Main Treatment-related Adverse Events Research Articles

Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer

BackgroundOCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC).AimsThe main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC).MethodsIn total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power).ResultsThe majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm.DiscussionOCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option.Trial registrationISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018.

Efficacy and Safety of Daratumumab in Combination with Bortezomib, Thalidomide, and Dexamethasone Regimens in Newly Diagnosed Multiple Myeloma with Renal Insufficiency in Real-World: A Non-Interventional Prospective Multicenter Observational Study

Background: Renal impairment (RI) is one of the common serious complications of MM. The DARE Phase 2 clinical study is daratumumab-based regimen for the treatment of MM patients with renal insufficiency, which is designed to use daratumumab in combination with dexamethasone for the treatment of RRMM with severe renal insufficiency. According to the updated data, after 8.3 months of follow-up, the 6-month PFS rate was 48.6%, ORR was 41.4%, renal response rate (RRR) was 20.7%. CASSIOPEIA phase III clinical study showed that with the extension of treatment time, the sCR rate and minimal residual disease (MRD) negative rate in D-VTd group were significantly improved compared with those in VTd group. According to the evidence from previous large phase III clinical trials of daratumumab in NDMM as well as its DARE phase II study and clinical case reports, daratumumab based treatment has a rapid onset of action in the treatment of MM patients with severe renal insufficiency, effectively response to the disease and improve the renal function of patients. An observational, multi-center, non-interventional study was designed to evaluate the safety and efficacy of daratumumab in combination with VTD in NDMM patients with renal dysfunction in real-world clinical practice. (NCT 05561049) Methods:NDMM patients older than 18 years and with a glomerular filtration rate(eGFR) of less than 40 ml/min were enrolled. Patients received VTD for C1, then go to DaraVTD for C2-4. The dose of Daratumumab was 16 mg/kg I.V. every week for 2cycles(cycles 2-3) , 16 mg/kg I.V. every 2 weeks for one more cycles;“Thalidomide”: 100 mg, P.O., Days 1-28/1-4 cycles;“Bortezomib”: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-4 cycles; Dexamethasone: 20-40mg, PO/I.V., qw/1-4 cycles. After induction therapy, patients entered consolidation therapy. Transplant eligable patients undergo stem cell collection and autologous stem cell transplantation followed by consolidation with DVTd regimen for 2 more cycles. Four more cycles of consolidation with DVTd were performed in transplant ineligible patients. The primary endpoint of this study is to evaluate VGPR+ rate after consolidation. The secondary endpoint is ORR, renal response rate (RRR), CR rate, MRD negativity after consolidation, and DOR, PFS, OS. NCI CTCAE V5.0 criteria were used to evaluate adverse events. Result: From Jan 1th to June 30 th 2023, 23 patients were enrolled. The median age of these 23 patients was 64 (34-78), 69.6%(16/23) was male.(Table 1) Among the 18 patients who have had response evaluation, the ORR was 94.4%. median onset time of response was 2 months. After induction therapy, the ORR was 100%, 50% patients had gotten CR. After consolidation, All patients were above VGPR and CR and were NGS MRD negative.55.5% patients(10/18) achieved renal remission after one cycle, while 86.7% after 2 cycles, 91.7% after 3 cycles and 100% after 4cycles. Among the 20 patients who have had adverse events evaluation. The main treatment-related adverse events were hematological toxicity, including neutropenia (n=10/20, grade 1-2 for 6 pts and grade 3-4 for 4 pts), lymphopenia (n=5/20, grade 1-2 for 5 pts) and thrombocytopenia (n=8/20, grade 1-2 for 6 pts and grade 3-4 for 2 pts). One patient with acute pancreatitis had to stop treatment. Other toxicities to date included pneumonia (n=5/20, grade 1 for 4 pts and grade 2 for 1 pts), peripheral neuropathy (n=10/20, grade 1 for 7 pts and grade 2 for 3 pts), and rash(n=5). The infusion related reactions were 37.5%(n=6/18, grade 1 for 4 pts and grade 2 for 2 pts). Conclusion: In Chinese NDMM patients with RI, quad-drug induction of DVTD with/without ASCT consolidation showed nice tolerability and high overall response of disease even with a high percentage of high-risk patients. This preliminary study also suggested excellent efficacy with rapid improvement in renal function. The most common adverse events were hematological toxicity. Updated results will be presented at the following phase.

