Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized,double-blind phase III trial

BackgroundTo establish the role of antiemetic therapy with neurokinin-1 (NK₁) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC.Patients and methodsIn this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25–120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0–120 and 0–24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points.ResultsThe fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated.ConclusionSingle-dose fosaprepitant added to a 5-HT₃ RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK₁ RA therapy as an i.v. formulation in a well-defined non-AC MEC population.ClinicalTrials.govNCT01594749 (https://clinicaltrials.gov/ct2/show/NCT01594749).     

5HT3RA plus dexamethasone plus aprepitant for controlling delayed chemotherapy‐induced nausea and vomiting in colorectal cancer

Delayed chemotherapy‐induced nausea and vomiting (CINV) is not well controlled in colorectal cancer (CRC) patients undergoing oxaliplatin (L‐OHP)‐based chemotherapy. Whether neurokinin‐1 receptor antagonist addition to a first‐generation 5HT₃ antagonist (1st 5‐HT₃RA) and dexamethasone (DEX) is beneficial to these patients remains controversial. Furthermore, whether palonosetron (PALO) or aprepitant (APR) is more effective in controlling delayed CINV is unclear. We, therefore, investigated whether PALO+DEX or 1st 5‐HT₃RA+DEX+APR was more effective in controlling delayed CINV, and the risk factors for delayed CINV, in CRC patients undergoing L‐OHP–based chemotherapy. Data were pooled from two prospective observational Japanese studies and a phase III trial to compare CINV incidence between the PALO + DEX (PALO) and 5‐HT₃RA+DEX+APR (APR) groups by propensity score–matched analysis. CINV risk factors were identified using logistic regression models. The CINV incidence was higher in the PALO group than in the APR group. Logistic regression analysis revealed alcohol consumption, motion sickness, and the PALO+DEX regimen as independent risk factors for delayed nausea, and female sex and the PALO+DEX regimen as those for delayed vomiting. Compared with prophylactic PALO + DEX, 1st 5‐HT₃RA+DEX+APR was more effective in controlling delayed CINV. Thus, CRC patients receiving L‐OHP–based chemotherapy should be treated with three antiemetics, including APR.     

A first-in-human phase 1 and pharmacological study of TAS-119, a novel selective Aurora A kinase inhibitor in patients with advanced solid tumours

Background This is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor.Methods Patients with advanced, refractory, solid tumours were enrolled into 5 dose escalation cohorts (70–300 mg BID, 4 days on/3 days off, 3 out of 4 weeks or 4 out of 4 weeks). The expansion part consisted of patients with small-cell lung cancer, HER2-negative breast cancer, MYC-amplified/β-catenin-mutated (MT) tumours or other (basket cohort).Results In the escalation part (n = 34 patients), dose-limiting toxicities were one grade 3 nausea, two grade 2 and one grade 3 ocular toxicity and a combination of fatigue, ocular toxicity and nausea in one patient (all grade 2) at dose levels of 150, 200, 250 and 300 mg, respectively. Most frequent treatment-related adverse events were fatigue (32%), diarrhoea (24%) and ocular toxicity (24%). Toxicity grade ≥3 in ≥10% of patients were diarrhoea (15%) and increased lipase (12%). The maximum tolerated dose was 250 mg BID. Due to one additional grade 1 ocular toxicity, the RP2D was set at 200 mg BID (4 days on/3 days off, 3 out of 4 weeks), which was further explored in the expansion part (n = 40 patients). Target inhibition in paired skin biopsies was shown.Conclusions TAS-119 has a favourable and remarkably distinct safety profile from other AurA inhibitors.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT02448589","term_id":"NCT02448589"}}NCT02448589.Subject terms: Drug development, Drug safety     

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese,multicenter, phase 1/2, safety and efficacy study

Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT02812706","term_id":"NCT02812706"}}NCT02812706.     

