![]() ![]() KEYNOTE-042 is a similar design however we select the patients over 1% and using overall survival as the primary endpoint. So KEYNOTE-024 is actually selecting the patients of PD-L1 expression 50% or more and a primary endpoint of progression free survival. KEYNOTE-042 is the sister trial of KEYNOTE-024 – 24, 42. Professor Tony Mok – Chinese University of Hong Kong, Hong Kong The premise of this test is that an increased number of nonsynonymous mutations result in the production of unique tumor neoantigens that can be recognized by the immune system, favoring tumor recognition and killing by adaptive ICs upon reinvigoration with ICIs ( 36, 37).Latest data from KEYNOTE 42: Pembrolizumab vs chemotherapy in treatment-naive patients (pts) with PD-L1 advanced NSCLC TMB refers to the number of somatic mutations found by DNA sequencing of a tumor specimen. Recently, tumor mutational burden (TMB) has arisen as another potential indicator of response to immune-checkpoint therapy. These studies had concordant main conclusions that (i) SP142 shows lower sensitivity than the other FDA-approved assays and a popular laboratory developed assay and (ii) that pathologists can concordantly read PD-L1 expression on TCs, but do not, even with training, concordantly read PD-L1 expression on ICs ( 33, 34). Only two of these-a study sponsored by the National Comprehensive Cancer Network and the Blueprint Project-have been prospectively statistically powered. Several studies have compared the sensitivity and reproducibility of these assays for detecting PD-L1 expression in both TCs and ICs ( 32). Currently, four PD-L1 assays are FDA approved in lung cancer. The IHC assay is done in a standard manner used by other IHC companion diagnostic tests such as ER and HER2 in breast cancer ( 31) and is read by pathologists, who estimate the percentage of TCs with an intensity of membranous expression (the TPS) and the percentage of ICs with similar expression (the IC proportion score). PD-L1 IHC was the first FDA-approved companion diagnostic test for ICIs. On the basis of these data, the FDA approved ABCP for the first-line treatment of patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations ( 26). 47.7%), primarily consisting of nausea, anorexia, diarrhea, neutropenia, febrile neutropenia, and thrombocytopenia. A higher incidence of grade ≥3 adverse events was observed in the atezolizumab combination group (55.7% vs. Interestingly, patients with EGFR and ALK alterations were also found to benefit from combination therapy with atezolizumab as we will discuss, the vast majority of ICI studies in NSCLC have excluded patients with these alterations. However, patients with 0% PD-L1 TC and IC expression had improved survival as well. Patients with all levels of PD-L1 expression in both tumor and ICs benefited, with benefit increasing with higher expression. 14.7 months) compared with the group treated with chemotherapy and bevacizumab ( 25). ![]() In patients without EGFR and ALK alterations, both the median PFS and OS were improved in the atezolizumab-containing group (median PFS 8.3 vs. IMpower 150 randomized patients to three groups: atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) ACP and BCP the data derived from comparing ABCP and BCP are now available. Two studies have examined the role of atezolizumab combined with chemotherapy for the first-line treatment of metastatic nonsquamous NSCLC. Combining ICIs and Cytotoxic Chemotherapy Fortunately, the majority of irAEs can be successfully managed with corticosteroids and other adjunctive medications. In clinical trials, up to 2% of patients treated with these agents have died from therapy-related toxicities ( 18). One study found that 7%–13% of NSCLC patients treated with PD-1 axis inhibitors experienced grade 3 or higher toxicities the incidence of high-grade irAEs among patients with all tumor types treated with PD-1 and PD-L1 inhibitors is thought to be less than 20% ( 18, 19). Immune-related toxicities range from the more commonly seen hypothyroidism or skin rash to rarer and more serious manifestations such as colitis, pneumonitis, autoimmune hepatitis, and encephalitis. The majority are immune-related adverse events (irAE) that result from nonspecific activation of the immune system and induction of autoimmune tissue destruction or alteration, although mechanisms differ based on the organ(s) involved ( 18). Nonsquamous allowed EGFR/ ALK alterationsĪlthough ICIs are generally well tolerated, they are not without toxicities. docetaxel: 0.61 (0.49–0.75) P < 0.0001įirst-line chemotherapy–checkpoint inhibitor combinations
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