Independent Radiology Review Committee Research Articles

Five-Year Follow-Up of POLARIS-01 Phase II Trial: Toripalimab as Salvage Monotherapy in Chinese Patients With Advanced Melanoma.

To investigate the efficacy and toxicity after long-term follow-up of anti-PD-1 antibody in advanced melanoma with predominantly acral and mucosal subtypes. In the POLARIS-01 phase II trial, 128 Chinese patients with advanced melanoma refractory to standard therapy received toripalimab until disease progression or unacceptable toxicity for ≤2 years. For those who progressed after discontinuation due to 2-year treatment completion, rechallenge was allowed. The primary objectives were safety and overall response rate (ORR). As of February 8, 2021, ORR was 17.3% (95% CI: 11.2-25.0) evaluated by the independent radiologic review committee. The median overall survival (OS) for patients with known melanoma subtypes was 16.3 m for acral, 41.5 m for nonacral cutaneous, and 10.3 m for mucosal melanoma. Thereafter, the evaluation was continued by investigators. As of November 4, 2022, 5 years after the last enrollment, median duration of response was 15.6 months (range, 3.7-64.5+), median progression-free survival (PFS) was 3.5 months (95% CI, 2.2-5.3), and 60-month OS rate was 28.5% (95% CI: 20.2-37.2). Thirteen patients completed a 2-year treatment of toripalimab, with the subtypes of acral (2/13), non-acral cutaneous (4/13), mucosal (3/13) and unknown primary (4/13). Five patients were rechallenged. Four of them, all of whom were non-mucosal, completed the rechallenge course of 2 years with PFS ≥ 24 months. This is the largest prospective anti-PD-1 trial with mature data in advanced melanoma in China. Toripalimab demonstrated a manageable safety profile and durable clinical response in Chinese patients with metastatic melanoma who had failed in standard therapy. Immunotherapy seems less efficacious for long-term responders with mucosal primaries as rechallenge therapy.

A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma

BackgroundNRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. MethodsWe conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. FindingsBetween November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred. InterpretationTunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial.

363 Background: First-line NIVO+IPI has provided substantial long-term survival benefits over SUN in patients (pts) with aRCC in CheckMate 214. We report survival, response per independent radiology review committee (IRRC) and safety after 6 y minimum (80 mo median) follow-up in all randomized pts, by IMDC risk and in pts with overall survival (OS) ≥ 6 y (long-term survivors; LTS). Longer follow-up data (minimum, 7.5 y) will be presented. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO 3 mg/kg Q2W vs SUN 50 mg QD for 4 wk on, 2 wk off. Endpoints: OS, progression-free survival (PFS) and objective response rate (ORR; both per IRRC using RECIST v1.1) in IMDC intermediate/poor risk (IP; primary), intent-to-treat (ITT; secondary) and favorable risk (FAV; exploratory) pts. Exploratory outcomes in LTS pts were assessed post hoc. Results: OS with NIVO+IPI vs SUN remained superior in ITT (HR 0.72) and IP (HR 0.68) pts; OS benefits were similar between arms in FAV pts (HR 0.87; Table). Median PFS was consistent with previous reports. ORR per IRRC was higher with NIVO+IPI vs SUN, with more ongoing responses in ITT (60% vs 50%) and IP (60% vs 50%) pts. In FAV pts, ORR was lower with NIVO+IPI vs SUN, yet more responses were ongoing (59% vs 52%, respectively). Median duration of response (DOR) was longer and complete response (CR) rate was higher with NIVO+IPI vs SUN regardless of IMDC risk. Incidence of any and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. In the LTS subgroup (NIVO+IPI, n = 208; SUN, n = 151), ORR was higher (66% vs 53%), more pts had a CR (27% vs 9%) and fewer progressed (4% vs 11%) with NIVO+IPI vs SUN. Median DOR was longer with NIVO+IPI (n = 137) vs SUN (n = 80) among LTS with confirmed response (76 vs 40 mo). Updated survival, response and safety data with 7.5 y minimum follow-up, along with additional subgroup analyses, will be presented. Conclusions: NIVO+IPI demonstrated long-term survival and more durable response benefits vs SUN in ITT and IP pts. CR rates were higher and median DOR was longer with NIVO+IPI vs SUN regardless of IMDC risk group, and in LTS pts. No new safety signals emerged. Clinical trial information: NCT02231749 . [Table: see text]

Deutenzalutamide, an oral deuterated androgen receptor inhibitor, vs placebo for patients with mCRPC who have experienced treatment failure with abiraterone and docetaxel: Results of the HC-1119-04 phase 3 trial.

