Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial

Background This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. Methods Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). Results As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1–2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3–5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. Conclusions Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient’s symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

Prognostic Impact of the SARC-F Score in Gastrointestinal Advanced Cancers

We sought to elucidate the prognostic impact of the SARC-F score among patients with gastrointestinal advanced malignancies (n = 421). A SARC-F score ≥ 4 was judged to have a strong suspicion for sarcopenia. In patients with ECOG-PS 4 (n = 43), 3 (n = 61), and 0–2 (n = 317), 42 (97.7%), 53 (86.9%) and 8 (2.5%) had the SARC-F score ≥ 4. During the follow-up period, 145 patients (34.4%) died. All deaths were cancer-related. The 1-year cumulative overall survival (OS) rate in patients with SARC-F ≥ 4 (n = 103) and SARC-F < 4 (n = 318) was 33.9% and 61.6% (p < 0.0001). In the multivariate analysis for the OS, total lymphocyte count ≥ 1081/μL (p = 0.0014), the SARC-F score ≥ 4 (p = 0.0096), Glasgow prognostic score (GPS) 1 (p = 0.0147, GPS 0 as a standard), GPS 2 (p < 0.0001, GPS 0 as a standard), ECOG-PS 2 (p < 0.0001, ECOG-PS 0 as a standard), ECOG-PS 3 (p < 0.0001, ECOG-PS 0 as a standard), and ECOG-PS 4 (p < 0.0001, ECOG-PS 0 as a standard) were independent predictors. In the receiver operating characteristic curve analysis on the prognostic value of the SARC-F score, the sensitivity/specificity was 0.59/0.70, and best cutoff point of the SARC-F score was two. In conclusion, the SARC-F score is useful in patients with gastrointestinal advanced malignancies.

Intestinal Microbiome Associated With Immune-Related Adverse Events for Patients Treated With Anti-PD-1 Inhibitors, a Real-World Study

AimImmune checkpoint inhibitors (ICIs) have updated the treatment landscape for patients with advanced malignancies, while their clinical prospect was hindered by severe immune-related adverse events (irAEs). The aim of this study was to research the association between gut microbiome diversity and the occurrence of ICI-induced irAEs.Patients and MethodWe prospectively obtained the baseline fecal samples and clinical data from patients treated with anti-PD-1 inhibitors as monotherapy or in combination with chemotherapy or antiangiogenesis regardless of treatment lines. The 16S rRNA V3-V4 sequencing was used to test the gene amplicons of fecal samples. The development of irAEs was evaluated and monitored from the beginning of therapy based on CTCAE V5.01.ResultsA total of 150 patients were included in the study and followed up for at least 6 months. A total of 90 (60%) patients developed at least one type of adverse effect, among which mild irAEs (grades 1–2) occurred in 65 patients (72.22%) and severe irAEs (grades 3–5) in 25 patients (27.78%). Patients with severe irAEs showed a visible higher abundance of Streptococcus, Paecalibacterium, and Stenotrophomonas, and patients with mild irAEs had a higher abundance of Faecalibacterium and unidentified_Lachnospiraceae. With the aid of a classification model constructed with 5 microbial biomarkers, patients without irAEs were successfully distinguished from those with severe irAEs (AUC value was 0.66).ConclusionCertain intestinal bacteria can effectively distinguish patients without irAEs from patients with severe irAEs and provide evidence of gut microbiota as an informative source for developing predictive biomarkers to predict the occurrence of irAEs.

A phase I study of the WT2725 dosing emulsion in patients with advanced malignancies

WT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1+ tumors in human leukocyte antigen (HLA)-A*0201+ and/or HLA-A*0206+ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, the WT2725 dosing emulsion was administered as a monotherapy to patients with advanced malignancies known to overexpress WT1, including glioblastoma. In part 1, 44 patients were sequentially allocated to four doses: 0.3 mg (n = 5), 0.9 mg (n = 5), 3 mg (n = 6), and 9 mg (n = 28). In part 2, 18 patients were allocated to two doses: 18 mg (n = 9) and 27 mg (n = 9). No dose-limiting toxicities were observed, so the maximum tolerated dose was not reached. Median progression-free survival was 58 (95% confidence interval [CI] 56–81) days (~ 2 months) across all patients with solid tumors; median overall survival was 394 days (13.0 months) (95% CI 309–648). Overall immune-related response rate in solid tumor patients was 7.5% (95% CI 2.6–19.9); response was most prominent in the glioblastoma subgroup. Overall, 62.3% of patients were considered cytotoxic T-lymphocyte responders; the proportion increased with increasing WT2725 dosing emulsion dose. WT2725 dosing emulsion was well tolerated. Preliminary tumor response and biological marker data suggest that WT2725 dosing emulsion may exert antitumor activity in malignancies known to overexpress the WT1 protein, particularly glioblastoma, and provide a rationale for future clinical development.Trial registration: NCT01621542.

