Overall Objective Response Rate Research Articles

Initial efficacy and safety of RP1 + nivolumab in patients with anti–PD-1–failed melanoma from the ongoing phase 1/2 IGNYTE study.

9509 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from the first 75 pts enrolled into the registration-directed (R-D) cohort in anti–PD-1–failed melanoma (target enrollment N = 125) from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts must have locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) on 2 assessments ≥28 days apart while on ≥8 consecutive weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy must have had PD confirmed by biopsy while on adjuvant therapy. RP1 is initially given intratumorally at 106 PFU/mL and then every 2 weeks (Q2W) at 107 PFU/mL for ≤8 total cycles (≤10 mL/dose) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then receive nivo alone (240 mg Q2W or 480 mg Q4W IV) for ≤2 years, with the option to reinitiate RP1 if specified criteria are met. Results: A total of 91 pts are included in this analysis (initial melanoma cohort, 16 pts; R-D cohort, 75 pts; data cut: Dec 30, 2022). The overall objective response rate (ORR) was 37.4% (initial cohort, 37.5%; R-D cohort, 37.3%) and 18.7% of pts achieved complete response (CR; Table). The response rates seen were also encouraging when evaluated by prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions in most responding patients, including in pts with bulky and visceral disease. The majority of responses were observed in pts with PD-L1–negative tumors at baseline (17 of 52 pts with PD-L1–negative tumors responded, compared to 15 of 26 pts with PD-L1–positive tumors, and 2 of 13 pts for whom PD-L1 status was unknown). 85.3% of responses were ongoing 3.7–36.6 months from initiating therapy. Most treatment-related adverse events (TRAEs) were Grade 1–2 with the most common (>20%) being fatigue, chills, pyrexia, and nausea. Conclusions: The initial data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated, with mostly on-target TRAEs. Additional and updated data will be presented. Clinical trial information: NCT03767348 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Off-the-shelf allogeneic T-cell therapies face the major challenges of graft-versus-host disease (GVHD) and graft rejection mediated by host and recipient alloreactive T cells, respectively. To address GVHD, we are using Epstein-Barr Virus-specific T cells (EBVST), which are virus specific rather than allo-specific and have not produced GVHD in over 300 allogeneic recipients. To prevent graft rejection, we modified the EBVST with a chimeric antigen receptor (CAR) targeting CD30, an antigen that is upregulated on allo-activated T-cells, which will consequently become targets for CD30.CAR EBVST. Hence, CD30.CAR EBVST can kill both CD30+ lymphoma cells and alloreactive T cells through their CAR, and may be boosted in vivo in EBV+ recipients via their native TCR. We are evaluating this approach in a phase 1 trial (NCT04288726) in patients with CD30+ lymphoma. We generated a bank of 7 CD30.CAR EBVST products by stimulating PBMC from healthy donors with overlapping EBV peptide mixtures followed by retroviral transduction with a 2nd generation, CD28-containing CD30.CAR. We have treated 16 patients (median age 36, range 22–53) with relapsed or refractory HL. Patients had undergone a median of 5 (range 3–7) prior lines of treatment. Escalating doses of 4 × 107 − 8 × 108 (DL1–4) CD30.CAR EBVST were infused after lymphodepletion. The frequency of CD30.CAR EBVST was measured by real time qPCR for the transgene in blood. Changes in the frequency of T-cells responding to EBV or tumor-associated antigens (epitope spreading) were measured by IFNɣ ELISpots. Clinical responses were assessed per Lugano criteria by PET/CT scans performed 4–8 wks post infusion. CD30.CAR EBVST were well tolerated, with no GVHD and only two patients having reversible grade 4 cytopenia. Five patients at DL3–4 had grade 1 cytokine release syndrome (CRS), but all resolved without treatment. Of the 16 patients treated, 6 had partial responses (PR) and 6/13 patients at DL2–4 had complete responses (CR), giving an overall objective response rate (ORR) of 75%. Despite these remarkable responses, qPCR for the CD30.CAR transgene showed near background levels by wk 1 post infusion. Although this could mean that CAR-T are quickly eliminated by alloreactive T-cells, additional infusions from the same donor product into the same patient can be associated with response (Figure 1); an alloreactive response would be anticipated to be amplified after each infusion and preclude additional responses. We are therefore analyzing tumor biopsy samples to determine the presence of CD30.CAR EBVST at tumor sites and characterize their phenotype for functionality. The research was funded by: Leukemia and Lymphoma Society SCOR (Heslop) and Tessa Therapeutics (Rooney/Ramos) through a grant to Baylor College of Medicine. Keywords: cellular therapies, Hodgkin lymphoma Conflicts of interests pertinent to the abstract C. A. Ramos Consultant or advisory role: Novartis, Genentech, CRISPR Therapeutics Research funding: Tessa Therapeutics, Athenex Therapeutics Other remuneration: Royalties: Tessa Therapeutics D. H. Quach Research funding: Tessa Therapeutics P. D. Lulla Research funding: Marker Therapeutics, Allovir R. H. Rouce Consultant or advisory role: Pfizer, Novartis Honoraria: Novartis, Medline Plus Research funding: Tessa Therapeutics B. J. Grilley Consultant or advisory role: Allovir, Marker Therapeutics, Tessa Therapeutics, Lokon Pharma, March Bio and Proxima Clinical Research Stock ownership: Allovir, QBRegulatory LLC N. Lapteva Consultant or advisory role: Tessa Therapeutics Research funding: Tessa Therapeutics M. K. Brenner Employment or leadership position: Founder Member Marker Therapeutics Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Athenex, Turnstone Biologics, Posedia, Tscan, Bluebird Bio, Adaptimmune Therapeutics, Adintus, Onkimure, Triumvira Immunologics, Bellicum Pharmaceuticals, Memgen LLC, Brooklyn Immunotherapeutics, Coya, Astrazeneca Pharmaceuticals Stock ownership: Allovir, Marker Therapeutics, Tessa Therapeutics, Turnstone, Bluebird Bio, Allogene, Walking Fish, AlloVir, Tessa, Tscan Other remuneration: Royalties: Takeda, Bellicum, Marker Therapeutics H. E. Heslop Consultant or advisory role: Gilead Biosciences, Novartis, Tessa Therapeutics, Marker Therapeutics, Kiadis, PACT Pharma, Mesoblast, Ankyra Therapeutics Stock ownership: Allovir, Marker Therapeutics, Fresh Wind Biotechnologies, CoRegen Inc. Research funding: Tessa Therapeutics, Athenex Therapeutics C. M. Rooney Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Cell Genix Stock ownership: Allovir, Marker Therapeutics Research funding: Tessa Therapeutics Other remuneration: Royalties: Takeda, Marker, Allovir, Bellicum

Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study.

Molecular targeted therapy combined with immunotherapy significantly improves the prognosis of patients with advanced liver cancer. Additionally, hepatic arterial infusion chemotherapy (HAIC) can improve the prognosis of patients with advanced liver cancer. This real-world study aimed to evaluate the clinical efficacy and safety of HAIC combined with molecular targeted therapy and immunotherapy in the treatment of primary unresectable hepatocellular carcinoma (uHCC). A total of 135 patients with uHCC were enrolled in this study. Progression-free survival (PFS) was the primary endpoint. The efficacy of the combination therapy was assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Overall survival (OS), adverse events (AEs) and surgical conversion rate were the secondary endpoints. Univariate and multivariate Cox regression analyses were performed to examine independent prognostic factors. For sensitivity analysis, inverse probability weighting (IPW) was used to balance the influence of the tested confounding factors between groups to verify the robustness of conversion surgery for survival benefits. The E-values were estimated to assess robustness to unmeasured confounders. The median number of therapies was three. Approximately 60% of the patients had portal vein tumour thrombosis (PVTT). The most common targeted drugs were lenvatinib and bevacizumab, whereas the most common immunotherapy drug was sintilimab. The overall objective response rate (ORR) was 54.1%, and the disease control rate (DCR) was 94.6%. A total of 97 (72%) patients experienced AEs of grades 3-4. Fatigue, pain and fever were the most common symptoms of grade 3-4 AEs. The median PFS was 28 months and 7 months in the successful and unsuccessful conversion groups, respectively. The median OS was 30 months and 15 months in the successful and unsuccessful conversion groups, respectively. Successful conversion surgery, sex, hapatic vein invasion, BCLC stage, baseline tumour size, AFP levels and maximum therapeutic response were independent prognostic factors for PFS. Successful conversion surgery, number of interventions, hapatic vein invasion and total bilirubin levels were independent prognostic factors for OS. After IPTW, no standardised differences exceeding 0.1 were found. IPW-adjusted Kaplan-Meier curves showed that successful conversion surgery was an independent prognostic factor for both PFS and OS. The E-values of successful conversion surgery were 7.57 and 6.53 for OS and PFS, respectively, which indicated a relatively robust impact of successful conversion surgery on the prognosis of patients. Patients with primary uHCC undergoing HAIC combined with immunotherapy and molecular targeted therapy have a higher tumour regression rate and the side effects are manageable. Patients undergoing surgery after combination therapy have survival benefits.

Abstract CT107: Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors

Abstract BACKGROUND: Intra-tumoral Clostridium novyi-NT (non-toxic) is an attenuated strain of C. novyi lacking alpha toxin replication within hypoxic tumor regions, causing tumor cell lysis and inflammation. Immunotherapy (IO) augments anticancer activity with intratumoral agents in prior preclinical and clinical studies. This phase 1b dose escalation study assessed safety and potential synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. METHODS: We enrolled patients with percutaneous injectable, solid tumors to receive single intratumoral injection of C. novyi-NT administered on Day 8 across 4 dose cohorts (3 × 10^4 to 100 × 10^4 spores, 3+3 design) with pembrolizumab 200mg IV Q3weekly starting on Day 0 up to 24 months. Primary objectives: Safety, tolerability and maximum tolerated dose (MTD) of combination. Secondary objectives: anti-tumor activity of combination in the injected tumor lesion and overall response by iRECIST 1.1. RESULTS: At data cutoff on October 24, 2022, 16 patients were enrolled and evaluable for toxicity and efficacy. It was well tolerated across all cohorts without dose limiting toxicities with median number of 5 cycles administered (1-34). 10 patients (63%) experienced progression; 1 withdrew consent; 1 completed therapy; 1 came off trial due to toxicity (immune related dermatitis) and 3 patients remain on trial. Median age was 62.5 years (40-71) while all patients (100%) had performance status of 1. 8 (50%) received prior IO and 7 (44%) had > 4 lines of prior therapies. Confirmed overall objective response rate (ORR) was 25% in 4 patients [non-keratinizing undifferentiated nasopharyngeal squamous carcinoma (NPC), human papilloma virus positive squamous cell carcinoma of base of tongue, vulvar melanoma and chordoma] with 3 partial responses (PR) and 1 complete response (CR). Among responders, median duration of response was 8.18 months and 1/4 (25%) had prior IO. NPC patient completed 24 months on trial to completion with best response at PR (-87%) while vulvar melanoma patient remains on trial with best response at CR (-100%). Median injected tumor size was 2.65cm (1-11) with confirmed ORR in injected lesions at 19% with 2 PRs and 1 CR. Most prevalent grade 1 and 2 adverse events were injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%) and anemia (13%). No grade 3 or 4 treatment related adverse events noted. Signs and symptoms of C. novyi-NT germination (infection) including fever, injection site pain, erythema, swelling, tenderness, and in some cases, ulceration, spontaneous drainage, tissue sloughing, bleeding, and malodor were observed in 5 patients. CONCLUSIONS: Intratumoral C. novyi-NT with pembrolizumab demonstrates clinical activity with favorable tolerability in patients regardless of tumor histology. This study is ongoing to define the recommended phase 2 dose (NCT03435952). Citation Format: Blessie Elizabeth Nelson, Filip Janku, Siqing Fu, Ecaterina I. Dumbrava, David S. Hong, Daniel Karp, Aung Naing, Jordi Rodon, Apostolia Tsimberidou, Rodabe N. Amaria, Anthony Conley, Senthil Damodaran, Kanwal P. Raghav, Brent L. Kreider, David Tung, Mary Varterasian, Khashayarsha Khazaie, Sarina Piha-Paul. Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT107.