Prevention of delayed chemotherapy-induced nausea and vomiting after moderately high to highly emetogenic chemotherapy: comparison of ondansetron, prochlorperazine, and dexamethasone

The purpose of this article is to assess the comparative antiemetic efficacy of prochlorperazine, ondansetron, and dexamethasone in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) after moderately high to highly emetogenic chemotherapy. Cancer patients (n = 232) receiving moderately high to highly emetogenic chemotherapy were randomized to 1 of 3 treatments: 15 mg prochlorperazine spansules twice daily; 8 mg ondansetron tablets twice daily; or 8 mg dexamethasone tablets twice daily on days 2 through 5. All patients received 24 mg ondansetron and 20 mg dexamethasone orally before chemotherapy. Daily assessment (days 1 through 5) included the number of episodes of retching and vomiting, severity of nausea, restlessness, difficulty concentrating and fatigue, treatment satisfaction, and overall quality of life (measured using a 10-cm VAS). The Functional Living Index-Emesis (FLIE) was completed on day 5. Other side effects attributed to antiemetic therapy were recorded daily. For acute CINV, total control, defined as no vomiting, retching, nausea <1 cm on a 10-cm visual analog scale, and no administration of rescue medications, was achieved in 78% in the overall group and was not significantly different in the patients randomized to the 3 treatment arms for delayed CINV. Delayed CINV was reported by 43% to 57% of patients, with the highest incidence reported on day 3. For delayed CINV, patients receiving prochlorperazine reported the lowest average nausea score on days 2 to 5, whereas patients receiving ondansetron reported the highest nausea score (P = 0.05). No statistically significant differences in CINV or side effects of antiemetic therapy were noted between treatment groups on days 2 to 5. For patients similar to those included in this study, there does not appear to be a clinically important difference in efficacy, adverse effects, or treatment satisfaction among dexamethasone, prochlorperazine, and ondansetron in the doses used in these delayed CINV regimens on days 2 to 5 in this study.     

A randomized phase III study evaluating the efficacy and safety of NEPA,a fixed-dose combination of netupitant and palonosetron,for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy

BackgroundAntiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK₁ receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT₃ RA, which targets dual antiemetic pathways.Patients and methodsThis multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline–cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25–120 h) phase in cycle 1.ResultsThe percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0–120 h) (74.3% versus 66.6%; P = 0.001) and acute (0–24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO.ConclusionsNEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.     

Phase 2 single-arm study on the safety of maintenance niraparib in Japanese patients with platinum-sensitive relapsed ovarian cancer

ObjectiveThe primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting.MethodsPhase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs).ResultsEnrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8–79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease).ConclusionThe incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03759587","term_id":"NCT03759587"}}NCT03759587     

Tislelizumab in Asian patients with previously treated locally advanced or metastatic urothelial carcinoma

Tislelizumab, an anti‐programmed death protein‐1 (PD‐1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody‐dependent phagocytosis, a mechanism of T‐cell clearance and potential resistance to anti‐PD‐1 therapy. This single‐arm phase 2 trial ({"type":"clinical-trial","attrs":{"text":"NCT04004221","term_id":"NCT04004221"}}NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD‐L1‐positive urothelial carcinoma who progressed during/following platinum‐containing therapy and had no prior PD‐(L)1 inhibitor treatment. Patients were considered PD‐L1 positive if ≥ 25% of tumor/immune cells expressed PD‐L1 when using the VENTANA™ PD‐L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow‐up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy‐evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression‐free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment‐related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3‐4 treatment‐related adverse events and occurred in ≥ 5% of patients. Three investigator‐assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD‐L1‐positive urothelial carcinoma and had a manageable safety profile.     

Clinical Impact of Plasma and Tissue Next‐Generation Sequencing in Advanced Non‐Small Cell Lung Cancer: A Real‐World Experience

