Publications by authors named "Solange Peters"

191 Publications

Blood First Assay Screening Trial (BFAST) in Treatment-Naïve Advanced or Metastatic Non-Small Cell Lung Cancer: Initial Results of the Phase 2 ALK-Positive Cohort.

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

Department of Internal Medicine, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA. Electronic address:

Introduction: The Blood First Assay Screening Trial (BFAST) is an ongoing open-label, multi-cohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies/immunotherapy in treatment-naïve advanced/metastatic NSCLC. We present data from the ALK-positive cohort.

Methods: Patients aged ≥18 years with stage IIIB/IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT™) received alectinib 600 mg twice-daily. Asymptomatic/treated central nervous system (CNS) metastases were permitted. Primary endpoint: investigator-assessed objective response rate (ORR; RECIST v1.1). Secondary endpoints: independent review facility (IRF)-assessed ORR; duration of response (DoR), progression-free survival (PFS), and overall survival; safety. Exploratory endpoints: investigator-assessed ORR in patients with baseline CNS metastases; relationship between circulating biomarkers and response.

Results: In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of cases. Of these, 119 (5.4%) patients had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range = 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by IRF. Investigator-confirmed 12-month DoR was 75.9% (95% CI: 63.6-88.2). In 35 (40%) patients with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib.

Conclusions: These results demonstrate the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.07.008DOI Listing
July 2021

Neutrophils in the era of immune checkpoint blockade.

J Immunother Cancer 2021 Jul;9(7)

IRCM, Inserm, Univ Montpellier, ICM, Montpellier, France, INSERM U1194, Montpellier, France

The immune checkpoint blockade-based immunotherapies are revolutionizing cancer management. Tumor-associated neutrophils (TANs) were recently highlighted to have a pivotal role in modulating the tumor microenvironment and the antitumor immune response. However, these cells were largely ignored during the development of therapies based on programmed cell death receptor or ligand-1 and cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitors (ICIs). Latest evidences of neutrophil functional diversity in tumor raised many questions and suggest that targeting these cells can offer new treatment opportunities in the context of ICI development. Here, we summarized key information on TAN origin, function, and plasticity that should be considered when developing ICIs and provide a detailed review of the ongoing clinical trials that combine ICIs and a second compound that might affect or be affected by TANs. This review article synthetizes important notions from the literature demonstrating that: (1) Cancer development associates with a profound alteration of neutrophil biogenesis and function that can predict and interfere with the response to ICIs, (2) Neutrophil infiltration in tumor is associated with key features of resistance to ICIs, and (3) TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-002242DOI Listing
July 2021

Early discharge after thoracoscopic anatomical pulmonary resection for non-small-cell lung cancer.

Interact Cardiovasc Thorac Surg 2021 Jul 19. Epub 2021 Jul 19.

Service of Thoracic Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

Objectives: Although video-assisted thoracic surgery (VATS) has shortened hospitalization duration for non-small-cell lung cancer (NSCLC) patients, the factors associated with early discharge remain unclear. This study aimed to identify patients eligible for a 72-h stay after VATS anatomical resection.

Methods: Monocentric retrospective study including all consecutive patients undergoing VATS anatomical resection for NSCLC between February 2010 and December 2019. Two groups were defined according to the discharge: 'early discharge' (within 72 postoperative hours) and 'routine discharge' (at >72 postoperative hours).

Results: A total of 660 patients with a median age of 66.5 years (interquartile range 60-73 years) (female/male: 321/339) underwent VATS anatomical pulmonary resection for NSCLC [segmentectomy in 169 (25.6%), lobectomy in 481 (72.9%), bilobectomy in 8 (1.2%) and pneumonectomy in 2 (0.3%) patients]. The cardiopulmonary and Clavien-Dindo III-IV postoperative complication rates were 32.6% and 7.7%, respectively. The median postoperative length of stay was 6 days (interquartile range 4-10 days). In total, 119 patients (18%) could be discharged within 72 h of surgery. On multivariable analysis, the factors significantly associated with an increased likelihood of early discharge were: body mass index >20 kg/m2 [odds ratio (OR) 2.37], absence of prior cardiopathy (OR 2), diffusing capacity of the lung for carbon monoxide >60% (OR 1.82), inclusion in an enhanced recovery after surgery protocol (OR 2.23), use of a single chest tube (OR 5.73) and postoperative transfer to the ward (OR 4.84). Factors significantly associated with a decreased likelihood of early discharge were: age >60 years (OR 0.53), American Society of Anaesthesiologists score >2 (OR 0.46) and use of an epidural catheter (OR 0.41). Readmission rates were not statistically different between both groups (5.9% vs 3.1%; P = 0.17).

