Looking for the best immune‐checkpoint inhibitor in pre‐treated NSCLC patients: An indirect comparison between nivolumab,pembrolizumab and atezolizumab

Immune‐checkpoint inhibitors represent the new standard of care in patients with advanced NSCLC who progressed after first‐line treatment. This work aim to assess any difference in both efficacy and safety profiles among Nivolumab, Pembrolizumab and Atezolizumab in pre‐treated NSCLC patients. Randomized clinical trials comparing immune‐checkpoint inhibitor versus docetaxel in pre‐treated patients with advanced NSCLC were included and direct comparison meta‐analysis of selected trials have been performed. Subsequently the summary estimates of Nivolumab, Pembrolizumab and Atezolizumab emerging from the direct meta‐analysis were selected to provide the pooled estimates of hazard ratio (HR) and relative risk (RR) for the indirect comparisons among these agents. A total of 5 studies met the selection criteria and were included in the meta‐analysis. Indirect comparisons for efficacy outcomes showed the RR for ORR nivolumab versus atezolizumab 1.66 (95% CI 1.07?2.58), pembrolizumab versus atezolizumab 1.94 (95% CI 1.30?2.90). No significant differences in both PFS and OS have been observed. Indirect comparisons for safety showed the RR for G3‐5 AEs nivolumab versus pembrolizumab 0.41 (95% CI 0.29?0.60), nivolumab versus atezolizumab 0.50 (95% CI 0.35?0.72). No significant differences in both pneumonitis and discontinuation rate have been observed. The results of this work revealed that nivolumab and pembrolizumab are associated with a significant increase of ORR as compared to atezolizumab and nivolumab is associated with a significant lower incidence of G3‐5 AEs as compared to the other drugs. These evidences could support the oncologists to select the best drug for each patient.     

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment‐related adverse event rate, overall survival (OS), and progression‐free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open‐label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03–2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78–0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72–1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03–2.19, p = 0.036) than that of monotherapy. This meta‐analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab‐ipilimumab‐sargramostim combination should be investigated further.     

Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer

Limited treatment options are available for stage IIIB/IV non‐small cell lung cancer (NSCLC). Nivolumab, a programmed cell death‐1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site‐assessed ORR, overall survival (OS), progression‐free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC‐assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site‐assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC‐assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment‐related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ?discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy. Clinical trial registration number: JapicCTI‐132072     

Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2)

IntroductionCheckpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2.MethodsCYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers.ResultsMedian follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5–2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54–1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708–3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3–5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519–1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772–4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms.ConclusionsDespite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs.     

Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma

Overexpression of programmed death‐1 (PD‐1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD‐1‐blocking antibody that inhibits the PD‐1 pathway and showed good efficacy in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was commenced in March 2015. We report data obtained at a cutoff of 16 March 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow‐up were 7.0 (1.4–10.6) months and 9.8 (6.0–11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval [CI]: 54.4–96.0%; 13/16 patients), with complete remission and partial remission in 4 and 9 patients, respectively. The overall survival (OS) and progression‐free survival (PFS) rates at 6 months were 100 and 60.0% (95% CI: 31.8–79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin.     

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

Long‐term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma

The immune checkpoint inhibitor nivolumab inhibits the programmed death 1 receptor and suppresses the immune resistance of cancer cells. This is a long‐term follow up of a single‐arm, open‐label, multicenter, phase II study of nivolumab in untreated Japanese patients with stage III/IV or recurrent melanoma. In addition, a post–hoc subgroup analysis stratified by melanoma types was performed. Nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression‐free survival (PFS), best overall response, the disease control rate and change in tumor diameter. Safety was assessed by recording treatment‐related adverse events (TRAE), including select immune‐related adverse events. Of the 24 patients initially included in the primary phase II study, 10 survived for over 3 years (41.7%). The ORR was 34.8% (90% confidence interval [CI]: 20.8, 51.9) for all patients. When analyzing by melanoma type, the ORR was 66.7% (90% CI: 34.7, 88.3) for superficial spreading, 33.3% (90% CI: 11.7, 65.3) for mucosal, and 28.6% (90% CI: 10.0, 59.1) for acral lentiginous tumors. The median OS was 32.9 months, the 3‐year OS rate was 43.5%, and the 3‐year PFS rate was 17.2%. A long‐term response was observed in all the tumor types. The most common TRAE included skin toxicity (45.8%) and endocrine disorders (29.2%). This study demonstrated the long‐term efficacy and tolerability of nivolumab in patients with advanced or recurrent melanoma, irrespective of melanoma type.     