Abstract CT152: A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer

Abstract Background: MET gene amplification is associated with poor prognosis in gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety from a phase 2 trial of savolitinib monotherapy in patients (pts) with MET-amplified advanced or metastatic GC/GEJ. (NCT04923932). Methods: Eligible pts had 2L+ GEJ or GC, with MET amplification and measurable lesions. Pts received savolitinib at 600 mg QD for body weight (BW) ≥50 kg, while 400 mg QD for BW <50 kg in 21-day cycles until disease progression or meeting other criteria for end of treatment. Savolitinib BID regimen has also been additionally explored. The primary endpoint was objective overall response rate (ORR) evaluated by Independent Review Committee (IRC). One interim analysis (IA) was pre-defined at the first 20 QD pts who had at least 2 tumor assessments. Results: As of IA, 20 pts were enrolled for QD regimen. Demographics and clinical outcomes are shown in table 1. The mean relative dose intensity of 93.07%. Median duration of exposure was 2.09 months. Confirmed ORR by IRC was 45%, and reached 50% in 16 patients with MET GCN (high) while only 1 PR was observed in 4 patients with MET GCN (low). Duration of response rate at 4-month was 85.7% with median follow up time of 5.5 months. The most common Gr≥3 TRAE (≥5%) were platelet count decreased, hypersensitivity, anemia, neutropenia and hepatic function abnormal. In all pts, only 1 patient discontinued treatment due to grade 4 liver function abnormal (TRAE) and no patient died due to TRAE. Conclusion: Savolitinib monotherapy had manageable safety and showed promising efficacy in pts with MET-amplified GEJ or GC, particularly in pts with MET high GCN. BID regimen is being investigated to further evaluate the efficacy and safety of savolitinib in pts with MET high GCN. Table 1. Pts baseline characteristics and clinical efficacy Baseline Characteristics ITT in IA (n=20) Median age (min, max), yearsSex (male/female), nECOG (0/1/2)Median BMI (min, max), (kg/m2)Primary location of tumor (GC/GEJ)Tumor stage (IV)Prior line of therapy (1/2/≥3)MET GCN (high/low) 57.00 (39.5, 76.8)17/33/15/220.8 (14.9, 25.8)16/4205/10/516/4 Clinical Efficacy By IRC By Investigator Confirmed objective response rateDisease control rate4m-DoR rate,% (95% CI) 45%65%85.7 (33.4, 97.9) 40%55%71.4 (25.8, 92.0) Citation Format: Zhi Peng, Hua Wang, Baorui Liu, Huiting Xu, Zhenyang Liu, Tianshu Liu, Jun Zhang, Yuxian Bai, Ying Yuan, Tao Wu, Feng Ye, Qinghua Pan, Jufeng Wang, Enxiao Li, Diansheng Zhong, Yueyin Pan, Yanru Qin, Yan Yang, Yusheng Wang, Aiping Zhou, Yongshun Chen, Dianbao Zhang, Hongli Liu, Xiujuan Qu, Shubin Wang, Ning Liu, Jinsheng Wu, Wei Li, Kejun Nan, Hongming Pan, Jianming Xu, Chunmei Bai, Heling Liu, Jia Wei, Runzhi Chen, Rongrong Li, Wei Li, Jinghong Zhou, Hongyan Yin, Qian Xu, Songhua Fan, Yongxin Ren, Weiguo Su, Lin Shen. A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT152.

Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: In recent years, tumor immunotherapy has become a viable treatment option for triple negative breast cancer (TNBC). Among these, immune checkpoint inhibitors (ICIs) have demonstrated good efficacy in advanced TNBC patients with programmed death-ligand 1 (PD-L1) positive expression. However, only 63% of PD-L1-positive individuals showed any benefit from ICIs. Therefore, finding new predictive biomarkers will aid in identifying patients who are likely to benefit from ICIs. In this study, we used liquid biopsies and next-generation sequencing (NGS) to dynamically detect changes in circulating tumor DNA (ctDNA) in the blood of patients with advanced TNBC treated with ICIs and focused on its potential predictive value. Methods: From May 2018 to October 2020, patients with advanced TNBC treated with ICIs at Shandong Cancer Hospital were included prospectively. Patient blood samples were obtained at the pretreatment baseline, first response evaluation, and disease progression timepoints. Furthermore, 457 cancer-related genes were evaluated by NGS, and patients' ctDNA mutations, gene mutation rates, and other indicators were determined and coupled with clinical data for statistical analysis. Results: A total of 11 TNBC patients were included in this study. The overall objective response rate (ORR) was 27.3%, with a 6.1-month median progression-free survival (PFS) (95% confidence interval: 3.877-8.323months). Of the 11 baseline blood samples, 48 mutations were found, with the most common mutation types being frame shift indels, synonymous single-nucleotide variations (SNVs), frame indel missenses, splicing, and stop gains. Additionally, univariate Cox regression analysis revealed that advanced TNBC patients with one of 12 mutant genes (CYP2D6 deletion and GNAS, BCL2L1, H3F3C, LAG3, FGF23, CCND2, SESN1, SNHG16, MYC, HLA-E, and MCL1 gain) had a shorter PFS with ICI treatment (p < 0.05). To some extent, dynamic changes of ctDNA might indicate the efficacy of ICIs. Conclusion: Our data indicate that ICI efficacy in patients with advanced TNBC may be predicted by 12 mutant ctDNA genes. Additionally, dynamic alterations in peripheral blood ctDNA might be used to track the effectiveness of ICI therapy in those with advanced TNBC.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations.

Despite immune checkpoint inhibitors (ICI) being widely used to treat patients with advanced non-small cell lung cancer (NSCLC), few studies examine the role of ICI in patients with proto-oncogene B-Raf, serine/threonine kinase (BRAF) mutations. A retrospective study was conducted for patients with BRAF-mutant NSCLC who received treatment at Shanghai Pulmonary Hospital between 2014 and 2022. Primary end point was progression-free survival (PFS). Secondary end point was best response (RECIST, version 1.1). The study involved a total of 34 patients with 54 treatments recorded. The median PFS for the whole cohort was 5.8 months and the overall objective response rate (ORR) was 24%. Patients who were treated with ICI combined with chemotherapy reported a median PFS of 12.6 months and an ORR of 44%. Those who were treated with non-ICI therapy came with a median PFS of 5.3 months and an ORR of 14%. Specifically, patients had better clinical benefits with first-line ICI-combined therapy. The PFS was 18.5 months whereas that of non-ICI group was 4.1 months. The ORR was 56% in ICI-combined group and 10% in non-ICI cohort. The findings observed an evidential and significant susceptibility to ICIs combined therapy in patients with BRAF-mutant NSCLC, especially in first-line treatment.

Comprehensive Analysis of Clinicopathological and Molecular Features to Predict Anti-PD-1-Based Therapy Efficacy in Patients with Advanced Gastric Signet Ring Cell Carcinoma.

Signet ring cell carcinoma (SRCC) is a specific type of gastric cancer. The clinicopathological and molecular characteristics that can be used to predict the response to anti-PD-1 therapy for these patients are still not clear. Patients with advanced SRCC who received first-line anti-PD-1-based treatment were enrolled in this study. The clinicopathological characteristics of these patients were obtained from their medical records. The molecular features of these patients were analyzed by means of a next-generation-sequencing-based panel. The predictive significance of clinicopathological and molecular features for efficacy was analyzed. A total of 71 patients with measurable lesions were included in this study, among which 46 patients had enough tissues for next-generation sequencing. The overall objective response rate (ORR) was 46.4%. ORR was significantly higher in mismatch repair (MMR)-deficient (dMMR) patients than in MMR-proficient (pMMR) patients, in patients with lymph node metastasis only than those with other metastasis sites, and in patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 than with a PS of 1 or 2. The progression-free survival was significantly longer in patients with dMMR, lymph node metastasis only, PD-L1 combined positive score (CPS) ≥ 5, and CDH1 wild type. Several clinicopathological and molecular features are associated with anti-PD-1 treatment efficacy in SRCC, which might be used to identify patients who can benefit most from these therapies.

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma.

To investigate the efficacy and safety differences between the cisplatin + paclitaxel (TP) and cisplatin + fluorouracil (PF) regimens in combination with or without immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC) first-line treatment and prognostic factors. We selected the medical records of patients with late stage ESCC admitted to the hospital between 2019 and 2021. Based on the first-line treatment regimen, control groups were divided into chemotherapy plus ICIs (n = 243) and non-ICIs (n = 171), 119 (49%) in the TP + ICIs group, 124 (51%) in the PF + ICIs group, 83 (48.5%) in the TP group, and 88 (51.5%) in the PF group in the control group. We analyzed and compared factors related to efficacy, safety, or response to toxicity and prognosis across four subgroups. The overall objective response rate (ORR) and disease control rate (DCR) of the TP plus ICIs group were 42.1% (50/119) and 97.5% (116/119), respectively, which were 6.6% and 7.2% higher than those of the PF plus ICIs group. Patients in the TP combined with ICIs group had higher overall survival (OS) and progression-free survival (PFS) than those in the PF combined with ICIs group [hazard ratio (HR) = 1.702, 95% confidence interval (CI): 0.767-1.499, p = 0.0167 and HR = 1.158, 95% CI: 0.828-1.619, p = 0.0055] ORR and DCR were 15.7% (13/83) and 85.5% (71/83) in the TP chemotherapy alone group, significantly higher than the PF group [13.6% (12/88) and 72.2% (64/88)] (p < 0.05), OS and PFS were also better in patients treated with TP regimen chemotherapy than PF (HR = 1.173, 95% CI: 0.748-1.839, p = 0.0014 and HR = 0.1.245, 95% CI: 0.711-2.183, p = 0.0061). Furthermore, following the combination of TP and PF diets with ICIs, the OS of the patients was higher than that of the group treated with chemotherapy alone (HR = 0.526, 95% CI: 0.348-0.796, p = 0.0023 and HR = 0.781, 95% CI: 0.0.491-1.244, p < 0.001). Regression analysis showed that the neutrophil-to-lymphocyte ratio (NLR), the control nuclear status score (CONUT), and the systematic immune inflammation index (SII) were independent prognostic factors for the efficacy of immunotherapy (p < 0.05). The overall incidence of treatment-associated adverse events (TRAEs) was 79.4% (193/243) and 60.8% (104/171) in the experimental and control groups, respectively, and there was no statistically significant difference in TRAEs between TP + ICIs (80.6%) and PF + ICIs (78.2%) (61.4%) and PF groups (60.2%) (p > 0.05). Overall, 21.0% (51/243) of patients in the experimental group experienced immune-related adverse events (irAEs), and all of these adverse effects were tolerated or remitted following drug treatment without affecting follow-up. The TP regimen was associated with better PFS and OS with or without ICIs. Furthermore, high CONUT scores, high NLR ratios, and high SII were found to be associated with poor prognosis in combination immunotherapy.

