Publications by authors named "Martin Reck"

279 Publications

IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous non-small cell lung cancer.

J Thorac Oncol 2021 Jul 23. Epub 2021 Jul 23.

LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany. Electronic address:

Introduction: We report final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with ≈ 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) in the Phase III IMpower150 study (NCT02366143).

Methods: In this randomized, open-label study (N = 1202), coprimary endpoints included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory endpoints included OS in ITT and PD-L1 subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays.

Results: At the final analysis with ACP vs BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 months), ACP showed numerical, but not statistically significant, improvements in OS (ITT-WT: median OS [mOS] 19.0 vs 14.7 months; hazard ratio [HR] 0.84; 95% CI, 0.71-1.00). OS benefit was sustained with ABCP vs BCP (ITT-WT: 19.5 vs 14.7 months; HR 0.80; 95% CI, 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups showed longer median OS with ABCP and ACP vs BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP vs BCP. Safety was consistent with that in earlier analyses (data cutoff: Jan 22, 2018).

Conclusions: At the final IMpower150 OS analysis, ACP showed numerically, but not statistically significant, OS improvement vs BCP. Updated data with an additional 20 months of follow-up showed continued OS improvement with ABCP vs BCP in all patients.
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http://dx.doi.org/10.1016/j.jtho.2021.07.009DOI Listing
July 2021

KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype?

Lung Cancer 2021 Jul 17;159:10-17. Epub 2021 Jul 17.

Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungenClinic, Wöhrendamm 80, D-22927 Grosshansdorf, Germany.

The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.006DOI Listing
July 2021

RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non-small Cell Lung Cancer.

Clin Cancer Res 2021 Jul 22. Epub 2021 Jul 22.

Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North.

Purpose: In -mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if -activating mutation subtypes impact treatment outcomes in the phase 3 RELAY study. Associations between mutation type and pre-existing co-occurring and treatment-emergent genetic alterations were also explored.

Experimental Design: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg) (RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survial (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses.

Results: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and co-mutational profiles. ne-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline co-mutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. mutation rate at progression was similar between treatment arms and by mutation type.

Conclusions: RAM+ERL provided significant clinical benefit for both ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these mutation types.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0273DOI Listing
July 2021

Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies.

Transl Lung Cancer Res 2021 May;10(5):2118-2131

Division of Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.

Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome.

Methods: Clinical, molecular, and radiologic characteristics of consecutive TKI-treated ALK NSCLC patients were analyzed using prospectively collected plasma samples and the 17-gene targeted AVENIO kit, which covers oncogenic drivers and all exons.

Results: In 56 patients, 139 instances of radiologic changes were analyzed, of which 133 corresponded to disease progression. Circulating tumor DNA (ctDNA) alterations were identified in most instances of extracranial progression (58/94 or 62%), especially if concomitant intracranial progression was also present (89%, P<0.001), but rarely in case of isolated central nervous system (CNS) progression (8/39 or 21%, P<0.001). ctDNA detectability correlated with presence of "short" echinoderm microtubule-associated protein-like 4 () fusion variants (mainly V3, E6:A20) and/or mutations (P<0.05), and presented therapeutic opportunities in <50% of cases. Patients with extracranial progression and positive liquid biopsies had shorter survival from the start of palliative treatment (mean 52 69 months, P=0.002), regardless of previous and subsequent therapy and initial ECOG performance status. Furthermore, for patients with extracranial progression, ctDNA detectability was associated with shorter next-line progression-free survival (PFS) (3 13 months, P=0.003) if they were switched to another systemic therapy (49/86 samples), and with shorter time-to-next-treatment (TNT) (3 8 months, P=0.004) if they were continued on the same treatment due to oligoprogression (37/86). In contrast, ctDNA detectability was not associated with the outcome of patients showing CNS-only progression. In 6/6 cases with suspicion of non-neoplastic radiologic lung changes (mainly infection or pneumonitis), ctDNA results remained negative.

Conclusions: Positive blood-based liquid rebiopsies in ALK NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of resistance mutations with other features of the high-risk V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment.
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http://dx.doi.org/10.21037/tlcr-21-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182700PMC
May 2021

Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.

Cancer Immunol Immunother 2021 Jun 14. Epub 2021 Jun 14.

Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, Heidelberg, Germany.

Introduction: The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood.

Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles.

Results: While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC =  - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC =  - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors.

Conclusion: Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.
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http://dx.doi.org/10.1007/s00262-021-02981-wDOI Listing
June 2021

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial.

