Non-Small Cell Lung Cancer (NSCLC) Immunotherapy Treatment Guide

Immunotherapy has revolutionized non-small cell lung cancer (NSCLC) treatment, becoming the standard of care for many patients. Understanding biomarker testing, treatment options, and sequencing is crucial for optimal outcomes.

**Understanding NSCLC and Immunotherapy**

NSCLC Basics:
- Accounts for 85% of all lung cancers
- Subtypes: adenocarcinoma (40%), squamous cell (25-30%), large cell (10%)
- Staging: I-II (early), III (locally advanced), IV (metastatic)
- Immunotherapy most impactful in advanced stages

Why Immunotherapy Works in Lung Cancer:
- High tumor mutational burden (TMB)
- Smoking-related mutations create neoantigens
- PD-L1 often expressed on tumor cells
- Responsive to checkpoint blockade

**Critical Biomarker Testing**

Essential Tests Before Treatment:

PD-L1 Expression (IHC):
- Tumor Proportion Score (TPS)
- <1% = Negative/low
- 1-49% = Intermediate
- ≥50% = High expression
- Guides first-line treatment selection

Molecular Profiling:
- EGFR mutations (15% Caucasian, 50% Asian)
- ALK rearrangements (5%)
- ROS1 fusions (1-2%)
- BRAF V600E mutations (2-3%)
- MET exon 14 skipping (3%)
- RET fusions (1-2%)
- KRAS G12C (13%)
- NTRK fusions (<1%)
- HER2 mutations (2-3%)

If Targetable Mutation Found:
- Targeted therapy usually preferred first-line
- Immunotherapy reserved for after progression
- Exception: May combine in some cases

Tumor Mutational Burden (TMB):
- ≥10 mutations/megabase = High TMB
- Predicts better immunotherapy response
- FDA approved indication for Keytruda

**First-Line Treatment by PD-L1 Status**

PD-L1 ≥50% (High Expression):

Preferred Regimen:
- Keytruda monotherapy
- 200 mg IV every 3 weeks or 400 mg every 6 weeks
- Continue up to 2 years
- Efficacy:
* Response rate: 45%
* Median PFS: 10.3 months
* Median OS: 30 months
* 5-year survival: 32%

Alternative:
- Keytruda + chemotherapy
- Higher response rate (70%) but more toxicity
- Consider if high disease burden

Advantages of Monotherapy:
- Avoid chemotherapy toxicity
- Better quality of life
- Oral medications only (if chemo avoided)
- Potentially durable responses

PD-L1 1-49% (Intermediate):

Standard Approach:
- Immunotherapy + chemotherapy combination
- More effective than chemotherapy alone
- Better than immunotherapy monotherapy in this group

Regimens:

Nonsquamous:
- Keytruda + carboplatin + pemetrexed × 4 cycles
- Then Keytruda + pemetrexed maintenance
- Median OS: 22 months

Squamous:
- Keytruda + carboplatin + paclitaxel/nab-paclitaxel × 4 cycles
- Then Keytruda maintenance
- Median OS: 17.1 months

Alternative (Nonsquamous):
- Tecentriq + bevacizumab + carboplatin + paclitaxel
- Higher response rates
- More toxicity

PD-L1 <1% (Negative/Low):

Standard Approach:
- Immunotherapy + chemotherapy
- Significantly better than chemotherapy alone

Regimens Same as PD-L1 1-49%:
- Keytruda + platinum-doublet chemotherapy
- Alternatively: chemotherapy alone if immunotherapy contraindicated

Do NOT Use Immunotherapy Monotherapy:
- Ineffective in PD-L1 <1%
- May be harmful compared to chemotherapy

**Special Populations**

EGFR-Mutated NSCLC:

First-Line:
- EGFR TKI (osimertinib preferred)
- NOT immunotherapy
- Immunotherapy less effective in EGFR-mutant
- Higher toxicity when combined with EGFR TKI

After EGFR TKI Progression:
- Chemotherapy typically preferred
- Immunotherapy may be considered
- Response rates lower than EGFR wild-type
- T790M testing for second-line osimertinib

ALK-Rearranged NSCLC:

First-Line:
- ALK TKI (alectinib, lorlatinib, brigatinib)
- NOT immunotherapy
- Sequential ALK TKIs for multiple lines

After ALK TKI Failure:
- Consider immunotherapy + chemotherapy
- Response rates modest

Brain Metastases (Common in NSCLC):

Treatment Approach:
- Small, asymptomatic: systemic therapy first
- Large or symptomatic: radiation (SRS or WBRT) then systemic therapy
- Immunotherapy can control brain metastases
- Combination therapy more effective than monotherapy

