Background

In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients with lung cancer treated with curative-intent radiotherapy (RT) were published (Faivre-Finn et al) aiming to reduce the number of hospital attendances and potential exposure of vulnerable patients to SARS-CoV-2. Here we describe the changes that have taken place.

Methods

COVID-RT Lung is a prospective multicentre UK data collection. Inclusion criteria are: patients with stage 1–3 lung cancer (biopsy-proven or diagnosed on cross-sectional imaging) referred for and/or treated with radical RT between 2/4/2020–2/10/2020. Both patients who had a change in their management and those who continue with standard management are included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, RT and systemic treatment, treatment-related toxicity, disease/patient status are collected. Each participating centre obtains local approval and anonymised data is collected on a central, cloud-based Research Electronic Data Capture system.

Results

1117 records from 20 UK RT sites were available for analysis on 30/11/2020. 562 (50%) female, median age 72 years (38–93 years). 15 patients (1%) were diagnosed with COVID-19, 9 prior to treatment. 160 patients (14%) had their diagnostic investigations affected by the pandemic. 415 patients (37%) had their treatment changed from their centre's standard of care (table). Patients with PS0-1 were more likely to have their treatment changed compared to patients with a poorer PS. The median number of RT fractions was 15 for patients who had their RT dose/fractionation changed compared to 20 for those who were treated as per standard of care.

Conclusions

This nationwide cohort shows that clinicians in the UK changed the management of patients with stage 1–3 lung cancer in line with national guidelines. The main changes are a reduction in chemotherapy use and an increase in RT hypofractionation.

Legal entity responsible for the study

University of Manchester.

Funding

Biomedical Research Centre, Manchester.

Disclosure

K. Thippu Jayaprakash: Travel/Accommodation/Expenses: Bayer UK; Travel/Accommodation/Expenses: Janssen Oncology; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Takeda; Research grant/Funding (self): UK National Institute of Health Research Clinical Research Network Eastern.

C. Peedell: Speaker Bureau/Expert testimony: Elekta; Speaker Bureau/Expert testimony: Boston Scientific; Speaker Bureau/Expert testimony: AstraZeneca.

C. Faivre-Finn: Research grant/Funding (institution): Elekta. All other authors have declared no conflicts of interest.

Background

For patients with early stage or medically inoperable lung cancer, stereotactic body radiotherapy (SBRT) is a general accepted and effective treatment option. While most successful data come from peripherally located tumours, the role of SBRT in ultra-central tumours remains controversial. The aim of this single-center cohort study was to evaluate the safety and efficacy of protracted SBRT with 60 Gy in 12 fractions (with a biological effective dose (BED₁₀) of 90 Gy) for patients with ultra-central lung tumours.

Methods

All patients with ultra-central lung tumours treated in our institution with 60 Gy in 12 fractions from January 2012 until April 2020 were included. Ultra-central tumours were defined as planning target volume (PTV) abutting or overlapping the main bronchi, trachea and/or oesophagus. Data regarding patient-, tumour-, and treatment-related characteristics were extracted from the institutional database. All patients were treated as per institutional protocol following International Commission on Radiation Units and Measurements (ICRU) guidelines.

Results

A total of 72 patients met the criteria for ultra-central tumour location. The PTV abutted the main bronchus, trachea or oesophagus in 78%, 21% and 21% of cases, respectively. At a median follow-up of 19 months, 1- and 2-years local failure-free survival rates were 98% and 85%, respectively. Overall survival rates at 1 and 2 years were 80% and 52% respectively. Grade 3 or higher toxicity was observed in 21%, of which 10 patients (14% of total) died of lung haemorrhage after a median time of 11 months. A significant difference between patients with or without ≥ grade 3 toxicity was found for the mean dose (D_mean) to the main bronchus (p = 0.015), where a D_meanBED₃ of ≥ 90 Gy increased the risk of ≥ grade 3 toxicity significantly.