Initial Safety and Efficacy of Daratumumab (DARA) in Combination with Bortezomib, Lenalidomide, and Dexamethasone in the Treatment of Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE-NDMM) Patients with Standard Risk Who Refused to Accept ASCT As First Line in China

Background: Despite the advent of numerously new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy. Autologous hematopoietic stem cell transplantation (ASCT) remains an important first line treatment for MM. In China, rate of utility of ASCT in front line was as low as 10%. There are many transplant-eligible (TE) patients who refuse ASCT for a variety of subjective and objective reasons,. Bortezomib, lenalidomide and dexamethasone (VRd) combination has been reported to demonstrate high efficacy in these patients (SWOG S0777), And recently, daratumumab combinations, such as D-VRd (GRIFFIN) and D-VTd (CASSIOPEIA), have shown good results in TE-NDMM patients who received ASCT as initial therapy. The observed benefits of these combination therapies have led us to explore the potential efficacy of D-VRd in standard risk TE-NDMM patients without ASCT. In addition, there were no studies assessing minimal residual disease (MRD) data after treatment with the D-VRd regimen in TE-NDMM patients who are unwilling to undergo ASCT in Chinese population , thus we chose MRD as the primary endpoint. This is the first open-label, single arm study to evaluate the efficacy and safety of D-VRd in TE-NDMM in standard risk without ASCT in China (NCT 05088330). Methods: This is a single-center prospective ongoing clinical study, planning to recruit 76 patients. NDMM patients as documented per IMWG criteria who were evaluated as transplant-eligible, but voluntary not to accept ASCT were enrolled. And t(4;14) or Del(17p) or t(14;16) or R-ISS stage III patients were excluded from this study. D-VRd regimen includes ‘daratumumab’ 16 mg/kg I.V. every week for 2 cycles, 16 mg/kg I.V. every 3 weeks for 6 more cycles, and then 16 mg/kg I.V. for 13 more cycles (Total: 21 cycles); ‘lenalidomide’: 25 mg, P.O., Days 1-14/1-8 cycles; ‘Bortezomib’: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-8 cycles; dexamethasone: 20 mg, P.O., Days 1, 2, 4, 5, 8, 9, 11, 12/1-8 cycles. The primary endpoint of this study was to evaluate the negativity of NGS MRD at 10-5 after 8 cycles of D-VRd. The secondary objectives of this study were to determine the ORR, sCR, ≥CR ≥VGPR, AE, TTR and DOR of treatment. Patients were recommended to have stem cells collection after 4 cycles of D-VRd treatment. Result: As of 30 June 2023, 24 patients including 6 safety-run-in patients were enrolled. The median (range) age of these 24 patients was 65 (50-74) years. 54.2% (13/24) were male. 62.5% of patients had a 1q gain. 16.7% (4/24) of patients had renal insufficiency with 30mL/min <CCR <60mL/min (Table 1). The median follow-up time was 3 (1-11) months, 8 patients completed 4 cycles and 2 patients completed 2 cycles. Among the 17 patients who had response evaluation, the ORR was 94.1%, 87.5% (7/8) of patients had VGPR or better after 4 cycles (Figure 1). All patients (6/6) above VGPR and CR had NGS MRD negativity. Both 2 patients who have completed the 8 cycles treatment achieved CR and MRD negativity. All patients had bone pain relief. The main treatment-related adverse events were hematological toxicity, which occurred in 22 patients including neutropenia (n=14, Grade 1-2 for 10 patients and Grade 3-4 for 4 patients), lymphopenia (n=13, Grade 1-2 for 10 patients and Grade 3-4 for 3 patients) and thrombocytopenia (n=19, Grade 1-2 for 15 patients and Grade 3-4 for 4 patients). One patient had to discontinue lenalidomide due to serious adverse event (SAE) of pulmonary embolism. Other toxicities to date include pneumonia (n=3, Grade 1 for 2 patients and Grade 2 for 1 patient), ALT/AST increase (n=10, all Grade 1), and rash (n=3). The infusion related reactions were reported in 25% of patients (n=6, Grade 1 for 4 patients and Grade 2 for 2 patients). Conclusion: In the safety-run-in phase, D-VRd induction therapy was well tolerated in the Chinese population in 6 patients. This preliminary study of D-VRd demonstrated excellent efficacy with rapid response even in a population with high 1q gain. The most common adverse events were hematological toxicities that were manageable after 2 cycles. The updated results will be presented in the following phase.

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

ObjectivesAXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. Materials and MethodsEscalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. Results21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7–10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. ConclusionBemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.

