Incidence Of Treatment-related Adverse Events Research Articles

Pembrolizumab for Early Triple-Negative Breast Cancer

BackgroundPrevious trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.MethodsIn this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab–chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo–chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.ResultsAt the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab–chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo–chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab–chemotherapy group and 46 of 390 patients (11.8%) in the placebo–chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab–chemotherapy group and 73.0% in the placebo–chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.ConclusionsAmong patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)

JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study

BackgroundThe efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis.MethodsIn this Phase IIa, open-label, multicenter study—OMEGA-3 (NCT02993250)—patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs).ResultsOverall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up.ConclusionsIn HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.

Local and disease control for nasal melanoma treated with radiation and concomitant anti-programmed death 1 antibody.

Mucosal melanoma of the nasal cavity is a rare disease that has been consistently associated with poor outcome. While complete surgical excision offers the only prospect of a cure, it is associated with a high risk of surgical morbidity due to the challenging anatomical location, and most patients still develop incurable metastatic disease. The efficacy of immunotherapy on mucosal melanoma is lower in comparison with cutaneous melanoma, and mucosal melanoma rarely has BRAF mutations. Although preclinical data have shown that combination treatment with immune checkpoint inhibitors and radiotherapy (RT) improve the response, there have been few reports on the combination of RT and anti-programmed death 1 therapy for mucosal melanoma of the nasal cavity. We retrospectively investigated 10 cases of mucosal melanoma of the nasal cavity in which combined treatment was applied. The local control (LC) rate of the primary lesion and regional lymph nodes was favorably 100%. On the other hand, the median progression-free survival (PFS) time was 29.6weeks (range, 2-82). The 6-month PFS rate was 60%. Although severe mucositis occurred in one patient, the incidence of treatment-related adverse events was not significantly increased. RT with anti-programmed death 1 antibody therapy for mucosal melanoma of the nasal cavity was tolerable and had the potential to improve LC and PFS.

IJU this issue

This issue deals with a wide range of clinical topics of urology, and contains three Review Articles, seven Original Articles and one Urological Note. Radiation cystitis is a specific type of iatrogenic injury to the bladder. Radiation cystitis can be a complication of radiation doses starting from 45 to 55 Gy, and the risk increases significantly at cumulative doses of ≥60 Gy. It is a potential, but often intractable, complication of pelvic radiation therapy for treatment of pelvic malignancies. Villeirs et al. (Ghent, Belgium) assessed the efficacy of hyperbaric oxygen therapy in reducing symptoms of radiation cystitis by systematic review of recent literature. Hyperbaric oxygen therapy was effective (the weighted average overall and complete response rates were 87.3% and 65.3%, respectively) in the treatment of radiation-induced cystitis, with minimal adverse events, but low availability and high cost. At present, as evidence is low, more prospective studies seem to be required. The term, bacillus Calmette–Guerin (BCG) failure, is ambiguous, and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional BCG therapy and who need to be treated with radical cystectomy, the new concept of “BCG unresponsive” was recently proposed. Kikuchi et al. (Kanagawa, Japan) demonstrated the definition of BCG unresponsive, and assessed the development of novel therapeutic options for BCG unresponsive disease. So far, the blockade of the programmed cell death-1/programmed cell death-ligand 1 pathway, which is considered to be activated by BCG therapy, is promising. Furthermore, clinical trials with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. It is well known that cisplatin has various toxicities, including myelosuppression, gastrotoxicity and ototoxicity, and the main dose-limiting side-effect is nephrotoxicity. Shiraishi et al. (Kyoto, Japan) evaluated the safety and efficacy of the combined regimen of paclitaxel and ifosfamide plus nedaplatin for patients with refractory or relapsed germ cell tumors and impaired renal function. Their results showed that paclitaxel, ifosfamide and nedaplatin chemotherapy can be considered a safe and effective (overall response rate: 60%) regimen that results in less nephrotoxicity in germ cell tumor patients with renal dysfunction. In patients who show prostate-specific antigen failure after external beam radiotherapy for local or locally advanced prostate cancer, salvage therapy targeting the prostate is currently an option. Yamada et al. (Kyoto, Japan) examined the effect of permanent salvage brachytherapy in prostate cancer patients suffering recurrence after three-dimensional conformal external beam radiotherapy. Permanent salvage brachytherapy was carried out in 13 patients who suffered prostate-specific antigen failure. Their results showed that targeted fusion biopsy-based three-dimensional cancer mapping should be used for permanent salvage brachytherapy treatment planning to reduce the incidence of treatment-related adverse events while maintaining good oncological outcomes. In contrast, Takeda et al. (New York, USA) examined a set of proposed eligibility factors for hemi-ablative focal therapy in prostate cancer, and determined the likelihood of residual extensive disease. Hemi-ablative focal therapy, which involves ablation of an entire half of the prostate, is most frequently carried out now. They retrospectively analyzed data from 98 patients with the focal therapy consensus meeting the inclusion criteria who underwent radical prostatectomy. Their results showed that an important number of patients meeting the focal therapy consensus meeting the inclusion criteria can present extensive disease. Interestingly, their study also implied that targeted biopsies might provide more accurate information about the selection of focal therapy candidates. Until recently, there has been only limited information about the clinicopathological features of malignant urachal tumors (MUTs) from a large population-based study. Nagumo et al. (Ibaraki, Japan) used the hospital-based cancer registry data to extract 456 MUT cases. Their results showed that MUTs are quite rare (0.4% of all malignant bladder cancers) in Japan, and most of those without metastasis are likely to be treated with surgery alone, even at advanced stages. The necessity of establishing a standard of care for MUT patients at advanced stages or with metastasis is also reported. None declared.