5065 Background: Deutenzalutamide (HC-1119) is a novel deuterated derivative of enzalutamide with a different metabolic profile while maintaining biologic activity at a lower dose. Abiraterone and docetaxel are widely used in mCRPC, however, resistance mechanisms eventually occur. Methods: The HC-1119-04 (NCT03851640), a multicenter, randomized, double-blind phase 3 trial in China enrolled patients with mCRPC who have failed abiraterone, or failed or were not eligible for docetaxel. Patients were randomized 2:1 to deutenzalutamide (80 mg orally daily) or placebo. Stratification factors included lesion site (visceral/non-visceral), prior docetaxel treatment (yes/no). The primary endpoint was investigator-assessed radiographic PFS. Secondary endpoints included: OS, independent radiologic review committee (IRC)-assessed rPFS, ORR, and PSA response. The hazard ratio (HR) and its 95% confidence interval (CI) between the two groups were calculated using a stratified Cox proportional hazards model. Results: The HC-1119-04 study enrolled 417 subjects between April 2019 – Nov 2021, with 276 randomized to deutenzalutamide and 141 to placebo. Demographics and disease characteristics were well-balanced across treatment arms. All subjects were previously treated with abiraterone. Most of the subjects received docetaxel (68.8% vs. 68.1%); visceral lesions accounted for 27.9% in the deutenzalutamide and 27.7% in the placebo group. The study met its primary endpoint with a 42% reduction in the risk of progression or death in the deutenzalutamide arm (HR = 0.58 [95% CI: 0.439, 0.770]; P= 0.001. The median rPFS (95% CI) was 5.55 (4.830, 7.360) months for deutenzalutamide vs 3.71 (2.860, 5.490) months for placebo. Results in the pre-specified subgroups, including visceral metastases, and prior docetaxel were consistent with the overall outcome. The median OS (95% CI) was 14.98 (9.560, -) months and 11.24 (9.890, 15.510) months in the deutenzalutamide and placebo group, respectively, with an HR (95% CI) of 0.88 (0.577, 1.331). Common treatment-related adverse events (TEAE) ( > 10%) with deutenzalutamide vs placebo included: weight decreased (23.4% vs 18.6%), platelet count decreased (12.8% vs 10.7%), lymphocyte count decreased (10.2% vs 7.9%), and hypercholesterolemia (10.9% vs 4.3%), mostly grade 1/2. The overall incidence of ≥ Grade 3 study drug related TEAEs in the deutenzalutamide group was not significantly different from placebo, except anemia (6.6% vs 2.9%) and hypertension (2.2% vs 0.7%). Conclusions: Deutenzalutamide demonstrated a statistically significant improvement of PFS vs placebo in a randomized phase 3 study in patients with mCRPC who have failed abiraterone, and who failed or were intolerant to docetaxel. Deutenzalutamide was well tolerated and has the potential as additional treatment option. Clinical trial information: NCT03851640 .

Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .

A phase 2 study of HLX07 as monotherapy or combination therapy in patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma.

4029 Background: Esophageal cancer is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. Most patients are diagnosed at the advanced stage, and the prognosis remains poor. About 40–84% of ESCC cases showed overexpression of EGFR which was related to shorter overall survival and disease-free survival, indicating that treatment targeting EGFR could be a new strategy. This study aimed to evaluate the efficacy and safety of HLX07, a novel recombinant humanized anti-EGFR monoclonal antibody (mAb), as monotherapy or combination therapy in patients with locally advanced, unresectable/metastatic ESCC. Methods: In this open-label, multicenter phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed locally advanced, unresectable/metastatic ESCC or esophageal adenosquamous carcinoma were enrolled. Patients with no prior systemic antitumor therapy were assigned to group A and given HLX07 1000 mg plus serplulimab 200 mg (anti-PD-1 mAb) and chemotherapy (5-FU 2400 mg/m2 + cisplatin 50 mg/m2), Q2W IV. Patients who had failed first-line immuno-chemotherapy combination or at least two lines of other systemic antitumor therapy were assigned to group B and given HLX07 monotherapy (1000 mg Q2W IV). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) assessed by an independent radiological review committee and investigators per RECIST v1.1. Secondary endpoints included other efficacy measures, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of February 4, 2023, 49 patients were enrolled in group A (n=30) and group B (n=19), with a median age of 64.5 and 59.0 years, respectively. 26 (86.7%) patients in group A and all patients in group B were male. The median follow-up duration was 2.9 months, and the preliminary efficacy was presented. Among the 42 efficacy evaluable patients (29 in group A and 13 in group B), investigator-assessed ORRs were 55.2% (95% CI 35.7–73.6%) and 23.1% (95% CI 5.0–53.8%) in the respective groups. Investigator-assessed median PFSs were not reached in group A and 1.5 months (95% CI 1.2–not evaluable) in group B. 15 (50.0%) patients in group A and 5 (26.3%) in group B had grade ≥3 treatment-emergent adverse events (AEs). AEs of special interest were observed in 16 (53.3%) and 11 (57.9%) patients, respectively, most commonly rash (43.3% vs 47.4%) and hypomagnesemia (33.3% vs 36.8%). No drug-related death was reported. Conclusions: The encouraging antitumor activity and manageable safety profile support further development of HLX07 as a new treatment option for patients with advanced ESCC, both in first-line and late-line settings. Clinical trial information: NCT05221658 .

