Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Management, risk factors and prognostic impact of checkpoint-inhibitor pneumonitis (CIP) in lung cancer - A multicenter observational analysis.

INTRODUCTION: Checkpoint-inhibitor pneumonitis (CIP) represents a major immune-related adverse event (irAE) in patients with lung cancer. We aimed for the clinical characterization, diagnostics, risk factors, treatment and outcome in a large cohort of patients from everyday clinical practice. PATIENTS AND METHODS: For this retrospective analysis, 1,376 patients having received checkpoint inhibitors (CPI) in any line of therapy from June 2015 until February 2020 from three large-volume lung cancer centers in Berlin, Germany were included and analyzed. RESULTS: With a median follow-up of 35 months, all-grade, high-grade (CTCAE ≥ 3) and fatal CIP were observed in 83 (6.0%), 37 (2.7%) and 12 (0.9%) patients, respectively, with a median onset 4 months after initiation of CPI therapy. The most common radiologic patterns were organizing pneumonia (OP) and non-specific interstitial pneumonia (NSIP) (37% and 31%). All except 7 patients with G1-2 CIP interrupted treatment. Corticosteroids were administered to 74 patients with a median starting dose of 0.75 mg/kg. After complete restitution (n = 67), re-exposure to CPI (n = 14) led to additional irAE in 43% of the cases. Thoracic radiotherapy targeting the lung was the only independent risk factor for CIP (odds ratio 2.8, p < 0.001) and pretherapeutic diffusing capacity for carbon monoxide inversely correlated with CIP severity. Compared with patients without CIP and non-CIP irAE, CIP was associated with impaired overall survival (hazard ratios 1.23, p = 0.24 and 2.01, p = 0.005). CONCLUSIONS: High-grade CIP accounts for almost half of all CIP cases in an allcomer lung cancer population. A continuous vigilance, rapid diagnostics and adequate treatment are key to prevent disease progression associated with impaired survival.

Endoscopic Lung Volume Reduction with One-Way Valves in Patients with Severe Chronic Obstructive Pulmonary Disease with Hypercapnia.

BACKGROUND: Robust clinical evidence on the efficacy and safety of endoscopic lung volume reduction (ELVR) with one-way valves in patients with severe lung emphysema with chronic hypercapnic respiratory failure is lacking. OBJECTIVE: The aim of this study was to compare patient characteristics, clinical outcome measures, and incidences of adverse events between patients with severe COPD undergoing ELVR with one-way valves and with either a partial pressure of carbon dioxide (pCO2) of ≤45 mm Hg or with pCO2 >45 mm Hg. METHODS: This was a multicentre prospective study of patients with severe lung disease who were evaluated based on lung function, exercise capacity (6-min walk test [6-MWT]), and quality-of-life tests. RESULTS: Patients with pCO2 ≤45 mm Hg (n = 157) and pCO2 >45 mm Hg (n = 40) showed similar baseline characteristics. Patients with pCO2 ≤45 mm Hg demonstrated a significant increase in forced expiratory volume in 1 s (p < 0.001), a significant decrease in residual volume (RV) (p < 0.001), and significant improvements in the quality of life and 6-MWT at the 3-month follow-up. Patients with pCO2 >45 mm Hg had significant improvements in RV only (p < 0.05). There was a significant decrease in pCO2 between baseline and follow-up in hypercapnic patients, relative to the decrease in patients with pCO2 ≤45 mm Hg (p = 0.008). Patients who were more hypercapnic at baseline showed a greater reduction in pCO2 after valve placement (r = -0.38, p < 0.001). Pneumothorax was the most common adverse event in both groups. CONCLUSIONS: ELVR with one-way valves seems clinically beneficial with a remarkably good safety profile for patients with chronic hypercapnic respiratory failure.

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions.

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

Endoscopic lung volume reduction with endobronchial valves in very low D LCO patients: results from the German Registry - Lungenemphysemregister e.V.