JAMA Oncol 2021 Jun 4. Epub 2021 Jun 4.

LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.

Importance: Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC).

Objective: To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC.

Design, Setting, And Participants: The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.

Interventions: Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab.

Main Outcomes And Measures: Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis.

Results: A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively.

Conclusions And Relevance: The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.
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http://dx.doi.org/10.1001/jamaoncol.2021.2301DOI Listing
June 2021

Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

Transl Lung Cancer Res 2021 Apr;10(4):1666-1678

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Background: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification.

Methods: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath).

Results: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%.

Conclusions: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions.
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http://dx.doi.org/10.21037/tlcr-20-1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107748PMC
April 2021

Afatinib as first-line treatment in patients with -mutated non-small cell lung cancer in routine clinical practice.

Ther Adv Med Oncol 2021 6;13:17588359211012361. Epub 2021 May 6.

Hemato-Oncology Hamburg, Hamburg, Germany.

Background: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (m+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) first-generation EGFR TKIs in m+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations.

Methods: In NCT02047903, a prospective non-interventional study in Germany, patients with m+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed.

Results: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon mutation and 51 patients (33.6%) had brain metastases. A starting dose of <40 mg was received by 39 (25.7%) patients. Overall, the 12-month PFS rate was 50.2% while the median PFS was 12.2 months. The ORR was 74.6% and the median OS was 30.4 months. In patients with brain metastases and uncommon mutations, the median PFS was 10.5 and 10.7 months, and the ORR was 77.3% and 83.3%, respectively. Treatment effectiveness was similar in patients with a starting dose of <40 mg (median PFS: 16.4 months; ORR, 81.3%) and a starting dose of 40 mg (median PFS: 10.8 months; ORR, 72.1%). Adverse drug reactions were manageable and consistent with the known afatinib safety profile.

Conclusion: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a <40 mg afatinib starting dose, supporting patient-tailored dosing.
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http://dx.doi.org/10.1177/17588359211012361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111535PMC
May 2021

Identification of molecular signatures associated with early relapse after complete resection of lung adenocarcinomas.

Sci Rep 2021 May 5;11(1):9532. Epub 2021 May 5.

LungenClinic Grosshansdorf, 22927, Grosshansdorf, Germany.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA-IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-021-89030-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099905PMC
May 2021

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50.

J Clin Oncol 2021 Jul 19;39(21):2339-2349. Epub 2021 Apr 19.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing or alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).

Methods: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.

Results: Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.

Conclusion: Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.
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http://dx.doi.org/10.1200/JCO.21.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280089PMC
July 2021

Fast progression in non-small cell lung cancer: results from the randomized phase III OAK study evaluating second-line atezolizumab versus docetaxel.

J Immunother Cancer 2021 Mar;9(3)

Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland.

Background: Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study.

Methods: The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer. FP rates and associated baseline factors were analyzed. FP was defined as either a ≥50% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan).

Results: Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a ≥50% SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), ≥3 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a ≥50% SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92)).

Conclusions: FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP.

Trial Registration Number: NCT02008227.
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http://dx.doi.org/10.1136/jitc-2020-001882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978260PMC
March 2021

Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

J Clin Oncol 2021 Apr 8;39(12):1349-1359. Epub 2021 Mar 8.

Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.

Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.

Results: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; = .37; median, 9.2 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).

Conclusion: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
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http://dx.doi.org/10.1200/JCO.20.02212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078251PMC
April 2021

History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Department of Oncology, IRCCS San Raffaele Hospital, via Olgettina 60, 20132 Milano, Italy.

Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.
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http://dx.doi.org/10.3390/cancers13050998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957518PMC
February 2021

-Paclitaxel Plus Durvalumab in Patients With Previously Treated Advanced Stage Non-small Cell Lung Cancer (ABOUND.2L+).

Front Oncol 2020 11;10:569715. Epub 2021 Feb 11.

Bristol Myers Squibb, Princeton, NJ, United States.

The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the -paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating mutations or translocations received -paclitaxel 100 mg/m (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. The -paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. ClinicalTrials.gov registration (NCT02250326). 2014-001105-41.
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http://dx.doi.org/10.3389/fonc.2020.569715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906015PMC
February 2021

DNA methylation profiles of bronchoscopic biopsies for the diagnosis of lung cancer.

Clin Epigenetics 2021 02 17;13(1):38. Epub 2021 Feb 17.