Conclusions

A protracted SBRT regimen of 60 Gy in 12 fractions for ultra-central lung tumours leads to high local control rates with acceptable toxicity, albeit at the risk of serious toxicity and even mortality. Therefore, possible risk factors of lung hemorrhage such as dose to the main bronchus, peri- or endobronchial tumour location and anti–vascular endothelial growth factor (anti-VEGF) or antithrombotic therapy should be taken into account.

Legal entity responsible for the study

University Medical Center Utrecht.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

AMG 757 simultaneously binds DLL3 on SCLC cells and CD3 on T cells leading to T cell- mediated tumor lysis. Data from an ongoing phase I study of AMG 757 in SCLC are reported.

Methods

Safety and efficacy were evaluated in a phase I trial of AMG 757 for patients (pts) with relapsed/refractory SCLC after >= 1 platinum-based regimen (NCT03319940). AMG 757 was administered intravenously (9 dose levels (DLs); dose range: 0.003−30 mg q2w, ± step dosing).

Results

As of 03 Nov 2020, 52 pts (median age, 64 [32−80] y; median prior lines of therapy, 2 [1−6]) were enrolled. 79% (41/52) of pts reported treatment (tx)-related adverse events (TRAEs) (Grade [Gr] >= 2, 29/52 [56%], Gr >= 3, 12/52 [23%], Gr >= 4, 4/52 [8%]). TRAEs accounted for 1 tx discontinuation and 1 death (Gr 5 pneumonitis, DL, 0.3 mg). Cytokine release syndrome (CRS; 44%; Lee criteria (2014): Gr 2, 5/52 [10%], Gr 3, 1/52 [2%], no Gr >= 4) was the most common TRAE and typically occurred in cycle 1. Median time to onset of CRS was 9 (3−52) h following an AMG 757 dose; median duration was 60 (3−197) h. Fever (31%), tachycardia (19%), and nausea (14%) were the most common CRS-related symptoms. Significant increases in cytokine (IL-8, MCP-1, IFN-g, IL-10, IL-6, MIP-1a, MIP-1b, TNF-a) levels from baseline in the 24 h following the first AMG 757 dose in cycle 1 were observed in pts experiencing CRS vs. pts who did not experience CRS symptoms. CRS did not result in tx discontinuation or deaths and was managed with supportive care, corticosteroids, and/or anti-IL-6R. 14% (7/51) of pts achieved a confirmed partial response (PR) (modified RECIST 1.1) in 4 DLs (0.3 mg [8% of PR], 1 mg [13%], 3 mg [33%], and 10 mg [20%]). Stable disease was seen in 24% (12/51). Median time to response was 1.8 months; the estimated duration of response was > 6 months in 83% (95% CI: 27%, 98%) of pts with a confirmed PR. An unconfirmed PR was noted in an additional pt (30 mg DL).

Conclusions

AMG 757 showed an acceptable safety profile and preliminary evidence for efficacy in pts with SCLC. The most common TRAE—CRS—occurred early in the dosing cycle, did not recur, was typically mild in severity, and manageable. The maximum tolerated dose has not been reached. Dose-finding for monotherapy is ongoing.

Clinical trial identification

NCT03319940.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Jacqueline Sayyah, PhD of Amgen Inc. and Sukanya Raghuraman, PhD of Cactus Life Sciences, part of Cactus Communications, and was funded by Amgen Inc.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