9001 Background: Patients (pts) with EGFRm+ NSCLC have high rates of CNS metastasis, few treatment options, and a poor prognosis. So far there are no solid evidence from head to head phase 3 trials in this setting. The potent EGFR TKI AZD3759 has high blood–brain barrier penetration, preliminary data has shown promising intracranial (IC) and systemic antitumor activity, and a tolerable safety profile. Methods: This was the first phase 3, open-label, multicenter, randomized controlled trial to compare the efficacy and safety of first-line AZD3759 with first generation EGFR TKIs specifically in pts with EGFRm+ (L858R and/or exon 19Del) NSCLC and CNS metastasis. Adult pts were randomized 1:1 to receive AZD3759 (200 mg twice daily) or first generation EGFR TKIs (the control group, gefitinib 250 mg or erlotinib 150 mg once daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Results: Between Feb 1, 2019, and Jan 12, 2021, 439 pts were randomized: 220 to AZD3759 and 219 to the control group. As of July 12, 2022, median follow-up was 20.4 months (mo) for both. Median PFS (95% CI) was significantly superior with AZD3759 vs the control group (9.6 [8.2–9.7] vs 6.9 [6.3–8.0] mo; HR 0.719, 95% CI 0.580–0.893; p=0.0024). The objective response rate (ORR; BICR/RECIST 1.1) was 68.6% for AZD3759 vs 58.4% for the control group ( p=0.027), with a trend toward longer median duration of response (DoR) with AZD3759 (8.2 vs 6.8 mo; p=0.0997). IC PFS, ORR, and DoR with AZD3759 were all superior vs the control group regardless of the assessor or evaluation criteria. The overall survival was immature. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs 94.0%). Grade ≥3 TRAEs occurred in 65.9% (AZD3759) and 18.3% (the control group) of pts. The main TRAEs were skin and subcutaneous tissue events, gastrointestinal system events and abnormal liver function. No new safety signals arose. Conclusions: First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm+ NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity. Clinical trial information: NCT03653546 . [Table: see text]

HER2-targeting antibody–drug conjugate RC48 alone or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma: a multicenter, real-world study

BackgroundPhase II trials showed the efficacy of anti-HER2 RC48-ADC (disitamab vedotin) for HER2-positive metastatic urothelial carcinoma (UC). This study evaluated RC48 alone verses in combination with immunotherapy for locally advanced or metastatic UC using real-world data.MethodsThis retrospective, multicenter, real-world study included patients with locally advanced or metastatic UC who received RC48 in five hospitals in China between July 2021 and April 2022. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events.ResultsThirty-six patients were included. The patients were 47–87 years, and 26 (72.2%) were male. Eighteen patients received RC48 alone, and 18 received RC48 combined with a programmed death-1 antibody. The median PFS was 5.4 months. The median OS was not reached. The 6-month and 1-year PFS rates were 38.8% and 15.5%, respectively. The 1-year OS rate was 79.6%. Fourteen (38.9%) patients achieved a partial response, and the ORR was 38.9%. Eleven patients had stable disease, and the DCR was 69.4%. The median PFS for patients who received RC48 combined with immunotherapy and those who received RC48 alone was 8.5 and 5.4 months, respectively. The main treatment-related adverse events included anemia, hypoesthesia, fatigue, and elevated transaminase. No treatment-related death occurred.ConclusionRC48 alone or combined with immunotherapy might benefit patients with locally advanced or metastatic UC, regardless of impaired renal function.

Inhibition of the CD47-SIRPα axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

Efficacy and optimal combination timing of chemotherapy combined with PD-1 inhibitor in advanced cervical cancer: a multicenter retrospective cohort study.

This study aimed to investigate the efficacy and safety of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of advanced cervical cancer and the effect of optimal combination timing on prognosis. From March 2020 to December 2021, the clinical data of 116 patients with advanced cervical cancer who received PD-1 inhibitors combined with chemotherapy were collected. The clinical characteristics and adverse events of the patients were recorded until the cut-off date of follow-up. The primary endpoints were progression-free survival (PFS), the objective response rate (ORR), and safety; the secondary endpoints were the disease-control rate (DCR) and overall survival (OS). Multivariate Cox proportional hazards regression was used to analyze the prognostic factors affecting the PFS of patients and to assess the effect of the timing of combination therapies on PFS. In total, 85 patients from 4 study centers were included in this study. The median PFS was 10.3 months [95% confidence interval (CI): 9.47-11.13 months], the ORR was 44.7%, the DCR was 75.3%, and the median OS was not reached. The multivariate Cox proportional hazards regression analysis showed that the early combination of chemotherapy with a PD-1 inhibitor provided better PFS than the late combination [hazard ratio (HR) 0.40, 95% CI: 0.24-0.67, P=0.001]. Lymph node metastasis (HR 2.04, 95% CI: 1.24-3.38, P=0.005), and previous treatment (HR 1.79, 95% CI: 1.09-3.00, P=0.023) were also independent risk factors for PFS. During the treatment and follow-up periods, the overall incidence of adverse events in this study was 56.5%, and that of grade ≥3 adverse events was 12.9%. Thrombocytopenia, neutropenia, anemia, and hypothyroidism were the main treatment-related adverse events, all of which were tolerated, and no serious adverse events leading to death were observed. There were no treatment-related deaths. PD-1 inhibitors combined with chemotherapy have good efficacy and controllable safety in patients with advanced cervical cancer. The early combination of PD-1 inhibitors and chemotherapy may provide better survival benefits than the late combination for patients.