Institute of Human Genetics, University Medical Center Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Background: Lung cancer is the leading cause of cancer-related death in most western countries in both, males and females, accounting for roughly 20-25% of all cancer deaths. For choosing the most appropriate therapy regimen a definite diagnosis is a prerequisite. However, histological characterization of bronchoscopic biopsies particularly with low tumor cell content is often challenging. Therefore, this study aims at (a) determining the value of DNA methylation analysis applied to specimens obtained by bronchoscopic biopsy for the diagnosis of lung cancer and (b) at comparing aberrantly CpG loci identified in bronchoscopic biopsy with those identified by analyzing surgical specimens.

Results: We report the HumanMethylation450-based DNA methylation analysis of paired samples of bronchoscopic biopsy specimens either from the tumor side or from the contralateral tumor-free bronchus in 37 patients with definite lung cancer diagnosis and 18 patients with suspicious diagnosis. A differential DNA methylation analysis between both biopsy sites of patients with definite diagnosis identified 1303 loci. Even those samples were separated by the set of 1303 loci in which histopathological analysis could not unambiguously define the dignity. Further differential DNA methylation analyses distinguished between SCLC and NSCLC. We validated our results in an independent cohort of 40 primary lung cancers obtained by open surgical resection and their corresponding controls from the same patient as well as in publically available DNA methylation data from a TCGA cohort which could also be classified with high accuracy.

Conclusions: Considering that the prognosis correlates with tumor stage at time of diagnosis, early detection of lung cancer is vital and DNA methylation analysis might add valuable information to reliably characterize lung cancer even in histologically ambiguous sample material.
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http://dx.doi.org/10.1186/s13148-021-01024-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890863PMC
February 2021

Phosphorylation of SMAD3 in immune cells predicts survival of patients with early stage non-small cell lung cancer.

J Immunother Cancer 2021 Feb;9(2)

Laboratory of Molecular and Tumor Immunology, Earle A Chiles Research Institute, Portland, Oregon, USA.

Background: The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment.

Methods: Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data.

Results: TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer.

Conclusions: TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
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http://dx.doi.org/10.1136/jitc-2020-001469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887360PMC
February 2021

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study.

J Clin Oncol 2021 Jul 29;39(21):2327-2338. Epub 2021 Jan 29.

LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.

Purpose: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population.

Methods: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing or aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival.

Results: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo.

Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable or aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.
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http://dx.doi.org/10.1200/JCO.20.03579DOI Listing
July 2021

First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1.

J Thorac Oncol 2021 04 21;16(4):665-676. Epub 2021 Jan 21.

Princess Alexandra Hospital, Woolloongabba, Australia.

Introduction: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs).

Methods: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted.

Results: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy.

Conclusions: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.
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http://dx.doi.org/10.1016/j.jtho.2020.12.019DOI Listing
April 2021

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial.

J Thorac Oncol 2021 05 19;16(5):860-867. Epub 2021 Jan 19.

Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.

Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method.

Results: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.

Conclusion: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).
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http://dx.doi.org/10.1016/j.jtho.2020.12.015DOI Listing
May 2021

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

Lancet Oncol 2021 02 18;22(2):198-211. Epub 2021 Jan 18.

Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany.

Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.

Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.

Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.

Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(20)30641-0DOI Listing
February 2021

Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133).

J Clin Oncol 2021 Feb 13;39(6):619-630. Epub 2021 Jan 13.

Vanderbilt University Medical Center, Nashville, TN.

Purpose: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.

Patients And Methods: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.

Results: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.

Conclusion: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
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http://dx.doi.org/10.1200/JCO.20.01055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078320PMC
February 2021

Biomarker testing in non-small cell lung cancer in routine care: Analysis of the first 3,717 patients in the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).

Lung Cancer 2021 02 2;152:174-184. Epub 2020 Nov 2.

Onkologie der Thoraxtumore, Thoraxklinik Heidelberg gGmbH, German Center for Lung Research (DZL), Germany.

Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the "real-world" setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.

Patients And Methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.

Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4-10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9-9.2) with druggable ALK alterations.

Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.012DOI Listing
February 2021

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA.

EBioMedicine 2020 Dec 9;62:103103. Epub 2020 Nov 9.

Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Center for Lung Research (DZL), Translational Lung Research Center Heidelberg, Germany. Electronic address:

Background: Targeted therapies (TKI) have improved the prognosis of ALK-rearranged lung cancer (ALK NSCLC), but clinical courses vary widely. Early identification and molecular characterisation of treatment failure have key importance for subsequent therapies. We performed copy number variation (CNV) profiling and targeted panel sequencing from cell-free DNA (cfDNA) to monitor ALK NSCLC.