Impact of the introduction of rituximab in first‐line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long‐term follow‐up

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty‐seven adult patients were referred with first‐line FL between 1996 and 2010 and are included in this study. The 103 pre‐rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression‐free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy‐one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3‐year PFS 72% [95% confidence interval (CI) 64–80%] versus 55% (95% CI 45–64%), p = 0.0039 and 3‐year OS 98% (95% CI 94–99%) versus 83% (95% CI 74–90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens. Copyright © 2014 John Wiley & Sons, Ltd.     

Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0?%, respectively, odds ratio 0.70; 95?% CI: 0.5?C1.0) and significantly shorter progression-free survival (PFS: median 112.0?days [3.7?months] vs. 150.0?days [4.9?months]; p?<?0.0001) and overall survival (OS: median 396.0?days [13.0?months] vs. 666.0?days [21.9?months]; p?<?0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p?=?0.0036), PFS (p?<?0.0001) and OS (p?<?0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63?% of patients. Overall, 7?% of patients discontinued and two patients (<1?%) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p?<?0.0001 PFS/OS) or diarrhea (p?=?0.004 OS; p?=?0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

Early sorafenib‐related adverse events predict therapy response of TACE plus sorafenib: A multicenter clinical study of 606 HCC patients

The purpose of our study was to test the hypothesis that sorafenib‐related dermatologic adverse events (AEs) as an early biomarker can predict the long‐term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (TACE‐S). The intermediate‐stage hepatocellular carcinoma patients who received either TACE‐S or TACE‐alone treatment were consecutively included into analysis. In the TACE‐S group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with < grade 2 were defined as nonresponders. In the TACE‐S group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; p = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval‐CI: 1.3–2.7; p = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0–30.8) among responders treated with TACE‐S vs.18.3 months (95% CI: 14.5–22.1) among those who received TACE‐alone (p = 0.046). The median time to progression was 13.1 months (95% CI: 4.4–21.8) in the TACE‐S group, a duration that was significantly longer than that in the TACE‐alone group [5 months (95% CI: 6.4–13.3), p = 0.014]. This study demonstrated that sorafenib‐related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for TACE‐S therapy. Sorafenib‐related dermatologic AEs, clinical biomarkers, can predict the efficacy of TACE‐S in future randomized controlled trials.     

Low-dose pembrolizumab and nivolumab were efficacious and safe in relapsed and refractory classical Hodgkin lymphoma: Experience in a resource-constrained setting

The efficacy and safety of low-dose anti-PD1 antibodies in relapsed/refractory classical Hodgkin lymphoma (cHL) require confirmation. Pembrolizumab (100 mg every 3 weeks, Q3W) or nivolumab (40 mg Q2W) were administered to patients with relapsed/refractory cHL. In the pembrolizumab cohort (N = 11), who had failed a median of three (1–6) therapies (brentuximab vedotin [BV]: 91%; autologous hematopoietic stem cell transplantation [auto-HSCT]: 18%), the overall response rate (ORR) by positron emission tomography–computed tomography was 100% (metabolic complete response [mCR]: 73%; partial response [PR]: 27%). Median cumulative dose for achieving best response was 400 (300–800) mg. Median progression-free survival (PFS) was 35 months. Median overall survival (OS) was not reached. Adverse events (AEs) of grade 1–2 were observed in three patients. In the nivolumab cohort (N = 6), who had failed a median of three (2–6) therapies (BV: 50%; auto-HSCT: 17%; allogeneic HSCT: 34%), the ORR was 100% (mCR: 67%; PR: 17%; indeterminate response: 17%). Median cumulative dose for achieving best response was 160 (160–360) mg. Median PFS was 33 months. Median OS was not reached. AEs of grade 1–2 were observed in four patients, two of whom had pre-existing autoimmune conditions. Five patients with Epstein–Barr virus (EBV) positive Reed–Sternberg cells underwent monitoring of plasma EBV DNA, which became negative in four mCR patients but remained positive in one PR patient who died ultimately from refractory lymphoma. Low-dose pembrolizumab and nivolumab were highly efficacious and safe in relapsed/refractory cHL. These observations have significant financial implications in resource-constrained settings.     