Conclusions: Age, pulmonary functions and comorbidities may influence discharge after VATS anatomical resection. The early discharge does not increase readmission rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/icvts/ivab187DOI Listing
July 2021

The CoVID-TE Risk Assessment Model for Venous Thromboembolism in Hospitalized Patients with Cancer and COVID-19.

J Thromb Haemost 2021 Jul 14. Epub 2021 Jul 14.

Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Background:  Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking.

Methods:  Among patients with cancer in the CCC19 cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19 associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.

Findings: From 3/17/2020 to 11/30/2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n=1423 vs. high-risk, 3+ points, n=1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% CI 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.

Interpretation: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15463DOI Listing
July 2021

SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial.

J Clin Oncol 2021 Jul 12:JCO2100276. Epub 2021 Jul 12.

Department of Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland.

Purpose: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab.

Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m and docetaxel 85 mg/m once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%.

Results: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related.

Conclusion: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00276DOI Listing
July 2021

Lurbinectedin in Refractory Diffuse Malignant Peritoneal Mesothelioma: Report of Two Cases.

Front Oncol 2021 18;11:704295. Epub 2021 Jun 18.

Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

Mesothelioma is a malignancy of serosal membranes. Parietal pleura is the most common site, with peritoneum being the second most frequent location. Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. The prognosis is often very poor with median overall survival ranging from 6 to 18 months in patients who are not candidates for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) due to non-resectable disease or comorbid conditions. For patients with resectable disease, CRS and HIPEC have become the standard of care. However, for patients with unresectable malignant mesothelioma there is unfortunately no effective systemic treatment beyond the first line. Based on the results of a recent phase II trial, lurbinectedin has clinical activity and acceptable toxicity in the second- and third-line treatment of malignant pleural mesothelioma. However, until present, no data have been available for patients with MPM and for patients who become refractory after multiple treatment lines. We report on two patients with metastatic MPM who achieved durable disease control of 10+ and 8 months with lurbinectedin in the fourth and fifth treatment line, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.704295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249751PMC
June 2021

Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data.

JMIR Res Protoc 2021 Jun 29;10(6):e30090. Epub 2021 Jun 29.

School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

Background: The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response.

Objective: The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations.

Methods: The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits.

Results: The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022.

Conclusions: The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner.

Trial Registration: ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064.

International Registered Report Identifier (irrid): DERR1-10.2196/30090.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/30090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278299PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-021-02981-wDOI Listing
June 2021

Imaging Features of Pulmonary Immune-related Adverse Events.

J Thorac Oncol 2021 Jun 1. Epub 2021 Jun 1.

Department of Radiodiagnostic and Interventional Radiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.

Pulmonary immune-related adverse events represent rare but potentially severe side effects of immunotherapies. Diagnosis is often challenging, as symptoms and imaging features are not specific and may mimic other lung diseases, thus potentially delaying appropriate patient management. In this setting, an accurate imaging evaluation is essential for a prompt detection and correct management of these drug-induced lung diseases. The purpose of this article is to review the different types of pulmonary immune-related adverse events, describe their imaging characteristics on both high-resolution computed tomography and positron emission tomography/computed tomography and stress their underlying diagnostic challenge by presenting the mimickers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.05.017DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-20-1168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107748PMC
April 2021

Oncologie et pandémie de Covid-19 : les patients au cœur des enjeux.

Rev Med Suisse 2021 05;17(739):955

Département d'oncologie, CHUV, Lausanne.

View Article and Find Full Text PDF

Download full-text PDF

Source
May 2021

[Telephone follow-up of SARS-CoV-2 positive patients at the Oncology Department of Lausanne University Hospital].

