The FDA granted accelerated approval to pembrolizumab (Keytruda®, Merck) for adults and children with previously treated unresectable or metastatic tumor mutational burden (TMB)–high solid tumors, defined as tumors with at least 10 mutations per megabase, who have no satisfactory alternative treatment option. The FDA also approved the FoundationOne® CDx assay (Foundation Medicine) as the companion diagnostic used to determine treatment eligibility.
The approval was based on data from a prospectively planned retrospective analysis of 10 cohorts of patients with a variety of previously treated unresectable or metastatic TMB-high solid tumors in the phase 2 KEYNOTE-158 trial (NCT02628067).
"Tumor mutational burden (TMB) has been correlated with response to CTLA-4 and PD-(L)1 inhibitors," wrote the KEYNOTE-158 investigators in their presentation abstract from the 2019 European Society of Medical Oncology (ESMO) Congress, led by first author Aurélien Marabelle, MD, PhD, Clinical Director of the Cancer Immunotherapy Program at the Institut Gustave Roussy, Villejuif, France. "TMB-high was associated with higher overall response rate in patients with select advanced solid tumors treated with pembrolizumab monotherapy, [suggesting] that TMB may be predictive of the efficacy of pembrolizumab monotherapy in patients with the tumor types included in KEYNOTE-158."
For the trial, patients were administered 200 mg of intravenous pembrolizumab every three weeks until disease progression or unacceptable toxicity, for primary efficacy end points of overall response rate and duration of response. Of 755 patients with evaluable TMB, 120 (15.9%) had TMB-high tumors. Pembrolizumab produced an overall response rate of 28.3% in patients with TMB-high tumors, compared with 6.5% in patients with TMB-low tumors. The median duration of response was not reached for either TMB-high or TMB-low tumors. Median progression-free survival was 2.1 months for both TMB-high tumors (range: 2.1 to 3.7 months) and TMB-low tumors (range: 2.1 to 2.3 months), with 12-month progression-free survival rates of 24.3% for TMB-high tumors and 14.0% for TMB-low tumors. However, median overall survival was lower for TMB-high than for TMB-low tumors (11.1 vs 13.3 months), with 12-month survival rates of 48.0% and 52.9%, respectively.
Adverse reactions occurring in at least 20% of patients taking pembrolizumab include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Immune-mediated reactions to pembrolizumab can include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Under a "Limitations of Use" heading, the prescribing information states that the safety and efficacy have not been established in pediatric patients with TMB-high central nervous system cancers.
For adults, the recommended dosage is 200 mg every three weeks or 400 mg every six weeks; for children, it is 2 mg/kg up to a maximum of 200 mg every three weeks.
For More Information
Marabelle A, Fakih MG, Lopez J, et al (2019). Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol (Abstract Book of the 44th ESMO Congress), 30 (suppl_5):v477-v478. Abstract 11920. DOI:10.1093/annonc/mdz253.018
US Food and Drug Administration (2020). FDA approves pembrolizumab for adults and children with TMB-H solid tumors. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-gemtuzumab-ozogamicin-cd33-positive-aml-pediatric-patients
Image credit: Steve Seung-Young Lee. Courtesy of the National Cancer Institute / University of Chicago Comprehensive Cancer Center