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Objective: BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non-small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts., Methods: We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAF V600E-targeting., Results: In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF-mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class., Conclusions: Patients with BRAF-mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF-mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors., Competing Interests: Conflict of interest statement Marcel Wiesweg—Honoraria: Boehringer Ingelheim, Novartis, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. Julia Roeper—Honoraria: Astra-Zeneca, Boehringer Ingelheim, Roche. Henning Reis—Consulting and advisory role: Bristol-Myers Squibb. Honoraria: Roche and Bristol-Myers Squibb. Travel support: Philips, Roche, Bristol-Myers Squibb. Research funding: Bristol-Myers Squibb. Share ownership: Bayer. Martin Metzenmacher—Honoraria: Merck, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Takeda. Wilfried Ernst Erich Eberhardt—Research funding to institution: Bristol-Myers Squibb, Astra Zeneca and Eli Lilly. Honoraria: Astra Zeneca, Bristol-Myers Squibb, Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Bayer, Johnson & Johnson, Amgen, Daichi Sankyo, Eli Lilly, Honoraria for educational lectures from Astra Zeneca, Bristol-Myers Squibb, Merck, Roche, Pfizer, Boehringer Ingelheim, Takeda, Amgen, Eli Lilly. Clemens Aigner—Research funding: Bristol-Myers Squibb. Kaid Darwiche—Consultancy/Advisory role: Boehringer Ingelheim, Novartis. Honoraria: Boehringer Ingelheim. Hans-Ulrich Schildhaus—Research grant: Novartis, Takeda. Honoraria: Pfizer, Novartis, Roche. Markus Tiemann—Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Takeda, Bristol-Myers Squibb, Merck. Frank Griesinger—Research funding to institution: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Siemens. Honoraria for educational lectures: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GlaxoSmithKline, Amgen, Honoraria: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GlaxoSmithKline, Siemens, Amgen. Martin Schuler—Consultant honoraria from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Roche, Takeda. Honoraria for educational lectures: Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis. Research funding to institution: Astra Zeneca, Boehringer Ingelheim, Bristol Myers-Squibb, Novartis. Other: Universität Duisburg-Essen (Patents). All remaining authors declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: This study aimed to describe treatment patterns and overall survival (OS) in patients with advanced non–small cell lung cancer (aNSCLC) in three countries between 2011 and 2020. Methods: Three databases (US, Canada, Germany) were used to identify incident aNSCLC patients. OS was assessed from the date of incident aNSCLC diagnosis and, for patients who received at least a first line of therapy (1LOT), from the date of 1LOT initiation. In multivariable analyses, we analyzed the influence of index year and type of prescribed treatment on OS. Findings: We included 51,318 patients with an incident aNSCLC diagnosis. The percentage of patients treated with a 1LOT differed substantially between countries, whereas the number of patients receiving immunotherapies/targeted treatments increased over time in all three countries. Median OS from the date of incident diagnosis was 9.9 months in the United States vs. 4.1 months in Canada. When measured from the start of 1LOT, patients had a median OS of 10.7 months in the United States, 10.9 months in Canada, and 10.9 months in Germany. OS from the start of 1LOT improved in all three countries from 2011 to 2020 by approximately 3 to 4 months. Conclusions: Observed continuous improvement in OS among patients receiving at least a 1LOT from 2011 to 2020 was likely driven by improved care and changes in the treatment landscape. The difference in the proportion of patients receiving a 1LOT in the observed countries requires further investigation. Observed continuous improvement in overall survival among patients receiving at least a first line of therapy from 2011 to 2020 was likely driven by improved care and changes in treatment landscape. The difference in the proportion of patients receiving a first line of therapy in the observed countries requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 x 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

• NSCLC patients with oligometastastic disease benefit from locally ablative and systemic therapy. • Neoadjuvant immunotherapy results in high pCR and MPR rates. • Neoadjuvant immunotherapy is a promising therapeutic concept for oligometastastic disease. Immune checkpoint inhibitors (ICI) have significantly improved outcome of patients with advanced NSCLC and recently also showed benefit in early-stage disease. Patients with oligometastatic disease (OMD) harbor limited metastases, resectable primary tumors and derive benefit from treatment with multimodal locally ablative and systemic therapy approaches. Nothing is known about feasibility and efficacy of neoadjuvant ICI in this setting. We here provide data from a multicenter retrospective study comprising 13 patients with NSCLC and OMD (≤3 distant metastases) from 5 university medical centers in Germany who have been treated with neoadjuvant ICI alone (n = 4) or in combination with chemotherapy (CT) (n = 9) prior to resection of the primary tumor. We analyzed complete (pCR) and major pathological remission (MPR) rates. These data show that neoadjuvant immunotherapy applied mostly in combination with CT results in high rates of pCR and MPR (54 and 69%, respectively). Up to now, 85% of patients are free of progression with a median follow-up of 9 months (3–28 months). Single cell RNASeq analysis of tumor tissue from one patient treated with CT-ICI indicates a strong predominance of adaptive immune cell populations over a small minority of epithelial (tumor) cells. Neoadjuvant ICI with or without CT is a promising therapeutic concept in patients with OMD. [ABSTRACT FROM AUTHOR]