Abstract CT208: Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study

Abstract Background: Immune checkpoint inhibitors (CPIs) targeting PD-(L)1 have become a standard of care for untreated, advanced melanoma, but demonstrated limited efficacy in mucosal melanoma. Tebotelimab, also known as MGD013, is a PD-1/LAG-3 bispecific tetravalent DART® molecule with synergistic antitumor activity shown in preclinical studies. We conducted an open-label, single-arm, multi-cohort phase 1 study (NCT04653038) to assess the efficacy and safety of tebotelimab in melanoma patients (pts) including those with CPI-naïve mucosal melanoma. Methods: The CPI-naïve cohort of this study enrolled pts with unresectable, recurrent or metastatic, mucosal or acral melanoma who had received no systemic therapy. Tebotelimab 600 mg was administered intravenously once every two weeks. The primary endpoint was overall response rate (ORR) assessed by independent radiologic review committee (IRC) per RECIST v1.1 in the efficacy analysis set consisting of pts who received ≥1 dose of tebotelimab. A post-hoc sensitivity analysis was conducted in the IRC-response evaluable set consisting of pts with IRC-assessed target lesions in the efficacy analysis set who received ≥1 post-baseline tumor assessment by IRC or died within 13 weeks after first dose. Results are reported for mucosal melanoma. Results: At data cut-off (January 19, 2022), 25 pts with mucosal melanoma were enrolled (median age, 61 years; male, 40%; ECOG 1, 40%; TNM Stage IV, 92%; metastatic, 80%). LAG-3 expression level was ≥1% in seven (28%), <1% in 15 (60%), and unknown in three (12%). PD-L1 expression was positive (CPS≥1) in three (12%), negative (CPS<1) in 19 (76%), and unknown in three (12%). All pts received ≥1 dose of tebotelimab. In the efficacy analysis set (n=25), three, three, and four pts achieved complete response (CR), partial response (PR), and stable disease (SD), respectively, leading to a confirmed ORR of 24% (95% confidence interval [CI], 9-45), with median duration of response (DOR) not reached, and a disease control rate (DCR) of 40% (95% CI, 21-61). In the IRC-response evaluable set (n=20), three, three, and four pts achieved CR, PR, and SD, respectively, leading to a confirmed ORR of 30% (95% CI, 12-54), with median DOR not reached, and a DCR of 50% (95% CI, 27-73). Immune-related treatment-emergent adverse events occurred in 11 (44%) pts, most commonly, hypothyroidism (20%), hyperthyroidism (16%), and white blood cell count decreased (12%). Grade ≥3 and serious treatment-related adverse events (TRAEs) were reported in three (12%) and four (16%) pts, respectively. TRAEs led to treatment discontinuation and death each in one (4%). Conclusions: Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma. Citation Format: Si Lu, Yu Chen, Meiyu Fang, Zhengyun Zou, Di Wu, Zhiguo Luo, Jian Zhang, Jing Chen, Gang Huang, Hongming Pan, Xiubao Ren, Ying Cheng, Haichuan Su, Yuan Xin, Qiong Hua, Jianmei Hou, Jun Guo. Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study [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 CT208.

