FDA Approves PD-L1 IHC 22C3 pharmDx as Companion Diagnostic for Pembrolizumab in TNBC

Nov 16, 2020

November 16, 2020 — The FDA has approved the PD-L1 IHC 22C3 pharmDx to aid in the identification of patients with triple-negative breast cancer who are eligible to receive the PD-1 inhibitor pembrolizumab.

The FDA has approved the PD-L1 IHC 22C3 pharmDx to aid in the identification of patients with triple-negative breast cancer (TNBC) who are eligible to receive the PD-1 inhibitor pembrolizumab (Keytruda), according to an announcement from Agilent Technologies, Inc.1

Previously, the test had also been approved to identify PD-L1 positivity in patients with non–small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, cervical cancer, urothelial carcinoma, and head and neck squamous cell carcinoma to determine eligibility for treatment with pembrolizumab.

This is the only companion diagnostic to receive FDA approval for use in the identification of patients with TNBC who should receive treatment with pembrolizumab plus chemotherapy, according to Agilent Technologies, Inc.

“Anti-PD-1 therapies, including [pembrolizumab], continue to offer new treatment options for a growing population of [patients with] cancer,” Nina Green, vice president and general manager of Companion Diagnostics at Agilent, “With the expanded FDA approval of PD-L1 IHC 22C3 pharmDx in TNBC, physicians will be able to access critical information to qualify even more patients who could benefit from these treatments. This new approval reinforces Agilent’s role as a worldwide leader in developing companion diagnostics for targeted therapies.”

On November 13, 2020, the FDA approved the combination of pembrolizumab and chemotherapy for use in patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 and have a combined positive score (CPS) of 10 or greater.

The decision was based on findings from the KEYNOTE-355 trial (NCT02819518), which demonstrated that the addition of the PD-1 inhibitor to chemotherapy led to a median progression-free survival (PFS) of 9.7 months versus 5.6 months with chemotherapy alone (HR, 0.65; 95% CI, 0.49-0.86; one-sided P =.0012).2

Moreover, in patients who had a PD-L1 CPS of 1 or greater, the median PFS with pembrolizumab/chemotherapy versus chemotherapy alone was 7.6 months versus 5.6 months, respectively (HR, 0.74; 95% CI, 0.61-0.90; P =.0014); although there was a numerical benefit with the combination, this was not determined to be statistically significant.

In the intent-to-treat (ITT) population, the median PFS also favored the pembrolizumab combination over chemotherapy alone, at 7.5 months versus 5.6 months, respectively; this translated to an 18% reduction in the risk of death, although statistical significance was not assessed in this group (HR, 0.82; 95% CI, 0.69-0.97).

In the multicenter, double-blind, randomized trial, investigators evaluated pembrolizumab in combination with investigator's choice of either nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine/carboplatin versus placebo in combination with 1 of the 3 chemotherapy agents in patients with previously untreated locally recurrent inoperable or metastatic disease.

To participate, patients had to be 18 years of age or older, have central determination of TNBC and PD-L1 positivity, and they must have completed treatment with curative intent at least 6 months prior their first disease recurrence. Also, patients had to have an ECOG performance status ranging from 0 to 1, a life expectancy of 12 weeks or longer from randomization, adequate organ function, no required use of systemic steroids, and no central nervous system metastases. They also could not have active immune disease.

In part 1 of the trial, investigators evaluated the safety and tolerability of pembrolizumab in combination with 1 of the chemotherapy regimens in 30 participants. Part 2 evaluated a total of 847 patients who were randomized in a 2:1 fashion to receive either placebo (n = 281) or pembrolizumab (n = 566) at an intravenous (IV) dose of 200 mg on day 1 of each 21-day cycle in combination with either nab-paclitaxel at 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; paclitaxel at 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; or 1000 mg/m2 of gemcitabine and area under the curve 2 of carboplatin on days 1 and 8 of each 21-day cycle.

The trial was not designed to compare the efficacy of the different chemotherapy regimens. Patients received treatment until disease progression or discontinuation of study therapy.

The coprimary end points of the trial comprised PFS and overall survival in patients with PD-L1–positive tumors and in the ITT population. Secondary end points included objective response rate, duration of response, disease control rate, and safety. Baseline characteristics were balanced between the 2 treatment arms.

Additional data from KEYNOTE-355 revealed during the 2020 ASCO Virtual Scientific Program showed a 1-year PFS rate of 39.1% with pembrolizumab/chemotherapy versus 23.0% with chemotherapy alone in patients whose tumors had a PD-L1 CPS of 10 or higher; at 6 months, these rates were 65.0% and 46.9%, respectively.3 The PFS benefit achieved in patients whose tumors had a PD-L1 CPS of 10 or higher was demonstrated across most subgroups analyzed in the trial, with the exception of those whose disease-free interval was 12 months or longer (HR, 1.00; 95% CI, 0.51-1.95).

For patients whose tumors had a PD-L1 CPS of 1 or higher, the 1-year PFS rate with pembrolizumab/chemotherapy was 31.7% versus 19.4% with chemotherapy alone; the PFS rates at 6 months were 56.4% and 46.6%, respectively.

In the ITT population, 1-year PFS rates with the addition of pembrolizumab versus chemotherapy alone were 29.8% versus 20.9%, respectively; the 6-month PFS rates in this group were 55.4% and 47.8%, respectively. The PFS benefit with pembrolizumab was observed across subgroups analyzed in the ITT population and in those with a PD-L1 CPS of 1 or higher.

Additionally, patients who had a CPS of 20 or higher, also experienced considerable benefit from the combination, with a median PFS of 9.5 months (HR, 0.61; 95% CI, 0.43-0.87).

Regarding safety, the most common toxicities experienced by patients who received the pembrolizumab/chemotherapy combination included fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache.


  1. Agilent receives expanded FDA approval for PD-L1 IHC 22C3 pharmDx in triple-negative breast cancer. News release. November 13, 2020. Accessed November 16, 2020. https://bit.ly/38R0mEa.
  2. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed November 16, 2020. https://bit.ly/3nqbQ5s.
  3. Cortes J, Cescon DW, Rugo HS. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000
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