BackgroundTargeted agents have improved the outcome of a subset of non‐small cell lung cancer (NSCLC). Molecular profiling by next‐generation sequencing (NGS) allows screening for multiple genetic alterations both in tissue and in plasma, but limited data are available concerning its feasibility and impact in real‐world clinical practice.MethodsPatients with advanced NSCLC consecutively referring to our Institution for potential eligibility to VISION trial ({"type":"clinical-trial","attrs":{"text":"NCT02864992","term_id":"NCT02864992"}}NCT02864992) were prospectively enrolled. They were already screened with standard method, and EGFR/ALK/ROS‐1 positive cases were excluded. NGS was performed in plasma and tissue using the Guardant360 test covering 73 genes and the Oncomine Focus Assay covering 59 genes, respectively.ResultsThe study included 235 patients. NGS was performed in plasma in 209 (88.9%) cases; 78 of these (37.3%) were evaluated also in tissue; tissue only was analyzed in 26 cases (11.1%). Half of the tissue samples were deemed not evaluable. Druggable alterations were detected in 13 (25%) out of 52 evaluable samples and 31 of 209 (14.8%) of plasma samples. Improved outcome was observed for patients with druggable alterations if treated with matched targeted agents: they had a longer median overall survival (not reached) compared with the ones who did not start any targeted therapy (9.1 months; 95% confidence interval, 4.6–13.6; p = .046). The results of NGS testing potentially also affected the outcome of patients treated with immunotherapy.ConclusionSystematic real‐life NGS testing showed the limit of tissue analysis in NSCLC and highlighted the potentiality of genetic characterization in plasma in increasing the number of patients who may benefit from NGS screening, both influencing the clinical decision‐making process and affecting treatment outcome.Implications for PracticeGenetic characterization of cancer has become more important with time, having had positive implications for treatment specificity and efficacy. Such analyses changed the natural history of advanced non‐small cell lung cancer (aNSCLC) with the introduction of drugs targeted to specific gene alterations (e.g., EGFR mutations, ALK and ROS‐1 rearrangements). In the field of cancer molecular characterization, the applicability of the analysis of a wide panel of genes using a high‐throughput sequencing approach, such as next‐generation sequencing (NGS), is still a matter of research. This study used NGS in a real‐world setting to systematically and prospectively profile patients with aNSCLC. The aim was to evaluate its feasibility and reliability, as well as consequent access to targeted agents and impact on clinical outcome whenever a druggable alteration was detected either in tumor tissue samples or through liquid biopsy.     

A phase II randomized,multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01)

BackgroundStandard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome.MethodsGlioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02209948","term_id":"NCT02209948"}}NCT02209948).ResultsFrom August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001).ConclusionsContinuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS.Key Points1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities.     

Clinical utility of circulating tumour cell-based monitoring of late-line chemotherapy for metastatic breast cancer: the randomised CirCe01 trial

Background CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC).Methods CirCe01 was a prospective, multicentre, randomised trial ({"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC.Results Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not.Conclusions Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring.Clinical Trial Registration NCT, {"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01349842","term_id":"NCT01349842"}}NCT01349842, registered 9 May 2011.Subject terms: Breast cancer, Prognostic markers     

Phase 2 trial results with the novel neurokinin‐1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy‐induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy

BACKGROUND:

This randomized, double‐blind, dose‐ranging, placebo‐controlled, phase 2 trial evaluated the neurokinin‐1 receptor antagonist casopitant mesylate in combination with ondansetron/dexamethasone (ond/dex) for the prevention of chemotherapy‐induced nausea and vomiting (CINV) related to moderately emetogenic chemotherapy (MEC).

METHODS:

Chemotherapy‐naive patients who were receiving MEC (N = 723) were randomized to receive either oral placebo or casopitant at doses of 50 mg, 100 mg, or 150 mg daily (on Days 1‐3) plus ondansetron (on Days 1‐3) and dexamethasone (Day 1). Two exploratory arms evaluated single‐dose casopitant (150 mg) plus ond/dex and a 3‐day casopitant regimen with once‐daily ondansetron and dexamethasone. Primary endpoints were rates of complete response (CR) (no vomiting, retching, rescue therapy, or premature discontinuation) and significant nausea (SN) (≥25 mm on a visual analog scale) over the first 120 hours after Cycle 1 of MEC. Secondary endpoints included acute and delayed CR and SN rates, rates of nausea, vomiting, and safety.

RESULTS:

All casopitant doses that were tested significantly increased the proportion of patients with CR: The CR rates were 80.8% with casopitant 50 mg, 78.5% with casopitant 100 mg, and 84.2% with casopitant 150 mg compared with 69.4% in the control group (P = .0127); casopitant 150 mg was identified as the minimally effective dose. In exploratory analyses, single‐dose casopitant demonstrated a 79.2% CR rate, and once‐daily ondansetron plus casopitant produced an 83.5% CR rate. Vomiting rates in the first 5 days after MEC were reduced with casopitant‐containing regimens (from 23% to 10%‐16%). Rates of SN did not differ among treatment arms (range, 28%‐29%). Casopitant appeared to be well tolerated with no notable differences in overall adverse event frequency.

CONCLUSIONS:

Casopitant plus ond/dex was more effective than ond/dex alone for the prevention of CINV. Cancer 2009. © 2009 American Cancer Society.     

First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02142738","term_id":"NCT02142738"}}NCT02142738.     

