Naiyer Rizvi, MD
The anti-PD-1 humanized antibody pembrolizumab (MK-3475) has robust antitumor activity as a first-line treatment for patients with advanced PD-L1-positive non–small cell lung cancer (NSCLC), according to results from the KEYNOTE-001 phase Ib study reported by Naiyer A. Rizvi, MD, at the 2014 ASCO Annual Meeting.
The study screened 84 patients for PD-L1, with 73 meeting the criteria for evaluable biopsy samples. Out of these patients, 57 (78%) were deemed PD-L1-positive. Forty-five patients met eligibility criteria for treatment with pembrolizumab, of whom 42 were evaluable by RECIST v1.1 criteria.
PD-L1 staining of tumor biopsies was completed using the 22C3 antibody with a prototype assay. Tumors were classified as positive based on ≥1% of tumor cells demonstrating expression of PD-L1, or any positive staining with the same reagent in tumor stroma. The same tissue samples were analyzed for the percent of tumor cells with membranous staining for PD-L1 with a clinical trial assay, also using 22C3.
Patients having received no prior systemic therapy for metastatic NSCLC whose tumors expressed PD-L1 were randomized to pembrolizumab at 10 mg/kg every 2 or 3 weeks until disease progression. The first 11 patients were randomized to 2 mg/kg and 10 mg/kg every 3 weeks.
“Eighty percent of these patients experienced some degree of reduction of tumor burden,” said Rizvi, medical oncologist, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. “Activity was observed across the 2 and 10 mg/kg dose levels, and between 2- and 3-week schedules.”
At the time of the March 3, 2014, data cutoff, the overall response rate by RECIST was 26% and was 47% by investigator-assessed immune-related response criteria (irRC). The disease control rates, defined as complete response, partial response, and stable disease, were 64% and 78% by RECIST and irRC, respectively.
The interim median progression-free survival was 27 weeks by RECIST and 37 weeks by irRC. “These are early data, with 56% of patients still on treatment at the time of data cutoff,” Rizvi said.
At the interim analysis, the median duration of response by either RECIST or irRC had not yet been reached with a median duration of follow-up of 36 weeks. Altogether, 100% of patients responding by RECIST and 90% by irRC continue to respond to treatment, with 64% and 86%, respectively, remaining on treatment.
Of the 45 patients treated, time on therapy was a mean of 154 days (median number of cycles = 9). With a minimum of 18 weeks of follow-up, 18% discontinued because of adverse events, only two of which were considered treatment-related (one patient with grade 3 pneumonitis and one with grade 2 acute kidney injury), 16% discontinued because of radiographic disease progression, and 11% because of investigator or patient choice, leaving 25 patients (56%) remaining on treatment at the time of data cutoff.
Treatment-related adverse events that occurred with >5% frequency were all grade 1/2. The most common treatment-related adverse events were fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhea (7%), dyspnea (7%), and rash (7%). There were three episodes of grade 3/4 treatment-related adverse events: one case each of grade 4 blood creatine phosphokinase elevation, grade 3 pericardial effusion, and grade 3 pneumonitis.
Pembrolizumab is a highly selective humanized IgG4-kappa isotype antibody against PD-1 that is designed to block the negative immune regulatory signaling of the PD-1 receptor by T cells. It exerts dual ligand (PD-L1 and PD-L2) blockade of the PD-1 pathway.
The variable region sequences of the very high affinity mouse and human PD-1 antibody were grafted into a humanized G4 immunoglobulin with a stabilizing Fc alteration. “The Ig4 immunoglobulin subtype does not engage Fc receptors or activate complement, thus avoiding the cytotoxic effects of the antibody that binds to the T cells that it’s intended to activate,” said Rizvi.
The phase III KEYNOTE-024 study is expected to open for enrollment in September 2014. This trial will compare pembrolizumab monotherapy to platinum-based doublet chemotherapy as a first-line treatment for patients with PD-L1-positive metastatic NSCLC.
Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s (suppl; abstr 8007).
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