First-line nab-paclitaxel plus carboplatin for patients with advanced non-small cell lung cancer: Final results of the NEPTUN study

Real-world data on the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) are still limited. The NEPTUN study evaluated effectiveness and safety of first-line nab-paclitaxel (Abraxane) plus carboplatin (nab-P/C) in patients with advanced NSCLC in routine clinical practice in Germany. Patients included in our study were aged ≥18 years, diagnosed with locally advanced or metastatic NSCLC and with decision for first-line nab-P/C in routine clinical practice. Primary objective was 6-month progression-free survival rate (PFS6), secondary objectives included overall survival (OS), overall response rate (ORR) and safety. From 2016 to 2019, 408 patients from 75 sites were enrolled. PFS6 was 39.5% (95% CI: 34.2-44.8), median PFS was 5.1 months (95% CI: 4.6-5.6), ORR was 42.9% (95% CI: 37.7-48.2). Median OS was 10.5 months (95% CI: 9.2-11.6). In subgroup analyses, median OS for squamous vs non-squamous histology was 11.5 months (95% CI: 9.2-13.8) vs 9.8 months (95% CI: 8.1-11.3) and for patients aged ≥70 vs <70 years median OS was 12.4 months (95% CI: 9.8-15.1) vs 9.6 months (95% CI: 7.7-11.1). Adverse events (AEs) related to nab-paclitaxel were reported in 247 (66.4%) patients, while carboplatin-related AEs were documented in 224 (60.2%) patients. Most frequently related AEs were leukopenia (22.3%) for nab-paclitaxel and anemia (20.2%) for carboplatin. Nab-P/C-related deaths were reported in 2 (0.5%) patients (sepsis and neutropenic sepsis). No new or unexpected safety signals emerged. These results support the effectiveness and safety of first-line nab-P/C in patients with advanced NSCLC reported in the pivotal trial and highlight the clinical value of this regimen in the real-world setting.     

Efficacy and Safety of Drug-Eluting Beads Transarterial Chemoembolization by CalliSpheres^® in 275 Hepatocellular Carcinoma Patients: Results From the Chinese CalliSpheres^® Transarterial Chemoembolization in Liver Cancer (CTILC) Study

The purpose of this study was to investigate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment in Chinese hepatocellular carcinoma (HCC) patients and the prognostic factors for treatment response as well as survival. A total of 275 HCC patients were included in this prospective study. Treatment response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST), and progression-free survival (PFS) as well as overall survival (OS) were determined. Liver function and adverse events (AEs) were assessed before and after DEB-TACE operation. Complete response (CR), partial response (PR), and objective response rate (ORR) were 22.9%, 60.7%, and 83.6%, respectively. The mean PFS was 362 (95% CI: 34.9–375) days, the 6-month PFS rate was 89.4±2.1%, while the mean OS was 380 (95% CI: 370–389) days, and the 6-month OS rate was 94.4±1.7%. Multivariate logistic regression revealed that portal vein invasion (p=0.011) was an independent predictor of worse clinical response. Portal vein invasion (p=0.040), previous cTACE treatment (p=0.030), as well as abnormal serum creatinine level (BCr) (p=0.017) were independent factors that predicted worse ORR. In terms of survival, higher Barcelona Clinic Liver Cancer (BCLC) stage (p=0.029) predicted for worse PFS, and abnormal albumin (ALB) (p=0.011) and total serum bilirubin (TBIL) (p=0.009) predicted for worse OS. The number of patients with abnormal albumin, total protein (TP), TBIL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were augmented at 1 week posttreatment and were similar at 1–3 months compared with baseline. The most common AEs were pain, fever, nausea, and vomiting, and no severe AEs were observed in this study. DEB-TACE was effective and tolerable in treating Chinese HCC patients, and portal vein invasion, previous cTACE treatment, abnormal BCr, ALB, and TBIL appear to be important factors that predict worse clinical outcome.     

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program

ObjectivesTo compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS).MethodsWe performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2.ResultsA total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0–1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively).No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2.ConclusionThis real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status.     