Abstract CT153: Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study

Abstract Background: Pemigatinib is a selective FGFR inhibitor that showed effectiveness and tolerability in patients with cholangiocarcinoma (CAA) with FGFR2 fusion or rearrangement. Data from prior data cutoffs (primary: Jan 29th, 2021; initial update: Dec 20th, 2021) showed that patients receiving pemigatinib had durable responses. Confirmed objective response rate (ORR) (60%) met the primary endpoint, median duration of response (DOR) was 8.3 months, median progression-free survival (PFS) was 9.1 months at the initial update (G-M. Shi et al. ASCO 2022). Safety results were also consistent with previously reported data on pemigatinib. Here we report updated overall survival (OS) results. Methods: Patients aged 18 years or older with recurrent or metastatic CCA that failed at least one prior systemic therapy were enrolled. Thirty-one subjects with documented FGFR2 fusion or rearrangement received 13.5 mg pemigatinib. The primary efficacy endpoint was ORR assessed by the independent radiological review committee (IRRC) per RECIST V1.1. And the second endpoints included disease control rate (DCR), DOR, PFS, and OS. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Results: At data cutoff (December 28th, 2022), a total of 30 patients were assessed (1 participant excluded due to inadequate FGFR2 aberrant frequency). Median age was 56 years (range, 28-68).With a median OS follow-up of 25.6 months (95% CI, 23.0-25.8), the median OS was 23.9 months (95% CI, 15.2-NC), with 16 (53.3%) OS events. Estimated OS rate at 12 month, 18 month and 24 month were 73.3% (95% CI, 53.7%-85.7%), 66.5% (95% CI, 46.7%-80.4%), and 41.4% (95% CI, 22.4%-59.4%), respectively. No new safety signals were observed. Conclusions: These updated results demonstrated encouraging and durable survival benefit of pemigatinib in Chinese patients with recurrent or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement. Clinical trial identification: NCT04256980. Editorial acknowledgment: Guoming Shi and Xiaoyong Huang contributed equally to this work. Jian Zhou is the corresponding author. Citation Format: Guoming Shi, Xiaoyong Huang, Tianfu Wen, Tianqiang Song, Ming Kuang, Haibo Mou, Lequn Bao, Haitao Zhao, Hong Zhao, Xielin Feng, Bixiang Zhang, Tao Peng, Yubao Zhang, Xiangcheng Li, Hongsheng Yu, Yu Cao, Yang Luo, Ye Chen, Mingxia Chen, Jia Fan, Jian Zhou. Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study [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 CT153.

Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study.

Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL. Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Report of adverse events of special interest (AESIs) for sintilimab plus a bevacizumab biosimilar (IBI305) in unresectable hepatocellular carcinoma.

530 Background: In the phase III Orient-32 trial (NCT03794440), sintilimab plus IBI305 demonstrated a meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs. sorafenib (Sor) in patients (pts) with unresectable HCC. Here we report the AESIs for sintilimab and IBI305 in Orient-32. Methods: 571 eligible pts with unresectable HCC were randomly assigned (2:1) to receive either sintilimab plus IBI305 or Sor (400 mg orally twice daily), until disease progression or unacceptable toxicity. The co-primary endpoints were OS and independent radiological review committee (IRRC)-assessed PFS according to RECIST 1.1. AESIs were defined by the sponsor and reported without judgement of causality. Analyses explored the incidence and severity of AESIs as well as correlation between AESIs and efficacy. Results: The safety set included 402 pts in the sintilimab plus IBI305 group and 184 pts in the Sor group. At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. Any AESIs (≥1%) for sintilimab plus IBI305 group and Sor group occurred in 77.9% pts and 53.3% pts, respectively. The incidence of treatment-related grade 3-4 AESI for sintilimab+IBI305 was 31.3% and treatment-related serious AESI was 13.9%. The most common any AESIs were proteinuria (61.7% ), hypertension (41.8%), hemorrhage (15.4%) and hyperthyroidism (14.2%) (Table). In the characteristics of baseline, ages can be a predictor of the onset of proteinuria, hypertension and hyperthyroidism. In addition, the occurrence of of proteinuria and hypertension can be a predictor for a better survival. Conclusions: AESIs for sintilimab and IBI305 were tolerable and manageable in Orient-32 trial. Further, the incidence and severity of AESIs were consistent with the known safety profiles of the individual agents. Clinical trial information: NCT03794440 . [Table: see text]

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m2) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m2) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48–0.75; P < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53–0.87; P = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov (NCT03958890).

Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer

BackgroundIGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. MethodsPatients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1–18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8–89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0–3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8–2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. ConclusionsIGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Bevacizumab biosimilar candidate TAB008 compared to Avastin® in patients with locally advanced, metastatic EGFR wild-type non-squamous non-small cell lung cancer: a randomized, double-blind, multicenter study.