Phase 4 Study in Patients From Asia With Gastroesophageal Reflux Disease Treated With Dexlansoprazole.

Background/AimsSince the use of dexlansoprazole in Asian subjects with gastroesophageal reflux disease (GERD) has not been adequately characterized, this study was conducted to evaluate the efficacy and safety of dexlansoprazole modified-release in Asian subjects with non-erosive reflux disease (NERD) and erosive esophagitis (EE).MethodsIn this phase 4, open-label, non-randomized, uncontrolled, multicenter, multi-country study sponsored by Takeda, subjects aged ≥ 20 years with persistent typical GERD symptoms for at least 6 months underwent endoscopy. Based on endoscopic findings, they were assigned to either dexlansoprazole modified-release 30 mg once-daily for 4 weeks (NERD group) or dexlansoprazole modified-release 60 mg once-daily for 8 weeks (EE group). The primary endpoint was the percentage of days that subjects did not experience any 24-hour heartburn or acid regurgitation.ResultsOf the 445 subjects screened from Hong Kong, South Korea, and Taiwan, 208 were enrolled in the NERD group (mean age: 53.6 years, male: 34.6%) and 88 in the EE group (mean age: 51.7 years, male: 55.7%). Over the treatment period, the median percentage of days that subjects did not experience any 24-hour heartburn or acid regurgitation was 26.9% and 65.5% in the NERD and EE groups, respectively; for nighttime heartburn or acid regurgitation the proportions were 59.3% and 83.3%, respectively. The treatment was well tolerated with low incidence of treatment-related adverse events in NERD and EE groups (6.7% and 5.7%, respectively).ConclusionIn Asian patients with GERD, treatment with dexlansoprazole modified-release indicates a favorable efficacy and safety profile in relieving heartburn and acid regurgitation symptoms.

Focal salvage low-dose-rate brachytherapy for recurrent prostate cancer based on magnetic resonance imaging/transrectal ultrasound fusion biopsy technique.

To examine the effect of permanent salvage brachytherapy in prostate cancer patients suffering recurrence after three-dimensional conformal external beam radiotherapy. The ultra-focal (target lesion alone), hemi-lobe (within a hemi-lobe) or focused whole-gland (focusing on the lesion, but extending into the whole gland) pattern was selected based on the Gleason score for the targeted biopsy, the numbers of positive cores in the targeted and systematic biopsies, and the locations of the positive cores. Novel dosimetry criteria derived from three-dimensional cancer mapping, which was based on targeted magnetic resonance imaging/transrectal ultrasound fusion biopsies, were used in these cases. Permanent salvage brachytherapy was carried out in 13 patients who suffered prostate-specific antigen failure (prostate-specific antigen 2.1-6.8ng/mL; age range 57-75years; Gleason score ≤7 [n=10], Gleason score ≥8 [n=2] and Gleason score not available [n=1]) since 2012. The targeted biopsy showed a single focus in three patients. The ultra-focal, hemi-lobe and focused whole-gland patterns were chosen in three, five and five patients, respectively. During the follow-up period (median duration 48months), prostate-specific antigen failure occurred in zero of three, one of five and three of five of the patients treated with the ultra-focal, hemi-lobe and focused whole-gland patterns, respectively. The 4-year biochemical recurrence-free survival rate was 74%. No grade3-4 adverse intestinal or urological events occurred. Targeted fusion biopsy-based three-dimensional cancer mapping should be used for permanent salvage brachytherapy treatment planning to reduce the incidence of treatment-related adverse events while maintaining good oncological outcomes.

