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Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer.Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors.Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP.This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansine Conjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansina Conjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansina Tusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Patients and methods Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Results Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Conclusions Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W. This work was supported by Sanofi, France (no grant number).

Immunotherapies have drastically improved clinical outcomes in a wide range of malignancies. Nevertheless, patient responses remain highly variable, and reliable biomarkers that predict responses accurately are not yet fully understood. Compelling evidence from preclinical studies and observational data from clinical cohorts have shown that commensal microorganisms that reside in the human gastrointestinal tract, collectively termed the ‘microbiome', can actively modify responses to chemotherapeutic agents and immunotherapies by influencing host immunosurveillance. Notably, microbial correlates are largely context specific, and response signatures may vary by patient population, geographic location and type of anticancer treatment. Therefore, the incongruence of beneficial microbiome signatures across studies, along with an emerging understanding of the mechanisms underlying the interactions between the microbiome, metabolome and host immune system, highlight a critical need for additional comprehensive and standardized multi-omics studies. Future research should consider key host factors, such as diet and use of medication, in both preclinical animal models and large-scale, multicenter clinical trials. In addition, there is a strong rationale to evaluate the microbiome as a tumor-extrinsic biomarker of clinical outcomes and to test the therapeutic potential of derived microbial products (e.g. defined microbial consortia), with the eventual goal of improving the efficacy of existing anticancer treatments. This review discusses the importance of the microbiome from the perspective of cancer immunotherapies, and outlines future steps that may contribute to wide-ranging clinical and translational benefits that may improve the health and quality of life of patients with cancer.

Inhibidor d'AKT; Càncer avançat; Fase I Inhibidor de AKT; Cáncer avanzado; Fase I AKT inhibitor; Advanced cancer; Phase I Background This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules. Patients and methods The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels. Results In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure. Conclusions Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. This work was supported by Genentech, Inc., a member of the Roche Group, and F. Hoffmann-La Roche Ltd. (no grant number).

International audience; Background: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinibresistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. Patients and methods: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. Results: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n ¼ 2 FGFR3-TACC3, n ¼ 1 KIF5B-RET, n ¼ 1 STRN-ALK fusions; n ¼ 2 BRAF V600E , n ¼ 1 KRAS G12V , n ¼ 1 KRAS G12R , n ¼ 1 KRAS G12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. Conclusions: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

Human papillomaviruses (HPV)-related gynecological cancers are a major health care issue, and a leading cause of cancer death in low- and middle-income countries (LMIC). In 2020, the World Health Organization launched a program aimed at cervical cancer elimination, by screening and vaccination strategies. Offering the best possible care to women diagnosed with invasive cancer is a complementary objective. Treatment of cervical cancer as per modern standards is complex and multimodal, mainly relying on surgery, external-beam radiotherapy (+/−chemotherapy) and brachytherapy. In parallel with the pivotal role of multidisciplinary discussion, international societies provide guidance to define the most effective and least toxic anti-cancer strategy, homogenize treatment protocols and provide benchmark quality indicators as a basis for accreditation processes. The challenge is to offer the appropriate diagnostic workup and treatment upfront and to avoid non- evidence-based treatment that consumes resources, impairs quality of life (QoL), and compromises oncological outcome. Various strategies may be applied for improving treatment quality: development of surgical mentorship, companion-training programs and international cooperation. The lack of radiotherapy/brachytherapy facilities is a major concern in LMIC. Reinforcing international support in terms of education, training, research and development and technical cooperation with national projects is required to increase access to minimum requirements but also introduce modern techniques, upgrade radiotherapy/brachytherapy services, and expand access to modern systemic treatments. In countries with robust economies, compliance to standards should also be increased. Integrative cancer care and multidisciplinary approaches are needed to tackle the dual challenge of increasing cure rates while minimizing QoL impairment. Appropriate dimensioning of the resources to avoid harmful treatment delays and access to expert referral centers is also a priority.

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.

