Advances in pharmacokinetics and pharmacodynamics of PD-1/PD-L1 inhibitors.

Background Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18–75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1–49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993). Findings Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0–41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8–-9·6 vs 4·2 months, 95% CI 4·2–4·3; HR 0·43, 95% CI 0·33–0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7–9·7 vs 4·2 months, 4·1–4·3; HR 0·37, 0·27–0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group. Interpretation Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease. Funding The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso. 

First-line penpulimab combined with paclitaxel and carboplatin for metastatic squamous non-small-cell lung cancer in China (AK105-302): a multicentre, randomised, double-blind, placebo-controlled phase 3 clinical trial.

Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI’s, combinations of CPI’s and combinations of CPI’s with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15–20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.

https://www.mdpi.com/2077-0383/10/12/2662/pdf

Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Background Penpulimab is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1. Penpulimab was engineered to eliminate Fc?R binding and ADCC/ADCP completely, as compared to majority of marketed IgG4 PD-1 antibodies with ADCC/ADCP activity. ADCC/ADCP effects can induce T-cell apoptosis and clearance and then compromise anti-tumor activity. The removal of Fc?R binding eliminates Fc receptor mediated immune-cell recruitment and activation and could potentially reduce immune-related adverse reactions. Penpulimab demonstrated a slower PD-1 antigen binding off-rate than marketed PD-1 antibodies, which result in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and may contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab. Methods AK105-201 (NCT03722147) is a multicenter, single-arm, open-label study of penpulimab in R/R cHL. All pts received penpulimab 200 mg q2w until progression or unacceptable toxicity. Eligible pts had R/R cHL after ASCT, or at least 2 lines of prior chemotherapy. The primary endpoint was ORR based on the Lugano 2014 criteria as assessed by an independent review committee (IRC). Key secondary endpoints included CR rate, DCR, PFS, duration of response (DoR), safety, and tolerability. Results As of 10 January, 2020, the median follow-up was 6.3 months (range, 3.5 to 17.0). The anti-tumor activity of penpulimab in the 73 pts evaluable for efficacy (defined as pts who had an opportunity to be followed for at least 16 weeks) is shown in the table 1. At data cutoff, 91.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 93.6% of pts (G3 in 13.8% [13/94], no G4 or G5, treatment discontinuation in 2.1% [2/94]). Treatment-related SAEs occurred in 3.2%. Most frequent TRAEs (≥15%) were fever (24.5%), hypothyroidism (21.3%), upper respiratory tract infection (18.1%), and ALT elevations (17.0%). Grade ≥3 TRAEs reported in ≥2 pts were platelet count decreased (2.1%). Immune-related AEs were reported in 42.6% of pts (G3 in 2.1%: psoriasis [n=1], IgA nephropathy [n=1]). Conclusions Penpulimab was shown to be highly active resulting in a high CR rate in pts with R/R cHL. With longer follow-up, CR rate for penpulimab in R/R cHL could be further increased. Penpulimab demonstrated notably lower rates of SAE, TRAE leading to discontinuation, and Grade Grade ≥3 immune-related AEs in pts with R/R cHL. Trial Registration NCT03722147

https://jitc.bmj.com/content/jitc/8/Suppl_3/A473.full.pdf

791 A phase II study of the anti-programmed cell death-1 (PD-1) antibody penpulimab in patients with relapsed or refractory classic hodgkin lymphoma (cHL)

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791 A phase II study of the anti-programmed cell death-1 (PD-1) antibody penpulimab in patients with relapsed or refractory classic hodgkin lymphoma (cHL)