Key Points:

• The KEYNOTE-522 trial showed a significant event-free survival benefit with the addition of pembrolizumab to standard neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery in patients with high-risk triple-negative breast cancer (TNBC), which spurred an ASCO rapid guideline update.
• The guideline update recommends pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, for patients with T1cN1-2 to T2-4N0 (stage II/III) early-stage TNBC.

A rapid update to the ASCO guideline on neoadjuvant therapy for breast cancer adds a recommendation on the use of pembrolizumab in patients with high-risk early-stage triple-negative breast cancer (TNBC).¹ The update follows a recent analysis from the randomized phase 3 KEYNOTE-522 trial that showed a significant event-free survival (EFS) benefit with the addition of pembrolizumab to standard neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery in patients with high-risk TNBC.²

The results from this study led to the U.S. Food and Drug Administration (FDA) approval of pembrolizumab in this setting.³ “This is the first FDA approval of an immunotherapy agent in early-stage breast cancer,” noted Larissa A. Korde, MD, MPH, FASCO, of the National Cancer Institute, and guideline co-chair.

“This is the first FDA approval of an immunotherapy agent in early-stage breast cancer.” – Dr. Larissa A. Korde

Updated Recommendation

In the 2022 ASCO guideline update, pembrolizumab (200 mg every 3 weeks or 400 mg every 6 weeks) is recommended in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, for patients with T1cN1-2 to T2-4N0 (stage II/III) early-stage TNBC.¹ Adjuvant pembrolizumab may be given concurrently with, or after completion of, radiation therapy. Under the previous version of the guideline, developed before these data were available, there was insufficient evidence to support adding immune checkpoint inhibitors to standard neoadjuvant chemotherapy for patients with TNBC.⁴ Thus, this rapid update provides an important revision to that recommendation.

Evidence for Guideline Update

KEYNOTE-522 was a randomized, multicenter, double-blind, placebo-controlled trial designed to compare neoadjuvant carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide plus either pembrolizumab (784 patients) or placebo (390 patients), followed by pembrolizumab or placebo administered every 3 weeks for up to 9 cycles after surgery, in patients with previously untreated stage II/III TNBC.²

After a median follow-up of 39.1 months, pembrolizumab plus neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery was associated with a significant improvement in EFS over placebo plus chemotherapy, with 3-year EFS rates of 84.5% and 76.8%, respectively (HR 0.63, 95% CI [0.48, 0.82]; P < .001). The overall survival (OS) data are not yet mature; 3-year OS rates are 89.7% and 86.9%, respectively.

The most frequent grade ≥ 3 treatment-related adverse events (TRAEs) were hematologic (Table 1). Endocrine disorders, including hypo- or hyperthyroidism, adrenal insufficiency, thyroiditis, and hypophysitis, occurred more frequently in the pembrolizumab-chemotherapy arm than in the placebo-chemotherapy arm, at 26.8% and 9.1%, respectively.

“Careful attention should be paid to screening and following patients for these side effects that can be lifelong among patients being treated with pembrolizumab,” said Dawn L. Hershman, MD, MS, FASCO, of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, and guideline co-chair. The guideline specifies the need for careful screening for, and management of, common toxicities, given that immune-related adverse events from pembrolizumab can be severe and permanent.

Ongoing Questions

Looking ahead, an area of interest is whether the EFS benefit with neoadjuvant and adjuvant pembrolizumab translates into an improvement in OS with continued follow-up. Dr. Korde noted that if the final KEYNOTE-522 OS analysis does show a significant survival benefit with pembrolizumab that “this would be an important step forward for patients with TNBC.” The guideline authors also note that uncertainty remains concerning the optimal adjuvant treatment for these patients. Clinical trials have demonstrated an independent benefit with adjuvant capecitabine in patients with TNBC and with adjuvant olaparib in patients with BRCA germline mutations, each without pembrolizumab.^5,6 There are no data to support the use of pembrolizumab in combination with either capecitabine or olaparib.