Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations.

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved “precision” drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.

Oncologists face challenges in the management of SARS-CoV-2 infections and post-SARS-CoV-2 cancer treatment. We analyzed diagnostic, clinical and post-SARS-CoV-2 scenarios in patients from three German cancer centers with RT-PCR confirmed SARS-CoV-2 infection. Sixty-three patients with SARS-CoV-2 and hematologic or solid neoplasms were included. Thirty patients were initially asymptomatic, 10 of whom developed COVID-19 symptoms subsequently. Altogether 20 (32%) patients were asymptomatic, 18 (29%) had mild, 12 (19%) severe and 13 (20%) critical courses. Lymphocytopenia increased risk of severe/critical COVID-19 three-fold (p = 0.015). Asymptomatic course was not associated with age, remission status, therapies or co-morbidities. Secondary bacterial infection accompanied more than one third of critical COVID-19 cases. Treatment was delayed post-SARS-CoV-2 in 46 patients, 9 of whom developed progressive disease (PD). Cancer therapy was modified in 8 SARS-CoV-2 survivors because of deteriorating performance or PD. At the last follow-up, 17 patients had died from COVID-19 (n = 8) or PD (n = 9) giving an estimated 73% four-month overall survival rate. SARS-CoV-2 infection has a heterogenous course in cancer patients. Lymphocytopenia carries a significant risk of severe/critical COVID-19. SARS-CoV-2 disruption of therapy is as serious as SARS-CoV-2 infection itself. Careful surveillance will allow early restart of the anti-cancer treatment.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.

EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.

Background/Objectives: Following findings of the PACIFIC trial, consolidation therapy with durvalumab was established as standard of care for patients with unresectable, stage III non-small cell lung cancer (NSCLC) and no disease progression after chemoradiotherapy (CRT). This study evaluated real-world effectiveness of durvalumab consolidation in clinical routine in Germany. Methods: Patients with unresectable, stage III NSCLC enrolled in the prospective, multicenter CRISP registry (August 2018–June 2023) were classified into two subgroups: treated with/without durvalumab consolidation therapy. Following stabilized inverse probability of treatment weighting, progression-free survival (PFS) and overall survival (OS) were assessed. Results: This analysis included 231 patients, 124 with and 107 without durvalumab consolidation therapy. In the two subgroups (with/without durvalumab), median age was 67.2/64.6 years, 51.6%/47.7% were female, and 83.1%/86.0% had Eastern Cooperative Oncology Group performance status ≤1. Most patients (87%) received concurrent CRT. In the weighted analysis, median PFS was significantly longer with durvalumab consolidation (18.6 months, 95% CI [12.8, 24.5] vs. 7.5 months, 95% CI [5.5, 8.4]; HR 0.52, 95% CI [0.37, 0.73]); median OS was numerically longer but did not reach statistical significance (34.4 months, 95% CI [25.4, not available/not reached] vs. 27.5 months, 95% CI [17.4, 59.6]; HR 0.67, 95% CI [0.44, 1.02]). Conclusions: This real-world study confirmed significant PFS improvements with durvalumab consolidation in unresectable, stage III NSCLC, with effect sizes comparable to PACIFIC. Although OS differences were not statistically significant, these findings provide valuable real-world evidence supporting the effectiveness of durvalumab consolidation in routine clinical practice.