QuoteReplyTopic: Keytruda (pembrolizumab) Posted: Nov 13 2020 at 2:36pm
FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer
On November 13, 2020, the Food and Drug Administration granted
accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co.) in
combination with chemotherapy for the treatment of patients with locally
recurrent unresectable or metastatic triple-negative breast cancer
(TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA
approved test.
FDA also approved the PD-L1 IHC 22C3 pharmDx (Dako North America,
Inc.) as a companion diagnostic for selecting patients with TNBC for
pembrolizumab.
Approval was based on KEYNOTE-355 (NCT02819518), a multicenter,
double-blind, randomized, placebo-controlled trial in patients with
locally recurrent unresectable or metastatic TNBC, who had not been
previously treated with chemotherapy in the metastatic setting. Patients
were randomized (2:1) to receive pembrolizumab 200 mg on day 1 every
3 weeks or placebo in combination with different chemotherapy treatments
(paclitaxel protein-bound, or paclitaxel, or gemcitabine plus
carboplatin) via intravenous infusion.
The main efficacy outcome measure was progression-free survival (PFS)
as assessed by blinded independent review according to RECIST 1.1,
tested in the subgroup of patients with CPS ≥10. Median PFS was 9.7
months (95% CI: 7.6, 11.3) in the pembrolizumab plus chemotherapy arm
and 5.6 months (95% CI:5.3, 7.5) in the placebo arm (HR 0.65; 95% CI:
0.49, 0.86; one-sided p-value=0.0012).
FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer
On July 26, 2021, the Food and Drug Administration approved
pembrolizumab (Keytruda, Merck) for 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.
FDA also granted regular approval to pembrolizumab in combination
with chemotherapy for patients with locally recurrent unresectable or
metastatic TNBC whose tumors express PD-L1 (Combined Positive Score
[CPS] ≥10) as determined by an FDA approved test. FDA granted
accelerated approval to pembrolizumab for this indication in November
2020.
The following trial was the basis of the neoadjuvant and adjuvant
approval, as well as the confirmatory trial for the accelerated
approval.
The efficacy of pembrolizumab in combination with neoadjuvant
chemotherapy followed by surgery and continued adjuvant treatment with
pembrolizumab as a single agent was investigated in KEYNOTE-522
(NCT03036488), a randomized, multicenter, double-blind,
placebo-controlled trial conducted in 1174 patients with newly diagnosed
previously untreated high-risk early-stage TNBC (tumor size >1 cm
but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in
diameter regardless of nodal involvement). Patients were enrolled
regardless of tumor PD-L1 expression.
Patients were randomized (2:1) to pembrolizumab in combination with
chemotherapy or placebo in combination with chemotherapy. Details of the
chemotherapy regimen are in the drug label linked below.
The main efficacy outcome measures were pathological complete
response (pCR) rate and event free survival (EFS). The pCR rate was 63%
(95% CI: 59.5, 66.4) for patients who received pembrolizumab in
combination with chemotherapy compared with 56% (95% CI: 50.6, 60.6) for
patients who received chemotherapy alone. The number of patients who
experienced an EFS event was 123 (16%) and 93 (24%), respectively (HR
0.63; 95% CI: 0.48, 0.82; p=0.00031).
The most common adverse reactions reported in ≥ 20% of patients in
trials of pembrolizumab in combination with chemotherapy were
fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite,
rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral
neuropathy, mucosal inflammation, stomatitis, headache, weight loss,
abdominal pain, arthralgia, myalgia, and insomnia.
The recommended dosage of pembrolizumab for TNBC is 200 mg every 3
weeks or 400 mg every 6 weeks as an intravenous infusion over 30
minutes. Pembrolizumab is administered in combination with chemotherapy
for neoadjuvant treatment for 24 weeks, and then as a single agent for
adjuvant treatment for up to 27 weeks.
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