Safety and efficacy of ICI plus anlotinib vs. anlotinib alone as third-line treatment in extensive-stage small cell lung cancer: a retrospective study

PurposeThe objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitor (ICI) plus anlotinib as third-line treatment in extensive-stage small cell lung cancer (ES-SCLC).MethodsA total of 120 patients with ES-SCLC who were admitted to Shandong Cancer Hospital between January 2019 and December 2020 were retrospectively analyzed. They were divided into the observation group (n = 62) and the control group (n = 58) according to their different treatment plans. The observation group was given ICI plus anlotinib, while the control group was given anlotinib alone. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and disease control rate (DCR). An efficacy evaluation was carried out every 6 weeks. Univariate and multivariate analyses were performed to identify the prognostic factors. The main treatment-related adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0.ResultsIn the observation group and the control group, the DCRs were 87.1% and 72.4% (p = 0.044), and the ORRs were 19.4% and 6.9% (p = 0.045), respectively. The median PFS was longer in the observation group (7.5 months) than in the control group (4.6 months) (p = 0.0033). In Cox regression analysis, the Eastern Cooperative Oncology Group performance status score, brain metastases and metastatic sites were prognostic factors of ICI plus anlotinib. Compared with the control group, grade 1–2 immune-related pneumonia and hypothyroidism of patients in the observation group were significantly increased (p < 0.05), but grade 3–4 treatment-related adverse reactions were not significantly increased (p > 0.05).ConclusionICI plus anlotinib showed promising efficacy and manageable toxicity in third-line treatment of ES-SCLC.

Phase 2 Suzhou MM02 Study: Chidamide with VRD Versus VRD in Newly Diagnosed High Risk Transplant Eligible Multiple Myeloma Patients

BackgroundBortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the induction treatment of multiple myeloma (MM) transplant eligible and ineligible patients. Deregulation of histone acetylation has been recognized to serve a critical role in the pathogenesis of MM, which histone deacetylase (HDACs) are overexpressed in plasma cells derived from patients with MM. Therefore, HDACs may promise targets for MM therapy, and panobinostat was approved by FDA for the treatment of relapsed/refractory MM in 2015. Chidamide, a novel oral benzamide type HDAC inhibitor independently developed and approved as anticancer drugs in China, selectively suppresses the activity of class I HDACs. Our studies have shown that chidamide can enhance cytotoxic effect of bortezomib or lenalidomide on MM cells in vitro, which suggested a synergistic combination of chidamide with bortezomib or lenalidomide at low dose. In ASH 2019 we reported Phase 1 Suzhou MM02 study in which chidamide at 4 dose levels (15mg/20mg/25mg/30mg d 0,3,7,10) were administered to 12 patients with VRd for 4-cycle induction therapy. No DLT in Chi-VRd group were observed. This phase 2 trial was designed to further assess the safety and efficacy of Chi-VRd versus VRd for induction treatment in patients with newly diagnosed high risk MM before autologous transplantation (NCT 04025450).MethodsIn this study, we enrolled patients from the First Affiliated Hospital of Soochow University and Soochow Hopes Hematology Hospital with newly diagnosed high-risk multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group diagnostic criteria. All the patients were randomly assigned to Chi-VRd and VRd group. Chi-VRd group patients received Chidamide 20mg orally on days -1,2,6 and 9 in combination with VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles. VRd group patients received VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles.All the patients proceed with ASCT after four cycles or continue VRd therapy for up to eight cycles, followed by maintenance therapy for up to 2 years. Primary efficacy endpoints were overall response rate (ORR), rate of very good partial response (VGPR) or better and rate of complete response (CR) for Chi-VRd and VRd. Safety data described rates of adverse events.ResultsBetween Mar 16, 2020, and Jul 22, 2021, 40 patients were enrolled and randomly assigned to either the VRd regimen (n=20) or the Chi-VRd regimen (n=20). In the Chi-VRd group, 1 patient was discharged due to severe tumor lysis syndrome, and another 1 patient was discharged from sick sinus syndrome (considering lenalidomide related). By the deadline for submission, 18 patients in the VRd group and 11 patients in the Chi-VRd group had completed induction chemotherapy. The total adverse events were listed in the table below. The main treatment-related adverse events were hematological toxicity, hepatotoxicity, constipation, and peripheral neuropathy. ORR was 90.9% (10/11) for Chi-VRd and was 100% for VRd. Response of VGPR or better was 81.8% (9/11) for Chi-VRd and was 83.3% (15/18) for VRd. And rate of CR was 63.6%(7/11) for Chi-VRd and was 44.4%(8/18) for VRd.ConclusionThe Chi-VRd group had more adverse events of thrombocytopenia, peripheral neuropathy and pulmonary. No treatment-related death was observed in two groups. Patients received Chi-VRd get more CR rate. Updated PFS and OS with comparison between VRd and Chi-VRd will be presented at the following study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A multicenter observational study of lenvatinib for unresectable hepatocellular carcinoma in Japan.

