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Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors
XmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report preliminary data from an ongoing, multicenter, Phase 1 study investigating the safety/tolerability, pharmacokinetics/pharmacodynamics, and clinical activity (RECIST 1.1) of XmAb20717 in patients with selected advanced solid tumors.
A 3+3 dose-escalation design was used to establish a maximum tolerated (MTD)/recommended dose for evaluation in parallel expansion cohorts, including melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), prostate cancer, and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI; n 20 each). XmAb20717 was administered as an infusion on Days 1 and 15 of each 28-day cycle.
As of 08Jul2020, 109 patients had been treated (Table 1), and 30 were continuing treatment. In escalation, 6 dose levels (0.15-10.0 mg/kg) were evaluated (n=34); an MTD was not established. Expansion cohorts were initiated at 10 mg/kg (n=72), and a 15 mg/kg escalation cohort was added (n=3). T-cell proliferation was noted in peripheral blood at doses as low as 3 mg/kg and was highest at 10 mg/kg. At this dose, consistent proliferation of CD8+ and CD4+ T cells was observed, indicative of dual PD-1 and CTLA-4 checkpoint blockade (Figure 1). Paired pre- and post-dosing biopsies showed increased intratumoral T-cell infiltration and IFN-response signatures following treatment. Grade 3/4 treatment-related adverse events (TRAEs) reported for 3 patients included rash (13%), transaminase elevations (7%), lipase increased (4% [2% with amylase increased]), and acute kidney injury (3%), all considered immune-related. There were 2 Grade 5 TRAEs: immune-mediated pancreatitis (in the presence of pancreatic metastases) and immune-mediated myocarditis (Grade 4) that contributed to respiratory failure. A complete response was reported as the best overall response for 1 patient (melanoma); partial responses were reported for 5 patients (2 melanoma, 2 NSCLC, 1 ovarian). The objective response rate was 13% overall and 21% at 10 mg/kg (6/46 and 6/29 evaluable patients, respectively). All responders had prior CI exposure. Responses were observed only at 10 mg/kg and, within the 10 mg/kg group, appeared to correlate with higher peak serum concentration and area under the curve.
XmAb20717 induced T-cell proliferation in peripheral blood consistent with dual-checkpoint blockade. Preliminary data indicate XmAb20717 was generally well-tolerated and associated with evidence of antitumor activity in CI-pretreated patients with various types of advanced solid tumors.
The study was approved by each institution's IRB.
Table 1. Demographics and Baseline Characteristics
| Characteristic | Escalation (n = 37) | Expansion Cohorts | ||||
| Melanoma (n = 20) | RCC (n = 8) | NSCLC (n = 20) | Prostate (n = 7) | Basket (n = 17) | ||
| Age, median (range) | 56 (32-81) | 67 (45-82) | 64 (55-85) | 72 (49-81) | 69 (63-74) | 61 (41-78) |
| Male | 60% | 60% | 75% | 75% | 100% | 24% |
| Months since initial diagnosis, median (range) | 43 (3-313) | 58 (6-511) | 74 (52-249) | 38 (8-113) | 85 (1-110) | 30 (1-165) |
| Lines of prior systemic therapy, median (range) | 4 (0-9) | 3 (0-9) | 4 (0-6) | 3 (0-9) | 0 (0-11) | 5 (0-8) |
| Prior checkpoint inhibitor therapy | 76% | 80% | 63% | 70% | 14% | 35% |