SAKK 19/17: safety analysis of first-line durvalumab in patients with PD-L1 positive, advanced nonsmall cell lung cancer and a performance status of 2.

INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.

Extended resection for potentially operable patients with stage III non-small cell lung cancer after induction treatment.

OBJECTIVE: Surgical treatment of locally advanced non-small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials. METHODS: A total of 197 patients with T3/T4 non-small cell lung cancer of 368 patients with stage III non-small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters. RESULTS: Patients' median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P < .001), but pretreatment N2 extension (177/197) showed no impact on overall survival. CONCLUSIONS: Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status.

Impact of CT convolution kernel on robustness of radiomic features for different lung diseases and tissue types.

OBJECTIVES: In this study, we aimed to assess the impact of different CT reconstruction kernels on the stability of radiomic features and the transferability between different diseases and tissue types. Three lung diseases were evaluated, i.e. non-small cell lung cancer (NSCLC), malignant pleural mesothelioma (MPM) and interstitial lung disease related to systemic sclerosis (SSc-ILD) as well as four different tissue types, i.e. primary tumor, largest involved lymph node ipsilateral and contralateral lung. METHODS: Pre-treatment non-contrast enhanced CT scans from 23 NSCLC, 10 MPM and 12 SSc-ILD patients were collected retrospectively. For each patient, CT scans were reconstructed using smooth and sharp kernel in filtered back projection. The regions of interest (ROIs) were contoured on the smooth kernel-based CT and transferred to the sharp kernel-based CT. The voxels were resized to the largest voxel dimension of each cohort. In total, 1386 features were analyzed. Feature stability was assessed using the intraclass correlation coefficient. Features above the stability threshold >0.9 were considered stable. RESULTS: We observed a strong impact of the reconstruction method on stability of the features (at maximum 26% of the 1386 features were stable). Intensity features were the most stable followed by texture and wavelet features. The wavelet features showed a positive correlation between percentage of stable features and size of the ROI (R2 = 0.79, p = 0.005). Lymph node radiomics showed poorest stability (<10%) and lung radiomics the largest stability (26%). Robustness analysis done on the contralateral lung could to a large extent be transferred to the ipsilateral lung, and the overlap of stable lung features between different lung diseases was more than 50%. However, results of robustness studies cannot be transferred between tissue types, which was investigated in NSCLC and MPM patients; the overlap of stable features for lymph node and lung, as well as for primary tumor and lymph node was very small in both disease types. CONCLUSION: The robustness of radiomic features is strongly affected by different reconstruction kernels. The effect is largely influenced by the tissue type and less by the disease type. ADVANCES IN KNOWLEDGE: The study presents to our knowledge the most complete analysis on the impact of convolution kernel on the robustness of CT-based radiomics for four relevant tissue types in three different lung diseases. .

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

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 versus 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 (AUCtraining=0.68-0.72 and AUCvalidation=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.

Impact of COVID-19 pandemic on treatment patterns in metastatic clear cell renal cell carcinoma.

BACKGROUND: The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic. METHODS: We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19. FINDINGS: For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%).In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both. CONCLUSION: mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12).

PURPOSE: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). METHODS AND MATERIALS: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. RESULTS: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). CONCLUSIONS: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.