e16118 Background: Lenvatinib is an oral tyrosine kinase inhibitor that has been available for treatment of unresectable hepatocellular carcinoma (uHCC) in Japan since March 2018. We conducted a multicenter prospective observational study to evaluate the safety and efficacy of lenvatinib in clinical practice. Methods: This study conducted as a prospective study, and enrolled patients with uHCC initially receiving lenvatinib as systemic therapy who gave informed consent from July 2018 through January 2019. The observation period per patient was 12 months and e-CRF was used. Results: 713 patients were registered at 133 clinical sites. The safety analysis set and efficacy analysis set were 703 patients. Patient baseline characteristics included median age:73.0 years (25 to 94), male/ female: 564/139, bodyweight: &lt; 60kg/≥60kg: 323/380, HBV/HCV/alcohol/NAFLD or NASH: 137/287/167/88, Child-Pugh classification A/B or higher: 624/75, BCLC stage A/B/C/D: 57/291/332/11, Vp 0/1/2/3/4: 520/31/52/60/22, with/without extrahepatic metastasis: 236/461. Previous treatment (local and systemic therapy) for hepatocellular carcinoma is with/without TACE: 513/190, median number of TACE treatment: 3.0 times (1 to 26), with/without HAIC: 74/629, with/without TKI pretreatment: 131/572. The initial dose was 8 mg (80.5%) and 12 mg (68.2%) in patients with &lt; 60 kg and ≥60 kg, respectively. Median relative dose intensity was 64.2% and the treatment continuation rate at 3 and 12 months after administration of lenvatinib were 67.3% and 24.8%. Regarding safety, the incidence of treatment-related adverse events (TRAEs) was 84.9% (grade 3 or higher: 42.5%). Common TRAEs (incidence rate ≥10%) were decreased appetite (23.9%), malaise (21.8%), hypertension (21.3%), proteinuria (18.3%), palmar-plantar erythrodysesthesia syndrome (16.5%), hypothyroidism (15.8%), and diarrhea (13.9%). TRAEs of grade 3 or higher （incidence rate ≥2.5%） were proteinuria (6.7%), hypertension (6.4%), malaise (3.8%), decreased appetite (3.6%), platelet count decreased (3.3%), palmar-plantar erythrodysesthesia syndrome (2.7%), diarrhea (2.7%) and hepatic encephalopathy (2.6%). The incidence of TRAEs leading to discontinuation of lenvatinib was 32.9％, and main TRAEs leading to discontinuation of lenvatinib were (incidence rate ≥2%) decreased appetite (6.3%), malaise (4.7%), proteinuria (3.3%) and hepatic encephalopathy (2.4%). Regarding efficacy, the ORR and DCR was 39.5% (95% CI: 35.1, 43.9) and 78.9% (75.1, 82.5) in 494 patients who were evaluated for the best response by mRECIST. The median OS was 498.0 days (95% CI: 439.0, -) in 703 patients. Conclusions: The incidence of TRAEs leading to discontinuation of lenvatinib tended to be higher than in phase 3 REFLECT trials (19.7%), but the safety profile and effectiveness findings for lenvatinib in this study were consistent with previous reports.

Efficacy and Safety of Anlotinib in Patients with Advanced Non-Small Cell Lung Cancer: A Real-World Study.

BackgroundAnlotinib is a multi-target tyrosine kinase inhibitor (TKI) independently developed by China, which can inhibit tumor angiogenesis and tumor cell proliferation. The ALTER 0303 study has suggested that anlotinib improved overall survival (OS) and progression-free survival (PFS) in the treatment of advanced non-small cell lung cancer (NSCLC). However, in the real world, the efficacy and safety of anlotinib is not clear. Although relevant retrospective studies have confirmed the efficacy and safety of anlotinib, the sample size is small. And the OS was not observed because of the follow-up time was short. Further studies are still essential to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC in real-world settings. Related studies have preliminarily shown that anlotinib combined with whole-brain radiotherapy (WBRT) can significantly prolong the survival of patients with brain metastases of NSCLC. This study also discusses the best treatment strategies of patients with brain metastases.MethodsA retrospective study was conducted on 206 patients with advanced NSCLC who had treated with anlotinib. The primary endpoints were PFS and OS. The secondary endpoints were objective response rate (ORR), disease control rate (DCR) and safety. Kaplan–Meier survival curves were applied to evaluate the efficacy. Univariate analysis was performed by Log rank testing. Cox regression analysis was utilized to evaluate the significance of potential risk factors obtained from the univariate analysis.ResultsThe median PFS (mPFS) was 4.0 (95% CI: 3.607–4.393) months, univariate analysis revealed that patients with longer PFS included epidermal growth factor receptor (EGFR) mutation-negative, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1, no brain metastases, no liver metastases, no adrenal metastases, or ≤2 distant metastases. Cox regression analysis indicated that patients with EGFR-negative and ECOG PS ≤1 had longer PFS. The median OS (mOS) was 8(95% CI: 6.495–9.505) months. EGFR mutation-negative, previous thoracic radiation therapy, no brain metastases, or ≤2 distant metastases were independent positive predictors of OS. The results of Cox regression indicated that the patients without previous thoracic radiation therapy (hazard ratio: 1.855; 95% CI: 1.162-2.960; p=0.010) had shortened OS. The objective response rate was 10.2%, and the disease control rate was 78.2%. The main treatment-related adverse events (AEs) were generally tolerated. All AEs observed during the trial were controlled after dose reduction or symptomatic treatments, and no death was found to be associated with anlotinib.ConclusionAnlotinib was well tolerated and effective in patients with advanced NSCLC. Patients with EGFR mutation-negative and ECOG PS ≤1 had longer PFS, and patients without previous thoracic radiation therapy (HR: 1.855, 95% CI 1.162–2.960; P = 0.010) had shorter OS. Further investigations are needed because of small sample.

