Checkpoint Inhibitors for Mesothelioma

What Are Checkpoint Inhibitors?

Checkpoint inhibitors are a type of immunotherapy that helps the immune system recognize and attack cancer cells. They work by blocking proteins that normally prevent immune cells from attacking, essentially “releasing the brakes” on the immune response.

For mesothelioma patients, checkpoint inhibitors have become a major treatment option, with two FDA-approved regimens now available as first-line therapy.

How Cancer Hides from the Immune System

Under normal circumstances, the immune system identifies and destroys abnormal cells, including cancer. However, cancer cells develop ways to evade detection:

The PD-1/PD-L1 Pathway:

1. T-cells (immune cells) have a protein called PD-1 on their surface
2. When PD-1 binds to PD-L1 (found on cancer cells), it sends a “stop” signal
3. The T-cell becomes exhausted and stops attacking
4. Cancer cells exploit this by expressing high levels of PD-L1

The CTLA-4 Pathway:

1. CTLA-4 is another “brake” protein on T-cells
2. It limits T-cell activation during the initial immune response
3. With CTLA-4 active, fewer T-cells are primed to attack cancer cells

How Checkpoint Inhibitors Work

PD-1 Inhibitors

Drugs: Nivolumab (Opdivo), Pembrolizumab (Keytruda)

Mechanism:

• Block PD-1 on T-cells
• Prevent the “stop” signal from PD-L1
• Reinvigorate exhausted T-cells
• Allow recognition and attack of cancer cells

CTLA-4 Inhibitors

Drug: Ipilimumab (Yervoy)

Mechanism:

• Block CTLA-4 on T-cells
• Allow more T-cells to be activated and expanded
• Broaden the initial immune response
• Create more cancer-fighting cells

Why Combine Both?

Combining PD-1 and CTLA-4 inhibitors targets both pathways simultaneously:

Checkpoint	What It Does	Drug That Blocks It
PD-1	Exhausts active T-cells	Nivolumab, Pembrolizumab
CTLA-4	Limits T-cell activation	Ipilimumab

The combination produces a stronger, broader immune response than either drug alone.

FDA-Approved Checkpoint Inhibitors for Mesothelioma

Nivolumab + Ipilimumab (Opdivo + Yervoy)

Approved: October 2020 Based on: CheckMate-743 trial For: First-line treatment of unresectable malignant pleural mesothelioma

Results:

• Median survival: 18.1 months (vs 14.1 months with chemo)
• 3-year survival: 23% (vs 15%)
• Response rate: 41%

Dosing:

• Nivolumab 360 mg IV every 3 weeks
• Ipilimumab 1 mg/kg IV every 6 weeks
• Continue up to 2 years

Pembrolizumab + Chemotherapy (Keytruda + Chemo)

Approved: September 2024 Based on: KEYNOTE-483 trial For: First-line treatment of unresectable malignant pleural mesothelioma

Results:

• Median survival: 17.3 months (vs 16.1 months with chemo alone)
• 3-year survival: ~25% (vs ~17%)
• Response rate: 47%

Dosing:

• Pembrolizumab 200 mg IV every 3 weeks
• Plus pemetrexed + platinum for 4 cycles
• Pembrolizumab maintenance thereafter

Choosing Between Options

Both regimens are effective, and the choice depends on individual factors:

Nivolumab + Ipilimumab may be preferred for:

• Non-epithelioid (sarcomatoid/biphasic) disease
• Patients wanting to avoid chemotherapy
• Those who can tolerate dual checkpoint inhibitor side effects

Pembrolizumab + Chemotherapy may be preferred for:

• Patients who may benefit from chemotherapy component
• Concerns about dual checkpoint inhibitor toxicity
• Oncologist recommendation based on specific situation

How They’re Administered

Checkpoint inhibitors are given as IV infusions at a cancer center:

1. Blood tests before each infusion
2. Infusion takes 30–60 minutes
3. Monitoring period after infusion
4. Cycles repeat every 2–3 weeks (drug dependent)

Treatment continues until:

• Disease progression
• Unacceptable side effects
• Maximum duration reached (typically 2 years)

Side Effects

Because checkpoint inhibitors activate the immune system, they can cause immune-related adverse events (irAEs), essentially the immune system attacking healthy tissues.

Common Side Effects

Side Effect	Frequency	Management
Fatigue	30–40%	Rest, activity pacing
Rash	20–30%	Topical steroids, antihistamines
Diarrhea	15–25%	Anti-diarrheals, steroids if severe
Thyroid dysfunction	10–20%	Hormone replacement
Nausea	10–15%	Anti-nausea medications

Serious Immune-Related Effects

These are less common but require prompt attention:

Pneumonitis (lung inflammation):

• Symptoms: Cough, shortness of breath
• Treatment: Steroids, possibly hold immunotherapy

Colitis (colon inflammation):

• Symptoms: Severe diarrhea, abdominal pain
• Treatment: Steroids, infliximab if needed

Hepatitis (liver inflammation):

• Symptoms: Often none; detected by blood tests
• Treatment: Hold treatment, steroids

Endocrine disorders:

• Thyroid: Hypo- or hyperthyroidism
• Adrenal: Adrenal insufficiency
• Pituitary: Hypophysitis

When to Call Your Doctor

Contact your care team immediately for:

• Fever over 100.4°F
• Severe or persistent diarrhea
• New or worsening cough or shortness of breath
• Yellowing of skin or eyes
• Severe fatigue or weakness
• New or worsening headaches

Who Should Not Receive Checkpoint Inhibitors?

Checkpoint inhibitors may not be appropriate for patients with:

• Active autoimmune diseases (lupus, rheumatoid arthritis, etc.)
• Organ transplants requiring immunosuppression
• Severe immune-related events from prior immunotherapy
• Very poor performance status

Always discuss your full medical history with your oncologist.

Predicting Response

Currently, no reliable biomarkers perfectly predict who will respond to checkpoint inhibitors in mesothelioma. However:

• PD-L1 expression may correlate with response in some cases
• Non-epithelioid histology shows particular benefit from nivolumab + ipilimumab
• Research is ongoing to identify better predictive markers

The Future of Checkpoint Inhibitors

Ongoing research includes:

• Triple combinations (two checkpoint inhibitors + chemotherapy)
• New checkpoint targets (LAG-3, TIGIT, TIM-3)
• Combinations with other therapies (CAR-T, vaccines, targeted drugs)
• Biomarker development for better patient selection