Combination of ATRA and High-Dose Dexamethasone As First-Line Treatment in Adult Immune Thrombocytopenia:a Randomized, Phase 2, Open-Label Trial

Introductions Immune thrombocytopenia (ITP) is an acquired thrombocytopenia caused by immune-mediated platelet destruction and impaired platelet production. As the immunosuppressive therapy, high-dose dexamethasone (HD-DXM) has been recommended as the standard first-line treatment. Nevertheless, approximately half of ITP patients relapse within 6 months and require further therapies. All-trans retinoic acid (ATRA) is a derivative of vitamin A that has an immunomodulatory effect on hemopoiesis. Our previous study demonstrated that ATRA could induce a more rapid and long-lasting response in patients with corticosteroid-resistant or relapsed ITP (Lancet haematology, 2017). In addition, we found that ATRA corrected impaired platelet production by regulating the complement-IL-1β loop and TNFAIP3/NF-κB/SMAD7 signaling pathway in ITP (Br J Haematol, 2018; Haematologica, 2019). These findings suggested that the addition of ATRA to HD-DXM in treatment-naive patients could improve sustained response rate based on the synergetic function. Here, we present the results of the first prospective, multicenter, randomized, controlled trial with the largest cohort to date comparing the efficacy and safety of HD-DXM plus ATRA vs HD-DXM as first-line therapy in newly diagnosed adult primary ITP patients. Methods In this open-label, randomized, phase 2 trial, we enrolled adult ITP patients from 6 different tertiary medical centers in China. Eligible subjects had confirmed newly-diagnosed, treatment-naive ITP; platelet counts &amp;lt;30×109/L or platelet counts &amp;lt; 50×109/L and significant bleeding symptoms (WHO bleeding scale 2 or above).Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral ATRA (10 mg twice daily) plus HD-DXM or HD-DXM monotherapy for 12 weeks. DXM was administered orally at 40 mg daily for 4 consecutive days to both arms. The 4-day course of dexamethasone was repeated on days 11 to 14 in the case of lack of response by day 10(Figure 1). The primary endpoint was 6-month sustained response (SR) defined as platelet counts maintained &amp;gt; 50×109/L without any additional ITP-modifying therapy at the 6-month follow up. Key secondary endpoints were initial response by day 14 (OR: platelet count ≥30×109/L and at least 2-fold increase of the baseline platelet count and absence of bleeding; CR: platelet count ≥100×109/L), duration of response (DOR), bleeding scores, and adverse events (AEs). Results Between June 2015, and July 2018, 300 patients were randomly allocated into either ATRA plus HD-DXM (n=150) or HD-DXM monotherapy (n=150). At the 6-month follow-up, the proportion of patients with SR was significantly higher in the ATRA plus HD-DXM group than in the HD-DXM monotherapy group (61% vs 37%, p= 0.009). So far, the increase of almost one quarter is very encouraging. The combination of ATRA and HD-DXM resulted in a higher incidence of early OR at day 14 compared with HD-DXM monotherapy (83% vs 67%, P=0.031), and the CR rate was 60.0% (ATRA+HD-DXM) vs 40.6% (HD-DXM) (P=0.015). Throughout the follow-up period, overall DOR was greater in the combination group, estimated by the Kaplan-Meier analysis. Fewer patients in the combination group than in the monotherapy group relapsed during follow-up (p&amp;lt; 0.001), and the median time to relapse was 75 days (ATRA+HD-DXM) vs 48 days (HD-DXM). Bleeding was more effectively controlled in the ATRA plus HD-DXM arm, with fewer bleeding events and lower bleeding scores. There was no difference between the 2 groups in terms of rescue treatments. All subjects tolerated the treatment well, and no grade 4 adverse events or treatment-related death were reported. No statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. Conclusions ATRA plus HD-DXM is an effective and safe treatment for ITP as a first-line therapy that can provide a sustained prolonged response in adults. This therapy could be a new treatment option for ITP subjects. Disclosures No relevant conflicts of interest to declare.