Background The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France. Patients and methods The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses. Results A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years. Conclusions In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years., Highlights • A reduction of the number of cancer patients attending cancer centers was observed in France from January to July 2020. • This reduction was observed only for newly diagnosed patients. • The reduction of new diagnosis was more pronounced in women, for breast cancer, and prostate cancer, and nonmetastatic cancer. • No compensation was observed for the last months of 2020. The magnitude of delays may be larger in centers within the same country. • An estimation of the excess cancer death resulting from these delays is presented.

Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients.

Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients.During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute.A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were70 years and 233 patients (17.7%) were70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045).Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent.

Background: The SARS-CoV-2 outbreak significantly affected Gustave Roussy cancer center Here, we report the Gustave Roussy experience on older patients (OP) with cancer during the SARS-CoV-2 outbreak Methods: Cancer pts with suspected SARS-CoV-2 infection were admitted at Gustave Roussy starting March, 12th Screening indications have been adapted over time All the COVID-19 pts positively tested and managed at Gustave Roussy between March 14th and April 15th have been included in a redcap database Pts and underlying oncological and COVID-19 diseases characteristics have been collected Cancer and COVID-19 managements, and outcomes have been assessed The primary endpoint of this analysis was the clinical deterioration, defined as the need for O2 supplementation of 6l/min or more, or death of any cause Results: Among the first 137 cancer pts diagnosed with SARS-CoV-2, 36 patients were aged 70 years old or over (26%) Most of them were female (61%) with a median age of 75 5 years old Most frequent underlying cancers were solid tumors (92%) including GI (19%), lung (17%), GYN (14%) and head and neck (14%) Most OP (36%) were ECOG Performans status 2 versus 24% in younger patients (YP) The diagnosis of SARS-CoV-2 infection was made by RT-PCR or thoracic CT scan alone in 97% and 3% of the cases, respectively in OP and in 92% and 8% in YP Most OP experienced symptoms prior to testing (92%) compared to YP (80%) Symptoms differed according to age with more cough with sputum production in OP (14% versus 5%), dyspnea (39% versus 31%), diarrhea (17% versus 9%), shivers (8% versus 0%), sore throat (8% versus 4%) and no anosmia nor agueusia The majority of OP was hospitalized (81%) compared to 72% of YP and treated with HCQ/AZI (15;52%) compared to 25 (35%) YP with inclusion in the ONCOVID trial (EudraCT: 2020-01250-21) They did not receive any IL-6 inhibitor Only one OP was admitted in the ICU (3%) Clinical deterioration occurred in 10 OP (29%) There was no impact of age on clinical worsening (HR=1 157;95%CI 0 55-2 42;p=0 7) However age was associated with worse overall survival (OS) (HR=2 45 95%CI 1 02-5 92;p=0 0463) Results will be updated at the meeting Conclusions: OP with cancer had a different disease presentation, same rate of clinical worsening but worse OS in SARS-CoV-2 infection Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Summary Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Background In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)—particularly near the cut-off defining positive status—and clinical outcomes have been limited by small sample sizes. Patients and methods Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%–19% ALK-positive cells; of ALK-negative patients, 2% had 10%–14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%–19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Background A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients. Patients and methods Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing. Results For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection. Conclusions Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone. Clinical Trials NCT01526928

The impressive progress recently observed in adult cancers through the introduction of new drugs has not yet been translated to adolescents 12-17 years of age [defined according to the International Conference on Harmonization (ICH) E11]. The current drug development landscape separates adult and paediatric drug development (Table 1). Adolescents are grouped with children, leading to a mismatch with a lack of trials for adolescents with relapsed cancer and delayed access to new, effective drugs already available for adults.

