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Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

This file provides supplementary methods for genomics, including TGS, CGH array, WES, RNAseq Analysis, IHC -MET.

Individual PFS2 vs PFS1 profile plot. Each patient has been aligned at time 0 of PFS2 and sorted by the sum of PFS1 and PFS2.

Genes that contain molecular alterations matched with therapies according to tumor type.

Supplementary Figure Legends

Supplementary tables and figures legends

Purpose: While immune checkpoint inhibitors are disrupting the management of patients with cancer, anecdotal occurrences of rapid progression (i.e., hyperprogressive disease or HPD) under these agents have been described, suggesting potentially deleterious effects of these drugs. The prevalence, the natural history, and the predictive factors of HPD in patients with cancer treated by anti-PD-1/PD-L1 remain unknown.Experimental Design: Medical records from all patients (N = 218) prospectively treated in Gustave Roussy by anti-PD-1/PD-L1 within phase I clinical trials were analyzed. The tumor growth rate (TGR) prior (“REFERENCE”; REF) and upon (“EXPERIMENTAL”; EXP) anti-PD-1/PD-L1 therapy was compared to identify patients with accelerated tumor growth. Associations between TGR, clinicopathologic characteristics, and overall survival (OS) were computed.Results: HPD was defined as a RECIST progression at the first evaluation and as a ≥2-fold increase of the TGR between the REF and the EXP periods. Of 131 evaluable patients, 12 patients (9%) were considered as having HPD. HPD was not associated with higher tumor burden at baseline, nor with any specific tumor type. At progression, patients with HPD had a lower rate of new lesions than patients with disease progression without HPD (P < 0.05). HPD is associated with a higher age (P < 0.05) and a worse outcome (overall survival). Interestingly, REF TGR (before treatment) was inversely correlated with response to anti-PD-1/PD-L1 (P < 0.05) therapy.Conclusions: A novel aggressive pattern of hyperprogression exists in a fraction of patients treated with anti-PD-1/PD-L1. This observation raises some concerns about treating elderly patients (>65 years old) with anti-PD-1/PD-L1 monotherapy and suggests further study of this phenomenon. Clin Cancer Res; 23(8); 1920–8. ©2016 AACR.See related commentary by Sharon, p. 1879

Sensitivity Prediction Score ROC Curve of the logistic regression model.

mutations' allele frequencies in tDNA and cfDNA

* To be clinically meaningful, estimates are computed for 10% variation in TGR

Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.Results: Among the 283 patients with tDNA–cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%–61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960–8. ©2016 AACR.

Practically, patients with SD, PD and HPD lead 4.9, 16.5 and 25.9 fold increase in the death the death hazard compared to patients with CR-PR, respectively. *HPD adapted RECIST classes: complete response (CR), partial response (PR) and stable disease (SD) remained as defined by RECIST 1.1. Regarding progressive disease patients, these were allocated to PD non-HPD and to HPD. HPD patients are defined as progressive disease (PD) by RECIST 1.1 at the first evaluation and an increase {greater than or equal to} two-fold in the TGR EXPERIMENTAL compared to REFERENCE period.

Figure S1 A: Distribution of the TGR EXPERIMENTAL/TGR REFERENCE ratio for HPD patients (as defined as PD estimated by the RECIST sum and TGR ratio {greater than or equal to} 2). The red dashed line represents the threshold of TGR=2 fold. Figure S1 B-F: Association between HPD and anatomo-clinical variables (B) Patterns of progression at the first tumor evaluation (N=49): Among patients with progressive disease by RECIST at the first evaluation, HPD patients exhibited a lower rate of new lesions than non-HPD progressing patients. (C) Distribution of the tumor burden at baseline (estimated by the RECIST sum) across the HPD (N=12) and the non-HPD patients (N=119) (D) Frequencies of the HPD patients among the different categories of Royal Marsden Hospital (RMH) prognostic score (E-F) Distribution of the lymphocytes (D) or LDH baseline level (E), across the HPD (N=12) and the non-HPD patients (N=119)

PDF file - 109K, CD4+CD8dim or CD4+NKG2D+ T cells can be found in other malignancies.

