Pembrolizumab Plus Chemotherapy for TNBC: Promising Results from the Keynote-522 Trial

The Keynote-522 clinical trial has produced groundbreaking results when it comes to the the treatment of early-stage triple-negative breast cancer (TNBC).

Initiated in 2017, this phase III study aimed to assess the efficacy of pembrolizumab combined with chemotherapy in improving patient outcomes compared to the standard chemotherapy regimen alone. With recent findings presented at the 2024 ESMO Congress in Barcelona, the trial has provided significant insights into the potential benefits of integrating immunotherapy in early TNBC management. 

“KEYNOTE 5 22 was the trial that added pembrolizumab or an immune checkpoint inhibitor to chemotherapy for patients with triple-negative breast cancer stage two or stage three neoadjuvantly. So patients received chemo plus the immune checkpoint inhibitor prior to surgery,” says Dr. Stephanie Graff, Director of breast oncology, Lifespan Cancer Institute at the Legorreta Cancer Center, Brown University, to SurvivorNet.

Patient Selection and Trial Design 

The Keynote-522 trial enrolled patients aged 18 years and older with newly diagnosed, nonmetastatic TNBC, classified as either stage T1c N1-2 or stage T2-4 N0-2. Eligible patients exhibited an ECOG performance status of 0 or 1 and adequate organ function. Importantly, the trial also included patients with bilateral or multifocal primary tumors, and those with inflammatory breast cancers, ensuring a diverse participant cohort. 

Patients were randomly assigned in a 2:1 ratio to receive either the pembrolizumab-chemotherapy (200mg) combination or a placebo-chemotherapy regimen. The treatment protocol involved neoadjuvant pembrolizumab plus chemotherapy for 24 weeks, followed by adjuvant pembrolizumab for up to 9 cycles post-surgery. The trial’s dual primary endpoints were pathological complete response (pCR) rate and event-free survival (EFS). Patients underwent adjuvant pembrolizumab or placebo for 9 cycles or until recurrence or unacceptable toxicity.

Key Findings from ESMO 2024 

At the ESMO 2024 Congress, updated results highlighted that perioperative pembrolizumab reduced the risk of death by 34% compared to the placebo group (HR, 0.66; 95% CI, 0.50-0.87). At a median follow-up of 75.1 months, the 5-year overall survival (OS) rate for the pembrolizumab group was 86.6% compared to 81.7% in the placebo group. The pembrolizumab regimen also demonstrated a significant improvement in EFS, with a 5-year EFS rate of 81.2% versus 72.2% in the placebo group. 

“The original result told us what the rate of pathologic complete response was, how many patients had no cancer left at the time of their surgery. And what was removed at the time of surgery was hopefully just dead cancer cells, healthy breast tissue cancer that had died and gone away as a result of the treatment. And we saw that the immune checkpoint inhibitor, the addition of the pembrolizumab had significantly increased that proportion of patients that had had a pathologic complete response. At ESMO 2024, we got the updated overall survival analysis and we saw that patients that had had the addition of the immune checkpoint inhibitor pembrolizumab had an improvement in overall survival of 5% points,” highlights Dr. Graff.

Implications for Clinical Practice 

The findings from Keynote-522 suggest that incorporating pembrolizumab into the treatment regimen for early-stage TNBC not only improves pCR and EFS but also provides a substantial survival benefit. This has the potential to shift the standard of care, particularly for patients with high-risk disease.

“It’s been a long time since we saw an improvement in overall survival for triple negative breast cancer and these incremental benefits. I know 5% doesn’t sound like a huge celebration, but it truly is because these little steps forwards are really how we advance the field. And so this is a huge advance Keynote 5 22,” points out Dr. Graff.

The study’s outcomes support the FDA’s 2021 approval of pembrolizumab in combination with chemotherapy as a neoadjuvant and adjuvant treatment for high-risk early-stage TNBC. 

“Adding pembrolizumab for patients with clinical stage two or stage three breast cancer has already been our standard of care in the United States since we got the earlier analysis, but this cements it in place and will help it stay at the standard of care for comparison in all future trial design and really just make sure that we continue to offer this therapy to patients everywhere,” she states.

“We need to be alert and monitoring labs among women treated on Keynote 522, we did see a fair proportion of thyroiditis or irritation of the thyroid elevation changes in the thyroid hormone levels as well as adrenal gland abnormalities. So we also monitor things like cortisol levels, particularly right before patients go to the operating room because we are receiving this and there is that stress response that happens during surgery,” Dr. Graff further explains.

“That’s hard for a relatively short amount of time. And on the other side of that, in all likelihood, they have a very full recovery back to their baseline, and we can certainly dive into the details of what those timelines all look like in terms of length of treatment and probability of recovery and timeline of recovery,” she continues.

Future Directions 

Future analyses will likely explore long-term survival benefits and potential biomarkers for treatment response. Additionally, ongoing studies may investigate pembrolizumab’s role in other breast cancer subtypes and settings, further refining its place in oncology practice. 

The Keynote-522 trial has set a new benchmark in the management of early-stage TNBC, offering a promising therapeutic strategy for a historically challenging cancer subtype. The continuous updates from this study will be crucial in guiding future therapeutic decisions and improving patient outcomes.