Rev Med Suisse 2021 Apr;17(733):703-707

Institut universitaire de formation et recherche en soins (IUFRS), Faculté de biologie et médecine, UNIL-CHUV, 1010 Lausanne.

Compared with the general population, oncology patients face a higher morbidity and mortality caused by the COVID-19 pandemic. As a result, health systems had to quickly adapt cancer care in order to maintain the best quality and patient safety. From March to May and from October to December 2020, 254 patients diagnosed with cancer and tested positive for SARS-CoV-2 benefited from a tele-health monitoring at the Oncology Department at CHUV. This article describes the key points of the development, implementation and operation of this tele-health monitoring, enabled by an interdisciplinary and inter-professional collaboration between different units and healthcare professionals.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2021

OncoAlert Round Table Discussions: The Global COVID-19 Experience.

JCO Glob Oncol 2021 04;7:455-463

Service d'oncologie médicale, CHUV, Lausanne, Switzerland.

The speed and spread of the COVID-19 pandemic has been affecting the entire world for the past several months. is a social media network made up of more than 140 oncology stakeholders: oncologists (medical, radiation, and surgical), oncology nurses, and patient advocates who share the mission of fighting cancer by means of education and dissemination of information. As a response to the COVID-19 pandemic, OncoAlert hosted We have documented this effort along with further discussion about the COVID-19 pandemic and the consequences on patients living with cancer to disseminate this information to our colleagues worldwide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/GO.20.00603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221235PMC
April 2021

The Promising Evolution of Targeted Therapeutic Strategies in Cancer.

Cancer Discov 2021 Apr;11(4):810-814

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

The upcoming decade of precision medicine for cancer is moving from the translation of specific genetic findings into clinically relevant improvement to the qualitative analyses of the genomic and immune tumor microenvironment, for an integrated treatment strategy in both metastatic and early disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-21-0124DOI Listing
April 2021

Treatment Decisions for Patients with Cancer during the COVID-19 Pandemic.

Cancer Discov 2021 06 2;11(6):1330-1335. Epub 2021 Apr 2.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Patients with cancer have been disproportionally affected by the COVID-19 pandemic, with high rates of severe outcomes and death. Similarly, treatment decisions in this vulnerable population have been altered to a major degree during the past year, with significant disruption of care reported. Although complex, therapeutic choices in patients with cancer in times of COVID-19 are critical, as they may save thousands of lives. A mounting body of evidence, in addition to clear recommendations by multiple international societies, can help oncologists decide appropriately the necessity to administer antineoplastic regimens, helping to avoid a surge in cancer-related deaths in the upcoming months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-21-0210DOI Listing
June 2021

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC).

Clin Lung Cancer 2021 Feb 19. Epub 2021 Feb 19.

Division of Hematology/Oncology, Columbia University Medical Center, New York, NY.

Background: The phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).

Patients And Methods: Treatment-naïve patients were randomized (1:1:1) to durvalumab, durvalumab + tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥ 25% using EORTC Quality of Life Questionnaire (QLQ)-C30/LC13. Changes from baseline (12 months) for prespecified PRO endpoints of interest were analyzed by mixed model for repeated measures (MMRM) and time to deterioration (TTD) by stratified log-rank tests.

Results: There were no between-arm differences in baseline PROs (N = 488). Between-arm differences in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for C30 fatigue: durvalumab (-9.5; 99% confidence interval [CI], -17.0 to -2.0), durvalumab + tremelimumab (-11.7; 99% CI, -19.4 to -4.1); and for C30 appetite loss: durvalumab (-11.9; 99% CI, -21.1 to -2.7). TTD was longer with at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for global health status/quality of life: durvalumab (hazard ratio [HR] = 0.7; 95% CI, 0.5-1.0), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0); and for physical functioning: durvalumab (HR = 0.6; 95% CI, 0.4-0.8), durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.5-0.9) (both C30); as well as for the key symptoms of dyspnea: durvalumab (HR = 0.6; 95% CI, 0.5-0.9), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0) (both LC13); fatigue: durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.4-0.8); and appetite loss: durvalumab (HR = 0.5; 95% CI, 0.4-0.7), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-0.9) (both C30).

