FDA Approves Pembrolizumab for High-Risk Early-Stage TNBC Plus Chemo as Neoadjuvant Treatment, Then as Single-Agent Adjuvant Treatment

The regulatory decision is based on data from the phase 3 KEYNOTE-522 trial (NCT03036488), which showed that when pembrolizumab was paired with chemotherapy in the form of carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide prior to surgery and continued as a monotherapy following surgery, it significantly prolonged event-free survival vs the same neoadjuvant chemotherapy regimens alone in previously untreated patients with stage II or stage III TNBC.

At a median of 39.0 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; P = .00031). The regimen also reduced the risk of death by 28% vs chemotherapy alone in this population (HR, 0.72; 95% CI, 0.31-1.02; P = .03214), although these data have not crossed the boundary for statistical significance.²

The agency has also converted the November 2020 accelerated approval of pembrolizumab plus chemotherapy for use in patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 with a combined positive score (CPS) of 10 or more³ to a regular approval based on findings from KEYNOTE-522.

“Even when TNBC is diagnosed early, 30% to 40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” Joyce O’Shaughnessy, MD, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas, stated in a press release. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”

After a median follow-up of 39.0 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of EFS events vs the chemotherapy/placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).

Additionally, the immunotherapy regimen resulted in a 28% reduction in the risk of death compared with the chemotherapy/placebo regimen (HR, 0.72; 95% CI, 0.51-1.02; P = .03214). However, these data have not crossed the boundary for statistical significance. The trial will continue to allow for follow-up of overall survival, which serves as a secondary end point.

“These highly anticipated EFS results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of [pembrolizumab] in these patients,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “KEYNOTE-522 is the first large, randomized phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.”

Previously, in March 2021, the FDA had issued a complete response letter to Merck stating that the regulatory decision for the supplemental biologics license application seeking the approval of pembrolizumab for use in patients with high-risk, early-stage TNBC plus chemotherapy as neoadjuvant treatment, then continuing as a single agent as adjuvant treatment following surgery, should be deferred.⁴

Ahead of the Prescription Drug User Fee Act action date for the application, the regulatory agency’s Oncologic Drugs Advisory Committee had voted 10 to 0 that a decision be deferred until further findings from KEYNOTE-522 trial become available.

In KEYNOTE-522, study participants were randomized 2:1 to receive pembrolizumab at 200 mg every 3 weeks (n = 784) or placebo (n = 390). All participants received 4 cycles of carboplatin plus paclitaxel, which was followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After surgery, adjuvant pembrolizumab was continued for 9 cycles or until patients experienced disease recurrence or unacceptable toxicity.

EFS and pathologic complete response (pCR) served as the dual primary end points of the study. pCR was defined as ypT0/Tis or ypN0, and EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause.

The trial enrolled patients with both node-negative and -positive disease. Tumor stage ranged from T1c N1/N2 to T2 to T4 and N0 to N2, per AJCC criteria. All participants had an ECOG performance status of 0 or 1. Patients were stratified by nodal status, tumor size, and carboplatin schedule (weekly vs every 3 weeks).

Findings from the primary interim analysis presented during the 2019 ESMO Congress indicated that pCR was achieved by 64.8% of patients who received the pembrolizumab regimen (n = 401) vs 51.2% of those who were given chemotherapy alone (n = 201; P = .00055).⁵ The immunotherapy regimen was found to produce benefit, irrespective of pCR definition. However, using the definition of ypT0 ypN0, the pCR rates in the investigative and control arms were 59.9% and 45.3%, respectively. Using the ypT0/Tis definition, the pCR rates in the pembrolizumab and placebo arms were 68.6% and 53.7%, respectively.

In a subgroup of 498 patients with PD-L1 positivity, defined as a CPS of 1 or greater, pembrolizumab elicited a pCR rate of 68.9% vs 54.9% with placebo; this translated to a percentage point increase of 14.2 (CI, 5.3-23.1). In 97 patients with PD-L1 negativity, defined as a CPS of less than 1, the pCR rates in the investigative and control arms were 45.3% and 30.3%, respectively; this translated to an 18.3 percentage point increase (95% CI, -3.3 to 36.8).

At 3 years, 84.5% of patients who received pembrolizumab plus chemotherapy were alive and had not experienced an EFS event vs 76.8% of those who received chemotherapy alone.

Moreover, in a prespecified exploratory subgroup analysis of EFS, the benefit achieved with the pembrolizumab regimen was noted, independent of PD-L1 expression. Among 973 patients with PD-L1 positivity, pembrolizumab/chemotherapy reduced the risk of EFS by 33% vs chemotherapy alone (HR, 0.67; 95% CI, 0.49-0.92). Among 197 patients with PD-L1 negativity, the pembrolizumab regimen reduced the risk of EFS events by 52% vs chemotherapy alone (HR, 0.48; 95% CI, 0.28-0.85).

Regarding safety, the treatment-related adverse effects (TRAEs) most commonly experienced by those in the pembrolizumab and placebo arms, respectively, during the neoadjuvant phase of the trial comprised nausea (62.7% vs 63.2%), alopecia (60.3% vs 56.6%), anemia (55.1% vs 55.3%), neutropenia (46.7% vs 47.0%), fatigue (41.1% vs 37.8%), diarrhea (29.4% vs 23.7%), alanine aminotransferase increase (25.5% vs 24.7%), vomiting (25.5% vs 21.9%), asthenia (24.5% vs 25.4%), constipation (23.7% vs 21.1%), neutrophil count decrease (23.7% vs 28.8%), rash (21.8% vs 15.2%), and peripheral neuropathy (19.7% vs 21.1%). Notably, fewer TRAEs were observed in the adjuvant phase of the trial.

TRAEs that were grades 3 to 5 were experienced by 5.7% of patients on the investigative arm vs 1.9% of those on the control arm. The TRAEs most frequently reported in the pembrolizumab and placebo arms included arthralgia (7.9% vs 6.7%, respectively), rash (4.9% vs 2.2%), and pruritus (4.2% vs 2.2%).

The toxicity profile of the regimen at the updated analysis proved to be consistent with what has been seen with each regimen utilized. No new safety signals were reported.

References

1. FDA approves KEYTRUDA (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed July 27, 2021. https://bit.ly/3rAtLtP
2. KEYTRUDA (pembrolizumab) plus chemotherapy before surgery and continued as a single agent after surgery showed statistically significant event-free survival (EFS) result versus neoadjuvant chemotherapy alone in high-risk early-stage TNBC. News release. Merck. July 15, 2021. Accessed July 27, 2021. https://bit.ly/3B6YQto
3. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed July 27, 2021. https://bit.ly/3nqbQ5s
4. Merck receives complete response letter from US FDA for supplemental biologics license application (sBLA) for KEYTRUDA (pembrolizumab) in high-risk early-stage triple-negative breast cancer (TNBC). News release. Merck. March 29, 2021. Accessed July 27, 2021. https://bwnews.pr/2PlIppT
5. Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann Oncol. 2019;30(suppl 5):V853-V854. doi:10.1093/annonc/mdz394.003