Safety of Mogamulizumab in Mycosis Fungoides and Sézary Syndrome: Final Results from the Phase 3 Mavoric Study

Safety of Mogamulizumab in Mycosis Fungoides and Sézary Syndrome: Final Results from the Phase 3 Mavoric Study

Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) vs sorafenib in patients with advanced HCC

Abstract We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced HCC in a multicenter, open-label and randomized setting. Patients not suitable for surgery or loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, ORR, OS and PFS. 46 patients (pts) were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority were male (72%). 40 pts (87%) were HBV carrier, and 42 pts (91%) had Child-Pugh A liver function. 30 pts (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis, 1 pt in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 pts (9%) and no pts achieved PR in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related AEs (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP.

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC.

e12566 Background: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 8 subjects with 3rd-line or greater TNBC have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.

e15787 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that sustained response against pancreatic cancer requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with recurrent metastatic pancreatic cancer was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 12 subjects with 3rd-line or greater metastatic pancreatic cancer were treated. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.

Randomized phase II trial of sorafenib, capecitabine, and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma.

e15630 Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.

Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC).

4042 Background: Immune checkpoint inhibitors have shown clinical benefit in advanced GC/GEJC. This phase 1b study evaluates the efficacy and safety of sintilimab, an anti-programmed cell death-1 antibody (PD-1 Ab) in combination with XELOX for GC/GEJC in first-line setting. Methods: This phase 1b study enrolled treatment-naïve unresectable locally advanced or metastatic GC/GEJC patients without HER2 amplification in cohort F. Patients received sintilimab 200mg IV q3w until disease progression, unacceptable toxicity or death, in combination with XELOX regimen (oxaliplatin 130mg/m2 IV D1 and capecitabine 1000mg/m2 PO BID D1-14) for up to 6 cycles. The primary objective was to evaluate the efficacy of the combination per RECIST v1.1 and safety and tolerability. Results: Totally 20 patients were enrolled in cohort F. As data cutoff (15 Jan 2019), median follow up was 5.8 months (range, 2.4 to 12.5). The median dose of sintilimab was 6.5 (range, 4 to 12). The objective response rate (ORR) was 85.0% (95%CI, 62.1 to 96.8) and disease control rate (DCR) was 100.0% (95%CI, 83.2 to 100.0). Among 17 patient with BOR of PR, two patients achieved a complete response (CR) of the target lesion. The median duration of response (DOR) and median progression free survival (PFS) had not been met. Three patients underwent resection of primary tumor after achieving a BOR of partial response (N=2) and stable disease (N=1). The incidence of treatment emergent adverse events (TEAEs) was 85.0%. Treatment-related AEs (TRAEs) occurred in 14 (70.0%) patients. The incidence of TRAE ≥ Grade 3 was 15%. AEs of immune-related etiology, occurred in 6 patients (30.0%). There were no AEs that resulted in death. As data cutoff, 12 patients were still in treatment and 8 had discontinued treatment and were under survival follow up. The biomarker analysis including PD-L1 expression in tumor specimen was ongoing. Conclusions: Sintilimab in combination with XELOX in first-line GC/GEJC shows promising anti-tumor efficacy and a tolerable safety profile. The further randomized, phase 3 study of Sintilimab in combination with XELOX in this setting is ongoing (NCT03745170). Clinical trial information: NCT02937116.

Adjuvant Therapy Options in Renal Cell Carcinoma: Where Do We Stand?

