Background: Pembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53-defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit. Methods: In this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated. Results: A total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% vs. 65%, P=0.13). Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRAS^G12C group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRAS^other and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRAS^G12C/TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRAS^other/TP53 mutations showed a dismal prognosis (ORR 27.3%, P=0.002; PFS 3.9 mo., P=0.001, OS 9.7 mo., P=0.02). Conclusions: A comprehensive assessment of KRAS subtypes and TP53 mutations allows a highly relevant prognostic differentiation of patients with metastatic, PD-L1 high LuAD treated upfront with pembrolizumab.

PD-L1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic non-small cell lung cancer (NSCLC) in the clinical routine, but has limited value to distinguish responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap. 696 consecutive patients with PD-L1 high (≥50%), non-squamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with ECOG-PS ≤1 and pembrolizumab as first-line palliative treatment were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of the TCGA lung adenocarcinoma cohort. Proportion of KRASmut and TP53mut were 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 co-mutations increased response rates (G12C: 69.7% vs. 46.5% (TP53mut vs. wt), p=0.004; non-G12C: 55.4% vs. 39.5%, p=0.03), progression-free (PFS; G12C: HR 0.59, p=0.009, non-G12C: HR 0.7, p=0.047) and overall survival (OS; G12C: HR 0.72, p=0.16, non-G12C: HR 0.56, p=0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest PFS and OS (33.7 and 65.3 months), correlated with high TIL densities in the TME and upregulation of IFNγ target genes. Pro-inflammatory pathways according to TP53 status (mut vs. wt) were less enhanced and not different in non-G12C and KRASwt, respectively. G12C/TP53 co-mutations identify a subset of patients with a very favorable long-term survival with ICI monotherapy, mediated by highly active IFNγ signaling in a pro-inflammatory TME.

We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. In total, 52 patients were included [median age 57 years (range 32–81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1–4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

Patient navigation initiatives aim to improve the coordination of healthcare by reducing the barriers patients encounter when seeking access to appropriate services. These types of interventions are currently being tested both within Germany and internationally. A common obstacle in such research, as with most clinical trials, is developing recruitment methods that successfully enroll enough participants from the target groups. The results presented here aim to share insights and experiences regarding a common challenge in healthcare research: identifying factors that influence patient participation and refusal in studies testing new interventions, and how these factors can guide study design. This study, part of a mixed-methods feasibility evaluation involving randomized and cohort components, systematically recorded the recruitment process for a patient-focused navigation program. Between June 2021 and September 2022, individuals with lung cancer or stroke were recruited from inpatient wards and specialized outpatient clinics across urban and rural regions of Germany. Data were collected on why some patients were excluded or not approached, as well as the reasons patients declined participation. Quantitative findings were analyzed descriptively, and thematic analysis was applied to interviews with recruitment staff to capture their perspectives. Among screened individuals, eligibility rates ranged from 74% to 76.5% for stroke patients and 91% to 93% for those with lung cancer. Of those eligible, recruitment efforts reached 44% to 46.9% of inpatients and 73% of outpatients. Factors preventing patients from approaching were primarily linked to organizational or situational constraints. Common reasons patients refused involvement included feelings of being overwhelmed (noted in stroke patients) and perceiving the study as irrelevant (noted in lung cancer patients). The lessons learned and recruitment challenges encountered during this feasibility study provide valuable insights for refining patient enrollment strategies in future trials focusing on age-related health conditions.