Searching for predictive factors

James Fleck: Anticancerweb 21(08), 2019

In April 2019 Lancet journal published the results of the Keynote-042 international trial, extending the use of exclusive immunotherapy with pembrolizumab (an anti-PD1 humanized IgG4 monoclonal antibody) into a wider range of metastatic and advanced non-small cell lung carcinoma's customized treatments. Eligibility criteria included patients with PD-L1 Tumor Proportion Score (TPS) ≥ 1% (using the IHC 22 C3 PharmDx standard test) who did not express EGFR mutation or ALK translocation. A total of 1274 patients were randomly assigned (1: 1) for exclusive immunotherapy (pembrolizumab 200 mg) versus exclusive chemotherapy (carboplatin AUC 5-6 combined with paclitaxel 200 mg/m2 or pemetrexed 500 mg/m2, according histological subtype). Accrued patients had a median age of 63 years-old, were predominantly male (70%), smokers (78%), non-squamous histology (63%), presenting metastatic disease (88%) and predominantly high TPS (PD-L1 ≥ 50%), which was shown in 47% of cases. No crossover was allowed at progression. After a median follow-up of 12.8 months, overall survival favored the exclusive use of pembrolizumab in all TPS subgroups and showed lower toxicity (grade ≥ 3) compared to exclusive chemotherapy. However, exploratory analysis of the TPS subgroup (PD-L1 1% - 49%) did not confirm the benefit with the exclusive use of pembrolizumab, which suggests that positive results observed in all TPS subgroups (PD-L1 ≥ 1%, PD-L1 ≥ 20% and PD-L1 ≥ 50%) could translate a contamination with a predominant number of patients (47%) expressing high TPS (PD-L1 ≥ 50%). This was also the only subgroup in which progression-free survival (PFS) favored the exclusive use of pembrolizumab. In subgroups including patients with lower TPS expression (PD-L1 ≥ 20% and PD-L1 ≥ 1%) DFS favored the use of exclusive chemotherapy. The study is further limited, since the percentage of patients in the higher TPS subgroup (PD-L1 ≥ 50%) exceeds the 30% expected in general population. Additionally, the study did not admit the crossover, especially in a timeline when multiple trials are revealing immunotherapy-induced advanced non-small cell lung carcinoma chronification. Fortunately, the Keynote-024 study, designed only for patients with high TPS (PD-L1 ≥ 50%) admitted crossover. A recent updated Keynote-024, published in the Journal of Clinical Oncology in March 2019, confirmed the benefit obtained from the exclusive use of pembrolizumab following the crossover analysis. 

The promising results observed with pembrolizumab immunotherapy in advanced non-small cell lung carcinoma EGFR-wild and without ALK translocation suggest high TPS expression (PD-L1 ≥ 50%) as a predictive factor (PF), since it is supported by prospective and randomized trials with adequate statistical power. At the same time, the CheckMate 227 trial identified high tumor mutational burden (TMB ≥ 10 mutations/megabase) as a new predictive factor of response to the combination of nivolumab (humanized anti-PD1 IgG4 monoclonal antibody) + ipilimumab (humanized anti-CTLA-4 IgG1 monoclonal antibody). Predictive impact of TMB occurs regardless the percentage of PD-L1 expression. Despite immature data, the results indicate a potential benefit using PF for a more personalized immunotherapy in non-small cell lung cancer.

References:

Tony S K Mok, Yi-Long Wu, Iveta Kudaba, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial, Lancet393: 1819–30, 2019

Reck M, Rodríguez-Abreu D, Robinson AG, et al: Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater, J Clin Oncol37(7):537-546, 2019

Hellmann MD, Ciuleanu TE, Pluzanski, A, et al: Nivolumab plus Ipilimumab in Lung Cancer with High Tumor Mutational Burden, N Engl J Med 378: 2093, 2018