Adjuvant therapy for non-metastatic renal cell carcinoma (RCC) remains controversial. Of the four reported randomized controlled trials evaluating adjuvant vascular endothelial growth factor (VEGF) inhibition, only one met its primary endpoint. The S-TRAC study demonstrated a statistically significant improvement in disease-free survival (DFS) of greater than 1year with adjuvant sunitinib compared to placebo in patients with high-risk localized RCC and earned it FDA approval. However, the larger ASSURE study which reported first did not find a difference in DFS or overall survival between 1year of adjuvant sunitinib or sorafenib compared to placebo. Given the discordant results of the two sunitinib studies, two other negative studies of adjuvant targeted therapy with pazopanib and axitinib, the lack of definite overall survival benefit in any study, and the high incidence of treatment-related adverse events with sunitinib, we do not recommend the routine use of adjuvant sunitinib. The decision to offer adjuvant sunitinib should be considered on an individual basis after an informed discussion of the potential toxicities and the risk/benefit ratio. Despite numerous efforts and recently published works, there is a paucity of prognostic and predictive molecular biomarkers in RCC. Further investigation is needed to discover new tools that can enhance the identification of patients who are most likely to benefit from adjuvant treatment beyond pathologic stage. Immune checkpoint inhibitors have great potential to significantly improve outcomes in high-risk localized RCC. Building on their established efficacy in the metastatic setting, several ongoing clinical trials are evaluating their value as single agents or in combination in the neoadjuvant and adjuvant settings. At this time, we recommend participation in clinical trials as the preferred therapeutic option for patients with high-risk, non-metastatic RCC planned for nephrectomy.

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice. To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types. PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018. Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included. Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis. Incidences of treatment-related adverse events and differences between different drugs and cancer types. This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54). Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.

TPS463 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that effective and sustained response against tumors requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we developed the NANT Cancer Vaccine (NCV), which combines metronomic low-dose chemotherapy, radiotherapy and multifaceted immunotherapy. In proof-of-concept trials, the NCV was tested in 10 patients with 3rd-line or greater pancreatic cancer. These trials showed that the NCV could be safely administered in an outpatient setting, with AEs that were manageable by dose-reduction, and preliminary survival results that exceed the standard of care in this heavily-treated population. We believe these results warrant further research, and this abstract describes our newly-designed trial. Methods: A phase 1b, single-arm, open-label trial of the NANT Cancer Vaccine in patients with recurrent metastatic pancreatic cancer has been initiated. Treatment will occur in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events. Secondary endpoints include ORR, DCR, PFS, and OS. A maximum of 24 patients will be enrolled. Clinical trial information: NCT03586869.

Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma.

365 Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p=0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p=0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p=0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p=0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.

Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study

ObjectiveTo evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).Methods373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months)...

Efficacy and Safety of Echinocandins for the Treatment of Invasive Candidiasis in Children: A Meta-analysis.

Echinocandins are recommended for the treatment of suspected or confirmed invasive candidiasis (IC) in adults. Less is known about the use of echinocandins for the management of IC in children. The aim of this study was to investigate the overall efficacy and safety of echinocandin class in neonatal and pediatric patients with IC. PubMed, Cochrane Central, Scopus and Clinical trial registries were searched up to July 27, 2017. Eligible studies were randomized controlled trials that evaluated the efficacy and safety of any echinocandin versus agents of other antifungal classes for the treatment of IC in pediatric patients. The primary outcome was treatment success with resolution of symptoms and signs, and absence of IC. In the meta-analysis a random effects model was used, and the odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Four randomized clinical trials (324 patients), 2 confirmed IC (micafungin vs. liposomal amphotericin B (L-AmB) and caspofungin vs. L-AmB) and 2 empirical therapy trials (caspofungin vs. deoxycholate amphotericin B and caspofungin vs. L-AmB) were included. There was no significant difference between echinocandins and comparator in terms of treatment success (OR = 1.61, 95% CI: 0.74-3.50) and incidence of treatment-related adverse events (OR = 0.70, 95% CI: 0.39-1.26). However, fewer children treated with echinocandins discontinued treatment because of adverse events than amphotericin B formulations (OR = 0.26, 95% CI: 0.08-0.82, P = 0.02). In the treatment of IC in children, echinocandins show non-inferior efficacy compared with amphotericin B formulations with fewer discontinuations than in comparator arm.

Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non–small-cell lung cancer: KEYNOTE-021 cohorts D and H

ObjectivesCombination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti‒programmed death 1 (PD-1) antibody pembrolizumab plus anti‒cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non–small-cell lung cancer (NSCLC). Materials and methodsEligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test. ResultsFifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%–45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4–5.8) months; median overall survival was 10.9 (95% CI, 6.1–23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3–5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively. ConclusionsIn patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.