A Multicenter, Single-Arm, Phase II Trial of RC48-ADC Combined with Radiotherapy, PD-1/PD-L1 Inhibitor Sequential GM-CSF and IL-2 (PRaG3.0 regimen) for the Treatment of HER2-Expressing Advanced Solid Tumors

Abstract

<h3>Purpose/Objective(s)</h3> The molecular detection and tumor microenvironment research give insights into the mechanism of cancer initiation and progression. Meanwhile, the progress of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy. Evidence has shown that radiotherapy can induce a systemic anti-tumor immune response, which may potentially sensitize PD-1/PD-L1 inhibitors. Previous phase II trial showed that radiotherapy combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results. RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumors. An exploratory multi-center, single-arm phase II trial was conducted to assess the initial clinical efficacy and safety of PRaG3.0 regimen (RC48-ADC combined with radiotherapy, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2) for treatment of HER2-expressing pan-cancer. <h3>Materials/Methods</h3> Patients with advanced, confirmed HER2-expressing (IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC (2.0 mg/kg d1), then stereotactic body radiation therapy or hypofractionated radiotherapy (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF (200μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of radiotherapy. PRaG3.0 regimen was repeated every 3 weeks for at least 2 cycles. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). <h3>Results</h3> By February 2022, a total of 8 patients were enrolled. The median number of metastatic lesions was 5.0 (95%CI, 3.0 to 14.0). Six patients had at least one tumor assessment, involved gastric cancer, breast cancer, cervical cancer, pancreatic cancer. The most common treatment-related adverse events were alopecia (37.5%), fatigue (25.0%), hepatic damage (25.0%) and rash (25.0%). No Grade 3 and higher adverse events occurred. The ORR was 66.7% and disease control rate was 83.3% (RECIST 1.1). One cervical cancer and one pancreatic cancer achieved complete remission. <h3>Conclusion</h3> The PRaG3.0 regimen is tolerated with acceptable toxicity. Our data suggest the PRaG3.0 regimen further improve the synergistic antitumor effects; this precise paradigm may provide a promising salvage treatment of HER2-expressing advanced solid tumors. This trial is registered with ClinicalTrials.gov, No. NCT05115500.