Initial Safety and Efficacy of Dose-Escalating HDACs Inhibitor Chidamide with VRD (Chi-VRD) Treatment for Newly-Diagnosed High-Risk Transplant Eligible Multiple Myeloma Patients

Background Deregulation of histone acetylation has been recognized to serve a critical role in the pathogenesis of multiple myeloma (MM), which histone deacetylase (HDACs) are overexpressed in plasma cells derived from patients with MM. Therefore, HDACs may promise targets for MM therapy, and panobinostat was approved by the FDA for the treatment of relapsed/refractory MM in 2015. Chidamide, a novel oral benzamide type HDAC inhibitor independently developed in China and approved as peripheral T-cell lymphoma, selectively suppresses the activity of class I HDACs. Studies have shown that chidamide can enhance cytotoxic effect of bortezomib or lenalidomide on MM cells in vitro, which suggested a synergistic combination of chidamide with bortezomib or lenalidomide at a low dose. This Phase I clinical trial was designed to investigate the efficacy and safety of dose-escalating chidamide with VRD as induction chemotherapy for newly-diagnosed high-risk multiple myeloma (MM) patients before autologous transplantation (NCT 04025450). Methods The de novo MM patients who had any one of the followings was defined as high-risk MM: a. high-risk cytogenetics including 17p-, t (4, 14), t (14, 16), t (14, 20), 1q gain, 1p-, double hit myeloma, triple hit myeloma. b. R-ISS stage III. c. IgD/IgE type. d. with measurable extra-medullary plasmacytoma. e. peripheral blood clonal plasma cell≥0.165% by 10-colour flow cytometry. Chidamide at 4 dose levels (15mg/20mg/25mg/30mg d0,3,7,10) were administered to 12 patients with VRD (bortezomib 1.3mg/m2 d1,4,8,11, lenalidomide 25mg d1-14, and dexamethasone 20mg/d d1-2,4-5,8-9,11-12), every 21 days for 4-cycle induction therapy. Safety, DLT and efficacy of Chi-VRD were observed. Pain sore before each cycle and the whole body DWI-MR before and after 4-cycles were done to see whether improvement in osteodynia and sclerotin reparation of patients. All patients will be collected autologous stem cell to see whether there is effect of the regimen on stem cells after 4-cycle induction therapy. Results The median age of these 12 patients was 57.5 (45, 65), 50.0% was male and 25% (3/12) patients had renal insufficiency with creatinine≥177umol/l or Ccr≤40ml/min. 2 patients were R-ISS stage III; 4 had measurable extra-medullary plasmacytoma; 7 had circulating plasma cells ≥0.165%; and one had t(4;14). The total adverse events were listed in the table below (table1). The main treatment-related adverse events were hematological toxicity, hepatotoxicity, edema, deterioration of renal function and heart failure. Two patients with renal insufficiency had to stop this induction therapy, one for serious adverse event of acute heart failure and acute renal failure at the first cycle in the 20mg dose group and another one for intermittent medication in the 15mg group. All patients had osteodynia relief. Among the 9 patients who have had response evaluation, the ORR was 100% and 77.8% (7/9) patients had gotten very good partial response (VGPR) or better after one cycle. Conclusion This was the first report of ChiVRD induction treatment for newly diagnosed high risk MM. The preliminary results of Chi-VRD suggested excellent efficacy with rapid response. The most common adverse events were hematological toxicity and hepatotoxicity. No dose limiting toxicity (DLT) was observed at 4 dose levels. Hematological toxicity and hepatotoxicity may increase with the dosage increase, but could be quickly controlled. Although chidamide does not affect renal function itself, patients with renal insufficiency may have more adverse reactions that may need dose adjustment. Updated results with comparison between VRD and Chi-VRD will be presented at the following phase II trial. Disclosures No relevant conflicts of interest to declare.