Bevacizumab (Avastin®) is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Used alone or in combination with chemotherapy and/or immunotherapy, Avastin® has shown promising efficacy in many cancers. This study compared the efficacy and safety of TAB008 with Avastin® sourced from the EU (bevacizumab-EU), in patients with non-squamous non-small cell lung cancer (nsNSCLC). In this randomized, double-blind, multicenter, phase III similarity study, treatment naïve for metastatic lung cancer., EGFR wild-type, locally advanced, metastatic, or recurrent non-squamous, non-small cell, lung cancer (nsNSCLC) patients were enrolled and randomized (1:1) into TAB008 or Avastin® groups. Patients received TAB008 or Avastin® 15mg/kg intravenously plus paclitaxel/carboplatin for 4-6 cycles followed by TAB008 or Avastin® 7.5mg/kg until disease progression, unacceptable toxicity or death. The primary endpoint compared the objective response rate (ORR) within 6 cycles as read by an independent radiological review committee (IRRC). Secondary endpoints compared disease control rate (DCR) Within 6 cycles, duration of response (DoR), progression-free survival (PFS), a year overall survival rate (OSR), overall survival (OS), safety, immunogenicity, and steady-state pharmacokinetics. A total of 549 nsNSCLC patients were enrolled (277 in TAB008 group and 272 in Avastin® group). In the full analysis set, ORRs were 55.957% for TAB008 and 55.720% for Avastin®, and the ORR ratio was 1 (90% CI 0.89-1.14), well within the predefined equivalence margin of 0.75-1.33. No significant differences were found in DCR within 6 cycles (95.703% vs 95.367%, p = 0.8536), DoR (8.17 vs 7.3months, p = 0.3526), PFS (9.10 vs. 7.97months, p = 0.9457), 1year overall survival rate (66.2% vs 68%, p = 0.6793), or OS (20.4 vs 17.6months, p = 0.6549). Serious adverse events (SAEs) occurred in 37.55% (104/277) of patients in the TAB008 group and 34.32% (93/271) in the Avastin® group. Anti-drug antibodies were reported in 3 of 277 (1.08%) TAB008 patients, and 5 of 271 (1.85%) Avastin® patients, neutralizing antibody (Nab) was positive in 1 patient on Avastin®, which became negative upon follow-up. The steady-state trough concentrations (Cssmin) were 106.13μg/mL in TAB008 group and 96.03μg/mL in Avastin® groups, with the treatment group ratio of LS geometric means fully contained within the bioequivalence limits of 80.00-125.00% (90% CI was 101.74-120.05%). TAB008 is similar to Avastin® in terms of efficacy, safety, and pharmacokinetic parameters, with comparable immunogenicity. ClinicalTrials.gov number; NCT05427305.

Serplulimab, a novel anti-PD-1 antibody, in patients with microsatellite instability-high solid tumours: an open-label, single-arm, multicentre, phase II trial

BackgroundMicrosatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumours have a high response rate to immunotherapy. Antitumour activity and safety of serplulimab, a novel humanised anti-PD-1 monoclonal antibody, were evaluated in this phase II study.MethodsIn this ongoing, single-arm, open-label, phase II trial, patients with previously treated unresectable or metastatic MSI-H/dMMR solid tumours received intravenous serplulimab 3 mg/kg every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included additional efficacy measures, safety, and tolerability.ResultsAs of 9 January 2021, 108 patients were enrolled, and 68 patients with confirmed MSI-H solid tumours were included in the main efficacy analysis population (MEAP). The median follow-up duration in the MEAP was 7.7 months, with an ORR of 38.2% (95% confidence interval, 26.7–50.8). Of the 108 patients, grade ≥3 treatment-emergent adverse events were reported in 53 (49.1%) patients; immune-related adverse events occurred in 52 (48.1%) patients.ConclusionsSerplulimab demonstrates a durable antitumour effect and a manageable safety profile in previously treated patients with MSI-H solid tumours. Serplulimab is a promising tissue-agnostic treatment for previously treated MSI-H solid tumours.Trial registrationNCT03941574.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. ClinicalTrials.gov Identifier: NCT04063163.

Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial (075)

