Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review.

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer.

Targeted Inhibition of CYP11A1 in Prostate CancerIn this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.

Antibody drug conjugates in older patients: State of the art.

More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE…) so that results can be more representative of this population outside of clinical trials.

Immunosuppressant mycophenolate mofetil for patients with steroid-refractory immune-related hepatitis induced by checkpoint inhibitors in oncology.

BACKGROUND: Immune-checkpoint inhibitor (ICI) hepatitis, which does not improve with steroids and requires additional immunosuppressant, is defined as steroid-refractory ICI hepatitis. The outcome of patients with steroid-refractory ICI hepatitis remains poorly determined. Herein, we investigated the incidence, clinical features, and outcome of patients treated with second-line immunosuppressant for steroid-refractory ICI hepatitis. METHODS: This is a retrospective analysis of patients who presented ICI hepatitis from 1st June 2016 to 30th September 2022. Steroid-refractory ICI hepatitis was defined as no clinical and biological improvement after systemic steroid therapy ≥1 mg/kg/d. Main objectives were to assess the frequency and risk factors associated with steroid-refractory ICI hepatitis and to evaluate the efficacy of second-line immunosuppressants. RESULTS: In total, 130 patients with grade ≥3 ICI hepatitis were screened, of them 60 (46.2%) were treated with systemic steroids. In total, 11/130 (8.5%) had steroid-refractory hepatitis. Statistically significant factors associated with steroid-refractory hepatitis included previous liver comorbidities (54.5% versus 11.6%; p < 0.01), hyperbilirubinemia (p < 0.001), and general symptoms (fever, jaundice, ascites, and/or encephalopathy) associated with hepatitis (72.7% versus 30.8%; p = 0.015). The 11 patients with steroid-refractory hepatitis were treated with mycophenolate mofetil. In total, resolution or return to grade ≤1 for hepatitis was observed in 81.8% (9/11) of patients. CONCLUSIONS: Steroid-refractory ICI hepatitis accounted for 8.5% of patients with grade ≥3 immune-related hepatitis and was statistically associated with previous liver comorbidities, hyperbilirubinemia, and general symptoms. Mycophenolate mofetil was a suitable option of therapy for steroid-refractory ICI hepatitis.

Combined Nivolumab and Ipilimumab in Octogenarian and Nonagenarian Melanoma Patients.

Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3-93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question.

Profile and outcome of cancer patients enrolled in contemporary phase I trials.

BACKGROUND: Phase I trials historically involved heavily pretreated patients (pts) with no more effective therapeutic options available and with poor expected outcomes. There are scare data regarding profile and outcomes of pts enrolled into modern phase I trials. Here, we sought to provide an overview of pts' profile and outcome into phase I trials at Gustave Roussy (GR). METHODS: This is a monocentric retrospective study, including all pts enrolled into phase I trials at GR from 2017 to 2021. Data regarding pts' demographics, tumour types, investigational treatments and survival outcomes were collected. RESULTS: In total, 9482 pts were referred for early phase trials; 2478 pts were screened, among which 449 (18.1%) failed screening; 1693 pts finally received at least one treatment dose as part of a phase I trial. Median age of pts was 59 years old (range, 18-88) and most common tumour types included gastrointestinal (25.3%), haematological (15%), lung (13.6%), genitourinary (10.5%) and gynaecologic cancers (9.4%). Amongst all pts treated and evaluable for response (1634 pts), objective response rate was 15.9% and disease control rate was 45.4%. Median progression-free survival and overall survival were, respectively, 2.6 months (95% confidence interval [95% CI], 2.3; 2.8) and 12.4 months (95% CI, 11.7; 13.6). CONCLUSION: As compared with historical data, our study shows that outcomes of pts included into modern phase I trials have improved and that these trials constitute nowadays a valid and safe therapeutic option. These updated data provide facts for adapting the methodology, role and place of phase I trials over the next years.

Safety and efficacy of immunotherapy according to the age threshold of 80 years.

