Pembrolizumab immunotherapy received FDA approval for all tumors with high tumor mutational burden

On 16 June 2020, the United States Food and Drug Administration (FDA) granted accelerated approval for all unresectable or metastatic, high tumor mutational burden (TMB-H) [TMB ≥10 per megabase] solid tumors in adult and pediatric patients using pembrolizumab (Keytruda), an immunotherapy medicine. For pembrolizumab to be used for this purpose, tumor mutational burden (TMB) must be determined with an FDA-approved test, the patient’s cancer must have progressed after previous treatment, and there must be no satisfactory alternative treatment options.

At the same time, the FDA also approved the FoundationOneCDx test as a companion TMB test for pembrolizumab.

The clinical study that led to FDA approval of pembrolizumab in TMB-high tumors

The efficacy of pembrolizumab was investigated in the multicenter, nonrandomized, open-label clinical trial called KEYNOTE-158 through a prospectively planned retrospective analysis of 10 cohorts of previously treated patients with unresectable or metastatic TMB-H solid tumors. Patients received 200 mg of pembrolizumab every 3 weeks until unacceptable side effects or documented disease progression.

The main efficacy outcome measures, assessed by blinded independent central review in patients who had received at least one dose of pembrolizumab, were overall response rate and duration of response.

Study results

• A total of 102 patients (13%) had tumors classified as TMB-H, defined as TMB ≥10 mut / Mb.
• The overall response rate in these patients was 29%, with a complete response rate of 4% and a partial response rate of 25%.
• Of these 102 patients, 34.3% had small-cell lung cancer, 16.2% had cervical cancer, 15.2% had endometrial cancer and 14.1% had anal cancer; the remaining 20% had other cancers.
• In the group whose TMB was not high, 12.7% had mesothelioma, 12.3% had neuroendocrine cancer, 12% had salivary gland cancer and 10.3% had endometrial cancer.
• At the time of the pembrolizumab analysis in patients with TMB-H, median duration of response had not been reached.
• A response duration of ≥12 months was achieved in 57% of patients, and a response duration of ≥24 months in 50%.

In patients with TMB‑H cancer enrolled in KEYNOTE-158, side effects were similar to those seen in patients with other solid tumors who received pembrolizumab as a single agent. The most common side effects of pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, itching, diarrhea, nausea, rash, pyrexia/fever, cough, shortness of breath, constipation, pain and abdominal pain. Pembrolizumab is associated with immune-mediated side effects such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and skin allergies.

The recommended pembrolizumab dose for TMB-H solid tumors is 200 mg every 3 weeks or 400 mg every 6 weeks for adults; for pediatric patients, 2 mg / kg every 3 weeks (up to a maximum of 200 mg). 

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