Dual immune checkpoint inhibitors or combined with anti-VEGF agents in advanced, unresectable hepatocellular carcinoma

BackgroundImmune checkpoint inhibitor monotherapy did not show superiority of survival over standard therapy in advanced hepatocellular carcinoma. The combination immunotherapy including dual immune checkpoint inhibitors or combined with anti-VEGF agents have become a trend, but not fully evaluated. This study aimed to evaluate and compare distinct combination immunotherapy on efficacy in advanced hepatocellular carcinoma. MethodsPubMed, Embase, Web of Science and Cochrane databases were systematically searched from inception to January 31, 2022. The primary endpoints were overall objective response rate (ORR), disease control rate (DCR), six-month progression-free survival rate (PFSR6m) and one-year overall survival rate (OSR1y). Results11 studies with 16 independent cohorts and 3342 patients were included in the meta-analysis. Compared with first-line sorafenib, combination immunotherapy resulted in a significant improvement in ORR (RR, 2.74; 95%CI, 1.55–4.85; p = 0.0006), PFS (HR, 0.57; 95%CI, 0.49–0.65; p<0.0001) and OS (HR, 0.65; 95%CI, 0.52–0.82; p = 0.0002). Based on RECIST 1.1, the pooled ORR, PFSR6m and OSR1y for combination immunotherapy were 24.6% (95%CI: 20.3%-29.6%), 42.0% (95%CI: 34.2%-50.3%) and 61.8% (95%CI: 57.7%-65.7%), respectively. In distinct combination regimens, PD-1/L1 inhibitors plus anti-VEGF agents showed a significant superiority of clinical benefit than PD-1/L1 inhibitors plus CTLA-4 inhibitors (ORR: 25.2% vs 23.4%, p = 0.033; PFSR6m: 47.4% vs 23.2%, p<0.001; OSR1y: 65.1% vs 55.0%, p = 0.001). ConclusionsThis study was the first meta-analysis to demonstrate the better survival benefit and tolerable toxicity of combination immunotherapy than standard therapy in advanced hepatocellular carcinoma. Compared with PD-1/L1 inhibitors plus CTLA-4 inhibitors, the regimens of PD-1/L1 inhibitors plus anti-VEGF agents may be associated with a significantly better clinical benefit. The difference in long-term survival and response population between two distinct combination regimens required further exploration.

The Efficacy and Safety of Ruxolitinib in Steroid-Refractory Graft-Versus-Host Disease in Chinese Patients: Systematic Review and Meta-Analysis

