Rainer Wiewrodt

PURPOSE Epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR -mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837 ). METHODS Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. RESULTS Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. CONCLUSION Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR -mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.

<b>Introduction:</b> The influence of blood group antigens on cancerogenesis is shown for distinct tumor types (<i>e.g.</i> gastric cancer). For lung cancer, however, the impact of Rhesus blood group factors is unknown. <b>Methods:</b> To investigate the impact of Rhesus blood groups on the course of NSCLC, a study collective from two academic medical centers was analyzed (n=516; mean age 62±10 yrs; 28% female; stage I/II 37%, stage III 27%, stage IV 36%; squamous cell carcinoma n=195 [38%], adeno carcinoma n=238 [46%], others n=83 [16%]). The variability of RhCE phenotypes was categorized into 9··ee9 (<i>i.e.</i> ccee, Ccee, CCee), 9ccE·9 (<i>i.e.</i> ccEe, ccEE) and 9C·E·9 (<i>i.e.</i> CcEe, CCEe, CcEE, CCEE). <b>Results:</b> In pulmonary adenocarcinoma patients with Rh 9··ee9 revealed improved overall survival (n=181, median 29 months, HR 1.00 [index]) compared to patients with Rh 9ccE·9 (n=29, median 19 m., HR 1.76 [1.15-2.70]), and Rh 9C·E·9 (n=28, median 10 m., HR 2.65 [1.70-4.12]). Differences were clinically meaningful both in univariate model (Log Rank p&lt;.001) and multivariate model (Cox propoprional hazard model p&lt;.001), respectively. Furthermore, Rh 9··ee9 was associated with reduced incidence of CNS-metastasis in stage IV adenocarcinoma (Kruskal-Wallis p=.011) and metastasis count (oneway-ANOVA p=.018). <b>Conclusion:</b> To the best of our knowledge, data demonstate for the first time an association of Rhesus blood groups and lung cancer course. Phenotypic RhCE expression in NSCLC is an independent prognostic factor for overall survival in pulmonary adenocarcinoma. Besides, metastatic spread in stage IV pulmonary adenocarcinoma shows RhCE dependent influence in total metastasis count and CNS-metastasis occurrence rate.

<b>Introduction:</b> To improve the prognosis of lung cancer patients, immunotherapy is expected to become a powerful therapeutic option. Several clinical studies demonstrate a positive prognostic effect of a targeted therapy against the programmed cell death receptor PD1 and its ligand PDL1 in solid tumors. For non-small lung cancer (NSCLC) however, the diagnostic, prognostic and predictive impact of these factors needs to be clarified. <b>Materials and Methods:</b> Immunohistochemistry was performed to evaluate the expression profile of PD1 and PDL1 in 398 NSCLC patients (median age: 66 years, 78% male sex, 45% squamous cell carcinoma (SCC) histology). Statistical analysis included Fisher9s Exact test, univariate and multivariate models. <b>Results:</b> 23% of the NSCLC samples expressed PDL1 and 11% of the investigated tumors displayed PD1 in tumor infiltrating lymphocytes (TILs). A positive correlation with PD1-positive lymphocytes was found for male sex (p=0.022), age below 70 years (p=0.039), adjuvant therapy (p=0.018) and Bcl-2 protein expression (p=0.012). PDL1 was associated with increased overall survival in SCC (p=0.031, log rank test; p=0.007, multivariate cox regression model: HR(95%CI)= 0.494(0.296-0.825)). <b>Conclusion:</b> In the context of immunotherapeutic approaches we present a histology-depending prognostic effect of PDL1 for NSCLC patients with SCC. With regard to the observed effect, further studies are required to evaluate the prospective impact of PD1 and PDL1 in NSCLC.