Conclusion: Durvalumab ± tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality of life in metastatic NSCLC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2021.02.010DOI Listing
February 2021

GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy.

Cancer Res 2021 May 22;81(9):2345-2357. Epub 2021 Mar 22.

Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils. SIGNIFICANCE: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-2870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137580PMC
May 2021

Severity of COVID-19 in patients with lung cancer: evidence and challenges.

J Immunother Cancer 2021 03;9(3)

Department of Oncology, Centre Hospitalier Universitaire Vaudois, CHUV, Lausanne, Switzerland

Cancer patients are highly vulnerable to SARS-CoV-2 infections due to frequent contacts with the healthcare system, immunocompromised state from cancer or its therapies, supportive medications such as steroids and most importantly their advanced age and comorbidities. Patients with lung cancer have consistently been reported to suffer from an increased risk of death compared with other cancers. This is possibly due to the combination of specific pathophysiological aspects, including underlying pulmonary compromise due to smoking history and the increased specific pressures on respiratory healthcare services caused by the related pandemic. Rationally and safely treating patients with lung cancer during the pandemic has become a continuous challenge over the last year. Deciding whether to offer, modify, postpone or even cancel treatments for this particular patient's population has become the crucial recurrent dilemma for lung cancer professionals. Chemotherapy, immunotherapy and targeted agents represent distinct risks factors in the context of COVID-19 that should be balanced with the short-term and long-term consequences of delaying cancer care. Despite the rapid and persistent trend of the pandemic, declared by WHO on March 11, 2020, and still ongoing at the time of writing (January 2021), various efforts were made by oncologists worldwide to understand the impact of COVID-19 on patients with cancer. Adapted recommendations of our evidence-based practice guidelines have been developed for all stakeholders. Different small and large-scale registries, such as the COVID-19 and Cancer Consortium (CCC19) and Thoracic Cancers International COVID-19 Collaboration quickly collected data, supporting cancer care decisions under the challenging circumstance created by the COVID-19 pandemic. Several recommendations were developed as guidance for prioritizing the various aspects of lung cancer care in order to mitigate the adverse effects of the COVID-19 healthcare crisis, potentially reducing the morbidity and mortality of our patients from COVID-19 and from cancer. These recommendations helped inform decisions about treatment of established disease, continuation of clinical research and lung cancer screening. In this review, we summarize available evidence regarding the direct and indirect impact of the COVID-19 pandemic on lung cancer care and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-002266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978268PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078251PMC
April 2021

Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project.

J Thorac Oncol 2021 06 26;16(6):990-1002. Epub 2021 Feb 26.

European Thoracic Oncology Platform, Bern, Switzerland.

Introduction: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849).

Methods: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored.

Results: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR) is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HR is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HR is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HR is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017).

Conclusions: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2021.02.016DOI Listing
June 2021

Impact of an enhanced recovery after surgery pathway on thoracoscopic lobectomy outcomes in non-small cell lung cancer patients: a propensity score-matched study.

Transl Lung Cancer Res 2021 Jan;10(1):93-103

Service of Thoracic Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.

Background: This study evaluates the effect of enhanced recovery after surgery (ERAS) pathways on postoperative outcomes of non-small cell lung cancer (NSCLC) patients undergoing video-assisted thoracic surgery (VATS) lobectomy.

Methods: We retrospectively reviewed all consecutive patients undergoing VATS lobectomy for NSCLC between January 2014 and October 2019 and assigned them to the relevant group ("pre-ERAS" or "ERAS"). Length of stay, readmissions and complications within 30 days were compared between both groups. A propensity score-matched analysis was performed based on sex, age, type of operation, comorbidities, American Society of Anesthesiologists (ASA) score and preoperative pulmonary functions.