Objectives: No standard of care in the 2L+ setting for women with recurrent or metastatic (R/M) cervical cancer. Cadonilimab (AK104) is a bi-specific antibody against PD-1 and CTLA4. We assessed the efficacy and safety of cadonilimab in immune checkpoint inhibitor (ICI) naïve patients (pts) with R/M cervical cancer, regardless of PD-L1 status. Methods: This multi-center, open-label, single-arm, phase II study enrolled pts with advanced cervical cancer who had progressed on or after two or fewer previous doublet chemotherapy with or without bevacizumab. Pts received cadonilimab 6 mg/kg every two weeks. The primary endpoint was ORR assessed by the independent radiological review committee (IRRC) per RECIST version 1.1, and the key secondary endpoint was the duration of response (DoR). Results: As of August 5, 2021, 111 pts had received at least one dose of cadonilimab. The median age was 52.0 years (range: 27-73 years). Thirty-six percent of pts had received two prior lines of systemic therapy, 92.8% had squamous cell disease, 56.8% had an ECOG score of 1, 25.0% had received bevacizumab. After median follow-up of 9.63 months (mo) (range: 0.7-21.4), the IRRC-assessed confirmed ORR in 100 pts evaluable for efficacy was 33.0% (95% CI: 23.9%-43.1%), with 12 (12.0%) CR and 21 (21.0%) PR. Median DoR was not reached (range: 0.95+-13.14+ mo); 6- and 12-mo DoR rates were 77.6% and 52.9%, respectively. Median PFS was 3.75 mo (95% CI: 2.00-6.41); 6-and 12 - mo PFS rates were 41.4% and 21.2%, respectively. Median OS was 17.51 mo (95% CI: 11.37 - NE); 6- and 12 - mo OS rates were 80.1% and 64.6%, respectively. Among 64 pts with PD-L1 positive tumors (CPS≥1), the ORR was 43.8% (95% CI: 31.4%-56.7%), the median PFS was 6.34 mo (95% CI: 3.12-11.17), and the median OS was not reached (95% CI: 17.51 mo-NE). Treatment-related adverse events (TRAEs) occurred in 96.4% of 111 patients. Grade 3 to 4 treatment-related adverse events occurred in 28.8% of 111 patients; the most common were anemia (7.2%) and decreased appetite (2.7%). Conclusions: Cadonilimab monotherapy is efficacious and safe as 2L+ treatment of R/M cervical cancer in ICI naïve pts, regardless of PD-L1 status. A phase III confirmatory trial to evaluate cadonilimab plus chemotherapy as 1L treatment for R/M cervical cancer is ongoing. Objectives: No standard of care in the 2L+ setting for women with recurrent or metastatic (R/M) cervical cancer. Cadonilimab (AK104) is a bi-specific antibody against PD-1 and CTLA4. We assessed the efficacy and safety of cadonilimab in immune checkpoint inhibitor (ICI) naïve patients (pts) with R/M cervical cancer, regardless of PD-L1 status. Methods: This multi-center, open-label, single-arm, phase II study enrolled pts with advanced cervical cancer who had progressed on or after two or fewer previous doublet chemotherapy with or without bevacizumab. Pts received cadonilimab 6 mg/kg every two weeks. The primary endpoint was ORR assessed by the independent radiological review committee (IRRC) per RECIST version 1.1, and the key secondary endpoint was the duration of response (DoR). Results: As of August 5, 2021, 111 pts had received at least one dose of cadonilimab. The median age was 52.0 years (range: 27-73 years). Thirty-six percent of pts had received two prior lines of systemic therapy, 92.8% had squamous cell disease, 56.8% had an ECOG score of 1, 25.0% had received bevacizumab. After median follow-up of 9.63 months (mo) (range: 0.7-21.4), the IRRC-assessed confirmed ORR in 100 pts evaluable for efficacy was 33.0% (95% CI: 23.9%-43.1%), with 12 (12.0%) CR and 21 (21.0%) PR. Median DoR was not reached (range: 0.95+-13.14+ mo); 6- and 12-mo DoR rates were 77.6% and 52.9%, respectively. Median PFS was 3.75 mo (95% CI: 2.00-6.41); 6-and 12 - mo PFS rates were 41.4% and 21.2%, respectively. Median OS was 17.51 mo (95% CI: 11.37 - NE); 6- and 12 - mo OS rates were 80.1% and 64.6%, respectively. Among 64 pts with PD-L1 positive tumors (CPS≥1), the ORR was 43.8% (95% CI: 31.4%-56.7%), the median PFS was 6.34 mo (95% CI: 3.12-11.17), and the median OS was not reached (95% CI: 17.51 mo-NE). Treatment-related adverse events (TRAEs) occurred in 96.4% of 111 patients. Grade 3 to 4 treatment-related adverse events occurred in 28.8% of 111 patients; the most common were anemia (7.2%) and decreased appetite (2.7%). Conclusions: Cadonilimab monotherapy is efficacious and safe as 2L+ treatment of R/M cervical cancer in ICI naïve pts, regardless of PD-L1 status. A phase III confirmatory trial to evaluate cadonilimab plus chemotherapy as 1L treatment for R/M cervical cancer is ongoing.

Efficacy and safety of serplulimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel in patients with advanced cervical cancer who have progressive disease or intolerable toxicity after first-line standard chemotherapy (074)