Phase I/II Study of MAK683 in Patients with Advanced Malignancies, Including Diffuse Large B-Cell Lymphoma

Introduction: Polycomb repressive complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Enhancer of zeste homolog 2 (EZH2) in conjunction with embryonic ectoderm development (EED) is a catalytic subunit of PRC2 and functions as a histone methyltransferase for H3K27. H3K27me3 appears to be a unifying component in many malignancies, inducing transcriptional repression. EED is a core component of PRC2 that modifies the epigenetic status of target genes, including cell cycle control genes. Dysregulation of this pathway leads to tumorigenesis in several diseases. MAK683 is a specific oral inhibitor that impairs EED binding to H3K27me3. This is a Phase I/II study of MAK683 in adult patients with advanced malignancies for whom no effective standard treatment is available. Here, we present data from a subset of patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients with DLBCL received escalating doses of MAK683 in fasted conditions. Patients were administered MAK683 10, 20, 40, 80, 120, 240, 300, 500, and 800 mg once daily (QD) or 60, 80, 120, 150, and 300 mg twice daily (BID) orally in 28-day cycles until unacceptable or dose-limiting toxicities (DLTs) had developed, disease progression, or death. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended Phase II dose (RP2D). Results: As of March 5, 2021, 31 patients with an Eastern Cooperative Oncology Group Performance Status of 0-2 were treated. Median age was 70 years (range: 33-84) and patients were heavily pre-treated, with a median of 4 (range: 1-16) prior lines of therapy. Overall, 30 patients (97%) discontinued treatment due to progressive disease (26 patients, 84%), adverse events (3 patients, 10%), and physician's decision (1 patient, 3%). In total, 21 (68%) patients experienced ≥1 treatment-related adverse event (TRAE) of any grade, and the most common (≥20%) TRAEs were thrombocytopenia (29%) and anemia (23%). Grade 3/4 TRAEs were reported in 14 (45%) patients, with ≥15% of patients reporting thrombocytopenia (19%), neutropenia, and decreased neutrophil count (16% each). DLTs were reported in 7 patients, all of which were hematological and therefore may be related to the underlying disease in this subset of patients. Patients in both the QD dosing group (120 mg, 240 mg, and 800 mg; n=1 each) and BID dosing group (60 mg, n=1; 80 mg, n=2; 150 mg, n=1) reported DLTs. There were no treatment-related deaths in this study. Overall response rate was 16% (95% CI: 5─34) and the disease control rate was 29% (95% CI: 14─48). Two patients (6%) achieved a complete response (CR) and 3 patients (10%) achieved a partial response. Four patients (13%) reported stable disease. Pharmacokinetic data showed rapid absorption of MAK683 across all dosing regimens tested and drug exposure increased with dose. Conclusions: MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL. Disclosures Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Michot: GSK: Honoraria; MSD: Consultancy, Honoraria; Celgene: Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Igleias: Merck Serono, MSD, BMS, Lilly, Roche, Bayer, Sanofi: Consultancy. Tan: Novartis, Bayer, Boehringer Ingelheim, MSD, Astra Zeneca, Eli-Lilly, Loxo: Consultancy; Astra Zeneca, Pfizer, Novartis: Research Funding; Merck, Pfizer, Novartis, Takeda, Bayer, Boehringer Ingelheim, Roche: Honoraria. Ma: Novartis, Merck, Y-Biologies, Taiho, Daiichi: Honoraria, Speakers Bureau; Novartis, Inglheim: Research Funding. Wainberg: Plexxikon, BMS, EMD Serono: Research Funding; Roche, Novartis, BMS, Merck, Pfizer, Lilly, Bayer, Astra Zeneca, Daiichi, Astellas, Amgen: Consultancy. Fan: Novartis Institutes for Biomedical Research: Current Employment. Suenaga: Novartis Pharma K.K.: Current Employment. Cheng: Novartis: Current Employment. Lai: Novartis: Current equity holder in publicly-traded company; Novartis Institutes for Biomedical Research: Current Employment. Yokota: AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, Ascent: Research Funding; Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, Eisai: Honoraria; Merck Biopharma, MSD, Rakuten Medical: Membership on an entity's Board of Directors or advisory committees.