Introduction Graft-versus-host disease (GvHD) is the most common long-term complication and also a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), frequently involving skin, digestive tract, liver, and lung. Corticosteroids are the first-line treatment and immunosuppressants are usually the second-line treatment for GvHD, but they have limited efficacy for steroid-refractory-GvHD (SR-GvHD). Ruxolitinib an oral tyrosine kinase-Janus kinase (JAK) 1/2 inhibitor was approved by FDA for the treatment of SR-GvHD. As direct head-to-head trials of Ruxolitinib in Chinese patients are not available, it was necessary to carry out systematic review and meta-analysis (SR&MA) to evaluate the efficacy and safety of Ruxolitinib in Chinese patients with SR-GvHD. Methods The present study was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statement. We searched the MEDLINE, EMBASE, Cochrane Library and relevant databases for clinical and observational studies evaluating the efficacy and safety of Ruxolitinib in Chinese patients with confirmed SR-GvHD from inception to December 2021. Data from the included studies was extracted in predefined extraction grid and study quality was evaluated to identify risk of bias. Outcomes of interest included overall objective response rate (ORR), complete response (CR), partial response (PR), non-response (NR); proportion of hormone reduction and withdrawal; overall survival (OS), mortality, safety, and tolerability. Meta-analysis of the included studies was performed using the Cochrane Collaboration recommended systematic review method and software (Stata 16). Results A total of 19 case series and cohorts with 775 patients with age between 0.9 to 64 years were included in the study. Ruxolitinib was administered at a dose of 10 to 20 mg/day, of which 561 (72.4%) received 5 to 10 mg bid. Among 339 patients with acute GvHD and 431 patients with chronic GvHD included in 13 studies, ORR, CR, PR, and NR were 86% and 77%, 56% and 36%, 28% and 41% and 14% and 21%, respectively (Table 1). The ORR in the subgroup of patients with skin, gastrointestinal and liver-GvHD was the highest among patients with aGvHD and cGvHD (85% and 84%, 73% and 71%, 69% and 70%) respectively. Four studies described a dose reduction or discontinuation of Corticosteroids: aGvHD (46.51% and 34.88%) and cGvHD (28.24% and 36.86%), respectively (Figure 1). Twelve months OS was reported in four studies, including 404 patients, 179 with aGvHD and 225 with cGvHD. Overall, 12-month survival was 71% (95% CI 63% -79%); aGvHD: 66% (95% CI 56% -76%) and cGvHD: 76% (95% CI 56% -76%), respectively. Among 579 patients with SR-GvHD; 298 with aGvHD and 281 with cGvHD, resulting in an overall mortality rate of 26% (95% CI 19% -34%); aGvHD: 31% (95% CI 21% -42%) and cGvHD: 21% (95% CI 12% -32%) respectively. Eighteen studies reported 760 adverse reactions, and 287 viral infections (36.0%) and 269 cytopenias (34.7%) were the most common adverse reactions. Briefly, Cytomegalovirus infection (18.7%) and Epstein-Barr virus infection (10.8%), thrombocytopenia (12.9%) and hemoglobin (11.1%) were the most frequent Cytopenias. Conclusion Results of the meta-analysis showed that Ruxolitinib could have a positive effect in the treatment of SR-GvHD in the Chinese population. Ruxolitinib was able to significantly reduce or discontinue steroid dosage in patients with SR-GvHD. The adverse drug reactions were mainly cytopenias and viral infections consistent with observations of the REACH studies. Ruxolitinib was generally well tolerated, and no new safety signals were observed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD30.CAR-Modified Epstein-Barr Virus-Specific T Cells (CD30.CAR EBVSTs) Provide a Safe and Effective Off-the-Shelf Therapy for Patients with CD30-Positive Lymphoma

Introduction Off-the-shelf allogeneic T-cell therapies face the major challenges of graft-versus-host disease (GVHD) and graft rejection mediated by host and recipient alloreactive T-cells respectively. To address GVHD, we are using Epstein-Barr Virus-specific T cells (EBVSTs), which are virus specific rather than allo-specific and have not produced GVHD in over 300 allogeneic recipients. To prevent graft rejection, we modified the EBVSTs with a chimeric antigen receptor targeting CD30, an antigen that is upregulated on allo-activated T-cells, which will consequently become targets for CD30.CAR EBVSTs. Hence, CD30.CAR EBVSTs can kill both CD30+ lymphoma cells and alloreactive T-cells through their CAR, and may be boosted in vivo in EBV+ recipients via their native TCR. We are evaluating this approach in a Phase I/II trial (NCT04288726) in patients with CD30-positive lymphoma. Methods We generated a bank of seven CD30.CAR EBVST lines by stimulating peripheral blood mononuclear cells (PBMC) from healthy donors with overlapping EBV peptide mixtures (pepmixes) followed by retroviral transduction with a second generation CD30.CAR containing a CD28 costimulatory endodomain. We have treated 14 patients (median age 36, range 22-53) with relapsed or refractory Hodgkin's lymphoma. Patients had undergone a median of 5 (range 3-6) prior lines of treatment. Escalating doses of 4 × 107 (DL1), 1 × 108 (DL2) or 4 × 108 (DL3) CD30.CAR EBVSTs were infused after lymphodepletion with cyclophosphamide and fludarabine. Blood drawn pre- and post- infusion was processed to isolate serum/plasma and PBMC for analysis. The frequency of CD30.CAR EBVSTs was measured by real time qPCR for the transgene. Changes in the frequency of T-cells responding to EBV or tumor-associated antigens (epitope spreading) were measured by IFNɣ ELISpots. Clinical responses were assessed by diagnostic PET/CT scans performed 4-8 weeks post infusion. Results CD30.CAR EBVSTs were well tolerated, with no GVHD and only two patients having reversible grade 4 cytopenia. Four patients at DL3 had grade 1 cytokine release syndrome (CRS), but all resolved without treatment. Of the 14 patients treated, 13 have been evaluated for responses per Lugano criteria; 4 had partial responses (PR) and 5/10 patients at DL2 and DL3 had complete responses (CR) giving an overall objective response rate (ORR) of 69.2%. Despite these remarkable responses, qPCR for the CD30.CAR transgene showed near background levels by week 1 post infusion. Possible explanations are that CD30.CAR EBVSTs; (1) Are eliminated by alloreactive T-cells, but persist sufficiently to eliminate tumors. (2) Can reactivate endogenous tumor-specific T-cells that are responsible for the tumor responses. (3) Rapidly eliminate tumors and are then lost due to being intrinsically short-lived. (4) Become tissue resident at the tumor site. We think explanation #1 cannot be a major contributor to the lack of circulating CD30CAR T cells since patient 10, who had bulky disease received 3 infusions from the same donor line and responded after each infusion as shown in Figure 1; an alloreactive response would be anticipated to be amplified after each infusion. Similarly, two additional patients receiving second infusions both achieved CR. While we cannot exclude explanation #2, we did not detect epitope spreading in patient PBMCs that would be expected if responses after infusion of CD30.CAR EBVSTs were primarily attributable to reactivation of host anti-tumor cells. We are therefore pursuing explanations #3 and #4 by analyzing tumor biopsy samples to determine the presence of CD30.CAR EBVSTs at tumor sites and characterize their phenotype for functionality. Conclusion We have shown CD30.CAR EBVSTs can be a safe and effective treatment for CD30+ lymphomas, and may avert GVHD and immediate rejection even after multiple infusions. We now seek to improve the durability of responses and test whether CD30.CAR EBVST can be used as a platform for other "off-the-shelf" CAR-T cell therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rare EGFR E709-T710delinsX: Molecular characteristics and superior response to afatinib treatment in NSCLC patients

