On 6 December 2023 at the San Antonio Breast Cancer Symposium, the results of the Phase III HER2CLIMB-02 trial were published. The trial compared Seagen’s Tukysa (tucatinib) in combination with Roche’s Kadcyla (ado-trastuzumab emtansine), a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC), against Kadcyla and placebo in patients with unresectable locally advanced or metastatic HER2+ breast cancer previously treated with Genentech’s Herceptin (trastuzumab) and a taxane. Tukysa is a HER2-targeting tyrosine kinase inhibitor (TKI) that was first approved by the FDA in April 2020 for patients with metastatic HER2+ breast cancer who have received one or more HER2-targeting therapies. The median progression-free survival (PFS) in the Tukysa + Kadcyla combination therapy arm of the trial was 9.5 months, compared to 7.4 months in the Kadcyla monotherapy arm (hazard ratio [HR], 0.76; 95% confidence interval [CI]: 0.61,0.95). A total of 44% of the patients in the trial had brain metastases at baseline. In this patient population, the median PFS was 7.8 months in the combination arm and 5.7 months in the monotherapy arm (HR, 0.64; 95% CI: 0.46, 0.89). This increase in PFS for patients with brain metastases is a marked improvement for an underserved patient population.

Unfortunately for Seagen, the overall survival (OS) for the two arms diverged after 18 months of the trial in favour of the monotherapy. However, the combination started to perform better than the monotherapy after 33 months. It is unlikely that there will be a statistically significant finding in favour of the combination once the OS analysis is complete. In addition to disappointing OS results, the FDA will be looking at the level of treatment-related adverse events, as 69% of patients receiving the combination experienced grade 3 or higher treatment-related adverse events compared to 41% of patients receiving Kadcyla alone. The toxicity of HER family-targeting TKIs like Tukysa is well known and can lead clinicians to choose other options. All this is futile, however, since the comparison arm of this trial, Kadcyla, is no longer the standard of care (SOC) for second-line patients in this indication. In May 2022, the FDA approved AstraZeneca’s Enhertu (trastuzumab deruxtecan), another HER2-targeting ADC, in the second line on the back of the DESTINY-Breast03 trial, which compared Enhertu and Kadcyla directly. It has since become the SOC for these patients. Enhertu has also had positive results in patients with brain metastases, competing directly with one of Tukysa’s main selling points.

Considering all of these factors, it seems unlikely the results of this trial will lead to FDA approval for this combination therapy as a second-line treatment in this indication. However, Seagen has already started a Phase III trial, HER2CLIMB-04, which combines Tukysa and Enhertu in the same treatment setting, with its primary completion date due in January 2024. GlobalData’s analyst consensus forecast for Tukysa indicates a large increase in global sales over the forecast period, from sales of $492m in 2023 to sales of $1.6bn in 2029. The 2029 analyst consensus sales forecast for Enhertu indicates sales of $10.7bn, while Kadcyla is forecast to have sales of $1.2bn in 2029, as increased competition and loss of exclusivity in 2026 limit its prospects. While the results of this trial might not deliver approval, there is still much for Seagen to be hopeful for as a future Tukysa + Enhertu combination could deliver better results.