GSK (GSK) and Hansoh (HKEX: 3692) detail ris-rez gains in relapsed osteosarcoma

Full results from ARTEMIS-011, the Chinese Phase 3 trial of risvutatug rezetecan (ris-rez) in relapsed osteosarcoma, were presented at the ESMO Congress in Madrid on 26 October. Median progression-free survival, assessed by blinded independent central review, was 5.5 months with the B7-H3-directed antibody-drug conjugate against 1.4 months with gemcitabine plus docetaxel, a hazard ratio of 0.33 (95% CI 0.20 to 0.55). Hansoh Pharma sponsored the study; GSK holds the rights outside mainland China, Hong Kong, Macau and Taiwan.

The open-label trial randomised 122 patients two to one, 80 to ris-rez and 42 to chemotherapy. All had disease that had progressed after, or could not tolerate, at least two prior lines of systemic therapy, and patients as young as 12 were eligible. At four months, 65% of the ris-rez group were alive without progression, compared with 33% of the control group, and disease control rates were 76% and 33% respectively. When the partners announced in July that the primary endpoint had been met, they gave no figures, so the congress presentation is the first opportunity to judge the size of the effect.

The headline result is less complete than it looks. Objective responses were uncommon: 15% with ris-rez against 2% with chemotherapy, with no complete responses in either arm, and the confidence interval around that comparison was very wide. Overall survival is immature. Median survival had not been reached in either group, and the hazard ratio of 0.51 (95% CI 0.21 to 1.23) is not statistically significant. Ten patients had died in each arm, which with a two-to-one randomisation represents 13% and 24% of the respective groups. The benefit, in other words, is mainly a delay in progression rather than tumour shrinkage or a proven extension of life.

The tolerability burden is substantial. Grade 3 or higher treatment-related adverse events occurred in 93% of ris-rez patients, against 83% with chemotherapy, and serious treatment-related events in 64% against 29%. Dose reductions were needed in 71% of the ris-rez group, compared with 26%, although permanent discontinuation for toxicity was rare in both arms, at 4% and 2%. One case of grade 2 interstitial lung disease was reported with ris-rez. In a cancer that commonly affects adolescents and young adults, that profile will shape how clinicians use the drug, even where the alternatives are poor.

Osteosarcoma is the most common primary bone cancer but remains rare, with a global incidence GSK puts at about 3.4 cases per million people a year, and no treatment is approved after two prior lines. The commercial value of this indication alone is therefore modest. Its significance lies in what it adds to the asset: ris-rez now has positive Phase 3 results in two tumour types, following the survival result in relapsed small-cell lung cancer. The FDA has granted breakthrough therapy designation in both relapsed or refractory osteosarcoma and extensive-stage small-cell lung cancer.

Both pivotal trials, however, were conducted in China by Hansoh against Chinese standards of care. Western regulators will expect evidence generated in their own populations, and GSK's sarcoma programme is at an earlier stage: EMBOLD Sarcoma-202 is a global Phase 1b/2 study in previously treated advanced sarcomas, including osteosarcoma. Hansoh plans a regulatory submission in China based on ARTEMIS-011, while GSK's July announcement set out no US or European filing plan for the indication.

For GSK, which has used licensed Chinese assets to rebuild its oncology pipeline, as its recent dealmaking shows, the question is whether ris-rez can become a broad B7-H3 franchise across lung, prostate and other solid tumours rather than a niche product. A near fourfold extension in median progression-free survival in a refractory bone cancer is credible evidence of activity. The toxicity, the immature survival comparison and the absence of global randomised data mean the larger opportunity has yet to be demonstrated.