L. Paz-Ares: Leadership role: Genomica; Leadership role: European Medicines Agency; Leadership role: ALTUM Sequencing; Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: MBS; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Servier; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Roche/Genetech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck; Advisory/Consultancy: Lilly; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Celgene; Advisory/Consultancy: Sysmex; Advisory/Consultancy: Incyte; Advisory/Consultancy: Bayer; Advisory/Consultancy: Advanced Accelerator Applications; Advisory/Consultancy: Blueprint Medicines. T.K. Owonikoko: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Lilly; Advisory/Consultancy: Sandoz; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AbbVie; Advisory/Consultancy: Eisai; Advisory/Consultancy, Research grant/Funding (institution): G1 Therapeutics; Advisory/Consultancy: Takeda; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: MedImmune; Advisory/Consultancy: BerGenBio; Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Xcovery; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Heron Pharmaceutical; Advisory/Consultancy: ARMO BioSciences; Shareholder/Stockholder/Stock options: Cambium Medical Technologies; Research grant/Funding (self): Stem CentRx; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): AstraZeneca/MedImmune; Research grant/Funding (institution): Corvus Pharmaceuticals; Research grant/Funding (institution): United Therapeutics; Research grant/Funding (institution): Loxo/Lilly; Research grant/Funding (institution): Fujifilm; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Aeglea Biotherapeutics; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Merck; Licensing/Royalties: Emory University School of Medicine, Atlanta, GA; Honoraria (self), Received fees for non-CME/CE services : Roche/Genentech; Honoraria (self), Received fees for non-CME/CE services: EMD Serono; Non-remunerated activity/ies: Reflexion Medical; Research grant/Funding (institution): Astellas Pharma. M. Johnson: Advisory/Consultancy: Otsuka; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Calithera Biosciences; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution): Loxo; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Mersana; Advisory/Consultancy, Research grant/Funding (institution): BeiGene; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Incyte; Advisory/Consultancy, Research grant/Funding (institution): Guardant Health; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution): Ribon Therapeutics; Advisory/Consultancy: Achilles Therapeutics; Advisory/Consultancy: Atreca; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy: Gristone Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen Oncology; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy: Association of Community Cancer Centers [ACCC]; Research grant/Funding (institution), Travel/Accommodation/Expenses: AbbVie; Travel/Accommodation/Expenses: Clovis Oncology; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Research grant/Funding (institution), Travel/Accommodation/Expenses: EMD Serono; Travel/Accommodation/Expenses: Exelixis; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Sysmex; Travel/Accommodation/Expenses: Vapotherm; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Kadmon; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Genmab; Research grant/Funding (institution): Stem CentRx; Research grant/Funding (institution): Checkpoint Therapeutics; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Tarveda Therapeutics; Research grant/Funding (institution): CytomX Therapeutics; Research grant/Funding (institution): Dynavax; Research grant/Funding (institution): Birdie; Research grant/Funding (institution): Corvus Pharmaceuticals; Research grant/Funding (institution): Genocea Biosciences; Research grant/Funding (institution): Gritstone Oncology; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Adaptimmune; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): Neovia Oncology; Research grant/Funding (institution): Acerta Pharma; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Shattuck Labs; Research grant/Funding (institution): Apexigen; Research grant/Funding (institution): Atreca; Research grant/Funding (institution): OncoMed; Research grant/Funding (institution): Immunocore; Research grant/Funding (institution): Jounce Therapeutics; Research grant/Funding (institution): University of Michigan; Research grant/Funding (institution): WindMIL; Research grant/Funding (institution): TCR2 Therapeutics; Research grant/Funding (institution): Arcus Biosciences. R. Govindan: Advisory/Consultancy: GSK; Advisory/Consultancy: Genentech/Roche; Honoraria (self), Advisory/Consultancy: AbbVie; Advisory/Consultancy: Pfizer; Advisory/Consultancy: AstraZeneca/MedImmune; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Lilly; Advisory/Consultancy: Nektar; Advisory/Consultancy: Celgene; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Phillips Gilmore Oncology; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Roche; Advisory/Consultancy: Janssen; Advisory/Consultancy: Amgen; Advisory/Consultancy: Achilles Therapeutics; Advisory/Consultancy: Inivata; Honoraria (self): Genentech; Honoraria (self): Geneplus. V. Lai: Advisory/Consultancy: PharmaMar; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Jazz Pharmaceuticals; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): AbbVie. H. Borghaei: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Honoraria (self), Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: EMD-Serono; Advisory/Consultancy: Boehringer-Ingelheim; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: Genmab; Advisory/Consultancy: Regeneron; Advisory/Consultancy: BioNTech; Advisory/Consultancy: Cantargia AB; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Axiom; Advisory/Consultancy: PharmaMar; Advisory/Consultancy, Officer/Board of Directors, Data and Safety Monitoring Board: Takeda; Advisory/Consultancy: HUYA Bioscience International; Advisory/Consultancy: GLG; Honoraria (self), Advisory/Consultancy: Daiichi; Research grant/Funding (institution): Millenium; Officer/Board of Directors, Data and Safety Monitoring Board: University of Pennsylvania [CAR T Progam; Officer/Board of Directors, Data and Safety Monitoring Board: Incyte; Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Sonnetbio; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Rgenix. M. Boyer: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Janssen; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Ascentage Pharma; Research grant/Funding (institution): Benitec Biopharma; Research grant/Funding (institution): Novartis. H-D. Hummel: Travel/Accommodation/Expenses: Janssen-Cilag; Travel/Accommodation/Expenses: Boehringer Ingelheim; Travel/Accommodation/Expenses: Amgen. F. Blackhall: Advisory/Consultancy: Regeneron; Advisory/Consultancy: Medivatin; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Cell Medica; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Amgen. A. Dowlati: Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Incuron; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Symphogen. Y. Zhang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. S. Mukherjee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. B. Sable: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. A. Pati: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. A. Shetty: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. N. Hashemi Sadraei: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen Inc. S. Champiat: Honoraria (self), Advisory/Consultancy: Amgen Inc.; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Janssen; Honoraria (self): Merck; Honoraria (self), Travel/Accommodation/Expenses: MSD; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies: Roche; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy: Agios Pharmaceuticals; Advisory/Consultancy: Argen-X Bvba; Advisory/Consultancy: Arno Therapeutics; Advisory/Consultancy: Astex Pharmaceuticals; Advisory/Consultancy: AstraZeneca Ab; Advisory/Consultancy: Aveo; Advisory/Consultancy: Basilea Pharmaceutica International Ltd; Advisory/Consultancy: Bayer Healthcare Ag; Advisory/Consultancy: Bbb Technologies Bv; Advisory/Consultancy: Beigene; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim; Advisory/Consultancy: Boston Pharmaceuticals; Advisory/Consultancy: Bristol Myers Squibb, Ca; Advisory/Consultancy: Celgene Corporation; Advisory/Consultancy: Chugai Pharmaceutical Co; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Cullinan-Apollo; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Debiopharm; Advisory/Consultancy: Eisai; Advisory/Consultancy: Eisai Limited; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Faron Pharmaceuticals Ltd; Advisory/Consultancy: Forma Tharapeutics; Advisory/Consultancy: Gamamabs; Advisory/Consultancy: Genentech; Advisory/Consultancy: Glaxosmithkline; Advisory/Consultancy: H3 Biomedicine; Advisory/Consultancy: Hoffmann La Roche Ag; Advisory/Consultancy: Imcheck Therapeutics; Advisory/Consultancy: Innate Pharma; Advisory/Consultancy: Institut De Recherche Pierre Fabre; Advisory/Consultancy: Iris Servier; Advisory/Consultancy, Research grant/Funding (institution): Janssen Cilag; Advisory/Consultancy: Janssen Research Foundation; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Kyowa Kirin Pharm. Dev; Advisory/Consultancy: Lilly France; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Lytix Biopharma As; Advisory/Consultancy, Non-remunerated activity/ies: Medimmune; Advisory/Consultancy: Menarini Ricerche; Advisory/Consultancy: Merck Sharp & Dohme Chibret; Advisory/Consultancy: Merrimack Pharmaceuticals; Advisory/Consultancy: Merus; Advisory/Consultancy: Millennium Pharmaceuticals; Advisory/Consultancy: Molecular Partners Ag; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: Nektar Therapeutics; Advisory/Consultancy: Novartis Pharma; Advisory/Consultancy: Octimet Oncology Nv; Advisory/Consultancy: Oncoethix; Advisory/Consultancy: Oncopeptides; Advisory/Consultancy: Orion Pharma; Advisory/Consultancy: Ose Pharma; Advisory/Consultancy, Research grant/Funding (institution), Non-remunerated activity/ies: Pfizer; Advisory/Consultancy: Pharma Mar; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Medicament; Advisory/Consultancy: Sanofi Aventis; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Sotio A.S; Advisory/Consultancy: Syros Pharmaceuticals; Advisory/Consultancy: Taiho Pharma; Advisory/Consultancy: Tesaro; Advisory/Consultancy: Xencor; Research grant/Funding (institution), Non-remunerated activity/ies: Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Onxeo; Research grant/Funding (institution): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: MBS; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: NH TherAGuiX. All other authors have declared no conflicts of interest.

