KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated,PD-L1-positive,advanced NSCLC

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m² every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.     

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

Background:

This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).

Methods:

Ninety patients were randomised to a standard dose of wPTX (80 mg m⁻²) or an escalated dose of wPTX (80–120 mg m⁻²) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.

Results:

The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).

Conclusion:

Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.     

Preoperative treatment with radiochemotherapy for locally advanced gastroesophageal junction cancer and unresectable locally advanced gastric cancer

Background.

To purpose of the study was to analyze the results of preoperative radiochemotherapy in patients with unresectable gastric or locoregionally advanced gastroesophageal junction (GEJ) cancer treated at a single institution.

Patients and methods.

Between 1/2004 and 6/2012, 90 patients with locoregionally advanced GEJ or unresectable gastric cancer were treated with preoperative radiochemotherapy at the Institute of Oncology Ljubljana. Planned treatment schedule consisted of induction chemotherapy with 5-fluorouracil and cisplatin, followed by concomitant radiochemotherapy four weeks later. Three-dimensional conformal external beam radiotherapy was delivered by dual energy (6 and 15 MV) linear accelerator in 25 daily fractions of 1.8 Gy in 5 weeks with two additional cycles of chemotherapy repeated every 28 days. Surgery was performed 4–6 weeks after completing radiochemotherapy. Following the surgery, multidisciplinary advisory team reassessed patients for the need of adjuvant chemotherapy. The primary endpoints were histopathological R0 resection rate and pathological response rate. The secondary endpoints were toxicity of preoperative radiochemotherapy and survival.

Results.

Treatment with preoperative radiochemotherapy was completed according to the protocol in 84 of 90 patients (93.3%). Twenty patients (22.2%) did not undergo the surgery because of the disease progression, serious comorbidity, poor performance status or still unresectable tumour. In 13 patients (14.4%) only exploration was performed because the tumour was assessed as unresectable or diffuse peritoneal carcinomatosis was established. Fifty-seven patients (63.4%) underwent surgery with the aim of complete removal of the tumour. Radical resection was achieved in 50 (55.6%) patients and the remaining seven (7.8%) patients underwent non-radical surgery (R1 in five and R2 in two patients). In this group of patients (n = 57), pathological complete response of tumour was achieved in five patients (5.6% of all treated patients or 8.8% of all operated patients). Down-staging was recorded in 49 patients (86%), in one patient (1.8%) the stage after radiochemotherapy was unchanged while in seven patients (12.3%) the pathological stage was higher than clinical, mainly due to higher pN stage. No death was recorded during preoperative radiochemotherapy. Most grade 3 and 4 toxicities were due to vomiting, nausea and bone marrow suppression (granulocytopenia). Twenty-six (45.6%) patients died due to GEJ or gastric carcinoma, one died because of septic shock following the surgery and a reason for two deaths was unknown. Twenty-eight patients (49.1%) were disease free at the time of analysis, while 29 patients (50.9%) developed the recurrence, mostly as distant metastases. At two years, locoregional control, disease-free survival, disease-specific survival and overall survival were 82.9%, 43.9%, 56.9% and 53.9%, respectively.

Conclusions.

Preoperative radiochemotherapy was feasible in our group of patients and had acceptable toxicity. Majority of patients achieved down-staging, allowing greater proportion of radical resections (R0), which are essential for patients’ cure.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

A randomized phase II selection trial in patients with advanced/recurrent gastric cancer: Trial for Advanced Stomach Cancer (TASC)

A randomized phase II clinical trial is being conducted for patients with advanced or recurrent gastric cancer, in order to select the most promising treatment for subsequent evaluation in a large-scale phase III trial. We compare four chemotherapeutic treatments, which include two sequential and two combination regimens using paclitaxel with 5-fluorouracil or S-1, an oral fluorouracil derivative. The primary endpoint is 10-month overall survival rate, while the secondary endpoints are adverse events, time to treatment failure and progression-free survival. A Bayesian method is used to provide a statistical rule for monitoring the trial. Forty patients per treatment regimen (160 in total) were randomized into one of the four regimens using a centralized dynamic method.     

A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data

Gastric Cancer - Nivolumab showed improvement in overall survival (OS) in ATTRACTION-2, the first phase 3 study in patients with gastric/gastroesophageal junction (G/GEJ) cancer treated...     

S-1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro-esophageal junction adenocarcinoma patients: a pilot study

The safety and efficacy of S-1 plus cisplatin in Chinese advanced gastric cancer patients in first line setting is unknown. In this pilot study, patients with advanced gastric or gastro-esophageal junction adenocarcinoma were enrolled and randomly assigned in a 1:1 ratio to receive S-1 plus cisplatin (CS group) or 5-FU plus cisplatin (CF group). The primary endpoint was time to progression (TTP). Secondary end points included overall survival (OS) and safety. This study was registered on ClinicalTrials. Gov, number {"type":"clinical-trial","attrs":{"text":"NCT01198392","term_id":"NCT01198392"}}NCT01198392. A total of 236 patients were enrolled. Median TTP was 5.51 months in CS group compared with 4.62 months in CF group [hazard ratio (HR) 1.028, 95% confidential interval (CI) 0.758-1.394, p = 0.859]. Median OS was 10.00 months and 10.46 months in CS and CF groups (HR 1.046, 95%CI 0.709-1.543, p = 0.820), respectively. The most common adverse events in both groups were anemia, leukopenia, neutropenia, nausea, thrombocytopenia, vomiting, anorexia and diarrhea. We find that S-1 plus cisplatin is an effective and tolerable option for advanced gastric or gastro-esophageal junction adenocarcinoma patients in China.     

Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma

Zolbetuximab is a chimeric monoclonal antibody that targets claudin-18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin-18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m² on cycle 1, day 1 followed by 600 mg/m² every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m² Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose-limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug-related treatment-emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single-agent activity in Japanese patients.