Search

Background: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. Patients and methods: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2: 1: 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. Results: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. Conclusions: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

Background While docetaxel/cisplatin/5‐fluorouracil (DCF) outperforms CF in first‐line gastric adenocarcinoma, toxicity remains an issue. Methods This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m2, C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m2, C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony‐stimulating factor (G‐CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN). Results A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression‐free survival and overall survival were 5.1 (95% CI, 3.2–6.5) and 8.2 months (95% CI, 6.0–14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0–6.9) and 11.9 months (95% CI, 7.4–15.9), respectively, in arm 2. Conclusions Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF., The DoGE multicenter study randomised prospectively patients with chemonaïve gastric cancer between fractionated weekly and fortnightly DCF regimens. Both regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF.

International audience; BACKGROUND: Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS: The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS: The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION: No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.

Introduction Central diabetes insipidus is a heterogeneous condition characterized by decreased release of antidiuretic hormone by the neurohypophysis resulting in a urine concentration deficit with variable degrees of polyuria. The most common causes include idiopathic diabetes insipidus, tumors or infiltrative diseases, neurosurgery and trauma. Temozolomide is an oral DNA-alkylating agent capable of crossing the blood-brain barrier and used as chemotherapy primarily to treat glioblastoma and other brain cancers. Cases Two men (aged 38 and 54 years) suddenly developed polyuria and polydispsia approximately four weeks after the initiation of temozolomide for a glioblastoma. Plasma and urine parameters demonstrated the presence of a urinary concentration defect. Management The clinical and laboratory abnormalities completely resolved with intranasal desmopressin therapy, allowing the continuation of temozolomide. The disorder did not relapse after cessation of temozolomide and desmopressin and relapsed in one patient after rechallenge with temozolomide. Discussion Our report highlights the importance of a quick recognition of this exceptional complication, in order to initiate promptly treatment with desmopressin and to maintain therapy with temozolomide.

Background The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib. Patients and Methods Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs. Results In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]). Conclusion Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC. ClinicalTrials.gov identifier NCT03148795

Background Colon adenocarcinoma occurs mainly in older patients (pts). Oxaliplatin based adjuvant chemotherapy has demonstrated an improvement on disease-free survival (DFS) after a stage III colon cancer resection in young pts. Nevertheless, the benefit of adjuvant chemotherapy is matter of debate in old pts. Methods The purpose of ADAGE trial is to compare the DFS obtain with oxaliplatin combined with fluoropyrimidine (F) to F alone in fit pts over 70 years (group 1) and F to observation in frail pts (group 2) after resection of a stage III colon cancer. We here report a preliminary tolerance analysis on 50% of the first pts enrolled in the study. Results The analysis was performed on 491 pts (378 in group 1 and 113 in group 2). Main pts characteristics were respectively for the group 1 and 2: male in 57% and 50%, median age of 76 and 83 years, ECOG=0 in 59% and 29%, abnormal IADL in 23% and 62%, no caregiver in 26% and 28%, fall ≤6 months in 9% and 14%, depression possible 28% and 40%, fail of one-leg balance in 20% and 59%, impaired cognition in 21% and 38%, G8 score