**Treatment Duration and Monitoring**

Standard Duration:
- Up to 2 years of immunotherapy
- Or until progression/toxicity
- Some continue beyond 2 years if responding

Imaging Schedule:
- Baseline CT chest/abdomen/pelvis
- Repeat every 6-9 weeks initially
- Every 12 weeks once response established
- Brain MRI if symptoms or high risk

Response Patterns:

Early Response (Weeks 6-12):
- Tumor shrinkage often rapid
- Indicates likely benefit

Delayed Response (Months 3-6):
- Some patients respond slowly
- Don't give up too early

Pseudoprogression:
- Initial growth followed by shrinkage
- Rare in lung cancer (<5%)
- Continue therapy if clinically stable

**Maintenance Therapy**

After Chemotherapy + Immunotherapy:

Options:
- Keytruda + pemetrexed (nonsquamous)
- Keytruda monotherapy (squamous)
- Tecentriq monotherapy
- Continue until progression

Importance:
- Improves survival compared to observation
- Maintains disease control
- Generally well-tolerated

**Second-Line Treatment**

After Immunotherapy Failure:

Docetaxel Chemotherapy:
- Standard option
- Response rate 10-15%
- Modest survival benefit

Ramucirumab + Docetaxel:
- Better than docetaxel alone
- For adenocarcinoma

Clinical Trials:
- Antibody-drug conjugates
- Novel targeted therapies
- Combination approaches

After Chemotherapy Failure (No Prior Immunotherapy):

OPDIVO or Keytruda Monotherapy:
- Approved in second-line
- Response rates 20%
- Durable responses in some patients
- Preferred if PD-L1 positive

Tecentriq Monotherapy:
- Similar efficacy to OPDIVO
- Option for PD-L1 positive patients

**Managing Side Effects**

Common Immunotherapy Side Effects in NSCLC:

Pneumonitis (2-5%):
- Most concerning in lung cancer patients
- Baseline lung function often impaired
- New cough, dyspnea, or infiltrates
- May require permanent discontinuation
- Close monitoring essential

Fatigue (25-30%):
- Most common side effect
- Usually mild to moderate
- Manageable with energy conservation

Skin Reactions (15-20%):
- Rash, pruritus
- Usually mild
- Topical steroids and antihistamines

Thyroid Dysfunction (5-10%):
- Hypothyroidism most common
- Simple levothyroxine replacement
- Rarely requires stopping treatment

**Combination Therapy Considerations**

Adding Chemotherapy to Immunotherapy:

Advantages:
- Higher response rates
- Better PFS in most PD-L1 groups
- May sensitize tumors to immunotherapy

Disadvantages:
- More toxicity (nausea, neuropathy, cytopenias)
- More clinic visits
- Higher cost
- Impact on quality of life

When Worth It:
- PD-L1 <50%
- High disease burden
- Symptomatic disease
- Need rapid response

**Survival Outcomes**

Historical (Chemotherapy Alone):
- Median survival: 8-10 months
- 5-year survival: <5%

Current Era (Immunotherapy):

PD-L1 ≥50% with Keytruda:
- Median survival: 30 months
- 5-year survival: 32%

Any PD-L1 with Chemo-Immunotherapy:
- Median survival: 18-22 months
- 5-year survival: 20-25%

Long-Term Survivors:
- 15-20% alive at 5 years with immunotherapy
- Some remain disease-free off treatment
- Potential for long-term remission

**Quality of Life**

Immunotherapy vs. Chemotherapy:

Quality of Life Benefits:
- Less nausea and vomiting
- Preserved cognitive function
- Better appetite
- Less fatigue (after initial adjustment)
- Maintained performance status longer

Considerations:
- Immune side effects can be unpredictable
- Requires vigilance for symptoms
- Some side effects permanent (thyroid)

**Questions to Ask Your Oncologist**

- What is my PD-L1 level?
- Do I have any targetable mutations?
- Should I get immunotherapy alone or with chemotherapy?
- What are my chances of responding?
- How long would I continue treatment?
- What happens if the treatment stops working?
- Am I eligible for clinical trials?

**Patient Success Story**

"I was diagnosed with stage IV NSCLC with PD-L1 of 80% in 2021. My oncologist recommended Keytruda monotherapy, sparing me from chemotherapy. After 3 months, my tumors had shrunk by 70%. I completed 2 years of Keytruda in 2023 and have been off treatment for 18 months with no evidence of disease. I feel fantastic and am living a completely normal life. Keytruda gave me a second chance I never thought possible with stage 4 cancer."

Our team can help you access immunotherapy for lung cancer and connect you with specialized thoracic oncology centers.