Several clinical trials have showed that combining an anti-CTLA-4 inhibitor and an anti-PD-(L)1 inhibitor increases the overall response compared with an anti-PD-(L)1 inhibitor alone. Bispecific antibodies targeting both PD-1 and CTLA-4 could be a new way to block CTLA-4 and PD-1. 

 Until now, 2 types of immune checkpoint inhibitors have shown clinical effectivity against a broad range of tumors: anti-CTLA-4 inhibitors (e.g. ipilimumab and tremelimumab) and PD-(L)1 inhibitors (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab). There is a rationale to combine these types of immune checkpoint inhibitors because anti-CTLA-4 inhibitors increase the expression of PD-L1 in some tumors and the combination of anti-CTLA-4 inhibition and PD-(L)1 inhibition favors effector T cell recruitment in preclinical tumor models [1]. In addition, several clinical trials have shown that combining an anti-CTLA-4 inhibitor and an anti-PD-(L)1 inhibitor increases the overall response compared with an anti-PD-(L)1 inhibitor alone [2]. However, the combination also induces more serious adverse events (grade ≥3).

Both MGD019 and AK104 are bi-specific, tetravalent antibodies targeting both CTLA-4 and PD-1. This makes these molecules potential new candidates to simultaneously block CTLA-4 and PD-L1, hence mimicking the clinical effect of a dual immune checkpoint blockade with e.g. nivolumab plus ipilimumab. Prof. Manish Sharma (START Midwest, Grand Rapids, USA) presented the results of phase 1, first-in-human, open-label, dose-escalation study of MGD019 in patients with advanced solid tumors [3]. At data cut-off, 33 patients (39% checkpoint-experienced, 3 median prior lines of therapy) were treated in dose escalation from 0.03 to 10 mg/kg. No maximum tolerated dose was defined.

Treatment-related adverse events occurred in 26 of 33 (78.8%) patients, most commonly fatigue (24%), nausea, arthralgia, pruritus, and rash (18% each). The rate of grade ≥3 treatment-related adverse events was 24.2%. Immune-related serious adverse events included enteritis, enterocolitis, pneumonitis, and myocarditis (n=1 each). Half-life of MGD019 was 12 days; full on-target binding to circulating T cells was observed at doses ≥3.0 mg every 3 weeks. Among 25 response-evaluable patients, 4 objective responses were observed also in tumor types that are typically not responsive to checkpoint blockade (microsatellite-stable colorectal cancer, metastatic thymoma [both confirmed partial response], anti-PD-L1-refractory serous fallopian tube carcinoma [unconfirmed partial response with >50% reduction of CA-125], and prostatic adenocarcinoma [confirmed complete response with resolution of PSA]); 9 patients had stable disease. Dose-dependent ICOS upregulation on circulating CD4-positive T cells was evident, consistent with CTLA-4 engagement. A phase 2 monotherapy in select expansion cohorts is forthcoming.

In addition, Prof. Michael Milward (University of Western Australia, Australia) presented results from a clinical phase 1 trial with AK104 in 18 patients with mesothelioma. Three out of 18 patients (16.7%) had a grade 3-4 treatment-related adverse event (fever, type 1 diabetes mellitus, and infusion-related reaction); and another 9 subjects experienced grade 1-2 treatment-related adverse events. Most commonly reported treatment-related adverse events were rash (6 patients) and infusion-related reaction (5 patients). Tumor assessment data was available for 15 patients. Confirmed objective response rate was 20%, with a disease control rate of 80%. Median progression-free survival (PFS) was 5.6 months; median PFS in patients who received AK104 in a dose of 4 mg/kg or more (n=16) was 12.9 months.

In conclusion, the initial results from both studies suggest that AK104 as well as MGD019 are well-tolerated and possess encouraging antitumor activity, which makes them potential new therapeutic options.

 

  1. Shi LZ, et al. Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy. Nat Commun. 2016; 7:12335.
  2. Yang Y, e al. Comparative Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Advanced Cancer: A Systematic Review and Meta-Analysis. Front Pharmacol. 2020; 11: 40.
  3. Sharma M, et al. A phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 x CTLA-4 DART® molecule in patients with advanced solid tumours. ESMO 2020 Virtual Meeting, abstract 1020O.
  4. Millward M, et al. Safety and antitumor activity of AK104, a bispecific antibody targeting PD-1 and CTLA-4, in patients with mesothelioma which is relapsed or refractory to standard therapies. ESMO 2020 Virtual Meeting, abstract 1021O