Summary Background Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of ...nivolumab in patients with treatment-refractory oesophageal cancer. Methods We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Findings Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9–14·3). 11 (17%, 95% CI 10–28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one 2%) patient each), grade 3 lung infection (five 8% patients), grade 3 decreased appetite (two 3% patients), grade 3 increased blood creatinine phosphokinase (two 3% patients), and grade 3 dehydration (two 3% patients). Serious adverse events that occurred during the study were lung infection (four 6% patients), dehydration (two 3%), interstitial lung disease (two 3%), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one 2% patient each). There were no treatment-related deaths. Interpretation Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Funding Ono Pharmaceutical, Bristol-Myers Squibb.
This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum.
Patients ...were randomly assigned to receive either paclitaxel (80 mg/m(2) on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m(2) on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy.
Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio HR, 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001).
No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.
Background
A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally ...advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS.
Methods
Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse.
Results
The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2–63.5%). The OS for the patients who underwent R0 resection (
n
= 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%).
Conclusions
Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.
The long‐term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in ...Japanese patients with treatment‐refractory advanced esophageal cancer who participated in an open‐label, single‐arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand‐1 (PD‐L1) and CD8+ status of tumors and tumor‐infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end‐points included objective response rate (ORR), overall survival (OS), progression‐free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD‐L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut‐off 1%) and OS (11.33 vs 6.24 months, cut‐off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long‐term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD‐L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.
An exploratory biomarker analysis was undertaken in Japanese patients with treatment‐refractory advanced esophageal cancer who were receiving nivolumab during the extension of a multicenter phase II study. Nivolumab showed continued efficacy in Japanese patients with esophageal squamous cell carcinoma, and the biomarker analysis suggested that higher levels of tumor‐infiltrating lymphocytes, especially CD8+ cells, could be associated with longer overall survival.
Summary
Background
In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic ...colorectal cancer (mCRC) that had progressed on all standard therapies. This
post hoc
analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial.
Methods
Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1–3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics.
Results
One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib (
n
= 67 and
n
= 438) or placebo (
n
= 33 and
n
= 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval CI 0.43–1.51) and 0.77 (95 % CI 0.62–0.94), respectively. Regorafenib-associated hand–foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable.
Conclusion
Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC.
To determine the association between sarcopenia and prognosis in patients with metastatic gastric cancer (mGC) receiving chemotherapy.
Our study retrospectively evaluated 231 consecutive Japanese ...patients with mGC who commenced first-line chemotherapy at our Institution between January 2013 and December 2015. Muscle loss during chemotherapy was defined as a ≥10% reduction in the skeletal muscle index and was evaluated for its association with time to treatment failure (TTF) and overall survival (OS).
Of 118 patients, 89% had baseline sarcopenia and 31% developed muscle loss. Muscle loss was significantly associated with shorter TTF and OS and was an independent prognostic factor for both these parameters; poor performance status and poorer differentiation on histology were also significant predictors of shorter OS. However, muscle loss was not significantly associated with increased grade 3 or higher toxicities.
Muscle loss during chemotherapy negatively affected survival among patients with mGC.
Background
In the phase II ATTRACTION-1 study, nivolumab demonstrated a promising antitumor activity among Japanese patients with treatment-refractory advanced esophageal cancer. Here, we report the ...follow-up results of ATTRACTION-1 of > 5 years.
Methods
We enrolled patients with esophageal cancer that was refractory or intolerant to a standard chemotherapy. Then, nivolumab (3 mg/kg) was administered every 2 weeks. The primary endpoint was a centrally assessed objective response rate.
Results
Nivolumab was administered to 65 patients with esophageal squamous-cell carcinoma (ESCC). The centrally assessed objective response rate was 17.2%. The overall survival rates at 3 and 5 years were 10.9% and 6.3%, respectively. Three-year survivors tended to have more reduced target lesions. A total of 63.1% of the patients exhibited treatment-related adverse events, and no new safety signal was observed. Patients with select adverse events tended to have better overall survival than those without. No apparent chronological order was observed between the first response and the onset of select adverse events.
Conclusion
Our follow-up analysis of more than 5 years is currently the longest and is the first to demonstrate that nivolumab has long-term efficacy and safety for advanced ESCC.
We carried out a phase I/II trial of adding 2‐weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2‐weekly DCF regimen) in esophageal cancer patients to investigate its safety and ...antimetastatic activity. Patients received 2‐weekly docetaxel (30 mg/m2 dose level (DL)1 or 40 mg/m2 DL2 with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed‐dose CF (80 mg/m2 cisplatin, day 1; 800 mg/m2 fluorouracil, days 1–5) repeated every 4 weeks. The primary endpoint was dose‐limiting toxicity (DLT) in phase I and central peer review‐based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty‐two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48–75%); median overall survival and progression‐free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment‐related death in one patient. The 2‐weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.
We conducted a phase I/II trial of adding 2‐weekly docetaxel to cisplatin plus fluorouracil therapy in esophageal cancer patients to investigate its and anti‐tumor activity. This regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group.
Background
The triplet-agent (5-fluorouracil/leucovorin, oxaliplatin, and irinotecan; FOLFOXIRI) combined with an anti-epidermal growth factor receptor antibody as a first-line treatment of ...metastatic colorectal cancer (mCRC) has shown promising results in Western trials. This phase Ib study assessed the safety of FOLFOXIRI plus cetuximab in Japanese patients with
RAS
wild-type mCRC.
Methods
Patients with previously untreated
RAS
wild-type mCRC received weekly cetuximab (400 mg/m
2
at week 1 and subsequently 250 mg/m
2
) plus FOLFOXIRI that consisted of irinotecan (100, 120, and 150 mg/m
2
defined as dose levels 0, 1, and 2), followed by oxaliplatin 85 mg/m
2
and
l
-leucovorin 200 mg/m
2
and then 5-fluorouracil 2400 mg/m
2
. The dose level of irinotecan was escalated starting at dose level 1 in a 3 + 3 manner. The primary endpoint was to determine the maximum-tolerated dose (MTD) and the recommended phase-2 dose (RP2D). Secondary endpoints included safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).
Results
Nine patients were enrolled. The MTD was not reached at dose level 2 and the RP2D was 150 mg/m
2
irinotecan. The most frequent grade 3/4 adverse events were neutropenia (44%), fatigue (11%), paronychia (22%), and acneiform rash (11%). No dose-limiting toxicities occurred in any of the enrolled patients. No treatment-related death was observed. The ORR was 89% (95% confidence interval 52–100%).
Conclusion
The safety profile of the combination of cetuximab and FOLFOXIRI was acceptable and promising anti-tumor activity was demonstrated, supporting further study in patients with
RAS
wild-type mCRC.
The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of ...tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 anti-PD-(L)1 antibody.
We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs).
In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed.
CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.
PDF
