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FDA Grants Breakthrough Therapy Designation to Pembrolizumab for NSCLC

Sandra Kear
Published: Monday, Oct 27, 2014

Dr. Roger M. Perlmutter

Roger M. Perlmutter, MD, PhD

The FDA has granted a breakthrough therapy designation to pembrolizumab (Keytruda), an anti-PD-1 therapy, for the treatment of patients with non-small cell lung cancer (NSCLC) who are EGFR mutation- or ALK rearrangement-negative and whose disease has progressed on or following platinum-based chemotherapy.1

“The emergence of immunotherapies for lung cancer means we are on the cusp of something really great, and the nice thing about immunotherapy is that it might work, even in the resistant patient,” said Roy S. Herbst, MD, PhD, of the Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, Connecticut, during his presentation at the 12th Annual International Congress on Targeted Therapies in Cancer.

Data from the ongoing phase Ib KEYNOTE-001 study, and updated findings recently presented at the 2014 European Society of Medical Oncology (ESMO) Congress formed a basis for the designation. Pembrolizumab was previously granted breakthrough status for advanced melanoma, and is being studied across more than 30 types of cancers, as monotherapy and in combination.1

Pembrolizumab is a high-affinity, humanized IgG4 PD-1 blocking antibody that exerts dual ligand blockade of the PD‐1 pathway and has similar reactivity to human and other primate PD‐1, but no reactivity to mouse or rat PD‐1. It has no antibody-dependent cell-mediated cytotoxicity (ADCC/CDC) activity. The agent also contains a stabilizing S228P sequence alteration. The drug is approved for use in the treatment of melanoma.2

In the phase I KEYNOTE-001 study, activity of pembrolizumab is being studied at 2- and 3-week intervals in NSCLC expansion cohorts (N = 307). Table 1 shows the best ORR in patients with PD-L1+ tumors at interim analysis.3

Table 1. Overall Response Rates in Patients With PD-L1+ Tumors at Interim Analysis3

  RECIST v.1.1, Central Review irRC, Investigator Review
  10 mg/kg Q2W
n =53
10 mg/kg Q3W
n = 106
10 mg/kg Q2W
n =58
10 mg/kg Q3W
n = 119
ORR (95% CI) 26 (15-40) 21 (13-30) 22 (13-35) 18 (11-26)
DCR (95% CI) 47 (33-61) 39 (29-49) 59 (45-71) 48 (39-57)
Time to response, weeks,
median (range)
10 (6-24) 9 (7-31) 9 (6-19) 9 (8-19)
Response duration, weeks,
median (range)
NR (0+ - 28+) 31 (0+ - 37+) NR (0 - 37+) NR (6+ - 28+)

ORR indicates overall response rate; DCR, disease control rate

In advanced lung cancer, the drug is being studied as monotherapy and in combination across lines of therapy and histologies, including exploring different tumor characteristics such as PD-L1 expression as predictors of responsiveness. There are 2 ongoing phase I and III studies in advanced lung cancer (KEYNOTE-010 and KEYNOTE-024) and an additional phase III study is planned to begin in the fourth quarter of 2014 (KEYNOTE-042).1

Pembrolizumab is indicated in the US at a dose of 2 mg/kg every 3 weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive. This indication is approved under accelerated approval. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

“The FDA’s breakthrough therapy designation of Keytruda underscores that new treatment approaches for advanced non-small cell lung cancer continue to be needed,” said Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories in a press release. “Our data investigating the use of Keytruda in this difficult-to-treat malignancy are very encouraging, and we look forward to working closely with the FDA to expedite our clinical program.”
  1. Merck Press Release. Merck receives FDA breakthrough therapy designation for KEYTRUDA® (pembrolizumab) in advanced non-small cell lung cancer. Accessed October 27, 2014.
  2. Keytruda (pembrolizumab) [Prescribing Information]. Whitehouse Station, NJ: Merck and Co; 2014.
  3. Garon EB, Gandhi L, Rizvi N, et al. LBA43 - Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non–small cell lung carcinoma (NSCLC). Presented at: ESMO 2014 Congress; SEP 28, 2014; Madrid, Spain. Abstract #LBA43.


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