<b>Objectives:</b> Limited effective treatments are available for advanced cervical cancer patients who have failed first-line chemotherapy. Historical data indicate that PD-1 antibodies and albumin-bound paclitaxel monotherapy have certain antitumor activity (ORR: 14.3% for pembrolizumab and 28.6% for albumin-bound paclitaxel) in recurrent/advanced cervical cancer patients. This study aimed to determine the efficacy and safety of serplulimab (a recombinant humanized anti-PD-1 monoclonal antibody) plus albumin-bound paclitaxel in patients with advanced cervical cancer who have progressed on or are intolerant to first-line standard chemotherapy. <b>Methods:</b> This is an ongoing, single-arm, open-label, multi-center phase II study (NCT04150575). Twenty eligible patients aged between 18 and 75 years, who had ECGO PS 0 or 1, with histologically or cytologically diagnosed cervical cancer and positive PD-L1 expression (combined positive score [CPS] ≥1) were planned to be enrolled and given intravenous infusions of serplulimab (4.5 mg/kg) plus albumin-bound paclitaxel (260 mg/m²) every three weeks. The primary endpoints of this study were the adverse events, serious adverse events, and ORR (assessed by independent radiological review committee [IRRC] per RECIST v1.1). After all patients completed two tumor evaluations (every six weeks), a safety evaluation and a preliminary evaluation of antitumor efficacy were conducted. <b>Results:</b> By cut-off date July 15, 2021, 21 eligible patients were enrolled with a median age of 50.8 years (range: 31-64) and an average CPS of 39.3 (1 ≤CPS <20: <i>n</i>=7 [33.3%], CPS ≥20: <i>n</i>=14 [66.7%]). The median follow-up duration was 12.5 months; 71.4% patients had ECOG PS 1. The ORR assessed by IRRC and investigators were 57.1% (<i>n</i>=12; 95% CI: 34.0%-78.2%) and 47.6% (<i>n</i>=10; 95% CI: 25.7%-70.2%), respectively. The disease control rate (DCR) assessed by IRRC and investigators were both 76.2% (<i>n</i>=16; 95% CI: 52.8%-91.8%). The median PFS assessed by IRRC was 5.7 months (95% CI: 3.0-not reached). The median OS was not reached (95% CI: 10.5 months-not reached). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were decreased neutrophil count (<i>n</i>=7, 33.3%), decreased white blood cell count (<i>n</i>=6, 28.6%) and anemia (<i>n</i>=5, 23.8%). The most common immune-related adverse events (irAEs) were hypothyroidism (<i>n</i>=6, 28.6%), hyperthyroidism (<i>n</i>=3, 14.3%) and pruritus (<i>n</i>=3, 14.3%), all of which were grade 1 to 2. No TEAEs leading to drug discontinuation were observed. <b>Conclusions:</b> The results demonstrated a manageable safety profile and encouraging efficacy (IRRC-ORR: 57.1%) of serplulimab plus albumin-bound paclitaxel in advanced cervical cancer patients who have progressive disease or intolerable toxicity to first-line standard chemotherapy, representing a novel potential treatment option that warranted further investigation.

Penpulimab for Relapsed or Refractory Classical Hodgkin Lymphoma: A Multicenter, Single-Arm, Pivotal Phase I/II Trial (AK105-201).

BackgroundNearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL).MethodsAdult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs).ResultsA total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred.ConclusionsPenpulimab was effective and safe in patients with R/R cHL.

S215: GEMSTONE-201: PRE-PLANNED PRIMARY ANALYSIS OF A MULTICENTER, SINGLE-ARM, PHASE 2 STUDY OF SUGEMALIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY EXTRANODAL NATURAL KILLER/T CELL LYMPHOMA (R/R ENKTL)

Background: R/R ENKTL is a rare and aggressive type of non-Hodgkin’s lymphoma. Responses to chemotherapy after failure of prior asparaginase-based regimen were not durable with a median OS of < 7 months (mos) and 1-year OS rate of < 20% (Lim et al, Ann Oncol 2017; Bellei et al, Haematologica 2018). The only targeted therapy approved in China for R/R peripheral T cell lymphoma (ENKTL included) showed an ORR of 18.8% and a CR rate of 6.3% (Shi et al, Ann Oncol 2015). Aims: Here, we present the primary analysis from GEMSTONE-201, the largest registrational study reported to date to evaluate an anti-PD-L1 mAb in R/R ENKTL. Sugemalimab (Suge) received breakthrough therapy designation from US FDA in 2021 for adult R/R ENKTL patients (pts) based on preliminary data of this study. Methods: Pts with ECOG PS of 0 or 1 and histologically confirmed ENKTL who failed prior asparaginase-based regimen were enrolled. Pts accepted suge at 1200 mg intravenously every 3 weeks, for up to 24 mos until progression, death, or withdrawal from study. The primary endpoint was ORR (CR+PR) assessed by independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included investigator-assessed ORR, CR and PR rate, DoR assessed by IRRC and investigators, and safety. Results: As of the data cutoff date, 10 November 2021, 80 pts were enrolled and treated (median follow-up of 13.4 mos). Median age was 48 years (range 29-74); 64% were males; 74% had ECOG PS of 1 at baseline; 68% had stage IV disease; about half (49%) received ≥ 2 lines of prior systemic therapy. The median duration of treatment was 5.2 mos (range 0.7-37.4); 23 pts remained on treatment. Among the 78 evaluable pts as per IRRC, ORR was 46.2% (95% CI: 34.8%, 57.8%); 29 (37.2%) pts achieved CR; median DoR was not reached (NR); 12-mo DoR rate was 86%. Investigator’s assessments in 79 evaluable pts were consistent with IRRC results, i.e., ORR of 45.6% (95% CI: 34.3%, 57.2%), 24 (30.4%) pts with CR, and median DoR of NR. The 1- and 2-year OS rates were 68.6% and 54.6%, respectively; median OS was NR (range 0.9-37.2+ mos). Of all pts, 96% (n = 77) had at least one AE. The most common AEs were pyrexia and WBC decreased (n = 24 each, 30%). Grade ≥ 3 AEs occurred in 31 (38.8%) pts. Suge-related AEs occurred in 61 (76%) pts and were mostly (60%) Grade 1 or 2. The most common immune-related AE assessed by sponsor was hypothyroidism (n = 13, 16%). SAEs occurred in 18 (23%) pts; 5 (6%) pts had suge-related SAEs which had all been resolved (1 with sequelae). Fatal AEs occurred in 5 (6%) pts and none were suge-related as assessed by investigators. Summary/Conclusion: Suge has demonstrated deep and durable anti-tumor activity in R/R ENKTL pts, with a high CR rate and a promising OS benefit trend comparing to historical data. Suge had a well-tolerated safety profile and no new safety signals were detected. Primary analysis indicates that suge could provide a new treatment option to R/R ENKTL pts.

