Immunotherapy for NSCLC: The right treatment for the right person

Abstract

Lung cancer is the leading cause of mortality from malignant tumors all over the world. Since most patients at the time of diagnosis already have stage III-IV of the disease, the search for new effective treatment strategies for advanced NSCLC is the most important problem of modern oncology. The results of the study of the anti-PDl monoclonal antibody pembrolizumab were a real breakthrough in the treatment of NSCLC. In the KEYNOTE-001 study, the expression of PD-Ll on tumor cells was validated as a predictive biomarker of the drug's efficiency. Pembrolizumab demonstrated the possibility of achieving long-term objective responses, and a 4-year OS with all histological types in the subgroup of pre-treated patients with PD-L1 expression> 50% was 24.8% and 15.6% in the PD-L1> 1% group. In a phase 2/3 randomized study KEYNOTE-10 in the 2nd line treatment of NSCLC with PD-L1 expression > 1% pembrolizumab significantly increased life expectancy compared to docetaxel and confirmed the possibility of long-term duration of objective responses, even after cessation of treatment. Then the focus of research shifted to the 1st line of treatment. About 30% of patients with NSCLC have a high level of PD-L1 expression on tumor cells and demonstrate the most impressive response to pembrolizumab therapy. A randomized phase 3 study KEYNOTE-024 compared the effectiveness of pembrolizumab monotherapy with a standard platinum combination in patients with advanced NSCLC with a high level of PD-L1 expression without EGFR mutations or ALK trans-location. Compared with the platinum doublet the administration of pembrolizumab significantly increased all estimated parameters, including the median of progression-free survival (mPFS was 10.3 months versus 6 months; HR = 0.50; 95% CI 0.37-0.68, p < 0.001), the objective response rate (ORR 44.8% versus 27.8%), duration of response (in the pembrolizumab arm the median was not reached, in the chemotherapy (CT) group — 6.3 months). Despite the approved crossover, the use of pembrolizumab in the 1st line of treatment more than doubled the life expectancy of NSCLC patients with high PD-Ll expression as compared to CT: the median overall survival (OS) was 30.0 months versus 14.2 months (HR = 0.63, p = 0.002), 1-year OS 70.3% versus 54.8%; 2-year OS — 51.5% versus 34.5%. The remaining population to study were untreated patients with any level of PD-L1 expression. A randomized phase 3 study KEYNOTE-189 evaluated the effectiveness of adding pembrolizumab to the platinum combination in the 1st line treatment of non-squamous NSCLC without EGFR and ALK mutations with any PD-L1 expression. The addition of pembrolizumab to the standard 1st line CT significantly increased all estimated efficacy indicators including OS, PFS and ORR. After a median follow-up of 10.5 months the median OS in the pembrolizumab combination group was not reached and in CT group was 11.3 months. The estimated 12-months survival was 69.2% and 49.4% respectively (HR = 0.49; 95% CI 0.38-0,64; p <0.001). The median PFS was 8.8 months versus 4.9 months, alive 1 year without progression 34.1% and 17.3% of patients respectively (HR = 0.52; p <0.001). The ORR in the group with pembrolizumab reached 47.6% versus 18.9% in CT group, moreover the tumor regressions were much longer. J Finally a randomized 3-phase study KEYNOTE-407 evaluated the effectiveness of adding pembrolizumab to lst-line CT of NSCLC with squamous histology with any PD-L1 expression. As the first analysis showed, the addition of permboli-zumab significantly increased OS of patients with squamous NSCLC, median OS 15.9 months versus 11.3 months in the groups of pembrolizumab + CT and placebo + CT respectively (HR = 0.64; 95% CI 0,49-0.95; p = 0.0006), median PFS 6.4 months and 4.8 months respectively (HR = 0.56; 95% CI 0.45-0.70; p <0, 0001) and ORR 57.9% versus 38.4%, the median response duration 7.7 months versus 4.8 months. ! Thus, the convincing advantages of using pembrolizumab in 1st line therapy were demonstrated in 3 randomized phase 3 ptudies: in monotherapy of NSCLC of any histological subtype with high PD-L1 expression, and in combination with CT in'squamous and non-squamous hystologies regardless of the level of PD-L1 expression.