ESMO: Merck's Keytruda achieves survival success in early triple-negative breast cancer

In 2021, the FDA criticized Merck for using an immature endpoint in its pursuit of approval for Keytruda in early-stage triple-negative breast cancer (TNBC). Despite this, Keytruda has now demonstrated significant overall survival benefits, reinforcing its efficacy. In the KEYNOTE-522 trial, Keytruda combined with neoadjuvant chemotherapy before surgery, followed by Keytruda post-surgery, showed a 34% reduction in the risk of death compared to pre-surgical chemotherapy alone in high-risk nonmetastatic TNBC patients. This finding came after a median follow-up of over six years. As of a data cutoff in March 2024, 14.7% of patients in the Keytruda group had died, compared to 21.8% in the control group. The five-year overall survival rate was estimated at 86.6% for the Keytruda group versus 81.7% for the control group. These results will be presented at the European Society for Medical Oncology (ESMO) 2024 annual meeting.

Keytruda’s new overall survival data reinforce its role as a perioperative therapy in early-stage TNBC, following its FDA approval in 2021. This approval was initially based on event-free survival (EFS) data, which indicated that Keytruda reduced the risk of disease recurrence, progression, new cancer development, or death by 37% compared to chemotherapy alone used in the pre-surgery phase. The FDA's 2021 approval came after an earlier rejection due to the use of pathological complete response (pCR) and immature EFS data. These endpoints, along with overall survival, are critical measures in the KEYNOTE-522 trial.

The current analysis confirms Keytruda’s robust EFS benefit, showing a 35% improvement over neoadjuvant chemotherapy alone. The five-year EFS rate was 81.2% for Keytruda and 72.2% for the control group. Dr. Alessandra Curioni-Fontecedro, director of oncology at the Hospital of Fribourg in Switzerland, noted that the combination of chemotherapy and immunotherapy before and after surgery appears to improve overall survival in many TNBC patients. This suggests that such a combination may sensitize TNBC to immunotherapy.

Keytruda’s success in the KEYNOTE-522 trial distinguishes it from Roche’s PD-L1 inhibitor Tecentriq. In a recent interim analysis, Roche halted its phase 3 IMpassion030 trial, which tested Tecentriq combined with chemotherapy as a post-surgical adjuvant therapy in TNBC, due to higher risks of recurrence or death compared to adjuvant chemotherapy alone. Similarly, the IMpassion031 trial, although showing significant pCR benefits for neoadjuvant Tecentriq, did not achieve statistical significance for EFS improvement, with only a numerical benefit. After approximately 40 months of follow-up, overall survival also favored Tecentriq but failed to reach statistical significance.

Merck aims to further enhance the KEYNOTE-522 regimen with a new approach involving its partner Kelun Biotech. They are testing an antibody-drug conjugate, sacituzumab tirumotecan (sac-TMT), in combination with Keytruda. In the phase 3 TroFuse-012 trial, this combination is being compared to Keytruda with or without chemotherapy in TNBC patients who did not achieve a pCR after neoadjuvant treatment based on the KEYNOTE-522 regimen. The study, which began in June, aims to enroll 1,530 patients and focuses on invasive disease-free survival as its primary endpoint. The trial is expected to be completed by late 2030.