Background Immune checkpoint inhibitors are an important tool in the therapeutic strategy against metastatic non–small cell lung cancer (NSCLC); however, radiological evaluation is challenging due to the emergence of atypical patterns of responses. Several evaluation criteria have been proposed, such as the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, immune -related RECIST (irRECIST) and iRECIST, but have not been systematically compared in a homogeneous population. Patients and methods We conducted a monocentric retrospective analysis of consecutive advanced NSCLC patients treated with an anti–programmed cell death-1 or anti–program death-ligand 1. Response patterns and the discordance between RECIST 1.1, irRECIST and iRECIST guidelines were described, and associations of response patterns and clinical outcome were explored. Results Overall, 160 patients treated between February 2013 and October 2016 were included. Atypical responses were observed in 20 patients (13%), including eight pseudoprogressions (PsPDs) (5%) and 12 dissociated responses (8%). Thirteen of the 20 patients demonstrated clinical benefit. Per the RECIST 1.1, 37 patients (23%) showed an objective response or stable disease, and 123 patients (77%) exhibited progression. Eighty progressive patients were assessable for irRECIST and iRECIST: 15 patients were assessed differently; however, only three (3.8%) mismatches with a theoretical impact on the therapeutic decision were identified. Patients with PsPD or dissociated response had higher overall survival than patients with true progression. Conclusion Atypical responses (PsPD/dissociated response) occurred in 13% of NSCLC patients under immune checkpoint inhibitors. Based on survival analyses, the RECIST 1.1 evaluation underestimated the benefit of immune checkpoint inhibitors in 11% of the progressive patients. Immune-related RECIST and iRECIST identified these unconventional responses, with a 3.8% discrepancy rate.