GEMSTONE-201: Preplanned primary analysis of a multicenter, single-arm, phase 2 study of sugemalimab (suge) in patients (pts) with relapsed or refractory extranodal natural killer/T cell lymphoma (R/R ENKTL).

7501 Background: R/R ENKTL is a rare and aggressive type of non-Hodgkin’s lymphoma. Responses to chemotherapy after failure of prior asparaginase-based regimen were not durable with a median OS of &lt; 7 months (mos) and 1-year OS rate of &lt; 20% (Lim et al, Ann Oncol 2017; Bellei et al, Haematologica 2018). The only targeted therapy approved in China for R/R peripheral T cell lymphoma (ENKTL included) showed an ORR of 18.8% and a CR rate of 6.3% (Shi et al, Ann Oncol 2015). Here, we present the primary analysis from GEMSTONE-201, the largest registrational study reported to date to evaluate an anti-PD-L1 mAb in R/R ENKTL. Suge received breakthrough therapy designation from US FDA in 2021 for adult R/R ENKTL pts based on preliminary data of this study. Methods: Pts with ECOG PS of 0/1 and histologically confirmed ENKTL who failed prior asparaginase-based regimen were enrolled. Pts accepted suge at 1200 mg Q3W, iv, for up to 24 mos, until progression, death, or withdrawal from study. The primary endpoint was ORR (CR+PR) assessed by independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included investigator-assessed ORR, CR and PR rate, DoR assessed by IRRC and investigators, and safety. Results: As of the data cutoff date, Nov 10, 2021, 80 pts were enrolled and treated (median follow-up of 13.4 mos). Median age was 48 years (range 29-74); 64% were males; 74% had ECOG PS of 1 at baseline; 68% had stage IV disease; about half (49%) received ≥ 2 lines of prior systemic therapy. The median duration of treatment was 5.2 mos (range 0.7-37.4); 23 pts remained on treatment. Among the 78 evaluable pts as per IRRC, ORR was 46.2% (95% CI: 34.8%, 57.8%); 29 (37.2%) pts achieved CR; median DoR was not reached (NR); 12-mo DoR rate was 86%. Investigator’s assessments in 79 evaluable pts were consistent with IRRC results, i.e. ORR of 45.6% (95% CI: 34.3%, 57.2%), 24 (30.4%) pts with CR, and median DoR of NR. The 1- and 2-year OS rates were 68.6% and 54.6%, respectively; median OS was NR (range 0.9-37.2+ mos). Of all pts, 96% (n = 77) had at least one AE. The most common AEs were pyrexia and WBC decreased (n = 24 each, 30%). Grade ≥ 3 AEs occurred in 31 (39%) pts. Suge-related AEs occurred in 61 (76%) pts and were mostly (60%) Grade 1/2. The most common irAE assessed by sponsor was hypothyroidism (n = 13, 16%). SAEs occurred in 18 (23%) pts; 5 (6%) pts had suge-related SAEs which had all been resolved (1 with sequelae). Fatal AEs occurred in 5 (6%) pts and none were suge-related as assessed by investigators. Conclusions: Suge has demonstrated deep and durable anti-tumor activity in R/R ENKTL pts, with a high CR rate and a promising OS benefit trend comparing to historical data. Suge had a well-tolerated safety profile and no new safety signals were detected. Primary analysis indicates that suge could provide a new treatment option to R/R ENKTL pts. Clinical trial information: NCT03595657.