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial

Background Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.Methods The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.Results Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.Conclusions FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases.ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00433927","term_id":"NCT00433927"}}NCT00433927.Subject terms: Oncology, Biomarkers     

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

A phase 1 trial of xentuzumab,an IGF‐neutralizing antibody,in Japanese patients with advanced solid tumors

Xentuzumab is an insulin‐like growth factor (IGF) ligand‐neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de‐escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti‐tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose‐limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug‐related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF‐1 and IGF‐2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid‐type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti‐tumor activity. This study was registered with www.clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02145741","term_id":"NCT02145741"}}NCT02145741).     

One-Day Versus Three-Day Dexamethasone with NK1RA for Patients Receiving Carboplatin and Moderate Emetogenic Chemotherapy: A Network Meta-analysis

BackgroundThe dexamethasone (DEX)-sparing strategy, which limits administration of DEX to day one, is reportedly non-inferior to conventional antiemetic regimens comprising multiple-day DEX. However, the usefulness of the DEX-sparing strategy in triplet antiemetic prophylaxis (neurokinin-1 receptor antagonist [NK1RA] + serotonin receptor antagonist [5HT3RA] + DEX) for carboplatin and moderate emetogenic chemotherapy (MEC) has not been clarified.Patients and MethodsWe systematically reviewed randomized controlled trials that examined the efficacy of antiemetics for preventing chemotherapy-induced nausea and vomiting associated with carboplatin and MEC. We conducted a network meta-analysis to compare the antiemesis efficacy of three-day DEX with NK1RA (3-DEX + NK1RA) and one-day DEX with NK1RA (1-DEX + NK1RA). The primary outcome was complete response during the delayed phase (CR-DP). The secondary outcome was no nausea during the delayed phase (NN-DP).ResultsSeventeen trials involving 4534 patients were included. The proportion who experienced CR-DP was 82.5% (95% credible interval [CI], 73.9-88.6) and 73.5% (95% CI, 62.8-80.9) among those who received 3-DEX + NK1RA and 1-DEX + NK1RA, respectively. There was no significant difference between the two regimens. However, 3-DEX + NK1RA tended to be superior to 1-DEX + NK1RA, with an absolute risk difference of 9.0% (95% CI, −2.3 to 21.1) in CR-DP and 24.7% (95% CI: −14.9 to 54.6) in NN-DP. 3-DEX + NK1RA also tended to be superior to 1-DEX + NK1RA in patients who received carboplatin-based chemotherapy, for whom the absolute risk difference was 12.3% (95% CI, −3.2 to 30.7).ConclusionsCare is needed when administering the DEX-sparing strategy in combination with NK1RA to patients receiving carboplatin and non-carboplatin MEC.     

A multicentre,randomised, open-label,parallel-group Phase 2b study of belotecan versus topotecan for recurrent ovarian cancer

Background This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer.Methods Patients with platinum-sensitive recurrent or platinum-resistant recurrent ovarian cancer (PRROC) were randomised 1:1 to receive belotecan 0.5 mg/m² or topotecan 1.5 mg/m² for five consecutive days every 3 weeks. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.Results A total of 140 (belotecan, n = 71; topotecan, n = 69) and 130 patients (belotecan, n = 66; topotecan, n = 64) were included in the intention-to-treat (ITT) and per-protocol (PP) populations. ORR did not differ significantly between the belotecan and topotecan groups (ITT, 29.6% versus 26.1%; PP, 30.3% versus 25%). Although PFS did not differ between the groups, belotecan was associated with improved OS compared with topotecan in the PP population (39.7 versus 26.6 months; P = 0.034). In particular, belotecan showed longer OS in PRROC and non-high-grade serous carcinoma (non-HGSC; PP, adjusted hazard ratios, 0.499 and 0.187; 95% confidence intervals 0.255–0.977 and 0.039–0.895). Furthermore, there were no differences in toxicities between the two groups.Conclusions Belotecan was not inferior to topotecan in terms of overall response for recurrent ovarian cancer.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT01630018","term_id":"NCT01630018"}}NCT01630018.Subject terms: Ovarian cancer, Chemotherapy     

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated,homologous recombination-deficient ovarian cancer

ObjectiveTo evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer.MethodsThis Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3–4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs.ResultsTwenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%.ConclusionEfficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03759600","term_id":"NCT03759600"}}NCT03759600     

First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

Background Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours.Methods This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.Results Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed.Conclusions ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Clinical trial registration The clinical trial registration number is {"type":"clinical-trial","attrs":{"text":"NCT03035591","term_id":"NCT03035591"}}NCT03035591.Subject terms: Drug development, Pharmaceutics, Prostate cancer, Breast cancer, Melanoma