PDF file - 84K, The combination therapy induced a profound lymphopenia.

PDF file - 38K, Synergistic effects of TCR or IL-15 stimulation with NKG2D engagement for Th1 polarization in CD4+NKG2D+T cells.

PDF file - 94K, 2D Clustering of LogRatios (D21/D0) of gene expression post- (D21) and pre-therapy (D0) with sorafenib/temozolomide.

PDF file - 1795K, T-cell infiltration and MICA/B expression in metastatic melanoma.

PDF - 115K, upplemental Figure 1. Activation of CD4+ T cells by CatmAb in mixed lymphocyte tumor cocultures. Supplemental Figure 2. Activation of CD8+ T cells by CatmAb in mixed lymphocyte tumor cocultures. Supplemental Figure 3. Activation of NK cells by CatmAb in mixed lymphocyte tumor cocultures.

PDF file - 197K, Supplemental Table 1. Characteristics of GIST patients for the immunohistochemistry study. Supplemental Table 2. Characteristics of GIST and STS patients studied in flow cytometry. Supplemental Table 3: Antibodies for flow cytometry and IHC. Supplemental Figure 1. Correlation between T and NK cell infiltrates and the 3-digit Miettinen score. Supplemental Figure 2. GIST TIls are mainly composed of CD4+ T cells.

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an “adjuvant” molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. Cancer Res; 74(1); 68–80. ©2013 AACR.

PDF file - 25K, Schedule of the sorafenib and temozolomide combination regimen.

PDF file - 119K

Introduction: Early guidelines for minimally important differences (MID) for the EORTC QLQ-C30 proposed ≥10 points change as clinically meaningful for all scales. Increasing evidence that MIDs can vary by scale, direction of change, cancer type and estimation method has raised doubt about a single global standard. This paper identifies MID patterns for interpreting group-level change in EORTC QLQ-C30 scores across nine cancer types. Methods: Data were obtained from 21 published EORTC Phase III trials that enrolled 13,015 patients across nine cancer types (brain, colorectal, advanced breast, head/neck, lung, mesothelioma, melanoma, ovarian, and prostate). Anchor-based MIDs for within-group change and between-group differences in change over time were obtained via mean change method and linear regression respectively. Separate MIDs were estimated for improvements and deteriorations. Distribution-based estimates were derived and compared with anchor-based MIDs. Results: Anchor-based MIDs mostly ranged from 5 to 10 points. Differences in MIDs for improvement vs deterioration, for both within-group and between-group, were mostly within a 2-points range. Larger differences between within-group and between-group MIDs were observed for several scales in ovarian, lung and head/neck cancer. Most anchor-based MIDs ranged between 0.3 SD and 0.5 SD distribution-based estimates. Conclusions: Our results reinforce recent claims that no single MID can be applied to all EORTC QLQ-C30 scales and disease settings. MIDs varied by scale, improvement/deterioration, within/between comparisons and by cancer type. Researchers applying commonly used rules of thumb must be aware of the risk of dismissing changes that are clinically meaningful or underpowering analyses when smaller MIDs apply.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8(+) T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

Background: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. Objective: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. Methods: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. Results: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. Limitations: English-speaking patients and professionals rated outcomes extracted from English language studies. Conclusion: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

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Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken.IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed.Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α.This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