BACKGROUND: To compare safety and efficacy of ICIs among patients<80 and those ≥80 years of age. METHODS: A single-center retrospective observational cohort study comparing patients<80 and ≥80 years of age matched for cancer site (lung vs others) and participation in a clinical trial. PRIMARY ENDPOINT: grade ≥2 toxicity during the first three months of ICI therapy. The two groups were compared using univariate and multivariate regression. RESULTS: Two hundred and ten consecutive patients were recruited, with the following characteristics: mean age: 66.5±16.8, 20% aged ≥80 years, 75% male, 97% ECOG-PS ≤ 2, 78% G8-index ≤ 14/17, 80% lung or kidney cancer, and 97% metastatic cancer. The grade ≥2 toxicity rate during the first three months of ICI therapy was 68%. Patients aged ≥80 years of age had a more significant (P<0.05) proportion of grade ≥2 non-hematological toxicities (64% vs 45%) than those aged<80 years: rash (14% vs 4%), arthralgia (7.1% vs 0.6%), colitis (4.7% vs 0.6%), cytolysis (7.1% vs 1.2%), gastrointestinal bleeding (2.4% vs 0%), onycholysis (2.4% vs 0%), oral mucositis (2.4% vs 0%), psoriasis (2.4% vs 0%), or other skin toxicities (25% vs 3%). Efficacy among patients ≥80 and<80 years of age was comparable. CONCLUSIONS: Although non-hematological toxicities affected 20% more patients aged ≥80 years, hematological toxicities and efficacy were comparable between patients aged ≥80 and<80 years with advanced cancer and treated with ICIs.

Pre-Therapeutic Sarcopenia among Cancer Patients: An Up-to-Date Meta-Analysis of Prevalence and Predictive Value during Cancer Treatment.

This study will address the prevalence of pre-therapeutic sarcopenia (PS) and its clinical impact during cancer treatment among adult cancer patients ≥ 18 years of age. A meta-analysis (MA) with random-effect models was performed via a MEDLINE systematic review, according to the PRISMA statement, focusing on articles published before February 2022 that reported observational studies and clinical trials on the prevalence of PS and the following outcomes: overall survival (OS), progression-free survival (PFS), post-operative complications (POC), toxicities (TOX), and nosocomial infections (NI). A total of 65,936 patients (mean age: 45.7-85 y) with various cancer sites and extensions and various treatment modes were included. Mainly defined by CT scan-based loss of muscle mass only, the pooled prevalence of PS was 38.0%. The pooled relative risks were 1.97, 1.76, 2.70, 1.47, and 1.76 for OS, PFS, POC, TOX, and NI, respectively (moderate-to-high heterogeneity, I2: 58-85%). Consensus-based algorithm definitions of sarcopenia, integrating low muscle mass and low levels of muscular strength and/or physical performance, lowered the prevalence (22%) and heterogeneity (I2 < 50%). They also increased the predictive values with RRs ranging from 2.31 (OS) to 3.52 (POC). PS among cancer patients is prevalent and strongly associated with poor outcomes during cancer treatment, especially when considering a consensus-based algorithm approach.

Prevalence of Four Sarcopenia Criteria in Older Patients with Cancer, and Their Predictive Value for 6-Month Mortality: The NutriAgeCancer National Prospective Cohort Study.

