As antibody-drug conjugates (ADCs) grow their importance in the oncology treatment space, efforts are underway to combine them with other agents. Enter Seagen.
The ADC pioneer showed that its small-molecule drug Tukysa could offer additional tumor progression benefits on top of Roche’s ADC Kadcyla in HER2-positive breast cancer. When used as a second-line treatment, Tukysa and Kadcyla reduced the risk of disease progression or death by 24.1% compared with Kadcyla alone, according to phase 3 data presented at the 2023 San Antonio Breast Cancer Symposium.
Patients who took the combination went a median 9.5 months without disease progression, versus 7.4 months for those in the control arm.
“The results from the HER2CLIMB-02 study reinforce the clinical activity of Tukysa in patients with HER2-positive metastatic breast cancer,” Seagen’s R&D chief, Roger Dansey, M.D., said in a statement.
But Seagen appears not ready to file for an FDA approval. Data on whether Tukysa’s addition can extend patients’ lives is not mature, and the company will continue to evaluate the trial data, Seagen said in response to Fierce Pharma’s inquiry about the company’s regulatory plan.
Unlike the positive tumor progression signal, the Tukysa-Kadcyla regimen preliminarily showed a 23% increased risk of death after a median follow-up of 24.4 months. By the interim data cutoff, 134 patients in the 463-subject trial have died. Among the deaths, 71 (31%) happened in the combo arm and 63 (27%) belonged to the Kadcyla group.
According to the overall survival curves presented at SABCS, differences started to show between the two treatment arms after about 18 months. Around that time, more patients on Kadcyla alone were alive compared with those on the Tukysa combo. In a relatively positive sign for the Seagen regimen, the combo started to perform better than Kadcyla monotherapy around month 33.
The final overall survival analysis is planned for when 253 patients have passed away.
A negative overall survival trend has become a big no-no at the FDA lately. The agency has required long-term data, limited the scope of an approval, or forced market withdrawals based on any hint of data suggesting a potential harm to survival. Having witnessed the agency’s actions, drugmakers have also learned not to push their luck when the survival data didn’t land in their favor.
In HER2CLIMB-02, grade 3 or above treatment-emergent adverse events were higher at 69% in the combo arm, versus 41% in control.
There’s another weakness in the HER2CLIMB-02 trial, the American Association for Cancer Research, the organizer of SABCS, noted in its own release. The Tukysa combo was not pitted against AstraZeneca and Daiichi Sankyo’s Enhertu, which has recently become the preferred agent over Kadcyla in the second-line HER2-positive setting.
In the phase 3 DESTINY-Breast03 trial, Enhertu cut the risk of disease progression or death by a massive 72% over Kadcyla in patients pretreated with Roche’s Herceptin and chemo. Both Enhertu and Kadcyla are HER2-directed ADCs.
Despite the availability of the ADCs, Tukysa has been holding onto a share of the second-line market mainly thanks to its ability to control brain metastases. Sara Hurvitz, M.D., from the Fred Hutchinson Cancer Center, who presented the HER2CLIMB-02 data at SABCS, also suggested that Tukysa could make a major difference in patients with brain metastases.
Among about 44% of HER2CLIMB-02 patients who had brain metastases at baseline, the Tukysa-Kadcyla regimen cut the risk of progression or death by 36.1% over Kadcyla alone. The median progression-free survival was 7.8 months and 5.7 months, respectively.
As for the proper ADC partner with Tukysa, Seagen is running a small phase 2 trial coded HER2CLIMB-04 that combines Tukysa with Enhertu in the second-line setting. The trial has a primary completion date in January 2024, according to ClinicalTrials.gov. Seagen also has its own HER2 ADC, disitamab vedotin, in-licensed from RemeGen.
Seagen is currently being acquired by Pfizer in a $43 billion deal.