An Innovative Regimen Basing on HFRT/SBRT and RC48-ADC Coactivation for Salvage Therapy in Patients with HER2-Expressing Advanced Solid Tumors

Abstract

It is now widely accepted that radiotherapy, especially hypofractionated radiation therapy (HFRT) or stereotactic radiotherapy (SBRT), can modulate tumor phenotypes, enhance antigen presentation and provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). The PRaG therapy is an innovative iRT, when combined with HFRT/SBRT, PD-1/L1 inhibitor and GM-CSF to activate the immune response and modulate the tumor microenvironment to exert the desired in abscopal effect. Previous studies have demonstrated encouraging efficacy of the PRaG regimen in the treatment of advanced refractory tumors. RC48-ADC is a promising anti-HER2 antibody-drug conjugate with inducing immunogenic cell death and widespread release of cancer cell antigens, synergize with immunotherapy by promoting effector T-cell activation. The aim of this study is to explore efficacy and safety of RC48-ADC combined with radiotherapy, PD-1/L1 inhibitor sequential GM-CSF and IL-2(PRaG3.0 regimen) for treatment of HER2-expressing advanced solid tumors. Participants with advanced, confirmed HER2-expressing (IHC3+, 2+ or 1+) solid tumors that had progressed after standard treatment, or intolerance were enrolled. In a PRaG3.0 regimen cycle, those received RC48-ADC (2.0 mg/kg d1, every 3 weeks), then HFRT (2-3 doses of 5-8 Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF (200 μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/L1 inhibitor was dosing within one week after completion of HFRT. After RC48-ADC combined with PD-1/L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT05115500. With the cutoff date of 31 December 2022, a total of 30 patients (n = 6 for gynecological cancer, n = 5 for pancreatic cancer, n = 19 for other cancers) were enrolled, in which 21 patients completed at least 1 tumor assessment. The objective response rate (ORR) was 42.9%, and the disease control rate was 71.4% by RECIST1.1. The ORR was 66.7% in gynecological cancer, 25.3% in pancreatic cancer, and 36.4% in other cancers. Median progression-free survival (PFS) for all patients was 7.0 months (95% CI: 3.4, 10.7). The most common treatment-related adverse events (TRAEs) included fatigue, fever, alopecia and anorexia. Grade ≥3 TRAEs occurred in two patients (6.7%). These preliminary results show that of PRaG3.0 regimen has a manageable safety profile and encouraging antitumor activity in heavily pretreated patients with HER2- expressing cancers. Ultimately the regimen achieved the accurate integration of RT, immunotherapy and targeted therapy.