin M ，Jung HA ，Sun JM ，Ahn JS ，Ahn MJ ，Choi YL ，Jeon MJ ，Kim TY ，Kim WB ，Kim SW ，Lee DH ，Jang SJ ，Kim SW ，Chung JH ，Kim TH ，Lee SH ... -  《-》