Antitumor activity and safety of camrelizumab combined with apatinib in patients with relapsed or refractory peripheral T-cell lymphoma: An open-label, multicenter, phase II study.

The treatment for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) is suboptimal. This open-label, multicenter, single-arm study aimed to investigate the antitumor activity and safety of camrelizumab (a PD-1 blockade) plus apatinib (an antiangiogenic agent) for patients with r/r PTCL. Eligible patients with r/r PTCL were enrolled and received camrelizumab 200 mg intravenously every 2 weeks and apatinib 500 or 250 mg orally once daily, 4 weeks as a cycle. The primary endpoint was overall response rate (ORR). A total of 20 patients were enrolled and received study medications in the study, with a median number of prior treatment line of 3 (range 1-6). At the cutoff date of March 4, 2022, the median follow-up was 27.2 months (range: 0.5-39.9), and three patients remained on treatment. Six patients had early discontinuation without tumor response evaluation. For all patients, the ORR was 30% (6/20) (95% confidence interval [CI], 11.9% to 54.3%), with two patients (10%) achieving complete response. The median progression-free survival (PFS) and median overall survival for all patients were 5.6 months (95% CI, 1.8 to not reached) and 16.7 months (95% CI, 2.8 to not reached), respectively. Patients with PD-L1 expression ≥50% (3 patients) had a numerically higher ORR and longer median PFS than those with PD-L1 expression < 50% (5 patients). The most commonly reported grade 3 or higher adverse events were hyperlipidemia (15%), hypokalemia (15%) and anemia (15%). No treatment-related deaths occurred. In this study, PD-1 inhibitors plus low-dose antiangiogenic drugs presented preliminary antitumor activity and manageable toxicity in patients with r/r PTCL.

Liu Y ，Song Y ，Zuo S ，Zhang X ，Liu H ，Wang J ，Wang J ，Tang Y ，Zheng W ，Ying Z ，Ping L ，Zhang C ，Wu M ，Zhu J ，Xie Y ... -  《Frontiers in Immunology》

Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002).

Shi Y ，Wu J ，Wang Z ，Zhang L ，Wang Z ，Zhang M ，Cen H ，Peng Z ，Li Y ，Fan L ，Guo Y ，Ma L ，Cui J ，Gao Y ，Yang H ，Zhang H ，Wang L ，Zhang W ，Zhang H ，Xie L ，Jiang M ，Zhou H ，Shuang Y ，Su H ，Ke X ，Jin C ，Du X ，Du X ，Liu L ，Xi Y ，Ge Z ，Feng R ，Zhang Y ，Zhou S ，Xie F ，Wang Q ... -  《Journal of Hematology & Oncology》

Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase II trial.

Previous trials showed that antiangiogenesis or anti-programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) monotherapy only showed marginal effect in triple-negative breast cancer (TNBC). Preclinical studies demonstrated that antiangiogenic therapy could sensitize breast cancer to PD-1/PD-L1 blockade via reprogramming tumor microenvironment. Combinational treatment of checkpoint blockade and antiangiogenesis for TNBC has not been reported. Patients with advanced TNBC with less than three lines of systemic therapy were enrolled in an open-label, non-comparative, two-arm, phase II trial at Sun Yat-sen Memorial Hospital. Camrelizumab (intravenously every 2 weeks) with apatinib orally at either continuous dosing (d1-d14) or intermittent dosing (d1-d7) was given until disease progression or unacceptable toxicities. Primary endpoint was objective response rate (ORR). From January 2018 to April 2019, 40 patients were enrolled, including 10 in the apatinib intermittent dosing cohort and 30 in the apatinib continuous dosing cohort. The ORR was 43.3% (13 of 30) in the continuous dosing cohort, while no objective response was observed in the intermittent dosing cohort. The disease control rate was 63.3% (19 of 30) in the apatinib continuous dosing cohort, and 40.0% (4 of 10) in the apatinib intermittent dosing cohort, respectively. The median progression-free survival (PFS) was 3.7 (95% CI 2.0 to 6.4) months and 1.9 (95% CI 1.8 to 3.7) months in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, the median PFS of patients with partial response (8.3 months, 95% CI 5.9 to not reached) was significantly longer than that of patients with stable disease/progressive disease/not evaluable (2.0 months, 95% CI 1.7 to 3.0). The most common adverse events (AEs) included elevated aspartate aminotransferase/alanine aminotransferase and hand-foot syndrome. Overall, 26.7% and 20.0% of patients experienced grade ≥3 AEs in the continuous dosing and intermittent dosing cohort, respectively. In the continuous dosing cohort, a high percentage of baseline tumor-infiltrating lymphocytes (>10%) was associated with higher ORR and favorable PFS (p=0.029, 0.054, respectively). The ORR by this chemo-free regimen was dramatically higher than previously reported ORR by anti-PD-1/PD-L1 antibody or apatinib monotherapy. Camrelizumab combined with apatinib demonstrated favorable therapeutic effects and a manageable safety profile in patients with advanced TNBC. NCT03394287.

Liu J ，Liu Q ，Li Y ，Li Q ，Su F ，Yao H ，Su S ，Wang Q ，Jin L ，Wang Y ，Lau WY ，Jiang Z ，Song E ... -  《Journal for ImmunoTherapy of Cancer》

Phase II clinical trial using camrelizumab combined with apatinib and chemotherapy as the first-line treatment of advanced esophageal squamous cell carcinoma.

Effective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma (ESCC). The incorporation of an immune checkpoint inhibitor and a molecular anti-angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects. Therefore, we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first-line treatment of advanced ESCC. In this single-arm prospective phase II trial, patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg, liposomal paclitaxel 150 mg/m2 , and nedaplatin 50 mg/m2 on day 1, and apatinib 250 mg on days 1-14. The treatments were repeated every 14 days for up to 9 cycles, followed by maintenance therapy with camrelizumab and apatinib. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. We enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow-up was 24.98 months (95% confidence interval [CI]: 23.05-26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%-92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%-99.9%). The median PFS was 6.85 months (95% CI: 4.46-14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months - not reached). The most common grade 3-4 treatment-related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment-related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and toxic epidermal necrolysis (3.3%). No treatment-related deaths occurred. Camrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first-line treatment demonstrated feasible anti-tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted. This trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: NCT03603756).

Zhang B ，Qi L ，Wang X ，Xu J ，Liu Y ，Mu L ，Wang X ，Bai L ，Huang J ... -  《Cancer Communications》

Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.

Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer. KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668. Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3). Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Geoerger B ，Kang HJ ，Yalon-Oren M ，Marshall LV ，Vezina C ，Pappo A ，Laetsch TW ，Petrilli AS ，Ebinger M ，Toporski J ，Glade-Bender J ，Nicholls W ，Fox E ，DuBois SG ，Macy ME ，Cohn SL ，Pathiraja K ，Diede SJ ，Ebbinghaus S ，Pinto N ... -  《-》