Background: ALK rearrangements occur in 3-6% of patients (pts) with lung adenocarcinoma. Lorlatinib, is a novel third generation ALK tyrosine kinase inhibitor (TKI) with proven efficacy for patients previously treated with second generation ALK TKI. Methods: The MATCH-R study is a prospective single-institution trial aiming to identify mechanisms of resistance to targeted agents and immunotherapy in pts with advanced cancer (NCT02517892). Patients that achieve an initial partial or complete response or stability of disease for at least 6 months with selected agents are included upon disease progression. Tumor biopsies are performed and serial blood samples are collected. Extensive molecular profiling with panel next-generation sequencing (NGS), whole exome sequencing (WES) and RNA sequencing (RNAseq) is performed on tumor samples. Patient-derived xenografts (PDX) in NOD scid gamma (NSG) or nude mice and patient-derived cell lines are developed. We report mechanisms of resistance in a cohort of pts with ALK-rearranged lung cancer treated with lorlatinib. Results: From June 29th 2015 to November 15th 2018, 113 pts treated with a TKI were included in the MATCH-R study, of which 14 (12%) received treatment with ALK TKI, 6 pts treated with lorlatinib and with adequate tumor biopsies for molecular analysis were included. Tumor types studied were lung adenocarcinoma (n=4), anaplastic thyroid carcinoma (ATC, n=1) and myofibroblastic inflammatory tumor (MIT, n=1). An NF2 frame-shift deletion was detected by NGS in the ATC sample and a TNIK Q674 missense mutation was detected in the MIT sample. In the four pts with lung cancer treated with lorlatinib, we identified novel ALK G1202R/F1174L compound mutations from the tumor biopsy in one case and characterized them with Ba/F3 models (ctDNA analysis will be presented). Induction of epithelial mesenchymal transition (EMT) with lorlatinib exposure was responsible for resistance in one patient-derived model and susceptible to combined ALK/SRC inhibition. This cell line also had ALK C1156Y/G1269A compound mutations, not contributing to lorlatinib resistance. In a third case, double deleterious events in NF2 were identified in temporo-spatial distinct tumor biopsies on progression to lorlatinib. We further validated the effect of these events in patient-derived cell lines developed from two different biopsies. Downstream mTOR pathway activation conferred resistance to lorlatinib, and was reversible with mTOR inhibitors. We performed NF2 knockout in H3122 cells using Crispr-Cas9 gene editing to validate these findings. The resistance mechanism to lorlatinib treatment is yet to be elucidated in one patient-derived model. Conclusions: Mechanisms of resistance to lorlatinib can be diverse and complex, involving compound mutations, EMT and bypass activation. The present evidence could provide new insights for the development of tailored treatments for patients. Citation Format: Gonzalo Recondo, Laura Mezquita, David Planchard, Anas Gazzah, Francesco Facchinetti, Ludovic Bigot, Ahsan Z. Rizvi, Jean-Paul Thiery, Jean-Yves Scoazec, Rosa L. Frias, Tony Sourisseau, Linda Mahjoubi, Justine Galissant, Aurelie Abou-Lovergne, Gilles Vassal, Rastislav Bahleda, Antoine Hollebecque, Claudio Nicotra, Maud Ngocamus, Stefan Michiels, Ludovic Lacroix, Catherine Richon, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Ken A. Olaussen, Eric Angevin, Alexander Eggermont, Fabrice André, Christophe Massard, Jean-Charles Soria, Benjamin Besse, Luc Friboulet. Diverse biological mechanisms drive resistance to Lorlatinib in ALK-rearranged Lung Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 311.

Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

Malignant cells express antigens that can be harnessed to elicit anticancer immune responses. One approach to achieve such goal consists in the administration of tumor-associated antigens (TAAs) or peptides thereof as recombinant proteins in the presence of adequate adjuvants. Throughout the past decade, peptide vaccines have been shown to mediate antineoplastic effects in various murine tumor models, especially when administered in the context of potent immunostimulatory regimens. In spite of multiple limitations, first of all the fact that anticancer vaccines are often employed as therapeutic (rather than prophylactic) agents, this immunotherapeutic paradigm has been intensively investigated in clinical scenarios, with promising results. Currently, both experimentalists and clinicians are focusing their efforts on the identification of so-called tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication, as well as to combinatorial immunostimulatory interventions with superior adjuvant activity in patients. Here, we summarize the latest advances in the development of peptide vaccines for cancer therapy.