In 2021, the FDA blasted Merck for using a premature endpoint to pursue a Keytruda approval in early-stage triple-negative breast cancer (TNBC). Now, the PD-1 inhibitor has gold-standard overall survival data to back its case.
Keytruda plus neoadjuvant chemotherapy before surgery, followed by Keytruda after surgery, reduced the risk of death by 34% compared with presurgical chemo alone in patients with high-risk nonmetastatic TNBC. The statistically significant result came from the KEYNOTE-522 trial after a median follow-up of more than six years.
At a prespecified data cutoff in March 2024, 14.7% of patients in the Keytruda arm had passed away, versus 21.8% in the control arm. Investigators estimated that the five-year overall survival rate was 86.6% versus 81.7%, respectively, between the two groups. The results will be presented at the European Society for Medical Oncology (ESMO) 2024 annual meeting.
The overall survival findings bolster Keytruda’s case as a perioperative therapy in early-stage TNBC following an FDA approval in 2021. For that approval, the agency considered event-free survival (EFS) data showing the therapy reduced the risk of disease recurrence, progression, development of new cancer or death by 37% over solo chemotherapy used only in the presurgery, neoadjuvant phase.
The 2021 approval came a few months after the FDA rejected Merck’s original bid to use pathological complete response (pCR)—which was defined as absence of invasive cancer in the breast and lymph nodes at the time of surgery—and immature EFS data in its application. EFS and pCR are the KEYNOTE-522 trial’s dual primary endpoints, and overall survival is a key secondary endpoint.
In the current analysis, Keytruda’s EFS benefit remained strong, with the drug showing a 35% improvement over neoadjuvant chemo alone. The five-year EFS rate was 81.2% for Keytruda and 72.2% for control.
“We had thought that breast cancer may not be sensitive to immunotherapy alone but giving it in combination with chemotherapy before surgery and then further afterwards improves overall survival in many patients,” Alessandra Curioni-Fontecedro, M.D., director of oncology at the Hospital of Fribourg in Switzerland, said in an ESMO-facilitated statement. “The finding suggests the possibility that the combination of treatments might lead to a sensitization of TNBC to immunotherapy.”
Keytruda’s KEYNOTE-522 win sets it apart from Roche’s PD-L1 inhibitor Tecentriq. Last year, following an interim analysis, Roche discontinued the phase 3 IMpassion030 trial, which was testing Tecentriq in combination with chemo as a postsurgical adjuvant therapy in TNBC. Data later revealed that the risk of recurrence or death appeared to be even higher for Tecentriq-chemo versus adjuvant chemo alone.
Then there’s the IMpassion031 trial, which, like KEYNOTE-522, evaluated Tecentriq alongside chemo before surgery followed by Tecentriq after surgery in early-stage TNBC. Although neoadjuvant Tecentriq showed a significant pCR benefit, the entire regimen only numerically improved EFS, as a 24% reduction in the risk of recurrence or death failed to cross the statistical significance bar.
After about 40 months of median follow-up from randomization, overall survival also favored Tecentriq with a 44% reduction in the risk of death, which again wasn’t statistically significant.
Merck is now trying to further improve upon the KEYNOTE-522 regimen with its Kelun Biotech-partnered antibody-drug conjugate sacituzumab tirumotecan (sac-TMT). In the phase 3 TroFuse-012 trial, the combination of Keytruda and the TROP2-directed ADC is being pitted against Keytruda with or without chemo in TNBC patients who didn’t achieve a pCR at surgery following neoadjuvant treatment based on the KEYNOTE-522 regimen.
Merck kicked off the study in June with the goal to enroll 1,530 patients. With invasive disease-free survival as the primary endpoint, the trial currently bears an estimated primary completion date in late 2030.