Older cancer patients have an elevated risk of sarcopenia. The aim was to estimate the prevalence of four criteria for sarcopenia case finding, assessment, diagnosis, and severity determination: abnormal strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F), low hand-grip strength (HGS), low arm circumference (AC, a muscle mass proxy), and low physical performance (PP). Sarcopenia (low HGS and AC) and severe sarcopenia (low HGS, AC, and PP) and their predictive values for 6-month mortality were estimated in the whole population and by metastatic status. We analyzed data from the NutriAgeCancer French nationwide study of cancer patients aged ≥70 referred for geriatric assessment before anti-cancer treatment. We performed Cox proportional hazards analysis for each criterion separately and all criteria combined. Overall, 781 patients from 41 geriatric oncology clinics were included (mean age: 83.1; females: 53%; main cancer types: digestive (29%) and breast (17%); metastases: 42%). The prevalence of abnormal SARC-F, low HGS, a low AC, low PP, sarcopenia, and severe sarcopenia were, respectively, 35.5%, 44.6%, 44.7%, 35.2%, 24.5%, and 11.7%. An abnormal SARC-F and/or low HGS, sarcopenia, and severe sarcopenia were associated with 6-month mortality in patients with metastases (adjusted hazard ratios [95% confidence interval]: 2.72 [1.34-5.49], 3.16 [1.48-6.75] and 6.41 [2.5-16.5], respectively). Sarcopenia was strongly predictive of 6-month mortality in patients with metastatic cancer.

Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Enrolment of older adults with advanced or metastatic non-small cell lung cancer in first-line clinical trials in the multicentre ESME cohort.

INTRODUCTION: There is a great need for data based on clinical trials for the older population in order to improve treatment. Historically, the inclusion rate of older adults in clinical trials has been low, but the rate specific to lung cancer is unknown, as are the factors associated with enrolment. MATERIALS AND METHODS: We used the national Epidemio-Strategy and Medical Economics Advanced or Metastatic Lung Cancer (AMLC) Data Platform, a multicentre real-life database. Inclusion criteria were patients with advanced or metastatic non-small cell lung cancer (AMNSCLC) aged 70 years or older, with at least one line of systemic treatment from 01 January 2015 to 31 December 2018. The primary objective was to evaluate the proportion of older adults enrolled in clinical trials. Secondary objectives were to identify factors associated with enrolment in clinical trials for older patients and to compare the overall survival of older adults included in trials versus those not included. RESULTS: There were 3488 patients aged ≥70 years (median age at AMNSCLC 75 years). Among older patients, 234 (6.7%) were enrolled in a clinical trial in the first-line setting. Significant factors associated with enrolment in the multivariable analysis in older patients were: good Eastern Cooperative Oncology Group (ECOG) Performance Status (PS 0) (p < 0.001), de novo versus recurrent presentation at diagnosis (p < 0.001), and non-central nervous system (CNS) metastases versus advanced setting or CNS metastases (p < 0.001). Medical history was associated with fewer inclusions (odds ratio [OR] = 0.74, 95% confidence interval [CI] [0.56; 0.99]). Among older patients, being enrolled in a trial in the first-line setting was not associated with better overall survival (OS) (hazard ratio [HR] = 1.03; 95%CI 0.86-1.22) in the multivariable analysis. DISCUSSION: In this large database, few older AMNSCLC patients were enrolled in a trial. Factors associated with enrolment were: good ECOG PS, absence of medical history, de novo AMNSCLC, and presentation with non-CNS metastases.

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. SIGNIFICANCE: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

BACKGROUND AND OBJECTIVES: D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. METHODS: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). RESULTS: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1 R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. DISCUSSION: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Predicting Immunotherapy Outcomes in Older Patients with Solid Tumors Using the LIPI Score.