ObjectivesCurrently, whether patients with rare epidermal growth factor receptor (EGFR) mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs) demands further studies. Limited clinical data are available regarding the molecular characteristics and clinical response in non-small-cell lung cancer (NSCLC) patients harboring EGFR E709-T710delinsX mutations, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR E709-T710delinsX mutated Chinese patients. MethodsNext-generation sequencing (NGS) tests were performed in 15,078 NSCLC patients. A multicenter retrospective cohort involving 17 advanced lung cancer patients with EGFR E709-T710delinsX was collected to evaluate clinical responses to diverse therapies. In silico protein structure modeling was conducted to predict drug response. Results5905 EGFR mutant patients (39.2%, 5905/15078) were identified, with 26 cases (0.44%, 26/5905) harbored EGFR E709-T710delinsD. Afatinib showed a better overall objective response rate (ORR) compared with the first-generation (1G) EGFR TKIs and chemotherapy with significant difference. Superior progression free survival (PFS) was also observed in patients treated with afatinib (afatinib 10.85 m vs 1G EGFR TKIs 4.0 m vs chemotherapy 2.8 m, p = 0.0007). In silico protein structure modeling predicts better binding of afatinib with EGFR E709-T710delinsD compared with other EGFR TKIs. ConclusionsThis is the largest studies for EGFR E709-T710delinsX, with 26 cases with EGFR E709-T710delinsX being identified (0.44% in EGFR mutant NSCLC, 0.17% in NSCLC patients). This study also firstly revealed that afatinib might exert superior antitumor activity to the 1G EGFR TKIs and chemotherapy in EGFR E709-T710delinsX mutant patients.

MOTION: A randomized, phase 3, placebo-controlled, double-blind study of vimseltinib (DCC-3014) for the treatment of tenosynovial giant cell tumor.

TPS11590 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths. TGCT is caused by upregulation of the colony-stimulating factor 1 (CSF1) gene, resulting in aberrant CSF1 expression and the recruitment of CSF1 receptor (R)-dependent inflammatory cells. Resection is the primary treatment, but nonsurgical treatment options are necessary for patients with symptomatic TGCT not amenable to surgical resection. Vimseltinib is an oral switch control TKI specifically designed to selectively and potently inhibit CSF1R. In a Phase 1/2 study in patients with TGCT, vimseltinib showed encouraging antitumor activity with an overall objective response rate (ORR) of 42% in the cohort receiving 30 mg twice weekly (recommended phase 2 dose; Gelderblom et al, ESMO 2021 Poster). Vimseltinib was also well tolerated, and the majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grades 1–2. Among these common TEAEs, the only Grade 3–4 event in the Phase 2, twice-weekly, 30-mg cohort was increased blood creatine phosphokinase (CPK); however, this elevated CPK was not associated with any symptoms (Gelderblom et al, ESMO 2021 Poster). Phase 1/2 efficacy and safety data support further development of vimseltinib; here, we describe the ongoing Phase 3 study for patients with TGCT not amenable to surgical resection. Methods: MOTION (NCT05059262) is a Phase 3, randomized, placebo-controlled, double-blind study that aims to evaluate the efficacy and safety of vimseltinib for the treatment of TGCT not amenable to surgical resection. Participants must be at least 18 years of age and have histologically confirmed and symptomatic TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. Prior CSF1R therapy is not permitted (previous imatinib and nilotinib is allowed). In Part 1 of the study, eligible participants will be randomized 2:1 to receive either vimseltinib 30 mg twice a week or matched placebo for 24 weeks. The primary outcome measure is ORR assessed by central read using Response Evaluation Criteria in Solid Tumors version 1.1 at 25 weeks. Secondary outcome measures include ORR per tumor volume score, range of motion, and patient-reported outcomes. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib in Part 2, a long-term treatment phase in which participants will receive open-label vimseltinib. This international study plans to randomize 120 participants and is currently enrolling. Clinical trial information: NCT05059262.

Mitoxantrone hydrochloride liposome injection in the treatment of recurrent/metastatic head and neck cancers: A multicenter, open-label, single-arm, phase Ⅰb study.