BACKGROUND: Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide (D LCO). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to D LCO for patients treated with ELVR. METHODS: We assessed D LCO at baseline and 3 months follow-up and compared pre- and postprocedural pulmonary function test, quality of life, exercise capacity and adverse events. This is a retrospective subanalysis of prospectively collected data from the German Lung Emphysema Registry. RESULTS: In total, 121 patients treated with ELVR were analysed. Thirty-four patients with a D LCO ≤20% and 87 patients with a D LCO >20% showed similar baseline characteristics. After ELVR, there was a decrease of residual volume (both p<0.001 to baseline) in both groups, and both demonstrated better quality of life (p<0.01 to baseline). Forced expiratory volume in 1 s (FEV1) improved significantly only in patients with a D LCO >20% (p<0.001 to baseline). Exercise capacity remained almost unchanged in both groups (p=0.3). The most frequent complication for both groups was a pneumothorax (D LCO ≤20%: 17.6% versus D LCO >20%: 16.1%; p=0.728). However, there were no significant differences in other adverse events between both groups. CONCLUSIONS: ELVR improves lung function as well as quality of life in patients with D LCO >20% and D LCO ≤20%. Adverse events did not differ between groups. Therefore, ELVR should be considered as a treatment option, even in patients with a very low D LCO.

Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.

Clinical trial and real-world data in non-small-cell lung cancer indicate that 10-60% of patients that progressed on first- or second-generation EGFR-targeting tyrosine kinase inhibitors (TKI) do not receive systemic second-line therapy. In our article, we discuss efficacy, safety and treatment duration with different EGFR-TKIs and stress the need for delivery of the most efficacious therapy in the first-line. We also provide our perspective on analysis of circulating tumor DNA and the role of EGFR-TKI in combined therapies. Finally, we review new therapeutic options to overcome resistance to EGFR-TKI. We believe that overall treatment duration and access to different medications in subsequent lines of therapy should be considered when planning the optimal treatment strategy.

Clinical Experience of Immunotherapy Treatment: Efficacy and Toxicity Analysis of the Compassionate Use Program of Nivolumab in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer.

BACKGROUND: Anti-PD1 monoclonal antibody nivolumab is an approved therapy option for the treatment of advanced squamous cell non-small cell lung cancer (SQ-NSCLC) patients. Data outside clinical trials about therapy efficacy and safety in later therapy line treatments have rarely been described until now. METHODS: We performed a retrospective data analysis of patients who were enrolled into the nivolu-mab Compassionate Use Program (CUP) in Germany. Sufficient clinical data of 40 patients were available for efficacy and safety analysis. RESULTS: Overall, 47.5% of all treated patients were not affected by any adverse events (AEs); 17.5% of patients suffered from severe AEs. The 1-year survival rate was 61.3%. Estimated median progression-free survival (PFS) was 5.3 months. Patients who received nivolumab as third or later therapy line treatment (77.5%) achieved similar median PFS and 12-month overall survival rate of 52%. CONCLUSION: Our findings of immunotherapy treatment outside clinical trials support the results of studies in the past and confirm the efficacy and favorable toxicity profile of nivolumab treatment in advanced SQ-NSCLC patients. In addition, we can present some rarely described information about nivolumab treatment of heavily pretreated patients, which provides some evidence that immunotherapy could also be useful in later therapy lines.

Tracheal, laryngeal and pulmonary mucormycosis followed by organizing pneumonia in a patient with Adult Onset Still's Disease.

We report a case of tracheal, laryngeal and pulmonary mucormycosis in a patient receiving immunosuppressive medication for an autoinflammatory fever syndrome. Mucormycosis was confirmed by histopathology from tracheal specimens and molecular evidence of Lichtheimia. A surgical approach was not possible because of the multifocal disease pattern and the extent of tracheal involvement. The patient was successfully treated with liposomal amphotericin B followed by posaconazole maintenance therapy. After 9 months, recurrent pulmonary mucormycosis was suspected but emerged as organizing pneumonia without evidence of active fungal infection.