Immunotherapy with immune checkpoint blockers (ICB) represents a valid therapeutic option in older patients for several solid cancer types. However, most of the data concerning efficacy and adverse events of ICB available are derived from younger and fitter patients. Reliable biomarkers are needed to better select the population that will benefit from ICB especially in older patients who may be at a higher risk of developing immune-related adverse events (irAEs) with a greater impact on their quality of life. The Lung Immune Prognostic Index (LIPI) is a score that combines pretreatment dNLR (neutrophils/[leukocytes − neutrophils]) and lactate dehydrogenase (LDH) and is correlated with outcomes in patients treated with ICB in non-small-cell lung cancer. We aimed to assess the impact of LIPI in ICB outcomes in a dedicated cohort of older patients. The primary objective was to study the prognostic role of LIPI score in patients aged 70 years or above in a real-life population treated with anti-programmed death-(ligand)1 (anti PD-(L)1). dNLR and LDH were collected in a prospective cohort of patients aged 70 years or above treated with PD-(L)1 inhibitors with metastatic disease between June 2014 and October 2017 at Gustave Roussy. LIPI categorizes the population into three different prognostic groups: good (dNLR ≤ 3 and LDH ≤ ULN­upper normal limit), intermediate (dNLR > 3 or LDH > ULN), and poor (dNLR > 3 and LDH > ULN). Anti PD-(L)1 benefit was analyzed according to overall survival (OS), progression free survival (PFS), and overall response rate (ORR) using RECIST v1.1. criteria. In the 191 older patients treated, most of them (95%) were ICB-naïve, and 160 (84%) had an ECOG performance status of 0−1 with a median age at ICB treatment of 77 (range, 70−93). The most common tumor types were melanoma (66%) and non-small-cell lung cancer (15%). The median follow-up duration was 18.8 months (95% CI 14.7−24.2). LIPI classified the population into three different groups: 38 (23%) patients had a good LIPI score, 84 (51%) had an intermediate LIPI score, and 43 (26%) had a poor LIPI score. The median OS was 20.7 months [95% CI, 12.6−not reached] compared to 11.2 months [95% CI, 8.41−22.2] and 4.7 months [95% CI, 2.2−11.3] in patients with a good, intermediate, and poor LIPI score, respectively (p = 0.0003). The median PFS was 9.2 months [95% CI, 6.2−18.1] in the good LIPI group, 7.2 months [95% CI, 5.4−13] in the intermediate LIPI group, and 3.9 months [95% CI, 2.3−8.2] in the poor LIPI group (p = 0.09). The rate of early death (OS < 3 months) was 37% in the poor LIPI group compared to 5% in the good LIPI group (<0.001). Poor LIPI score was associated with a poorer outcome in older patients treated with anti PD-(L)1. LIPI is a simple and accessible worldwide tool that can serve as a prognostic factor and can be useful for stratification benefit from ICB.

Evaluation of supportive care needs, sexuality and quality of life in phase 1 trials: a prospective monocentric study.

PURPOSE: Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1. METHODS: Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time. RESULTS: At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004). CONCLUSIONS: There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Implementing the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets in a Comprehensive Profiling Program: Impact on Precision Medicine Oncology.

PURPOSE: To facilitate implementation of precision medicine in clinical management of cancer, the European Society of Medical Oncology proposed in 2018 a new scale to harmonize and standardize the reporting and interpretation of clinically relevant genomics data (ESMO Scale of Actionability of molecular Targets [ESCAT]). This study aims to characterize the clinical impact of matching targetable genomic alterations (GAs) in patients with advanced cancer according to ESCAT. MATERIAL AND METHODS: Analysis of next-generation sequencing results from 552 patients is included in two prospective precision medicine studies at Gustave Roussy. End points included objective response rates, progression-free survival, and overall survival according to ESCAT. RESULTS: Molecular data from 516 patients were available and discussed within a Molecular Tumor Board. The most common tumor types were GI (n = 164; 30%), lung (n = 137; 25%), and urologic tumors (n = 68; 13%). Overall, 379 GAs were considered as actionable targets according to ESCAT in 348 (67%) patients. In 31 (6%) patients, two concomitant actionable targets were identified. On the basis of ESCAT, GAs were considered to be classified as tier I in 120 patients (29%), II in 25 patients (5%), III in 80 patients (16%), and IV in 153 patients (30%). A total of 136 patients (27%) received a matched therapy. ESCAT was significantly associated with objective response rates and clinical benefit rates. The median progression-free survival was 6.5 months (95% CI, 4.2 to 8.9), 3 months (95% CI, 1 to not available), 3 months (95% CI, 2.2 to 3.8), and 4 months (95% CI, 2.8 to 6.3) for ESCAT I, II, III, and IV, respectively (P = .0125). CONCLUSION: Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.