e18028 Background: Mitoxantrone is an anthraquinone antibiotic antitumor agent, and mitoxantrone hydrochloride liposomes have been approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in China. The current study aimed to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in patients (pts) with recurrent/metastatic head and neck cancers. Methods: This study is a multicenter, open-label, single-arm, phase Ⅰb study. The pts with histologically confirmed diagnosis of head and neck squamous cell carcinoma (including nasopharyngeal carcinoma) were enrolled. Mitoxantrone hydrochloride liposome was administered at 20 mg/m2 by an intravenous infusion, every 21 days (q3w, 1 cycle) until disease progression, intolerable toxic reaction, death, or withdrawal by investigator or patient decision (a maximum of 8 cycles). The primary objective was to determine the safety of mitoxantrone hydrochloride liposome. Secondary objective was to assess the efficacy of mitoxantrone hydrochloride liposome in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Efficacy assessment was performed every 2 cycles after dosing as per RECIST v1.1. Results: From July 8, 2021 through November 5, 2021, 34 pts with median age of 48 years (range 20-69 years) were enrolled, including 23 with nasopharyngeal cancer and 11 with non-nasopharyngeal cancer (5 with tongue cancer, 2 with hypopharynx, 2 with tonsil cancer, and 1 each with larynx and gum cancer). The most common treatment-emergent adverse events (TEAEs) were white blood cell decreased (41.2%), anemia (41.2%) and lymphocyte count decreased (29.4%). TEAEs were generally Grade (G) 1-2; 13 pts reported G3 TEAE. The summary of all-grade TEAEs (≥ 10%) are shown in the table below. Nineteen pts had undergone at least 1 efficacy evaluation (including 18 pts with nasopharyngeal cancer and 1 with non-nasopharyngeal cancer). The overall objective response rate (ORR) was 42.1% (8/19) and disease control rate (DCR) was 78.9% (15/19). ORR for nasopharyngeal cancer was 38.9% (7/18) and DCR was 77.8% (14/18). One case of hypopharyngeal cancer was evaluated as partial remission (PR). Conclusions: The preliminary data of mitoxantrone hydrochloride liposome has showed manageable safety and evidence of efficacy in pts with recurrent/metastatic head and neck squamous cell carcinoma. An expanded sample size is still needed for further validation in the future study. Clinical trial information: NCT04902027. [Table: see text]

Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC).

9013 Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for &gt; 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (&gt; 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]

Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review.

Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.

Clinical benefits of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer: a systematic review and meta-analysis

BackgroundImmunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC.MethodsWe searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab.ResultsFourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00–0.04), 0.04 (95% CI 0.05–0.26), 0.27 (95% CI 0.22–0.32), and 0.44 (95% CI 0.30–0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06–0.31) and 0.50 (95%CI 0.35–0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72–0.92) and 0.30 (95% CI 0.20–0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30–0.51) and 0.04 (95% CI 0.00–0.09), respectively.ConclusionsPD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected.Trial registrationWe have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601.

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer

ObjectiveComparison of olaparib (OLA) monotherapy versus chemotherapy in patients with platinum-sensitive (PSOC) or platinum-resistant ovarian cancer (PROC). MethodsPatients with measurable disease and ≥ 1 prior line of chemotherapy (CT) were randomized 2:1 to OLA (300 mg tablets, BID) or physician's choice CT.: for PSOC: Carboplatin-Pegylated-Liposomal-Doxorubicin (PLD) or Carboplatin-Gemcitabine; for PROC: PLD, Topotecan, Paclitaxel or Gemcitabine. Results160 patients (60 with PSOC and 100 with PROC) were randomized 2:1 to OLA (n = 107) or CT (n = 53). Baseline characteristics were similar between both arms. Overall objective response rate (ORR) for OLA and CT were similar (24.3% (26/107) and 28.3% (15/53), respectively). Clinical benefit rate (≥ 12 weeks) was similar with 54.2% (58/107) and 56.6% (30/53), respectively. In PSOC, ORR was 35.0% (14/40) and 65.0% (13/20) for OLA and CT (p = 0.053); in PROC, ORR was 17.9% (12/67) and 6.1% (2/33) for OLA and CT (p = 0.134). ORR in heavily pretreated PROC (>4 prior lines) was 22.9% (8/35) with OLA versus 0% (0/14) for CT. ORR of 35.7% (5/14) and 13.2% (7/53) was observed in BRCA-mutated and -wildtype PROC cases, respectively. Median PFS in PROC was not significantly different with 2.9 months (95% CI 2.8–5.1 in the OLA group versus 3.8 months (95% CI 3.0–6.4) in the CT group (hazard ratio [HR] 1.11 [95% CI 0.72–1.78]; log-rank p = 0.600). ConclusionOLA monotherapy showed overall an equal response rate in relapsed ovarian cancer compared with CT. In PROC, ORR and TFST tended to be higher with OLA than with CT. In heavily pretreated patients (four lines or more) with PROC disease, OLA treatment seemed to be more effective than CT.

Treatment efficacy of HER2-mutant lung adenocarcinoma by immune checkpoint inhibitors: a multicenter retrospective study.

Despite the remarkable clinical advance of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, there are limited studies focused on evaluating efficacy of ICIs for patients with human epidermal growth factor receptor 2 (HER2)-mutant lung adenocarcinoma. We conducted a multicenter retrospective study of patients with HER2-mutant lung adenocarcinoma who received ICIs therapy at Shanghai Pulmonary Hospital, Shanghai Chest Hospital and the First Affiliated Hospital of Wenzhou Medical University between 2016 and 2021. Response was defined with reference to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Among the 26 patients enrolled in our study, the overall objective response rate (ORR) was 38.5%, disease control rate (DCR) was 84.6% and median progression-free survival (PFS) was 7.4months. Majority of patients were treated with immunochemotherapy combination regimens (16/26, 61.5%), with a median PFS of 8.4months. Among the 9 patients receiving ICIs-based therapy as first-line treatment, 5 patients had partial response (PR) and 4 patients had stable disease (SD), with a median PFS of 9.1months. Of the entire cohort, 5 patients who received ICIs before epidermal growth factor receptor (EGFR)/HER2-targeting drugs achieved a median PFS of 8.4months. Our retrospective study provides clinical evidence that front line of ICIs-based therapy is also worth considering for the treatment to improve survival outcomes of patients with HER2-mutant lung adenocarcinoma.