Results: A total of 307 records (164 male/143 female; 140 ERAS/167 pre-ERAS; median age: 67) were reviewed. There was no statistical difference in patient's characteristics. Overall ERAS compliance was 81%. The ERAS group presented significantly shorter length of stay (median 5 7 days; P=0.004) without significant difference in cardiopulmonary complication rate (27.1% 35.9%; P=0.1). Readmission (3.6% 5.4%; P=0.75) and duration of drainage (median 2 3 days; P=0.14) were similar between groups. The propensity score-matched analysis showed that the length of hospital stay was reduced by 1.4 days (P=0.034) and the postoperative cardiopulmonary complication rate by 13% (P=0.044) in the ERAS group.

Conclusions: Adoption of an ERAS pathway for VATS lobectomies in NSCLC patients has decreased the length of hospital stay and the cardiopulmonary complication rate without affecting the readmission rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-20-891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867780PMC
January 2021

Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression.

Cancer Discov 2021 Jun 9;11(6):1490-1507. Epub 2021 Feb 9.

Swiss Cancer Center Leman, Lausanne, Switzerland.

Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution. SIGNIFICANCE: Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-1274DOI Listing
June 2021

Abscopal effect in a patient with malignant pleural mesothelioma treated with palliative radiotherapy and pembrolizumab.

Clin Transl Radiat Oncol 2021 Mar 1;27:85-88. Epub 2021 Jan 1.

Service of radiation oncology, Lausanne University Hospital, Rue du Bugnon, 46, CH-1011 Lausanne, Switzerland.

The abscopal effect describes the ability of locally administered radiotherapy to induce systemic antitumor effects. Although mentioned for the first time in the 1950s, records of abscopal effects, considered to be immune-mediated, are scarce with radiotherapy alone. However, with the continued development and use of immunotherapy, reports on the abscopal effect have become increasingly frequent during the last decade. Here, we report a patient with advanced malignant pleural mesothelioma who had progressive disease while on the anti-PDL1 inhibitor pembrolizumab and showed an abscopal response after palliative radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctro.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829099PMC
March 2021

A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma.

Oncoimmunology 2021 01 11;10(1):1860586. Epub 2021 Jan 11.

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

Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, = .00074), CD45+ cells (HR = 0.61, = .01) and total TILs (HR = 0.62, = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, = .0055) and CD45+ cells (AUC = 0.73, = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, = .72) and PD-L1 protein expression (AUC = 0.68, = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1860586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808386PMC
January 2021

Strength in numbers: predicting response to checkpoint inhibitors from large clinical datasets.

Cell 2021 Feb 27;184(3):571-573. Epub 2021 Jan 27.

Oncology Department, Lausanne University Hospital, Lausanne, Switzerland. Electronic address:

The advent of immune checkpoint blockers for cancer therapy has spawned great interest in identifying molecular features reflecting the complexity of tumor immunity, which can subsequently be leveraged as predictive biomarkers. In a thorough big-data approach analyzing the largest series of homogenized molecular and clinical datasets, Litchfield et al. identified a set of genomic biomarkers that identifies immunotherapy responders across cancer types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.01.008DOI Listing
February 2021

[2020 oncology update].

Rev Med Suisse 2021 Jan;17(723):201-205

Service d'oncologie médicale, Département d'oncologie, CHUV, 1011 Lausanne.

The COVID-19 pandemic that has swept around the world in early 2020 has changed our daily practice and habits. Fortunately, however, 2020 also brings its share of new approaches and therapeutic combinations as well as new therapies. These advances are improving the outcomes and quality of life of our patients across the spectrum of oncological diseases. This article summarises the latest oncological advances and novelties for 2020 in the following tumor entities : lung, breast, digestive, gynecological, urological and ENT.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2021

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Lancet 2021 01 21;397(10272):375-386. Epub 2021 Jan 21.

Bichat-Claude Bernard University Hospital, AP-HP, Université de Paris, Paris, France.

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.

Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m intravenously] plus cisplatin [75 mg/m intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.

Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).

Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

Funding: Bristol Myers Squibb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(20)32714-8DOI Listing
January 2021

Radiomics Feature Activation Maps as a New Tool for Signature Interpretability.

Front Oncol 2020 8;10:578895. Epub 2020 Dec 8.

