The U.S. Food and Drug Administration (FDA) has conditionally approved Keytruda (pembrolizumab) for the treatment of pediatric and adult patients with inoperable or metastatic solid tumors with high tumor mutational burden (TMB-H).
This is the second time the FDA approved Merck‘s immune checkpoint inhibitor Keytruda for cancer patients with specific genetic features in their tumors rather than a specific tumor type.
Full approval for this indication, which includes patients who have progressed following prior treatment and who have no satisfactory alternative treatment options, will depend on positive results on confirmatory trials.
Of note, the label for this indication states that Keytruda’s safety and effectiveness in pediatric patients with TMB-H central nervous system cancers (those involving the brain and spinal cord) have yet to be established.
“We’re pleased that our collaborative efforts to advance biomarker research have resulted in our ability to provide a new treatment option that addresses a high unmet medical need for these patients with cancer,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, said in a press release.
“It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers,” said Roy S. Herbst, MD, PhD. Herbst is chief of medical oncology at the Yale Cancer Center and Smilow Cancer Hospital and associate cancer center director for translational research at Yale Cancer Center.
Patients’ eligibility for this therapy will be evaluated using Foundation Medicine’s FoundationOne CDx test, which was approved simultaneously by the FDA as a companion diagnostic for Keytruda to identify patients with TMB-H solid tumors who may benefit from the immunotherapy.
FoundationOne CDx, an FDA-approved comprehensive genomic-profiling assay for all solid tumors, assesses four classes of mutations across 324 genes known to be drivers of solid tumors, as well as genomic biomarkers, including the number of mutations in the DNA.
High levels of these genomic biomarkers (more mutations) make it easier for the immune system to differentiate tumors from normal cells, particularly when immunotherapies such as Keytruda boost anti-cancer immune responses.
“It’s critical that healthcare professionals have access to a validated genomic test to measure TMB in clinical tumor assessments and pinpoint those who are more likely to respond. We’re proud to be collaborating with Merck to help match appropriate patients to this important treatment,” said Brian Alexander, MD, Foundation’s chief medical officer.
Keytruda, an immune checkpoint inhibitor marketed by Merck (known as MSD outside North America), works by preventing an immune evasion mechanism involving the interaction between PD-L1 in cancer cells and the PD-1 receptor in immune T-cells.
The FDA’s decision marks the second biomarker-based approval for Keytruda, which was approved previously for a similar patient population, but whose cancers had high microsatellite instability or deficient mismatch repair. Both are indicators of impaired DNA repair that increase the number of mutations in a tumor.
“For the second time, Keytruda monotherapy is now approved based on a biomarker rather than the location in the body where the tumor originated,” Ebbinghaus said.
This accelerated approval was based on a retrospective subgroup analysis of the open-label, global, KEYNOTE-158 Phase 2 trial (NCT02628067), which is evaluating Keytruda responses in adult patients with previously treated inoperable or metastatic solid tumors. The trial is still recruiting across 32 sites worldwide.
Participants, divided into 10 groups of different types of solid cancers, are given 200 mg of Keytruda, directly into the bloodstream, every three weeks.
TMB was analyzed in a subset of 790 patients with sufficient tissue for testing, of which 102 (13%) had TMB-H tumors — deemed as having 10 or more mutations per megabase (one million building blocks) of DNA.
Most (81%) of these participants with TMB-H tumors were white and their median age was 61 years (range 27–80), with 34% being 65 and older. More than half (56%) received at least two prior therapy lines. These patients were treated with Keytruda for a median of 4.9 months.
Among this subgroup, 29% of the patients responded to Keytruda, including 25% with a partial response and 4% with a complete response. These responses were generally durable, with 57% of responders showing a response for at least one year and 50% for at least two years.
In a pre-specified analysis of the 70 patients with a TMB of 13 or more, the objective response rate was 37% (34% partial responses and 3% complete responses). Again, more than half of these responders had no signs of disease progression for at least one (58%) or two (50%) years.
An exploratory analysis of the 32 patients whose tumors had a TMB between 10 and 13 showed that four (13%) responded to Keytruda, two achieving complete responses and two showing partial responses.
Since more than half of Keytruda responses were still ongoing after a median follow-up of 11.1 months, researchers could not assess the median duration of response in any of these TMB subgroups.
The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, decreased appetite, itchy skin, diarrhea, nausea, rash, fever, cough, shortness of breath, constipation, pain, and abdominal pain.
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