Pembrolizumab/Chemo Improves EFS Vs Chemo in High-Risk TNBC

"These results provide further support for pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery, regardless of the pCR outcome, as a standard-of-care treatment regimen for patients with high-risk, early-stage TNBC," according to Peter Schmid, FRCP, MD, PhD.

Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy and adjuvant pembrolizumab elicited improvements in event-free survival (EFS) compared with neoadjuvant chemotherapy regardless of pathologic complete response (pCR) in those with high-risk triple-negative breast cancer (TNBC), according to updated findings from the phase 3 KEYNOTE-522 trial (NCT03036488) presented at the 2023 European Society for Medical Oncology Congress (ESMO).¹

“These results provide further support for pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery, regardless of the pCR outcome, as a standard-of-care treatment regimen for patients with high-risk, early-stage TNBC,” Peter Schmid, FRCP, MD, PhD, professor of cancer medicine; centre lead, Centre of Experimental Cancer Medicine; and director, Barts Breast Cancer Centre, Barts Cancer Institute, said during a presentation of the data at the congress.

5-Year Results

At the congress, Schmid presented data from the sixth interim analysis of EFS results after a median follow-up of 63.1 months (range, 53.9-72.0; data cutoff, March 23, 2023).

At 5 years, the EFS rate among patients treated with pembrolizumab plus chemotherapy was 81.3%, compared with 72.3% in the placebo arm, reducing the risk for recurrence, progression, complications, or death by 37% (HR, 0.63; 95% CI, 0.49-0.81). The median EFS was not reached in either group.

“What's also striking is that the [Kaplan-Meier] curves are starting to flatten out, which is something we expect in triple-negative breast cancer where two-thirds of the events would normally occur in the first 2 to 3 years,” Schmid added.

EFS benefit was consistent across subgroup stratified by nodal status, tumor size, carboplatin schedule, PD-L1 status, age, and ECOG performance status.

When evaluating EFS by pCR, pembrolizumab was also beneficial. Among those with a pCR, the 5-year EFS rate was 92.2% with pembrolizumab vs 88.2% with placebo, reducing the risk for events by 35% (HR, 0.65; 95% CI, 0.39-1.08). In patients with no pCR, the rates were 62.6% and 52.3%, respectively, reducing the risk for events by 28% (HR, 0.72; 95% CI, 0.54-0.96).

According to the abstract, the most common first EFS event was distant recurrence, which occurred in in 72 patients (9.2%) in the pembrolizumab group, compared with 55 patients (14.1%) in the placebo group. Five-year rates of distant disease progression- or distant recurrence-free survival were 84.4% with pembrolizumab, compared with 76.8% with placebo (HR, 0.64; 95% CI, 0.49-0.8).

KEYNOTE-522 Trial

According to Schmid, KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant settings.

Patients were randomized to receive neoadjuvant therapy with either 200 mg pembrolizumab or placebo every 3 weeks plus paclitaxel and carboplatin (cycles 1 through 4) and doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide (cycles 5 through 8). Following surgery, patients then received either adjuvant pembrolizumab or placebo plus chemotherapy every 3 weeks for up to 9 cycles.

From March 2017 through September 2018, 1174 patients were randomized between the treatment arms, including 784 intent-to-treat patients in the pembrolizumab arm and 390 patients in the placebo arm.

Patients were eligible for the trial if they were 18 years of age or older, had newly diagnosed TNBC of either T1cN1-2 or T2-4N0-2, an ECOG performance status of 0 to 1, and had tissue sample for PD-L1 assessment.

Patients were stratified by nodal status (positive vs negative), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (weekly vs every 3 weeks).

In the investigative arm, patients were a median age of 49 years (range, 22-80). Further, only 13.5% had an ECOG performance status of 1, the majority were PD-L1 positive (83.7%), just over half received carboplatin every week (57.3%), most had T1/T2 disease (74.0%), and a little over 50% were positive for nodal involvement (51.7%).

The primary end points were pCR in those with ypT0/T1ypN0 disease and EFS. Secondary end points included pCR in those with ypT0ypN0 and ypT0/T1 disease; pCR, EFS, and overall survival in the PD-L1 population; and safety.

In the first interim analysis of the trial, Schmid explained that neoadjuvant pembrolizumab plus chemotherapy results in a statistically significant and clinically meaningful increase in pCR (13.6% percentage points; P = .00055).

In the fourth planned interim analysis of the trial, published in The New England Journal of Medicine, the estimated EFS at 36 months was 84.5% (95% CI, 81.7%-86.9%) with the addition of pembrolizumab, compared with 76.8% (95% CI, 72.2%-80.7%) in the placebo group (HR, 0.63; 95% CI, 0.48-0.82; P < .001) at a median follow-up of 39.1 months (data cutoff, March 23, 2021).²

“Based on these results [from the previously reported interim analyses], the FDA and EMA have approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery for high-risk, early-stage TNBC,” Schmid said.

References

1. Schmid P, Cortés J, Dent RA, et al. Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Onc. 2023;34(S2):S1256-S1257. doi:10.1016/j.annonc.2023.10.008.
2. Schmid P, Cortes J, Dent R, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651.