Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. PATIENTS AND METHODS: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

Short course radiotherapy versus radiochemotherapy for locally advanced rectal cancers in the elderly (UNICANCER PRODIGE 42/GERICO 12 study): Quality of life and comprehensive geriatric assessment.

BACKGROUND: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. PATIENTS AND METHODS: In all, 101 patients ≥75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks ± 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. RESULTS: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. CONCLUSION: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged ≥75 treated for locally advanced rectal cancer.

The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers.

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14lowCD16high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

Geriatric Assessment Implementation before Chemotherapy in MEtastatic Prostate Cancer, Results from the Real-Life Study GAMERS.

Geriatric assessment (GA) can predict and improve treatment tolerance and estimate overall survival in older patients with cancer. Several international organizations promote GA; however, data related to its implementation in daily clinical practice are still limited. We aimed to describe GA implementation in patients over 75 years old with metastatic prostate cancer treated with docetaxel as first-line treatment, and with positive G8 screening test or frailty criteria. This retrospective real-world study included 224 patients treated from 2014 to 2021 in four French centers, including 131 patients with a theoretical indication of GA. Among the latter, 51 (38.9%) patients had GA. The main barriers to GA were the lack of systematic screening (32/80, 40.0%), unavailability of geriatric physician (20/80, 25.0%), and absence of referral despite a positive screening test (12/80, 15.0%). With GA performed in only one-third of the patients with a theoretical indication in daily clinical practice, mostly due to an absence of screening test, the use of GA is currently sub-optimal.

Association of chemotherapy and comorbidities with overall survival in elderly patients with early breast cancer: a French population-based propensity score-matched analysis.

BACKGROUND: Additional systemic treatment for early breast cancer in elderly is challenged by increasing comorbidities with age. We aimed to examine the effect of additional chemotherapy on overall survival in patients aged 70 years or older and the impact of comorbidities on chemotherapy benefit. METHODS: This retrospective monocentric cohort study includes data from all patients aged 70 years and older who underwent surgery for an early breast cancer from 1997 to 2016. A propensity score analysis allowed adjustment for chemotherapy prescription preferences based on tumour characteristics. RESULTS: Of 15,599 patients who had surgery for an early breast cancer, 1743 (11.2%) over 70 years old were included, of whom 269 (15.4%) had received additional chemotherapy. Median follow-up was 5.3 years. Multivariate analyses on the propensity-score weighted cohort (n = 1 354) identified improved overall survival in patients with chemotherapy versus without (HR 0.54, 95% CI 0.31-0.92). Chronic obstructive pulmonary disease (HR, 2.16, 95% CI 1.40-3.34) and polypharmacy (HR 1.40, 95%CI 1.07-1.84) were associated with worse overall survival. No statistically significant interactions were identified between these comorbidities and chemotherapy prescription. CONCLUSION: Additional chemotherapy in elderly with early breast cancer is feasible and associated with overall survival benefit, supporting the importance of chemotherapy considerations in this population, and of avoiding undertreatment based on chronological age considerations alone.

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade.

BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Interest and preferences for physical activity programming and counselling among cancer patients aged over 70 years receiving oncological treatments.

OBJECTIVE: The objective of this study is to assess the physical activity interest and preferences of cancer patients aged over 70 years during oncological treatments and to explore how demographic characteristics may modulate preferences. METHODS: From April to May 2018, this cross-sectional study collected data from self-administered questionnaire regarding physical activity interest and preferences in cancer patients receiving oncological treatments in a regional cancer centre. RESULTS: A total of 144 patients completed the questionnaire. Two thirds (n = 95) showed interest in participating in dedicated physical activity programme during oncologic treatments. Patients preferred to exercise in group activities, under the supervision of an exercise instructor, once a week, at a moderate intensity, for 30 min session, in a community fitness centre. Women significantly preferred exercises to improve flexibility (p = 0.03) and to receive counselling in a group (p = 0.03), whereas men preferred to practise strength training (p = 0.02) and to receive counselling with brochures (p = 0.02). As age increases, participants were significantly more inclined to practise physical activity to improve their balance (p = 0.01). CONCLUSION: These preliminary results will facilitate the design of programmes considering current physical activity preferences in older adults with cancer, which could ensure better adherence to physical activity programmes and, in turn, improved health outcomes.

Precision medicine for patients with gastro-oesophageal cancer: A subset analysis of the ProfiLER program.

BACKGROUND: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. METHODS: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. RESULTS: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. CONCLUSION: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

Treatment and outcomes of older versus younger women with HER2-positive metastatic breast cancer in the real-world national ESME database.

BACKGROUND: Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes according to age. METHODS: Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70). RESULTS: Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1-52.4), 35.3 (95% CI, 31.5-37.0) and 54.2 months (95% CI, 50.8-55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3-13.3), 11.1 (95% CI, 10.0-12.3) and 13.2 months (95% CI, 12.7-13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 [95% CI: 2.05-3.79]; endocrine therapy and/or anti-HER2 1.96 [95% CI: 1.43-2.69]). CONCLUSIONS: In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.