Methods: 271 longitudinal plasma DNA samples from 73 patients with TKI-treated metastatic ALK NSCLC were analysed by capture-based targeted (average coverage 4,100x), and shallow whole genome sequencing (sWGS, 0.5x). Mutations were called using standard algorithms. CNVs were quantified using the trimmed median absolute deviation from copy number neutrality (t-MAD).

Findings: cfDNA mutations were identified in 58% of patients. They included several potentially actionable alterations, e.g. in the genes BRAF, ERBB2, and KIT. sWGS detected CNVs in 18% of samples, compared to 6% using targeted sequencing. Several of the CNVs included potentially druggable targets, such as regions harboring EGFR, ERBB2, and MET. Circulating tumour DNA (ctDNA) mutations and t-MAD scores increased during treatment, correlated with markers of higher molecular risk, such as the EML4-ALK variant 3 and/or TP53 mutations, and were associated with shorter patient survival. Importantly, t-MAD scores reflected the tumour remission status in serial samples similar to mutant ctDNA allele frequencies, and increased with disease progression in 79% (34/43) of cases, including those without detectable single nucleotide variant (SNV).

Interpretation: Combined copy number and targeted mutation profiling could improve monitoring of ALK NSCLC. Potential advantages include the identification of treatment failure, in particular for patients without detectable mutations, and broader detection of genomic changes acquired during therapy, especially in later treatment lines and in high-risk patients.

Funding: This work was supported by the German Center for Lung Research (DZL), by the German Cancer Consortium (DKTK), by the Heidelberg Center for Personalized Oncology at the German Cancer Research Center (DKFZ-HIPO), and by Roche Sequencing Solutions (Pleasanton, CA, USA).
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http://dx.doi.org/10.1016/j.ebiom.2020.103103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670098PMC
December 2020

Dual EGFR-VEGF Pathway Inhibition: A Promising Strategy for Patients With EGFR-Mutant NSCLC.

J Thorac Oncol 2021 02 20;16(2):205-215. Epub 2020 Oct 20.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address:

The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
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http://dx.doi.org/10.1016/j.jtho.2020.10.006DOI Listing
February 2021

First-Line Immune Checkpoint Inhibition for Advanced Non-Small-Cell Lung Cancer: State of the Art and Future Directions.

Drugs 2020 Nov;80(17):1783-1797

Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK.

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.
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http://dx.doi.org/10.1007/s40265-020-01409-6DOI Listing
November 2020

Ramucirumab or placebo plus erlotinib in EGFR-mutated, metastatic non-small-cell lung cancer: East Asian subset of RELAY.

Cancer Sci 2020 Dec 14;111(12):4510-4525. Epub 2020 Oct 14.

Kindai University Faculty of Medicine, Osaka, Japan.

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.
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http://dx.doi.org/10.1111/cas.14655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734014PMC
December 2020

Comprehensive serial biobanking in advanced NSCLC: feasibility, challenges and perspectives.

Transl Lung Cancer Res 2020 Aug;9(4):1000-1014

Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.

Background: Availability of tumor material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially for the application of targeted therapies like tyrosine kinase inhibitors and for immune checkpoint inhibitor treatment. Here we report the experience of prospective biomaterial acquisition in advanced NSCLC from a pilot project.

Methods: Main objective was the longitudinal collection of high-quality, cryoconserved biopsies in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires.

Results: Over five years, 205 patients were enrolled for the project, yielding 387 cryoconserved biopsies and 1,098 serum, plasma and buffy-coat samples. The feasibility of obtaining the cryoconserved biopsies in addition to the FFPE biopsies was 89% for newly diagnosed cases, but dropped down to 56% and 47% at first and second disease progression, respectively. While forceps biopsy was the preferred procedure for tissue acquisition, the highest tissue amounts were received using the cryobiopsy method. Biopsies had a median tumor cellularity of 34% and yielded in median 13.6 µg DNA and 12 µg RNA (median RIN =8). During the five-year project, a maximum of 38 follow-up blood samples per patient were assembled in up to four therapy lines.

Conclusions: Despite the poor condition and limited prognosis of most NSCLC patients, this serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible to support individualized management. The standardized collection of high-quality material has enabled and enriched several translational research studies that can advance therapeutic options.
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http://dx.doi.org/10.21037/tlcr-20-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481602PMC
August 2020

Non-interventional LUME-BioNIS study of nintedanib plus docetaxel after chemotherapy in adenocarcinoma non-small cell lung cancer: A subgroup analysis in patients with prior immunotherapy.

