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Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent ‘on-target, off-tumor’ toxicity and a maximum tolerated dose of 1.0 × 108 cells.

Highlights • Risk of distress/burnout amongst oncology professionals continues to worsen since COVID-19 despite improved job performance. • Female and younger (≤40 years old) colleagues continue to be at higher risk of poor well-being and feeling burnout. • Job demands have increased, with nearly half now feeling overwhelmed with workload. • Concerns regarding career development/training, job security, and international fellowship opportunities remain high. • A quarter of oncology professionals reported considering changing their career, including leaving the oncology profession. Background COVID-19 has had a significant impact on the well-being and job performance of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate and monitor well-being since COVID-19 in relation to work, lifestyle and support factors in oncology professionals 1 year on since the start of the pandemic. Methods An online, anonymous survey was conducted in February/March 2021 (Survey III). Key outcome variables included risk of poor well-being or distress (expanded Well-Being Index), feeling burnout (single item from expanded Well-Being Index), and job performance since COVID-19. Longitudinal analysis of responses to the series of three surveys since COVID-19 was carried out, and responses to job demands and resources questions were interrogated. SPSS V.26.0/V.27.0 and GraphPad Prism V9.0 were used for statistical analyses. Results Responses from 1269 participants from 104 countries were analysed in Survey III: 55% (n = 699/1269) female, 54% (n = 686/1269) >40 years, and 69% (n = 852/1230) of white ethnicity. There continues to be an increased risk of poor well-being or distress (n = 464/1169, 40%) and feeling burnout (n = 660/1169, 57%) compared with Survey I (25% and 38% respectively, P < 0.0001), despite improved job performance. Compared with the initial period of the pandemic, more participants report feeling overwhelmed with workload (45% versus 29%, P < 0.0001). There remain concerns about the negative impact of the pandemic on career development/training (43%), job security (37%). and international fellowship opportunities (76%). Alarmingly, 25% (n = 266/1086) are considering changing their future career with 38% (n = 100/266) contemplating leaving the profession. Conclusion Oncology professionals continue to face increased job demands. There is now significant concern regarding potential attrition in the oncology workforce. National and international stakeholders must act immediately and work closely with oncology professionals to draw up future-proof recovery plans.

Background: Immune-related Adverse Events (IrAEs) present a new challenge to patient safety. The use of Patient-Reported Outcomes (PROs) to monitor adverse events is increasing. Existing measures like the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) do not offer clear guidance how to select the symptoms to monitor in different populations. The wide spectrum of toxicities of more recent treatments such as Immune Checkpoint Inhibitors (ICIs) is not fully covered. We aimed to a) reach expert consensus on PRO-CTCAE symptom to be monitored in cancer patients treated with ICIs; b) gather expert opinion on additional symptom terms that could be used to broaden its reach in the ICI toxicity spectrum; and c) reach expert consensus on a set of priority symptom terms to monitor symptomatic IrAEs in this population. Methods: We conducted a Delphi study with an international panel of eleven experts across four rounds. In round 1, experts assessed the relevance of PRO-CTCAEsymptom terms and suggested additional terms. Subsequent rounds aimed at consensus on the importance-to-monitor on three levels (level1 ¼ highest; level 3 ¼ lowest) of all relevant symptom terms. Results: All (n¼80) PRO-CTCAE Symptom terms were considered relevant. By round 4, consensus on the importance-to-monitor was reached for 82% (n¼65). Thirty terms reached consensus on level 1 importance, followed by 33 on level 2 and 2on level 3. Experts agreed on a set of 54 additional symptom terms to be considered to monitor ICI-related toxicities. Consensus on the importance-to-monitor was reached for 87% (n¼47) of these terms. Conclusions: To our knowledge, this is the first consensus of a prioritized list of symptom terms that should be considered for prospective surveillance of ICI-related toxicities. Additionally, they reveal the need to improve existing PRO measures to address the complex nature of IrAEs, and provide a first consensus on what symptom terms should be targeted by future work.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision‐making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune‐ or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE‐006 and CHECKMATE‐067/‐066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan‐Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population‐based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3‐year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long‐term survival is possible. The prognosis of ineligible patients with advanced melanoma in real‐world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM., What's new? By necessity, randomized controlled trials (RCTs) exclude many patients. However, these ineligible patients are often still treated with new systemic therapies on an individual basis. In this study, the authors examined how various subgroups of ineligible patients fared following treatment for advanced melanoma. They found that several criteria were strongly associated with prognosis in these patients, including lactate dehydrogenase (LDH) levels. These results should provide clinicians with a decision tree of prognostic factors to help guide treatment decisions.

Background Nivolumab (NIVO) alone or with ipilimumab (COMBO) immune checkpoint blockade (ICB) prior to curative surgery has shown promising results in multiple tumor types. We completed a phase Ib/II study with neoadjuvant NIVO or COMBO in resectable head and neck squamous cell carcinoma (HNSCC) and show safety, efficacy and correlative biomarker results. Methods 32 stage II-IVB HNSCC patients indicated for curative (salvage) surgery were treated with NIVO (240mg, weeks 1&3, N=6) or NIVO (240mg, weeks 1&3) + IPI (1mg/kg, week 1, N=26) prior to surgery in week 5. Imaging was performed at baseline and week 4. AEs were reported in terms of CTCAE. Pathological response (pR) was defined as % change in viable tumor cells from baseline to on-treatment; ≥90% pR was considered (near-) complete response (pCR). WES and RNAseq were performed on paired tumor biopsies. Results 32 (31 HPV-negative) patients started treatment (stage II n=3, III n=8, IVA-B n=11, recurrent disease n=10). 6 patients included with recurrent disease had had previous (C)RT. 1 patient discontinued ICB after one course due to patient’s preference. Surgery was not postponed in any patient. 3/32 patients did not undergo surgery: 1 due to unresectable PD and 2 due to reasons unrelated to ICB or disease. Grade 3-4 irAEs in 11/32 patients were well manageable. (Near-)pCR in the primary tumor was seen in 9/29 evaluable patients (31%). Another 31% of patients had 20-89% pR. At 14 months median FU, RFS for patients with (near-)pCR was 100%, significantly better than patients with