FDA Approves Pembrolizumab and Chemotherapy for High-risk Early-Stage TNBC

The FDA has granted approval to pembrolizumab (Keytruda) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery, announced Merck, in a press release.¹

Data from the phase 3 KEYNOTE-522 serve as the basis for the FDA approval after pembrolizumab in combination with chemotherapy of carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide before surgery and continued as a single agent after surgery demonstrated significant improvement in event-free survival (EFS) compared with the same neoadjuvant chemotherapy regimens alone in patients with previously untreated stage II or stage III TNBC. Overall, there was 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) with pembrolizumab plus chemotherapy.

“Even when TNBC is diagnosed early, 30-40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Joyce O’Shaughnessy, MD, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, US Oncology Network, Dallas, Texas, in the 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.”

In the randomized, double-blind KEYNOTE-522 trial (NCT03036488), 784 patients were randomized 2:1 to receive received 200 mg of pembrolizumab every 3 weeks combined with paclitaxel and carboplatin for 4 cycles, followed by pembrolizumab plus cyclophosphamide and doxorubicin or epirubicin prior to surgery, then after surgery, pembrolizumab alone every 3 weeks for up to 9 cycles. Placebo was given with chemotherapy in the same design as the pembrolizumab group to 390 patients.

In an earlier analysis of KEYNOTE-522, a statistically significant increase was observed among those treated with pembrolizumab. Specifically, the pCR of 64.8% (95% CI, 59.9%-69.5%) versus 51.2% (95% CI, 44.1%-58.3%) in patients receiving placebo. The estimated difference was 13.6 percentage points (95% CI, 5.4-21.8; P < .001).²

Patients were followed for a median of 15.5 months (range, 2.7-25.0 months). About 7% of patients who received pembrolizumab and chemotherapy versus 11.98% (of those who receved placebo and chemotherapy had disease progression and died from any cause, had local or distant recurrence or a second primary tumor, or precluded surgery (HR, 0.63; 95% CI, 0.43-0.93).

No new safety signals were seen during the early analysis of EFS and the safety profile of pembrolizumab was consistent with previously reported studies. Fatal adverse events occurred in 0.9% of patients who received pembrolizumab, including one each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. There were also serious AEs observed in 44% of patients, which included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).¹

Twenty percent of patients in the study discontinued treatment due to AEs. The most common AEs that led to treatment discontinuation were aminotransferase (ALT, 2.7%), increased aspartate aminotransferase (AST, 1.5%), and rash (1%).

Further, greater than 2% of patients had interruptions of treatment due to AEs. Of these, the most common were neutropenia (26%), thrombocytopenia and increased ALT (6% each), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia and leukopenia (2.8% each), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). The most common adverse reactions (all grades ≥20%) were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

Immune-related adverse events (IRAEs) can occur with pembrolizumab and chemotherapy, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. According to Merck, it is best to catch these early and treat them with corticosteroids, if appropriate.

“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the [United States] in younger women and in Black women,” said Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a statement. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with Keytruda is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”

Also, based on KEYNOTE-522, the FDA has converted an accelerated approval of n combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (combined positive score ≥10) as determined by an FDA-approved test to a full approval based on the newly available data. The accelerated approval was originally granted in 2020 and supported by findings from KEYNOTE-355 (NCT02819518).

Based on the new approval of pembrolizumab combined with chemotherapy for the treatment of patients with high-risk early-stage TNBC, pembrolizumab now has 30 indications.

_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/3BNscgP}

_{2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020; 382(9):810-821. doi: 10.1056/NEJMoa1910549}