Department of Radiation Oncology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Introduction: In the field of personalized medicine, radiomics has shown its potential to support treatment decisions. However, the limited feature interpretability hampers its introduction into the clinics. Here, we propose a new methodology to create radiomics feature activation maps, which allows to identify the spatial-anatomical locations responsible for signature activation based on local radiomics. The feasibility of this technique will be studied for histological subtype differentiation (adenocarcinoma squamous cell carcinoma) in non-small cell lung cancer (NSCLC) using computed tomography (CT) radiomics.

Materials And Methods: Pre-treatment CT scans were collected from a multi-centric Swiss trial (training, n=73, IIIA/N2 NSCLC, SAKK 16/00) and an independent cohort (validation, n=32, IIIA/N2/IIIB NSCLC). Based on the gross tumor volume (GTV), four peritumoral region of interests (ROI) were defined: lung_exterior (expansion into the lung), iso_exterior (expansion into lung and soft tissue), gradient (GTV border region), GTV+Rim (GTV and iso_exterior). For each ROI, 154 radiomic features were extracted using an in-house developed software implementation (Z-Rad, Python v2.7.14). Features robust against delineation variability served as an input for a multivariate logistic regression analysis. Model performance was quantified using the area under the receiver operating characteristic curve (AUC) and verified using five-fold cross validation and internal validation. Local radiomic features were extracted from the GTV+Rim ROI using non-overlapping 3x3x3 voxel patches previously marked as GTV or rim. A binary activation map was created for each patient using the median global feature value from the training. The ratios of activated/non-activated patches of GTV and rim regions were compared between histological subtypes (Wilcoxon test).

Results: Iso_exterior, gradient, GTV+Rim showed good performances for histological subtype prediction (AUC=0.68-0.72 and AUC=0.73-0.74) whereas GTV and lung_exterior models failed validation. GTV+Rim model feature activation maps showed that local texture feature distribution differed significantly between histological subtypes in the rim (p=0.0481) but not in the GTV (p=0.461).

Conclusion: In this exploratory study, radiomics-based prediction of NSCLC histological subtypes was predominantly based on the peritumoral region indicating that radiomics activation maps can be useful for tracing back the spatial location of regions responsible for signature activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.578895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753181PMC
December 2020

A Blood-based Assay for Assessment of Tumor Mutational Burden in First-line Metastatic NSCLC Treatment: Results from the MYSTIC Study.

Clin Cancer Res 2021 Mar 22;27(6):1631-1640. Epub 2020 Dec 22.

AstraZeneca, Gaithersburg, Maryland.

Purpose: Tumor mutational burden (TMB) has been shown to be predictive of survival benefit in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors. Measuring TMB in the blood (bTMB) using circulating cell-free tumor DNA (ctDNA) offers practical advantages compared with TMB measurement in tissue (tTMB); however, there is a need for validated assays and identification of optimal cutoffs. We describe the analytic validation of a new bTMB algorithm and its clinical utility using data from the phase III MYSTIC trial.

Patients And Methods: The dataset used for the clinical validation was from MYSTIC, which evaluated first-line durvalumab (anti-PD-L1 antibody) ± tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody) or chemotherapy for metastatic NSCLC. bTMB and tTMB were evaluated using the GuardantOMNI and FoundationOne CDx assays, respectively. A Cox proportional hazards model and minimal value cross-validation approach were used to identify the optimal bTMB cutoff.

Results: In MYSTIC, somatic mutations could be detected in ctDNA extracted from plasma samples in a majority of patients, allowing subsequent calculation of bTMB. The success rate for obtaining valid TMB scores was higher for bTMB (809/1,001; 81%) than for tTMB (460/735; 63%). Minimal value cross-validation analysis confirmed the selection of bTMB ≥20 mutations per megabase (mut/Mb) as the optimal cutoff for clinical benefit with durvalumab + tremelimumab.

Conclusions: Our study demonstrates the feasibility, accuracy, and reproducibility of the GuardantOMNI ctDNA platform for quantifying bTMB from plasma samples. Using the new bTMB algorithm and an optimal bTMB cutoff of ≥20 mut/Mb, high bTMB was predictive of clinical benefit with durvalumab + tremelimumab versus chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3771DOI Listing
March 2021
-->