Lung Cancer 2020 10 8;148:159-165. Epub 2020 Aug 8.

Department of Pathology, Aberdeen Royal Infirmary, Foresterhill Rd, Aberdeen AB25 2ZN, United Kingdom. Electronic address:

Objectives: To evaluate the effectiveness and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) previously treated with both chemo- and immunotherapy.

Materials And Methods: LUME-BioNIS is a European, prospective, multicenter, non-interventional study of patients with advanced adenocarcinoma NSCLC, who initiated nintedanib plus docetaxel after first-line chemotherapy in routine practice according to the approved nintedanib EU label. The primary objective is to explore whether molecular biomarkers can predict overall survival (OS). Information on clinical or radiologic progression and death, and adverse drug reactions (ADRs)/fatal adverse events (AEs) was collected during follow-up. Here, we report a subgroup analysis evaluating outcomes in immunotherapy-pretreated patients.

Results: Of 260 enrolled patients, 67 (25.8%) had prior immunotherapy and were included in this subgroup analysis. Prior immunotherapy was administered in first-line in 20 patients (29.9%; combined with chemotherapy in 4 patients [6.0%]) and later-lines in 47 patients (70.1%), and most commonly comprised nivolumab (39 patients; 58.2%), atezolizumab (14 patients; 20.9%) and pembrolizumab (11 patients; 16.4%). Nintedanib plus docetaxel was given in second-line in 10 patients (14.9%) and in later-lines in 57 patients (85.1%). Median OS was 8.8 months (95% confidence interval [CI]: 7.0-11.5) and median progression-free survival (PFS) was 4.6 months (95% CI: 3.5-5.7). Among 55 patients with available data, rates of objective response and disease control were 18.2% and 78.2%, respectively. In 65 patients evaluable for safety, the most common on-treatment ADRs/AEs were malignant neoplasm progression (19 patients; 29.2%), diarrhea (21 patients; 32.3%) and nausea (10 patients; 15.4%).

Conclusions: Used according to the approved nintedanib label in routine practice, nintedanib plus docetaxel demonstrated clinical effectiveness, with no unexpected safety findings, in patients with prior chemotherapy and first- or later-line immunotherapy. These data add to the real-world evidence that can inform clinical decisions in the changing therapeutic landscape.
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http://dx.doi.org/10.1016/j.lungcan.2020.08.004DOI Listing
October 2020

Efficacy of Docetaxel Plus Ramucirumab as Palliative Third-Line Therapy Following Second-Line Immune-Checkpoint-Inhibitor Treatment in Patients With Non-Small-Cell Lung Cancer Stage IV.

Clin Med Insights Oncol 2020 19;14:1179554920951358. Epub 2020 Aug 19.

Hämato-Onkologie Hamburg, Praxis, Hamburg, Germany.

Background: Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects with chemotherapy. Effects might be even stronger after immune-checkpoint-inhibitor (ICI) therapy. The purpose of this analysis was to evaluate the efficacy of ramucirumab plus docetaxel (R + D) as third-line treatment after failure of a first-line platinum-based chemotherapy and a second-line ICI treatment in patients with non-small-cell lung cancer (NSCLC) stage IV.

Methods: Retrospective data were collected from 9 German thoracic oncology centers. Only patients who had received at least 1 cycle of third-line R + D were included. The numbers of cycles, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated.

Results: Sixty-seven patients met the criteria for inclusion. Third-line treatment with R + D achieved an ORR of 36% and a disease control rate (DCR) of 69%. Median PFS for third-line therapy was 6.8 months with a duration of response (DOR) of 10.2 months. A median OS of 29 months was observed from the start of first-line therapy with a median OS of 11.0 months from the start of third-line treatment. No unexpected toxicities occurred.

Conclusion: R + D is a highly effective and safe third-line treatment after failure of second-line programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PD-L1)-derived ICI therapy irrespective of NSCLC histology. As there may be synergistic effects of second- and third-line treatments, this sequence is a very suitable option for patients not treated with first-line ICI. In addition, R + D should continue to be investigated as a second-line treatment option after failure of chemotherapy plus ICI in the palliative first-line treatment.
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http://dx.doi.org/10.1177/1179554920951358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440727PMC
August 2020
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