Risvutatug Rezetecan Improves PFS in Relapsed/Refractory Osteosarcoma

At the 2026 European Society for Medical Oncology (ESMO) Congress, primary results from the phase 3 ARTEMIS-011 trial (NCT06935409) were presented, which showed that risvutatug rezetecan (ris-rez; formerly HS-20093 or GSK5764227) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs gemcitabine plus docetaxel in patients with heavily pretreated relapsed or refractory osteosarcoma.¹

Per blinded independent central review (BICR), the median PFS was 5.5 months (95% CI, 4.1-7.4) with ris-rez vs 1.4 months (95% CI, 0.8-2.7) with gemcitabine plus docetaxel, translating to a 67% reduction in the risk of disease progression or death (HR, 0.33; 95% CI, 0.20-0.55; P <.0001). The 4-month PFS rates were 65% and 33%, respectively.

Risvutatug rezetecan is an antibody-drug conjugate (ADC) that pairs an anti–B7-H3 IgG1 monoclonal antibody with a TOP1 inhibitor payload via a cleavable linker, with a drug-to-antibody ratio of approximately 4. B7-H3 is an immunosuppressive checkpoint protein that is highly expressed in many tumors, including sarcoma, whereas its expression in normal tissue is limited. The agent previously showed promising antitumor activity in patients with heavily pretreated relapsed/refractory sarcomas in the phase 2 ARTEMIS-002 study (NCT05830123).

ARTEMIS-011 was a multicenter, open-label, randomized, controlled trial that enrolled patients aged 12 years or older with pathologically confirmed osteosarcoma who had experienced progression on, or intolerance to, at least 2 prior lines of therapy. Eligible patients also had at least 1 measurable target lesion per RECIST v1.1 and an ECOG performance status of 0 or 1.

Patients were randomly assigned 2:1 to receive ris-rez at 12.0 mg/kg intravenously on day 1 every 3 weeks (n = 80) or gemcitabine at 1000 mg/m² on days 1 and 8 plus docetaxel at 75 mg/m² on day 8 every 3 weeks (n = 42). Randomization was stratified by age (12 to younger than 18 years vs 18 years or older) and the presence of lung metastases. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent, and patients in the control arm who met crossover criteria could switch to ris-rez following objective disease progression.

The primary end point was PFS by BICR per RECIST v1.1. Secondary end points included overall survival (OS); investigator-assessed PFS; objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) by BICR and investigator; and safety. The trial was designed assuming a median PFS of 5.0 months with ris-rez vs 2.5 months with chemotherapy (HR, 0.5), with 71 PFS events needed to achieve 80% power at a one-sided alpha of 0.025. As of the June 17, 2026, data cutoff, 72 BICR-assessed PFS events had occurred.

A total of 122 patients were randomly assigned and received at least 1 dose of study drug, and the median follow-up was 7.1 months. The median age was 22.0 years in the ris-rez arm and 21.0 years in the chemotherapy arm, and 25% and 26% of patients, respectively, were aged 12 to younger than 18 years. Most patients had metastatic disease involving the lungs and other sites (74% vs 64%) or the lungs only (25% vs 31%). Patients had received a median of 2.5 and 3.0 prior lines of systemic therapy, respectively; all had received prior chemotherapy, 26% in each arm had received immunotherapy, and 69% and 79% had received targeted therapy.

At data cutoff, BICR-assessed PFS events had occurred in 51% of patients in the ris-rez arm and 74% of those in the chemotherapy arm. The PFS benefit was consistent across prespecified subgroups, including patients aged 18 years or older (HR, 0.37; 95% CI, 0.21-0.67) and those aged 12 to younger than 18 years (HR, 0.26; 95% CI, 0.10-0.65), patients with baseline lung metastases (HR, 0.36; 95% CI, 0.21-0.59), and those who had received 2 (HR, 0.28; 95% CI, 0.13-0.58) or at least 3 prior lines of therapy (HR, 0.38; 95% CI, 0.19-0.76).

The BICR-assessed ORR was 15% with ris-rez vs 2% with chemotherapy (odds ratio [OR], 7.1; 95% CI, 0.9-56.1), and the DCR was 76% vs 33%, respectively (OR, 6.2; 95% CI, 2.8-14.0). No patient in either arm achieved a complete response. The median DOR by BICR was 7.6 months with ris-rez and was not reached in the chemotherapy arm, in which only 1 patient achieved a partial response. Investigator-assessed outcomes were consistent with BICR results, including a median PFS of 5.6 months (95% CI, 4.2-7.4) vs 1.0 month (95% CI, 0.7-2.3; HR, 0.30; 95% CI, 0.19-0.50) and a DCR of 83% vs 31%.

OS data were immature but suggested a numerical trend toward benefit with ris-rez. Ten deaths had occurred in each arm, representing 13% of patients in the ris-rez arm and 24% of those in the chemotherapy arm; median OS was not reached in either arm (HR, 0.51; 95% CI, 0.21-1.23). Seventeen patients in the chemotherapy arm crossed over to ris-rez following disease progression.

Regarding safety, the median treatment duration was 4.5 months with ris-rez vs 1.5 months for gemcitabine and 1.4 months for docetaxel. All patients in both arms experienced treatment-related adverse events (TRAEs), which were grade 3 or higher in 93% and 83% of patients and serious in 64% and 29%, respectively. TRAEs led to dose reductions in 71% vs 26% of patients, dose delays or interruptions in 48% vs 40%, and permanent treatment discontinuation in 4% vs 2%. No fatal TRAEs occurred.

The most common TRAEs of any grade and of grade 3 or higher in both arms were hematologic. In the ris-rez arm, grade 3 or higher decreases in white blood cell count (80%), neutrophil count (79%), platelet count (71%), and lymphocyte count (59%), as well as anemia (63%), were reported. Common lower-grade TRAEs with ris-rez included pyrexia, nausea, vomiting, hypoalbuminemia, increased alanine aminotransferase, and infusion-related reactions. Treatment-related interstitial lung disease was observed in 1 patient in the ris-rez arm and was grade 2.

Despite higher rates of adverse events, ris-rez was associated with a longer treatment duration and a manageable safety profile, the investigators noted. They concluded that the ARTEMIS-011 findings suggest ris-rez represents a promising treatment option for patients with previously treated relapsed or refractory osteosarcoma.

Reference

Xie L, Yao W, Hua Y, et al. Risvutatug rezetecan versus gemcitabine and docetaxel in heavily pretreated patients with relapsed or refractory osteosarcoma: primary results from the phase 3 ARTEMIS-011 study. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA9.