A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer.

PURPOSE: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. PATIENTS AND METHODS: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1). RESULTS: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); and arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively. CONCLUSIONS: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.

Individualised physical activity programme in patients over 65 years with haematological malignancies (OCAPI): protocol for a single-arm feasibility trial.

INTRODUCTION: Older adults with cancer suffer from the combined effects of ageing, cancer disease and treatment side effects. The main treatment for patients with haematological malignancies is chemotherapy, associated with significant toxicities. Chemotherapy can alter patients' physical function and quality of life which are often already diminished in older patients due to ageing and comorbidities. It therefore seems essential to develop and to evaluate interventions capable of preventing physical and psychosocial decline and its consequences. Promoting physical activity is a promising approach to improve physical function and quality of life in older adults with cancer, but there are limited data on the feasibility of such interventions among older patients with haematological malignancies, concomitant to chemotherapy. METHODS AND ANALYSIS: OCAPI (OnCogeriatric and Individualized Physical Activity) is a single-arm, interdisciplinary, prospective, interventional, feasibility study. It is intended to include 40 patients (20 patients with acute myeloid leukaemia and 20 patients with non-Hodgkin's lymphoma) over 65 years in an individualised 6-month physical activity programme. The programme consists of individually supervised exercise sessions with an increasing volume of physical activity either at home and/or in a laminar airflow room (depending on the disease and treatment regimen) followed by unsupervised sessions and phone follow-ups. Patients will receive an activity tracker during the 6 months of the programme. Evaluations will take place at inclusion and at 3, 6 and 12 months to assess the feasibility of the programme and to explore potential changes in physical, psychosocial and clinical outcomes. The results will generate preliminary data to implement a larger randomised controlled trial. ETHICS AND DISSEMINATION: The study protocol was approved by the French ethics committee (Comité de protection des personnes Est I, N°ID-RCB 2019-A01231-56, 12 July 2019). All participants will have to sign and date an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences. TRIAL REGISTRATION NUMBER: NCT04052126.

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.

LESSONS LEARNED: The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. BACKGROUND: This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. METHODS: Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. RESULTS: Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 µg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. CONCLUSION: Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

Prediction of docetaxel toxicity in older cancer patients: a Bayesian network approach.

Chemotherapy is an essential therapy in the fight against cancer. Polypathology and polymedication are often encountered in elderly patients, making this population especially at risk for adverse drug reactions, and particularly with cytotoxic drugs. The objective of this study was to build a model to predict high-grade toxicity in elderly patients treated with docetaxel. Data from the trial TAX-108 have been used to create the model. The variable to predict was the occurrence of grade 3 or 4 toxicity. The explanatory variables entered in the model were anthropometric and biological characteristics of patients at inclusion; fragility criteria (SMAF, CIRS-G, performance status); location of the primary tumor; chemotherapy history, radiotherapy or surgery; weekly dose of docetaxel, cumulative dose administered. A Bayesian network model was developed using a global search procedure and an Expectation-Maximization algorithm. A 10-fold cross-validation was performed. A toxicity of grade 3 or higher was observed in 54% of patients. The variables providing the most information were the primary site (19.4%), the dose per course (17.5%), and albuminemia (13.1%). The area under the curve of the model obtained after cross-validation was 74 ± 1.4%. The model built allows classifying correctly 71.21 ± 0.9% of patients in our sample in the cross-validation procedure. The sensitivity and specificity of the model were 75 and 67%, respectively, and the positive and negative predictive values were 73 and 69%. The encouraging results from this first study show that Bayesian networks could help assess the benefit-risk ratio of chemotherapy in elderly patients.

Geriatric assessment in oncology: Moving the concept forward. The 20 years of experience of the Centre Léon Bérard geriatric oncology program.

OBJECTIVES: The management of cancer in aging people remains a challenge for physicians. Specialists agree on the assistance provided by a multidimensional geriatric assessment (MGA) to guide the cancer treatment decision-making process. We aim to explore the use of MGA in treatment decision and to identify MGA parameters likely to influence the planned cancer treatment. MATERIAL AND METHODS: We conducted a single-site retrospective study in patients older than 65 years suffering from various types of cancer who underwent MGA before cancer treatment decision. Logistic regression analyses were used for identification of predictive variables. RESULTS: In the 266 patients' population, the mean age was 75.8 ±â€¯7.4 years and 155 (58%) patients were men. Patients had solid tumors (95.4%) or hematologic malignancies (4.6%). Most of patients were in advanced setting (57%). The MGA revealed malnutrition (47%), cognitive/mood impairment (48%), functional decline (53%), and led to adjust medical care through reinforcing health status and fostering successful completion of cancer treatment plan for 259 (97%) patients. The MGA changed cancer treatment in 47 (18%) patients. Functional and/or cognitive impairment, risk of falls, and polypharmacy were associated with treatment change in univariate analysis. No multivariate model was possible. CONCLUSIONS: MGA leads to modification of treatment in only few patients. However, MGA enables a better understanding of patients' strengths and weaknesses essential to improve care management. Further improvements with integration of innovative specific tools are warranted to help decision-process in the increasing complexity of treatment plans available in older adults.