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis

Osimertinib is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI). A meta-analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment-naïve patients with EGFR-TKI-sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6-month PFS 83% (95% CI 80–87%), and 12-month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier-generation EGFR-TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6-month PFS 63% (95% CI 58–69%), and 12-month PFS 32% (95% CI 17–47%). EGFR-TKI-naïve patients with EGFR-positive mutations tend to have longer median PFS than EGFR-TKI-pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation-positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation-positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.     

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study

Background

We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy.

Methods

In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs).

Results

Overall, 256 patients received a median of 6.0 doses (range: 1–52) of nivolumab over a median duration of 72.5 days (range: 1–736). Median OS was 9.5 months [95% confidence interval (CI) 8.2–12.0] and median PFS was 2.1 months (95% CI 1.8–2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9–11.9) and 3.5 months (95% CI 2.3–5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis.

Conclusions

Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

     

Phase III, randomized, open-label, first-line study in Asia of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: evaluation of patients recruited from mainland China

Aim: In the IRESSA Pan‐Asia Study (IPASS), 1217 patients in East Asia with pulmonary adenocarcinoma who were never‐smokers or ex/light‐smokers received first‐line gefitinib (250 mg/day) or carboplatin/paclitaxel (area under the curve 5/6; 200 mg/m²). Efficacy analyses were pre‐planned in patients in China. Methods: In China, 372 patients (30.6% of the overall group) were randomized. The primary end‐point was progression‐free survival (PFS). Secondary end‐points were overall survival (OS), objective response rate (ORR), health‐related quality of life (HRQoL), symptom improvement, safety and tolerability. Results: For patients in China, PFS did not significantly differ from the overall IPASS population (interaction test P= 0.427). PFS was numerically longer (hazard ratio [HR] 0.79; 95% CI 0.62–1.01; P= 0.065; median PFS 6.8 months for both treatments) and ORR significantly higher (ORR 44.6 vs 29.8%; odds ratio 1.88; 95% CI 1.22–2.89; P= 0.004) for gefitinib than carboplatin/paclitaxel. OS (mature data) was similar for both treatments (HR 0.92; 95% CI 0.73–1.17; P= 0.511; median OS gefitinib 18.1 months vs 18.3 months carboplatin/paclitaxel). HRQoL improvement rates favored gefitinib; symptom improvement rates were similar for both treatments. Gefitinib had a more favorable tolerability profile than carboplatin/paclitaxel. Efficacy by epidermal growth factor receptor biomarker status (exploratory analyses) was difficult to interpret due to low patient numbers with known biomarker status. Conclusion: For the Chinese subgroup of IPASS, gefitinib demonstrated improved PFS and ORR, similar OS, higher HRQoL, similar symptom improvement rates and a more favorable tolerability profile than carboplatin/paclitaxel, generally consistent with the overall IPASS population.     

S-1-based therapy versus S-1 monotherapy in advanced gastric cancer: a meta-analysis

This study aimed to derive a more precise estimate of the prognostic significance of S-1-based therapy over S-1 monotherapy in patients with advanced gastric cancer (AGC), including overall survival (OS) time, progression-free survival (PFS) time, objective response rate (ORR), and adverse events (AEs). Studies stratifying OS, PFS, ORR, and AEs in AGC patients in an S-1-based therapy versus an S-1 monotherapy setting were eligible for analysis by systematic computerized PubMed, Embase and Cochrane Library searches. Data from these studies were pooled using STATA package version 11.0. Six studies that investigated outcomes in a total of 913 AGC cases, of which 443 (48.5 %) received S-1-based therapy and 470 (51.5 %) received S-1 monotherapy, were included in the meta-analysis. Median OS and median PFS were significantly prolonged in AGC patients receiving S-1-based therapy compared with those receiving S-1 monotherapy (hazard ratio [HR] 0.83, 95 % confidence interval [CI] 0.71–0.96, P?=?0.015, and HR 0.69, 95 % CI 0.60–0.80, P?=?0.000, respectively). The ORR favored patients with S-1-based therapy (OR 1.65, 95 % CI 1.34–2.06, P?=?0.000). Higher incidence of grade 3/4 neutropenia was found in patients with S-1-based therapy (P?=?0.000). For the Asian population, S-1-based therapy significantly improved OS and PFS and enhanced ORR in comparison to S-1 monotherapy. The safety profile was poorer in patients with S-1-based therapy, but could be considerable between the S-1-based therapy and S-1 monotherapy group. Our conclusion needs to be confirmed via high-quality trials and the results need to be reproduced in other regions and populations.