Background: We report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic TKI (nintedanib = [N]) with an anti-PD1 immunotherapy (pembrolizumab = [P]). Methods: Patients (Pts) with aMM that relapsed after at least one line of platinum-based combination were treated with a combination of oral [N] (150mg BID) & IV [P] (200mg Q3W) with 7 days [N] lead-in preceded [P] initiation. Baseline and on-treatment fresh tumor & blood samples were prospectively phenotyped immune cells by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated by multiplex ELISA on tumor secretome and plasma. Results: 30 aMM Pts were treated and 29 evaluable for response. Median age was 68 years old (38-85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1-3) related to the combination were liver enzymes increase, fatigue, nausea and diarrhea. 4 (13.3%) Pts developed grade 3-5 immune- related AE. Patients died of cancer progression (n=14), myocarditis with thrombo-embolic event (n=1) and COVID-19 (n=1). Median follow-up was 14.8 months (95%CI [9.70-18.2]). Best Overall Response Rates (BORR) were Partial Response (PR;n=7), Stable Disease (SD;n=17) and Progressive Disease (PD;n=5). Disease Control Rate (DCR) (defined as PR + SD) was 68.4% and 46.6% at 3 and 6 months, respectively. Analyses on fresh tumor biopsies showed that all patients increased their CD3+ T-cells and circulating levels of soluble PD1 and CXCL9 under treatment. Pts developing PR had significantly higher CD45+ and CD3+ tumor infiltrative cells at baseline compared to Pts with SD & PD as BORR. Pts with DCR at 6 months had significantly higher expression of integrins on circulating effector memory CD4+ & CD8+ T cells by FC, and higher NK, T, and myeloid dendritic cells infiltrates on baseline tumor RNAseq. Pre & on-treatment IL6 and IL8 levels in tumor secretome & plasma were higher among Pts with PD. Conclusions: With a BORR of 23% and a DCR of 47% at 6 months, [P]+[N] combination provided valuable therapeutic benefits for Pts with aMM. Flow cytometry and secretome on fresh baseline tumor biopsies are simple techniques which could be used to predict treatment efficacy in aMM Pts. Clinical trial identification: NCT02856425. Legal entity responsible for the study: Gustave Roussy. Funding: Funding: Boehringer Ingelheim;Drug supply: Boehringer Ingelheim & MSD;Sponsor: Gustave Roussy. Disclosure: C. Baldini: Financial Interests, Personal, Invited Speaker: Sanofi;Financial Interests, Personal, Invited Speaker: BMS;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Research Grant: Seattle Genetics;Financial Interests, Institutional, Research Grant: Iteos;Financial Interests, Institutional, Invited Speaker: Tahio;Financial Interests, Institutional, Research Grant: BMS. N. Chaput: Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: BMS;Financial Interests, Institutional, Research Grant: GSK;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Sanofi;Financial Interests, Institutional, Research Grant: Cytune Pharma. G. Zalcman: Financial Interests, Personal, Invited Speaker, outside the submitted work: BMS;Financial Interests, Personal, Invited Speaker, outside the submitted work: MSD;Financial Interests, Personal, Invited Speaker, outside the submitted work: AstraZeneca;Financial Interests, Personal, Invited Speaker, outside the submitted work: Boehringer Ingelheim;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: Roche;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: Takeda;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: AstraZeneca;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: AbbVie. C. Massard: Non-Financial Interests, Personal, Advisory Role: Amgen;Non-Financial Interests, Personal, Advisory