What are immune checkpoint inhibitors and which are most commonly used in non‑small cell lung cancer?

What Are Immune Checkpoint Inhibitors and Which Are Most Commonly Used in Non-Small Cell Lung Cancer?

Immune checkpoint inhibitors (ICIs) are antibodies that block inhibitory immune pathways—primarily PD-1/PD-L1 and CTLA-4—allowing T-cells to recognize and destroy cancer cells, and the most commonly used agents in NSCLC are pembrolizumab, nivolumab, atezolizumab, and durvalumab. 1, 2

Mechanism of Action

ICIs work by disrupting the immune system's natural "brakes" that cancer cells exploit to evade detection. The two main pathways targeted are:

• PD-1/PD-L1 pathway: When PD-1 receptors on T-cells bind to PD-L1 on tumor cells, the immune response is suppressed. Blocking this interaction reactivates anti-tumor immunity.
• CTLA-4 pathway: CTLA-4 inhibits T-cell activation earlier in the immune response; blocking it enhances overall immune activation.

These mechanisms produce distinctly durable responses compared to traditional chemotherapy, which historically offered only modest and rarely sustained benefits. 2

Most Commonly Used ICIs in NSCLC

Based on the most recent NCCN guidelines (2025), the following agents are standard of care 1:

PD-1/PD-L1 Inhibitors (Primary Agents)

1. Pembrolizumab (anti-PD-1)

   • First-line monotherapy for PD-L1 ≥50% (any histology)
   • First-line combination with chemotherapy for PD-L1 <50%
   • Adjuvant therapy post-resection (up to 1 year)
   • Dosing: 200 mg every 3 weeks or 400 mg every 6 weeks

2. Nivolumab (anti-PD-1)

   • Perioperative setting (neoadjuvant + adjuvant)
   • Dosing: 480 mg every 4 weeks for up to 13 cycles
   • Subcutaneous formulation available (nivolumab-hyaluronidase)

3. Atezolizumab (anti-PD-L1)

   • Adjuvant therapy for PD-L1 ≥1% post-resection
   • Second-line therapy for advanced disease
   • Dosing: 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks
   • Subcutaneous formulation available (atezolizumab-hyaluronidase)

4. Durvalumab (anti-PD-L1)

   • Consolidation therapy after chemoradiation for stage III unresectable disease
   • Perioperative setting (neoadjuvant + adjuvant)
   • Dosing: 1500 mg every 4 weeks for up to 12 cycles

CTLA-4 Inhibitors (Less Common in NSCLC)

• Ipilimumab: Used primarily in combination strategies, though less commonly than PD-1/PD-L1 inhibitors in NSCLC 3, 4

Clinical Application Algorithm

For Advanced/Metastatic NSCLC 1, 2

Step 1: Molecular Testing

• Test for EGFR mutations (exon 19 deletion, exon 21 L858R)
• Test for ALK, ROS1, RET rearrangements
• Measure PD-L1 expression (tumor proportion score, TPS)

Step 2: Treatment Selection Based on Results

If driver mutations present (EGFR, ALK, ROS1, RET):

• Use targeted therapy FIRST (osimertinib for EGFR, alectinib for ALK)
• ICIs are LESS effective in this population and should NOT be first-line 1

If no driver mutations:

• PD-L1 TPS ≥50%: Pembrolizumab monotherapy (first choice)
• PD-L1 TPS 1-49%: Pembrolizumab + chemotherapy (pemetrexed/carboplatin for non-squamous; carboplatin/paclitaxel for squamous)
• PD-L1 TPS <1%: Pembrolizumab + chemotherapy (benefit unclear for monotherapy)

Second-line (after chemotherapy progression):

• Nivolumab, pembrolizumab (if PD-L1 >1%), or atezolizumab regardless of prior ICI exposure 2

For Resectable NSCLC (Stages IB-IIIB) 1

Adjuvant Setting (post-surgery):

• PD-L1 ≥1%, no EGFR/ALK mutations: Atezolizumab for 1 year after adjuvant chemotherapy
• Any PD-L1, no EGFR/ALK mutations: Pembrolizumab for 1 year after adjuvant chemotherapy (benefit unclear if PD-L1 <1%)

Perioperative Setting (neoadjuvant + adjuvant):

• Nivolumab + chemotherapy (neoadjuvant) → surgery → nivolumab alone (adjuvant)
• Durvalumab + chemotherapy (neoadjuvant) → surgery → durvalumab alone (adjuvant)

For Stage III Unresectable:

• Durvalumab consolidation after concurrent chemoradiation (standard of care)

Critical Contraindications and Pitfalls 1

Absolute contraindications:

• Active autoimmune disease requiring systemic immunosuppression
• Current use of immunosuppressive agents (>10 mg prednisone equivalent daily)

Relative contraindications (less benefit expected):

• EGFR exon 19 deletion or exon 21 L858R mutations
• ALK, RET, or ROS1 rearrangements
• These patients should receive targeted therapy first

Common pitfall: Using ICIs in EGFR/ALK-positive patients as first-line therapy—this is INCORRECT. These patients derive minimal benefit from ICIs and should receive targeted therapy. 1

Important consideration: Do NOT switch immunotherapy agents during perioperative treatment—complete the regimen with the same ICI used initially. 1

Biomarker Testing Requirements 2

Mandatory before ICI initiation:

• PD-L1 expression (IHC testing with validated assays: 22C3, 28-8, SP263, or SP142)
• EGFR mutation testing
• ALK rearrangement testing

Recommended baseline assessments:

• CT chest/abdomen/pelvis (88% consensus)
• Thyroid function tests (81% consensus)
• Consider brain MRI, creatinine clearance, pulmonary function tests based on clinical context

Emerging Evidence and Future Directions

Recent data show that in elderly patients (≥65 years), ICIs probably result in little to no improvement in overall survival when used alone, though they increase disease-free survival, event-free survival, and pathological response rates. 5 This suggests that combination strategies may be more appropriate than monotherapy in older populations.

The evidence for ICIs in NSCLC is robust, with multiple phase III trials demonstrating survival benefits. However, PD-L1 expression is neither fully sensitive nor specific as a predictive biomarker—patients with low or negative PD-L1 can still respond, particularly when ICIs are combined with chemotherapy. 2