Keytruda beaten by Summit’s bispecific in NSCLC

On 8 September 2024, Summit Therapeutics and Akeso published results for the Phase III HARMONi-2 trial, which tested ivonescimab, a bispecific monoclonal antibody that binds to vascular endothelial growth factor A and programmed cell death protein 1 (PD-1), head-to-head with Merck‘s Keytruda, a PD-1 binding checkpoint inhibitor, in non-small cell lung cancer (NSCLC) patients with a PD-L1 tumour proportion score (TPS) above 1%. The trial, which took place in China, was hotly anticipated as Keytruda has been the standard of care in this lucrative setting since its approval in 2017. Approximately 80% of patients have a PD-L1 TPS above 1%; however, patients with actionable mutations such as epidermal growth factor receptor or anaplastic lymphoma kinase were excluded from this trial.

The trial enrolled 398 patients who were randomised to the ivonescimab and Keytruda arms at a ratio of one to one. Median progression-free survival (PFS) was 11.14 months in the ivonescimab arm compared to 5.82 months in the Keytruda arm (hazard ratio/HR 0.51, 95% confidence interval/CI: 0.38, 0.69, p<0.0001). Median PFS was clinically significant across all subgroups; the PD-L1 TPS ≥50% subgroup had a PFS stratified HR of 0.46 (95% CI: 0.28, 0.75) while the PD-L1 TPS 1-49% subgroup had a PFS stratified HR of 0.54 (95% CI: 0.37, 0.79). Patients with squamous histology had a PFS stratified HR of 0.48 (95% CI: 0.31, 0.74) while patients with non-squamous histology had a PFS stratified HR of 0.54 (95% CI: 0.36, 0.82). Overall response rate (ORR) data was also published, with the ivonescimab arm achieving an ORR of 50.0% (95% CI: 42.8%, 57.2%) and the Keytruda arm having an ORR of 38.5% (95% CI: 31.7%, 45.6%). One potential area of concern is the safety data, as 29.4% of patients receiving ivonescimab experienced grade 3 and above treatment-related adverse events (TRAEs), compared to 15.6% of the Keytruda arm. However, only 1.5% of ivonescimab patients discontinued due to TRAEs, whereas 3% of patients in the Keytruda arm did. Two patients in the Keytruda arm and one patient in the ivonescimab arm had a grade 5 TRAE.

While the results of this trial are positive overall and could result in approval in China, it is unlikely that the US Food and Drug Administration (FDA) will approve a drug off the back of this trial alone. In 2022, the FDA issued a complete response letter to Eli Lilly for its PD-1 inhibitor that had only been trialled in China, indicating the requirement of a multiregional trial for approval consideration. Summit has proactively started the preparations for a new multiregional trial, HARMONi-7. This trial has more restricted patient eligibility, only including patients with a PD-L1 TPS 50% and above, or about a third of the total NSCLC patient population. While the results in this subgroup were marginally better, they do not justify excluding the PD-L1 TPS 1-49% patient population. Summit might have prioritised based on financial rather than clinical considerations associated with running a multiregion trial. If the results of HARMONi-2 are similar to HARMONi-7, ivonescimab has the potential to be practice-changing. According to leading data and analytics company GlobalData’s analyst consensus forecast, ivonescimab is projected to reach $1.7bn in global sales in 2030 while Keytruda’s sales are forecast to peak in 2027 at $34.3bn and drop to $23.2bn in 2030. Merck should not just be worried about Keytruda’s patent expiry in 2028, but also look out for competition from upcoming innovative therapies.