Background Radiotherapy association with immunotherapy has a strong rationale. This study evaluates this combination before surgery in locally advanced rectal cancer (RC). Methods R-IMMUNE (NCT03127007), a multicentric phase Ib/II prospective trial includes patients with stage II/III RC treated with a preoperative combination of radio-chemotherapy (45-50 Gy/25 fractions, 5FU 225 mg/m2/d, 5d/w from week 1-5) + atezolizumab 1200 mg/infusion (ATZ). The phase Ib had a 3+3 design with a safety period up to surgery and evaluated a single infusion of ATZ at week 3. The phase II, in progress, evaluates 4 infusions of ATZ at weeks 3, 6, 9 and 12. Surgery is planned at week 15. Primary objectives are safety and efficacy based on pathological complete response rate (pCR). Based on a 2-stage Simon design, 36 patients are needed in the phase II to detect a pCR rate increase from 15% to 35% (α = 0.1 and β = 0.1). At least 4 pCRs must be observed among 19 patients treated in the 1st stage to move the 2nd stage. Results This analysis concerns 26 patients treated with the study treatment (median age 66 y-old, 48% male, 88% stage III). Safety was evaluated in 6 patients from phase Ib and 20 from phase II. Overall, 151 AEs were reported and 20 (13%) were grade 3-4 on 9/26 patients, including 2/20 (10%) anastomotic leakage/infections, 4/20 (20%) urinary infections, 1/20 (5%) renal function impairment and 1/20 (5%) immune thrombocytopenia. Three grade 2 immune endocrine disorders were observed. Efficacy was evaluable on 25/26 patients after 1 exclusion for inclusion criteria deviation. Four among 19 patients included in the 1st stage of phase II had a pCR. Overall, 6/25 (24%) pCRs were observed. Conclusions R-IMMUNE interim analysis reveals an acceptable safety profile. Observed pCR rate until now supports the pursuit of the trial. Clinical trial identification NCT03127007.

Background Immunoscore® is an in vitro diagnostic test predicting the risk of relapse in early-stage Colon Cancer (CC), by measuring the host immune response at the tumor site. This risk-assessment tool provides independent and superior prognostic value than the usual risk parameters and is intended to be used as an adjunct to the TNM classification for clinical decision. In the present study, we investigated Immunoscore® clinical performance in the Asian population from the international SITC-led validation study (Pagès et al. The Lancet 2018). Methods Out of the 2681 eligible stage I-III patients of the international Immunoscore® study, 423 were collected from 4 expert centers in Asia including Japan (n=330), China (n=35), and India (n=58). Patients were classified by Immunoscore® based on pre-defined cutoffs, either in 5 (IS 0-4) or 2 categories: IS Low (IS 0-1) and IS High (IS 2-4). Time to recurrence (TTR) was compared between Immunoscore® categories. Results Immunoscore® Low and High were observed in 37% (n=158) and 63% (n=265) of the Asian cohort, respectively. Immunoscore® was positively and significantly correlated with TTR. After 5 years, 86.9% (95% CI 82.7-91.4), and 77% (95% CI 70,5-84,1) of Immunoscore -High and -Low patients respectively were event free (HR =0.52; 95% CI 0.32-0.86; p=0.0085). When adjusting the model with Immunoscore®, age, gender, T-stage, N-stage, sidedness and MSI, and when stratified by center, Immunoscore® remained a significant parameter (HR=0.45; 95% CI 0.22-0.91; p=0.027). When stratified into 5 Immunoscore® categories, TTR rates at 5 years were 100%, 96%, 84%, 80%, and 73.5% for IS4, IS3, IS2, IS1, IS0, respectively. These results were similar to those found in European and North American patients. Conclusions Immunoscore® is a strong prognostic indicator of the risk of recurrence in stage I-III CC patients who receive standard of care treatment in real-life clinical practice in Asia. This first standardized immune-based assay risk assessment tool can be used reliably to guide clinical decision according to each patient information.

Background Pathological response (PR) of resected CRCM after preop treatment is a recognized prognostic factor. Retrospective studies reported that BEV + oxaliplatin-based chemotherapy increased PR compared to irinotecan-based chemotherapy. In this trial, we aim to demonstrate that preop BEV + FOLFOX would increase PR. Methods BEV-ONCO (NCT01858649) is a multicenter prospective randomized (1/1) phase II trial evaluating PR on resected CRCM after 3 to max 6 cycles of mFOLFOX (ARM A) or FOLFIRI (ARM B) + BEV (5mg/kg/2 weeks). Primary endpoint is the major pathological response rate (MPRR) defined as the % of patients presenting CRCMs with a mean tumor regression grade (TRG)