Overall Survival Data Confirm Benefit of Pembro in TNBC

BARCELONA, Spain — Long-awaited overall survival data from the KEYNOTE-522 trial has lifted spirits in the triple-negative breast cancer (TNBC) community. 
The trial confirmed the survival benefit of adding perioperative pembrolizumab to standard chemotherapy in stage II or III disease.
“We reduced the risk of death by 34%, which is the first time we have ever achieved this in TNBC,” said lead investigator Peter Schmid, MD, from the Center for Experimental Cancer Medicine at Bart’s Cancer Institute, Queen Mary University of London, London, United Kingdom, at a press conference at the 2024 European Society of Medical Oncology (ESMO) Congress.
“This is a group of patients that really had few options in terms of improving outcomes,” said Rebecca Dent, MD, from the National Cancer Centre, Singapore, study co-investigator and scientific chair of ESMO. 
But now the treatment landscape for this challenging disease is starting to transform.
“This study shows improvements with immunotherapy in patients with the most aggressive subtype of breast cancer, where previously we could only offer chemotherapy,” said Alessandra Curioni-Fontecedro, professor of oncology at the University of Fribourg, Fribourg, Switzerland, who spoke at the press conference but was not involved in the study. 
Pembrolizumab has already been approved by the US Food and Drug Administration in this setting, based on previously reported event-free survival results from this trial. At the meeting, the key secondary endpoint of overall survival was reported after a median follow-up of 75 months. 
KEYNOTE-522 included 1174 patients with newly-diagnosed early-stage TNBC (stage T1c N1-2 or T2-4 N0-2), with a median age of 49 years. These patients were randomized to neoadjuvant pembrolizumab (n = 784) along with standard chemotherapy (four cycles of paclitaxel plus carboplatin, then four cycles of doxorubicin or epirubicin plus cyclophosphamide), or standard chemotherapy plus placebo (n = 390). After definitive surgery, the experimental arm then received adjuvant pembrolizumab for nine cycles or until recurrence or unacceptable toxicity.
The new results showed a statistically significant and clinically meaningful improvement in overall survival at 5 years for the pembrolizumab plus chemotherapy arm vs chemotherapy alone (86.6% vs 81.7%; hazard ratio [HR], 0.66; P = .0015), which was stable across various subgroups including programmed death–ligand 1 status, nodal status, tumor size, or disease stage, noted Schmid.
Updated 5-year event-free survival also held stable at 81.2% in the experimental arm compared with 72.2% in controls (HR, 0.65). 
“Most of the recurrence events tended to occur relatively early,” he added. “And now we can clearly see that the event-free survival curves are flattening out.”
A preplanned analysis also examined survival based on tumor response to neoadjuvant treatment. 
“We found that if patients achieved a pathological complete response with the help of immunotherapy, the outlook was better than if they had that same complete response just with chemotherapy,” Schmid explained during the press conference. This suggests that “the immune therapy changes the biology of the cancer.”
“But possibly, even more importantly,” he added, “if you look at the patients who did not have a pathological complete response — in whom, arguably, the treatment didn’t work because they still had cancer, which had to be removed at the time of surgery — we see the outcome is still remarkably better if they received immunotherapy in terms of recurrences and also overall survival.”
Specifically, among patients who did not achieve a pathological complete response after neoadjuvant treatment, the 5-year overall survival rate was 71.8% among those who received immunotherapy compared with 65.7% among those treated who did not (HR, 0.76). And among patients with a pathological complete response, the 5-year overall survival rate was 95.1% for those who received immunotherapy compared with 94.4% for those who didn’t (HR, 0.69).
“We had thought that breast cancer may not be sensitive to immunotherapy alone but giving it in combination with chemotherapy” before and after surgery improved overall survival, said Curioni-Fontecedro, also director of oncology at the Hospital of Fribourg, Switzerland. These findings suggest “the possibility that the combination of treatments might lead to a sensitization of TNBC to immunotherapy.”
Patients Struggle With Toxicities
“Looking at the long-term safety data, the short answer is we have not seen any new signals,” said Schmid. “In the neoadjuvant phase, toxicities are clearly dominated by chemotherapy, with subtle differences in patients treated with chemotherapy plus pembrolizumab.”
Zooming in specifically on immune-mediated side effects related to pembrolizumab, Schmid said there was nothing unexpected, with the most common side effect being hypothyroidism (15%).
Commenting on the results, Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, Netherlands, drew attention to the toxicity. “In general the treatment is considered ‘tolerable,’ but we are talking about young women, and we don’t know, for example, the longterm consequences for fertility,” she said. 
“Also, though rare, there are endocrinopathies and adrenal gland insufficiencies that have a huge impact. In the clinic, I see patients struggling with these toxicities,” she said during the press conference.
In an interview with Medscape Medical News, Kok underscored the importance of future research to determine whether all patients in this population require the full course of both neoadjuvant plus adjuvant immunotherapy. “Can some patients be spared? And how long do we need to treat? We should analyze biomarkers,” she suggested.
Neverthless, Kok called the findings “clinical practice changing.”
“This is — or should be — the new standard of care for stage II or III triple negative breast cancer,” she concluded.
The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Schmid disclosed receiving honoraria and research finding from Merck, along with other companies.
Kok disclosed receiving research grants from AstraZeneca/Daiichi, Bristol Myers Squibb, and Roche; Speaker’s fees from AstraZeneca/Daiichi and Gilead; compensation for advisory work from Alderaan Biotechnology, AztraZeneca/Daiichi, BioNTech, Bristol Myers Squibb, Domain Therapeutics, Gilead, MSD, Novartis, and Roche; and nonfinancial support from Natera.
 
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