Background

Small-cell lung cancer (SCLC) is an aggressive disease associated with poor prognosis despite curative-intent treatment. Recurrences within high-dose radiotherapy field can indicate radio-resistance. We aim to identify areas of relapse and whether they occurred within high-dose areas.

Methods

Patients with limited-stage SCLC treated at The Christie as part of the phase III CONVERT trial from 2008 were included in the analysis. Patients received either 45 Gy in 30 twice-daily (BD) fractions or 66 Gy in 33 daily (OD) fractions with concurrent chemotherapy. Elective nodal irradiation was not given. All follow-up CT scans were retrospectively reviewed for evidence of relapse. Patients were classified as thoracic-only relapses (i.e. within radiotherapy field), distant metastases or relapse in both areas. For thoracic relapses all lesions that progressed were contoured on the relapse CT by a radiation oncologist. We estimated the planned mean dose over each relapse lesions by mapping the planning dose from the planning CT onto the relapse CT using non-rigid registrations (Elastix). As extreme anatomical changes existed for some patients, registration was repeated using NiftyReg. Lesions that resulted in disagreement of 2 Gy were visually checked and manually tuned.

Results

49 of 90 patients had evidence of relapse. 20 patients had thoracic-only relapses, 19 had only distant metastases and 10 patients relapsed in both areas. Of the 30 thoracic relapses 25 sets of scans were available for mapping analysis. We identified 67 lesions in total, a mean of 2.7 lesions per patient (range 1–9). Mean size of lesions was 18.8 cm³ (range 0.01 cm³–549 cm³). 16 of 25 patients relapsed within 95% isodose region (11/25 received BD radiotherapy) and 6 also had distant metastases. The remaining 9 of 25 thoracic relapses progressed within 20% to 95% isodoses (6/9 received OD radiotherapy).

Conclusions

3 out of 4 patients who relapsed had thoracic progression. The mapping analysis showed that the majority of thoracic relapses (64.0%) occurred within the high-dose radiotherapy region. This suggest that there is scope for further local treatment intensification.

Clinical trial identification

06_DOG07_68 ISRCTN91927162 CONVERT Trial protocol: Version 3, 10JUN2008.

Legal entity responsible for the study

Corinne Faivre-Finn.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Non-small cell lung cancer (NSCLC) displays frequent DNA damage response (DDR) defects. DDR defects leading to platinum sensitivity widely overlap with those underlying Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity. PIPSeN (NCT02679963) is a randomized double-blind phase II study that evaluated the PARPi olaparib as maintenance treatment in patients (pts) with platinum-sensitive advanced NSCLC.

Methods

Chemonaïve ECOG PS 0–1 pts with stage IIIB-IV NSCLC with no EGFR or ALK/ROS alteration were eligible in this Gustave Roussy-sponsored AstraZeneca-funded academic study. Pts with partial or complete response after 4–6 cycles of platinum-based chemotherapy were randomized (R) between olaparib maintenance (O, 300 mg BID) or placebo (P). Primary objective was progression-free survival (PFS) from R according to RECIST v1.1. Secondary objectives included overall survival (OS) and safety. R was stratified according to age, histology and country. With an anticipated HR = 0.65, 500 enrolled pts were required to randomize 144 pts. Because of the registration of anti-PD-L1 agents in the first-line setting, the trial was closed prematurely.