Role: Astellas Pharma;Non-Financial Interests, Personal, Advisory Role: AstraZeneca;Non-Financial Interests, Personal, Advisory Role: Bayer;Non-Financial Interests, Personal, Advisory Role: BeiGene;Non-Financial Interests, Personal, Advisory Role: BMS;Non-Financial Interests, Personal, Advisory Role: Celgene;Non-Financial Interests, Personal, Advisory Role: Debiopharm Group;Non-Financial Interests, Personal, Advisory Role: Genentech/Roche;Non-Financial Interests, Personal, Advisory Role: Ipsen;Non-Financial Interests, Personal, Advisory Role: Janssen;Non-Financial Interests, Personal, Advisory Role: Lilly;Non-Financial Interests, Personal, Advisory Role: MSD;Non-Financial Interests, Personal, Advisory Role: Novartis;Non-Financial Interests, Personal, Advisory Role: Pfizer;Non-Financial Interests, Personal, Advisory Role: Sanofi;Non-Financial Interests, Personal, Advisory Role: Orion;Non-Financial Interests, Personal, Advisory Role: Taiho Pharmaceuticals;Non-Financial Interests, Personal, Advisory Role: Blueprint Medicinces;Non-Financial Interests, Personal, Advisory Role: Innate Pharma;Non-Financial Interests, Personal, Advisory Role: PharmaMar;Non-Financial Interests, Personal, Advisory Role: Faron Pharmaceuticals. J-C. Soria: Financial Interests, Personal, Stocks/Shares: AstraZeneca;Financial Interests, Personal, Stocks/Shares: Gritstone Oncology;Financial Interests, Personal, Stocks/Shares: Relay Therapeutics;Financial Interests, Personal, Member of the Board of Directors: Hookipa Pharmaceuticals;Financial Interests, Personal, Full or part-time Employment, sept 2017 to dec 2019: AstraZeneca. A. Marabelle: Financial Interests, Personal, Invited Speaker: Roche/Genentech;Financial Interests, Personal, Invited Speaker: BMS;Financial Interests, Personal, Invited Speaker: Merck Serono;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Invited Speaker: Amgen;Financial Interests, Personal, Invited Speaker: Sanofi;Financial Interests, Personal, Invited Speaker: Servier;Non-Financial Interests, Personal, Principal Investigator: Roche/Genentech;Non-Financial Interests, Personal, Principal Investigator: BMS;Non-Financial Interests, Personal, Principal Investigator: MSD;Non-Financial Interests, Personal, Principal Investigator: Pfizer;Non-Financial Interests, Personal, Principal Investigator: Lytix Pharma;Non-Financial Interests, Personal, Principal Investigator: Eisai;Non-Financial Interests, Personal, Principal Investigator: AstraZeneca;Non-Financial Interests, Personal, Principal Investigator: Tesaro;Non-Financial Interests, Personal, Principal Investigator: Chugai;Non-Financial Interests, Personal, Principal Investigator: Ose Immunotherapeutics;Non-Financial Interests, Personal, Principal Investigator: Sotio;Non-Financial Interests, Personal, Principal Investigator: Molecular Partners;Non-Financial Interests, Personal, Principal Investigator: IMCheck;Non-Financial Interests, Personal, Principal Investigator: Pierre Fabre;Non-Financial Interests, Personal, Principal Investigator: Adlai Nortye;Financial Interests, Personal, Stocks/Shares: Pegascy SAS;Financial Interests, Personal, Stocks/Shares: Centessa Pharmaceuticals;Financial Interests, Personal, Stocks/Shares: HiFiBio;Financial Interests, Personal, Stocks/Shares: Shattuck Labs;Financial Interests, Institutional, Research Grant: Merus;Financial Interests, Institutional, Research Grant: BMS;Financial Interests, Institutional, Research Grant: Boehringer Ingelheim;Financial Interests, Institutional, Research Grant: Transgene;Financial Interests, Institutional, Research Grant: Fondation MSD Avenir;Financial Interests, Institutional, Research Grant: Sanofi. All other authors have declared no conflicts of interest.

