Pembrolizumab (Keytruda) for Mesothelioma

Pembrolizumab, marketed as Keytruda, is a humanized monoclonal antibody that blocks the programmed death-1 (PD-1) immune checkpoint receptor. It is one of the most widely used immunotherapy drugs in oncology, with FDA approvals spanning more than 20 cancer types. Although pembrolizumab is not specifically FDA-approved for mesothelioma, it is used off-label — primarily as second-line therapy for patients whose disease has progressed after initial pemetrexed-based chemotherapy.¹

Like nivolumab, pembrolizumab works by blocking the PD-1 receptor on T cells, preventing cancer cells from engaging the PD-1/PD-L1 immune evasion pathway. When PD-L1 on tumor cells binds to PD-1 on T cells, it sends an inhibitory signal that prevents the T cell from attacking. By blocking this interaction, pembrolizumab restores the T cell's ability to recognize and destroy cancer cells. The two drugs share the same target and mechanism, though they differ in their molecular structure — pembrolizumab is a humanized antibody while nivolumab is a fully human antibody.²

Clinical interest in pembrolizumab for mesothelioma has been driven by several trials showing promising activity, particularly in patients with PD-L1-positive tumors. The KEYNOTE-028 and KEYNOTE-158 basket trials demonstrated objective response rates of 20–22% in PD-L1-positive mesothelioma patients, with some responses lasting more than a year. However, the phase III PROMISE-meso trial comparing pembrolizumab to single-agent chemotherapy in previously treated patients did not meet its primary endpoint of improved progression-free survival, though overall survival trends favored pembrolizumab.³

PD-L1 expression on tumor cells has emerged as a potential biomarker for predicting response to pembrolizumab in mesothelioma. Patients with PD-L1 tumor proportion scores (TPS) of 1% or higher tend to have higher response rates and longer survival on pembrolizumab. However, PD-L1-negative patients can also respond, and the biomarker is not used as an absolute selection criterion in clinical practice.⁴

Pembrolizumab is used in several clinical contexts for mesothelioma, though none is specifically FDA-approved:¹

Second-Line Monotherapy

The most common use of pembrolizumab in mesothelioma is as second-line treatment after progression on pemetrexed-based chemotherapy:²

• Pembrolizumab — 200 mg as a 30-minute intravenous infusion every 3 weeks, or 400 mg every 6 weeks
• Duration — Up to 2 years or until disease progression or unacceptable toxicity
• PD-L1 testing — Immunohistochemistry for PD-L1 expression is recommended but not required for treatment decisions

Key Clinical Trial Data

• KEYNOTE-028 — Phase Ib basket trial in PD-L1-positive mesothelioma patients (TPS ≥1%). Objective response rate of 20% (5/25 patients), with median duration of response of 12 months. Median overall survival was 18 months³
• KEYNOTE-158 — Phase II basket trial that included 118 mesothelioma patients. Objective response rate of 8% overall, but 18% in PD-L1-positive patients (combined positive score ≥1). Median duration of response was 14.3 months⁴
• PROMISE-meso — Randomized phase III trial comparing pembrolizumab to single-agent chemotherapy (gemcitabine or vinorelbine) in previously treated mesothelioma. Pembrolizumab did not significantly improve progression-free survival (median 2.5 vs. 3.4 months). However, overall survival numerically favored pembrolizumab (10.7 vs. 11.7 months), and crossover was permitted, confounding the OS analysis⁵

Combination Approaches Under Investigation

Pembrolizumab is being studied in combination with chemotherapy (pemetrexed/platinum), other immunotherapy agents, and novel targeted therapies for first-line and second-line mesothelioma treatment. Early-phase trials have shown promising response rates with pembrolizumab plus pemetrexed/cisplatin or carboplatin, potentially offering an alternative to the nivolumab/ipilimumab combination.²

Pembrolizumab offers meaningful clinical activity in a subset of mesothelioma patients, though identifying optimal responders remains an area of active research:³

• Response rates — Approximately 8–22% of patients achieve an objective response depending on PD-L1 status and trial population, with higher rates in PD-L1-positive patients
• Durable responses — When patients do respond, the duration of response is often impressive, with median durations of 12–14 months and some responses lasting more than 2 years
• Disease control — An additional 40–50% of patients achieve stable disease, meaning the cancer does not progress during treatment even without measurable tumor shrinkage
• Predictive factors — PD-L1 expression, epithelioid histology, and lower tumor burden are associated with better outcomes on pembrolizumab

Pembrolizumab's side effect profile is similar to other PD-1 inhibitors and generally more tolerable than traditional chemotherapy:²

• Fatigue — The most common side effect, reported by 20–30% of patients. Usually mild to moderate and may improve with structured rest, light exercise, and adequate nutrition. Persistent fatigue should be evaluated for thyroid dysfunction
• Immune-mediated pneumonitis — Inflammation of the lungs occurring in 3–5% of patients. Particularly concerning in mesothelioma patients with pre-existing lung compromise from disease or prior treatment. Any new cough, worsening breathlessness, or chest pain should be reported immediately
• Thyroid dysfunction — Hypothyroidism (underactive thyroid) occurs in 8–10% of patients, often preceded by a transient hyperthyroid phase. Symptoms include fatigue, weight gain, and cold intolerance. Thyroid function tests are monitored every 6 weeks. Most cases are managed with levothyroxine replacement therapy
• Skin reactions — Rash, pruritus, and vitiligo occur in 10–15% of patients. Most are mild and managed with topical corticosteroids and antihistamines
• Colitis — Diarrhea and intestinal inflammation occur in 5–8% of patients (less frequent than with ipilimumab-containing regimens). Severe cases require corticosteroid treatment and treatment interruption
• Hepatitis — Elevated liver enzymes in 3–5% of patients, monitored on routine blood tests before each cycle. Usually asymptomatic and managed with treatment interruption and corticosteroids if needed
• Infusion reactions — Mild reactions (fever, chills, flushing) occur rarely and are managed with supportive care. Severe anaphylactic reactions are very rare

Patients should keep an immunotherapy treatment card and inform all healthcare providers about pembrolizumab therapy. Immune-related adverse events can emerge at any point during treatment or even months after the last dose.²