Tepotinib in NSCLC patients with METex14 mutations: interim results from the phase II VISION study

Abstract Background Activating MET exon 14 skipping (METex14) mutations can be detected by liquid biopsy (LBx) or tumor biopsy (TBx) and are sensitive to MET inhibition. We report interim data from the phase II VISION study of tepotinib, a highly selective MET inhibitor, in NSCLC patients with METex14 mutations (NCT02864992). Methods Patients (pts) with advanced EGFR/ALK wild-type NSCLC harboring METex14 mutation identified by RNA-based testing with LBx or TBx (both ≥60 pts; overlap of LBx/TBx anticipated), enrolled at 113 sites in 8 countries (13 sites in Japan), receive tepotinib 500mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint is ORR by independent review committee (IRC); secondary endpoints include investigator assessed ORR (INV) and safety. Results To date, 90 pts are enrolled, 15 are from Japan. At data cut-off (16/10/2018), in 35 evaluable LBx pts ORR (95% CI) was 51.4% (34.0, 68.6) by IRC with a median duration of response (mDoR) (range) of 9.8 months (1.1, 18.0) and 63.9% (46.2, 79.2) by INV with a mDOR of 17.1 months (1.3, 21.5). In 41 evaluable TBx pts, ORR was 41.5% (26.3, 57.9) by IRC and 58.5% (42.1, 73.7) by INV; mDoR was 12.4 months (1.1, 18.0; IRC) and 14.3 months (1.3, 21.5; INV). Of 11 evaluable Japanese pts, 6 were METex14 positive by LBx and 9 by TBx (overlap occurred). Confirmed responses were reported in 4/6 LBx pts and 3/9 TBx pts by IRC and in 4/6 LBx pts and 4/9 TBx pts by INV. Safety was evaluable in 69 pts. Main treatment-related adverse events (TRAEs; ≥15%) of any grade were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%). The safety profile was similar in Japanese pts. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). No TRAEs led to death. Conclusion In NSCLC pts with METex14 mutations, tepotinib had promising clinical efficacy. Similar activity was observed in Japanese pts. The safety profile was favorable. Recruitment, including a MET amplification cohort, is ongoing.

Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis

ObjectiveTo provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.DesignSystematic review and network meta-analysis.Data sourcesElectronic databases (PubMed, Embase,...

Prevention of chemotherapy-induced nausea and vomiting — standards versus clinical practice

In patients’ perception, chemotherapy-induced nausea and vomiting (CINV) are the main treatment-related adverse events of anti-cancer treatment. The probability of CINV incidence depends on the treatment regimen, dose, administration route, and patient-dependent factors. According to the current guidelines, a combination of setrons, neurokinin-1 receptor antagonists, and glucocorticoids results in control of acute emesis in 80–90% of patients and delayed emesis in 60–80%. Despite the availability of recommendations for prophylaxis CINV, the level of adherence to the guidelines in clinical practice is lower than observed in trials. Only half of the patients with highly and moderately emetogenic chemotherapy receive prophylaxis consistent with recommendations. Overuse of 5-hydroxytryptamine-3 receptor antagonists, incorrect dosing of corticosteroids, and overuse of metoclopramide in prophylaxis of delayed emesis are the main issues of non-adherence. Possible reasons for non-adherence are: insufficient knowledge of the guidelines, inappropriate CINV risk assessment, underestimation of symptoms reported by the patients, and difficulties in communication between a patient, medical personnel, and physician. To improve adequate control of CINV and adherence to the guidelines repetitive educational, administrative, and scientific actions need to be taken.

The efficacy advantage of evolocumab (AMG 145) dosed at 140 mg every 2 weeks versus 420 mg every 4 weeks in patients with hypercholesterolemia: Evidence from a meta-analysis

BackgroundEvolocumab (AMG 145), a PCSK9 inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels. Doses of 140mg administered every 2weeks (Q2W) and 420mg administered every 4weeks (Q4W) are widely used, and both dosing schedules were effective in clinical trials. However, some researchers have speculated that 140mg Q2W administration has equal or even greater efficacy. This meta-analysis was performed to assess the differences in efficacy and safety between the two doses. MethodsWe searched the PubMed, EMBASE, and Web of Science databases to identify relevant clinical trials published before January 2016. A total of 2403 patients from 8 randomized controlled trials were identified and included in the analysis. ResultsEvolocumab administered at 140mg Q2W resulted in a greater percent change from baseline in LDL-C concentration (−7.27; 95% confidence interval (CI), −10.36 to −4.18) and had greater efficacy in achieving the treatment goal of LDL-C ≤1.8mmol/L with an relative risk (RR) of 1.09 (95% CI, 1.00 to 1.18) compared with 420mg Q4W in patients who were concomitantly treated with statins. These findings were not significantly different between the 140mg Q2W and 420mg Q4W groups when evolocumab was administered as monotherapy. There was no difference in the rate of occurrence of the main treatment-related adverse events between the two doses. ConclusionsEvolocumab administered at 140mg Q2W was more effective than the 420mg Q4W dosage at lowering lipid concentrations, especially in patients who concomitantly received stable statin therapy.