Background: The COVID-19 pandemic deeply threatens the rigorous conduct of clinical trials, notably by delaying site initiation visits, patient enrolment, treatment administration, trial-associated procedures, and data monitoring. Unlike most other medical specialties, clinical trials are an integral part of patient care in oncology. Limiting access to clinical trials therefore results in a loss of chance for patients. Methods: In this retrospective single-center study, we collected clinical trial-specific items (including patient-related or trial management-related items) during the first pandemic wave (March– June 2020) and lockdown (March 17th-May 11th) at Gustave Roussy, and compared them to those of the same period in 2019. Results: In March 2020, 84 phase I (P1) and 210 phase II/III (P2/3) trials were open. During the first pandemic wave, 21 (25%) P1 and 20 (9%) P2/3 trials were temporarily halted, following a unilateral sponsor decision in virtually all cases;all but one were industry-sponsored. Despite this, all important metrics of the P1/2 trial activity remained similar to those of 2019, including the number of patients referred for inclusion (599 vs 620), inclusion consultations (215 vs 247), patients starting treatment (130 vs 130), Internal Review Board (IRB) submissions (14 vs 16), and site initiation visits (11 vs 15), all in 2020 vs 2019, respectively. The impact of the first lock-down was more marked on P2/3, with 152 patient inclusions (vs 346 in 2019), 125 randomizations (vs 278), 43 IRB submissions (vs 50) and 34 site initiation visits (vs 40). However, in parallel, 475 patients were included in three “COVID and cancer” trials. Among the 443 P1 and 2851 P2/3 patients, 198 and 628 COVID-19 PCR were performed internally, and five and 15 (2.5%) were positive, respectively. One patient with a community-based COVID-19 died after transfer in intensive care. Conclusions: Cancer clinical trials can, and must be maintained despite challenges brought by COVID-19. Sharing experiences and retrospectively evaluating the impact on patients’ safety and cancer-related outcomes will be critical to durably improve the clinical trials conduct and to anticipate at best challenges brought by future similar crises. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: Outcomes and risk factors associated with COVID-19 worsening among cancer patients have previously been reported. However, the actual impact of SARs-Co-V2 infection on the cancer treatment strategy remains unknown. Here, we report the Gustave Roussy (GR) experience, one year after the onset of the pandemic focusing on the impact of COVID-19 in patients with ongoing management of oncohematological disease. Methods: All patients positively tested for SARS-CoV-2 and managed at GR between Mar 14th 2020 and Feb 15th 2021 (data cut-off) have been included. Patients underlying oncohematological disease and COVID19 characteristics have been collected. Cancer and COVID-19 management and outcomes have been assessed. Primary endpoint was the overall impact of COVID-19 on oncological and hematological treatment strategy assessed at 1, 3, 6 and 12 months. Results: At the time of the analysis, 423 patients (median age: 62 years) were found positive for SARS-CoV-2 and managed at GR with a median follow up of 5.6 months (0-13 months). Among them, 284 (67%) were admitted due to COVID-19. Clinical deterioration occurred in 87 patients (21%), 43 patients (10%) were transferred in intensive care unit and 123 (29%) patients died, among which 47 (11%) died from COVID-19. Overall, 329 (78%) patients were on active treatment for underlying oncohematological disease at time of COVID diagnosis. Impact of COVID-19 on cancer treatment strategy in those patients is presented in the Table. The majority (N=268, 81%) had no change in oncological strategy. For those who experienced a delay, median delay in treatment was 21 days (N=99, [1-77]), 30 days (N=15, [15-56]), 7 days (N=8,[3-35]) for systemic treatment, surgery and radiotherapy respectively. [Formula presented] Conclusions: COVID-19 outbreak is associated with a significant mortality in patients with cancer. However, for patients who did not die from COVID-19, we provide the first report supporting that ongoing treatment was maintained or could be resumed in the majority of cases in a timely manner. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background Immune check-point blockade agents have shown clinical activity in cancer patients but are associated with immune-related adverse events that could limit their development. The aim of this study was to describe the gastrointestinal immune-related adverse events (GI-irAE) in patients with cancer treated with anti-PD-1. Methods this is a retrospective study of consecutive adult patients who had a suspected GI-irAE due to anti-PD-1 antibodies between 2013 and 2016. Patients were recruited through a pharmacovigilance registry. Patients’ data were reviewed by a multidisciplinary committee that included gastroenterologists, oncologists and a pathologist. Quantitative variables are described by median (range), qualitative variable by frequency (percentage). Results Forty-four patients were addressed to a Gastroenterology unit for a suspected GI-IrAE. Twenty patients had a confirmed GI-irAE related to anti-PD-1, which occurred 4.2 months (0.2; 22.1) after the initiation of anti-PD-1. GI-IrAE incidence rate under anti-PD-1 treatment was estimated to be 1.5%. Among patients with GI-IrAE, main symptoms were diarrhoea (n = 16, 80%), abdominal pain (n = 13, 65%), nausea and vomiting (n = 11, 55%), intestinal obstruction (n = 1, 5%), and haematochezia (n = 2, 10%). No patient had colectomy. Four distinct categories of GI-irAE were observed: acute colitis (n = 8, 40%), microscopic colitis (n = 7, 35%), upper gastrointestinal tract inflammation (n = 4, 20%) and pseudo-obstruction (n = 1, 5%). Response rates to corticosteroids were 87.5% (7/8) in acute colitis, 57% (4/7) in microscopic colitis and 75% (3/4) in upper gastrointestinal tract inflammation. Median time to resolution was 36 days (6–172) in acute colitis, and 98 days (42–226) in microscopic colitis. Conclusion This study suggests that GI-irAE are different and less frequent with anti PD-1 than with anti CTLA-4.

Background We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. Patients and methods 125 patients with treatment-naive stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. Results 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with ≥5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with

Background Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by theT790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib whenT790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advancedEGFR-mutant NSCLC patients. Material and methods ctDNAT790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. ProgressingT790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage ofT790M positive inctDNA. Results ThectDNAT790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4–NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. Conclusion(s) ctDNA from liquid biopsy can be used as a surrogate marker forT790M in tumour tissue.

Background The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Patients and methods Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, andKRAS but not withTP53 mutation.EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. Conclusions PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.

Purpose We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Patients and methods Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days. Results Forty-five patients received BMS-599626 (100–660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated Cmax and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated. Conclusion BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

The tumor microenvironment (TME) is an integral part of cancer. Recognition of the essential nature of the TME in cancer evolution has led to a shift from a tumor cell-centered view of cancer development to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. Accordingly, novel targets within the TME have been uncovered that can help direct and improve the actions of various cancer therapies, notably immunotherapies that work by potentiating host antitumor immune responses. Here, we review the composition of the TME, how this attenuates immunosurveillance, and discuss existing and potential strategies aimed at targeting cellular and molecular TME components.