Results

182 pts were enrolled and 60 pts randomized (33 and 27 in the O and P arms, respectively); median age was 63; 63% had adenocarcinoma, 3% were never-smokers. Pts and tumor characteristics were well-balanced between arms, except for bone/peripheral metastasis (14/11 and 8/4 in O and P arms, respectively). Median PFS was 2.3 and 2.1 months in the O and P arms, respectively (HR = 0.89, IC 95% 0.51–1.55; p = 0.68); median OS was 9.5 and 14.1 months in the O and P arms, respectively (HR = 1.29 IC 95% 0.68–2.45; p = 0.44). Grade ≥3 adverse events (AEs) occurred in 14 and 4 pts in O and P arms; 10 AEs (8 in the O arm) led to treatment discontinuation; 38 pts (23 in O and 15 in P arms) received second-line systemic therapy, including immunotherapy in 12 and 9 pts in the O and P arms, respectively.

Conclusions

PIPSeN was terminated early with only 50% of the pre-planned pts population available for analysis, thus being statistically underpowered. Although well tolerated, olaparib maintenance did not improve median PFS nor median OS in this sample of pts with platinum-sensitive NSCLC.

Clinical trial identification

NCT02679963.

Legal entity responsible for the study

Gustave Roussy.

Funding

AstraZeneca.

Disclosure

S. Postel-Vinay: Research grant/Funding (institution): Boehringer Ingelheim, Roche, Merck KGaA, AstraZeneca; Research grant/Funding (institution), Principal or co-investigator of clinical trials: AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicine. D. Planchard: Advisory/Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung; Travel/Accommodation/Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer; Research grant/Funding (institution), Principal or co-investigator of clinical trials: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. A. Gazzah: Research grant/Funding (institution), Principal or co-investigator of clinical trials: AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicine. J-C. Soria: Honoraria (self), Advisory/Consultancy: AstraZeneca, Bayer, Blend Therapeutics, Boehringer-Ingelheim, Clovis, Eli Lilly, Gammamabs, Merus, Mission Therapeutics, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symphogen, Tarveda; Shareholder/Stockholder/Stock options: Gritstone; Full/Part-time employment, Sept 2017 to Dec 2019: AstraZeneca. B. Besse: Research grant/Funding (institution): AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, P. All other authors have declared no conflicts of interest.

Background

Appropriate treatment for advanced non-small cell lung cancer (NSCLC) remains a challenging problem. Newly clinically applied immune checkpoint inhibitors (ICIs) still show a low response rate. Therefore, more effective therapies are still needed. Here, we report the results of a phase II clinical trial combining DCVAC/LuCa to chemotherapy as treatment for stage IV non-squamous NSCLC.

Methods

Patients with stage IV, non-squamous NSCLC without genetic variants and had not received systemic therapy for NSCLC prior to treatment, were enrolled in this study. DCVAC/LuCa were manufactured after collecting peripheral blood mononuclear cells (PBMC) from the patients. DCVAC/LuCa was applied since the third cycle of chemotherapy. Primary endpoint for efficacy was overall survival (OS). For safety analysis, we assessed adverse events (AEs), treatment-related AEs (TRAEs) and AEs of special interest (AESIs).

Results

Between January 2016 and March 2018, 61 patients were enrolled. The OS rate at 2 year in mITT population was 52.57% and the median OS was not reached (95% CI, 19.4 to could not be calculated). The median PFS was 8.0 months (95% CI 5.4 to 11.9). ORR was 31.82% and median TTP was 10.2 months (95% CI 3.6 to 15.7). Patients’ prognosis was significantly related to the number of doses of DCVAC. Eight (13.33%) of the sixty assessed patients had grade 3 or over 3 TRAEs, none of which were related to leukapheresis or DC vaccination. Six grade 1 TRAEs were considered associated with leukapheresis. No DCVAC-induced AEs were observed.

Conclusions

In stage IV, non-squamous NSCLC without genetic variants, the combination therapy of DCVAC/LuCa with pemetrexed plus carboplatin has a clinical activity and a favorable tolerability profile. Our results are a foundation for further randomized controlled clinical trials of this therapy.

Clinical trial identification

NCT02669719.

Legal entity responsible for the study

The authors.

Funding

Shanghai Chest Hospital affiliated to Shanghai Jiaotong University.

Disclosure

All authors have declared no conflicts of interest.