441O - A Phase I/II Study of Alk Inhibitor CH5424802 in Patients With Alk-Positive Nsclc; Safety and Efficacy Interim Results of the Phase II Portion

ABSTRACT Background Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal gene translocation in a subset of non-small cell lung cancer (NSCLC). CH5424802, an oral ALK inhibitor, was well tolerated with promising efficacy in patients (pts) with ALK-positive NSCLC in the phase I portion (ASCO 2012). Here we report the interim results of the ongoing phase II portion. Methods The primary objective of the phase II portion was to investigate the efficacy and safety at the recommended dose (RD) determined in the phase I portion. Pts with ALK-positive NSCLC, measurable disease, and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity. Results As of March 23, 2012, 34 pts have been enrolled: median age; 46 years, M/F; 16/18, ECOG PS 0/1; 17/17, never-smoker; 62%, number of prior chemotherapy 1/2/3/ > 4; 18/6/0/10. Among the first 15 pts, the response rate was 73.3% with 1 CR and 10 PRs. Main treatment-related adverse events (AEs) among the 34 pts were AST increased (7 pts), ALT increased (6), neutropenia (5), rash (4), nausea (4), myalgia (3), dysgeusia (3), constipation (3), blood CPK increased (3), blood bilirubin increased (3), and blood ALP increased (3), which were mostly Grade 1 except for neutropenia. Grade 3 treatment-related AEs were two cases of neutropenia. For treatment-related eye disorders which are frequent in crizotinib, only one Grade 1 case (vision blurred) was observed. No treatment-related AEs led to dose reduction. At the time of submission, 30 pts are on study (range 1 - 8 months). Conclusion CH5424802 demonstrated clinically meaningful antitumor activity with well tolerated toxicity profile. A phase I/II study in ALK-positive NSCLC pts previously treated with or without crizotinib is ongoing in the US. Disclosure M. Nishio: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. K. Kiura: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. K. Nakagawa: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. T. Seto: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. A. Inoue: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. Maemondo: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Hida: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. Harada: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. H. Yoshioka: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Tamura: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.

Phase II study evaluating the efficacy and safety of sagopilone (ZK-EPO) in patients with metastatic breast cancer that has progressed following chemotherapy

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models, including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose previous chemotherapy regimen included a taxane and an anthracycline received sagopilone 16 or 22 mg/m(2) as a 3-h intravenous infusion every 21 days. Efficacy (using modified Response Evaluation Criteria in Solid Tumors), safety, and tolerability were assessed in this population. A total of 65 patients received sagopilone at either 16 mg/m(2) (N = 39) or 22 mg/m(2) (N = 26). Patients received a median of two cycles of sagopilone. Among the 65 patients who were evaluable for efficacy, there were three confirmed tumor responses over both treatment arms; however, the primary target of the study was not reached. The main treatment-related adverse events were sensory neuropathy (81.5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC.

Clindamycin/Benzoyl Peroxide Gel (BenzaClin??)

Clindamycin 1%/benzoyl peroxide 5% (BenzaClin) is a combination gel indicated for use twice daily, or as directed by a physician, for the topical treatment of inflammatory and noninflammatory lesions of acne vulgaris. In well designed clinical trials in patients with mild to moderately severe acne, the efficacy of once- or twice-daily clindamycin/benzoyl peroxide in the reduction of inflammatory lesion counts was greater than that of benzoyl peroxide alone, clindamycin alone, or tretinoin plus clindamycin, and not significantly different from that of erythromycin/benzoyl peroxide. In the reduction of noninflammatory lesion counts, the efficacy of once- or twice-daily clindamycin/benzoyl peroxide was greater than that of clindamycin alone, but not significantly different to that observed with benzoyl peroxide, tretinoin plus clindamycin, or erythromycin/benzoyl peroxide. Clindamycin/benzoyl peroxide has a fairly rapid onset of action, with acne improvement usually recorded within 2-4 weeks. Despite widespread use, bacterial resistance is not associated with clindamycin/benzoyl peroxide. The product is generally well tolerated, and the main treatment-related adverse events in clinical trials were application-site dryness, irritation, peeling, and erythema. Thus, clindamycin/benzoyl peroxide is an effective and well tolerated option for the management of mild to moderately severe acne.