Pharmacotherapeutic Management of Breast Cancer in Elderly Patients: The Promise of Novel Agents.

As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level. Breast cancer biology has been incompletely deciphered in this age group. New therapeutic agents continue to expand the available treatment options at every stage, and for each subtype of breast cancer. In the estrogen receptor-positive subtype, agents to overcome endocrine resistance have been introduced; CDK 4/6 and mTOR inhibitors have already been approved in this setting. In addition, more potent agents targeting the HER2 pathway are actively being trialed. Besides trastuzumab, pertuzumab, or lapatinib, new agents like neratinib or PI3K inhibitors are currently being tested in clinical trials. Finally, even though chemotherapy remains the cornerstone of the treatment of triple negative tumors, alternative promising approaches such as immunotherapy, notably antibodies against PD-1/PD-L1 or targeted therapies (PARP or androgen inhibitors), are currently being investigated in this specific subtype.

Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study.

BACKGROUND: LY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours. METHODS: This was a non-randomised, open-label, dose escalation and dose expansion trial. Patients harbouring molecular alterations of the PI3K/AKT/mTOR pathway received once daily (QD) oral LY2780301 (400 or 500 mg) in combination with intravenous gemcitabine (750 or 1000 mg/m2) on days 1, 8 and 15 of a 28-d cycle. Dose escalation followed a 3 + 3 design. Assessments included adverse events (AEs), PK and preliminary antitumour activity. RESULTS: Fifty patients (median age, 53 years; 74% female) predominantly with mutations/amplifications of PI3K (60%) and phosphatase and tensin homologue (PTEN) gene/protein inactivation (42%) were treated for up to 14 cycles. The MTD was LY2780301 500 mg QD with gemcitabine 750 mg/m2. DLTs during cycle 1 were grade IV thrombocytopenia, grade III skin rash and grade III increase in alkaline phosphatase, gamma glutamyltransferase and alanine aminotransferase, occurring in one patient each. Most common AEs were anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%). Among the efficacy-evaluable population, two patients (5%) had a partial response; the disease control rate was 74% at cycle 2. CONCLUSIONS: Addition of LY2780301 to gemcitabine showed manageable toxicity and encouraging antitumour activity in patients with molecular alterations of the PI3K/AKT/mTOR pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT02018874.

Role of geriatric intervention in the treatment of older patients with cancer: rationale and design of a phase III multicenter trial.

BACKGROUND: In the general geriatric population, programs linking geriatric evaluation with interventions are effective for improving functional status and survival of the patients. Whether or not these interventions improve health related quality of life (HRQoL) or overall survival (OS) in older patients with cancer is not yet clear. Indeed, randomized data on the effect of such interventions on survival and HRQoL are rare and conflicting. We describe the rationale and design of a phase III multicenter trial aimed at assessing the efficacy of geriatric intervention in the management of elderly patients with cancer. METHODS/DESIGN: Approximately 1200 patients, 70 years and older, considered in need of a geriatric intervention based on the G8 screening tool will be randomized into two intervention arms. The 'Usual-care' arm involves standard oncological care based on pre-defined oncological protocols. In addition to the standard oncological care, the 'Case-management' arm involves a multidimensional geriatric assessment and interventions tailored for the patient. Efficacy will be assessed using a co-primary endpoint encompassing OS and HRQoL. DISCUSSION: This trial has been designed to assess whether focused geriatric case management can either improve OS or HRQoL in elderly cancer patients considered in need of geriatric assessment. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02704832 .

Impact of comorbidities on the treatment of non-Hodgkin's lymphoma: a systematic review.

Treating non-Hodgkin's lymphoma in patients with comorbidities can be challenging because of possible interactions that may alter the treatment efficacy. We conducted a systematic review to determine the impact of comorbidities on various outcomes, evaluate the current data, and provide recommendations for future research. Twenty-one articles were selected. However, the study populations and design were greatly heterogeneous, and the quality of reporting was generally weak. The majority of studies demonstrated significant impact of comorbidity on survival, reporting poorer survival rates for patients with comorbidities compared to those with no comorbidities. However, the existing evidence is limited and of insufficient quality to establish solid conclusions and to guide treatment decisions. Prospective, well-designed studies are warranted.

Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study.

BACKGROUND: Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). PATIENTS AND METHODS: The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. RESULTS: Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P =  0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. CONCLUSION: With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy.