What is the optimal next‑line therapy for a 73‑year‑old female with metastatic lung adenocarcinoma, no actionable driver mutations, unknown PD‑L1 expression, who has progressed on carboplatin/pemetrexed chemotherapy and pembrolizumab (Keytruda)?

Optimal Second-Line Therapy After Progression on Pembrolizumab Plus Chemotherapy

For this 73-year-old woman with metastatic lung adenocarcinoma who has progressed on carboplatin/pemetrexed/pembrolizumab, docetaxel plus ramucirumab is the recommended second-line treatment. 1

Primary Treatment Recommendation

Docetaxel with ramucirumab should be offered as the standard second-line therapy for patients who have already received platinum-based chemotherapy combined with immunotherapy. 1 This represents a strong recommendation (moderate evidence quality, strong strength) from the most recent 2025 ASCO guidelines for patients in this exact clinical scenario. 1

Supporting Evidence for Docetaxel/Ramucirumab

• The combination of docetaxel plus ramucirumab is specifically recommended for NSCLC patients with good performance status who have progressed after platinum-based chemotherapy and immunotherapy. 1
• Real-world data demonstrate an objective response rate of 32.5% and disease control rate of 62.4% when docetaxel/ramucirumab is used after first-line chemo-immunotherapy failure, with median progression-free survival of 3.9 months. 2
• This regimen is appropriate regardless of PD-L1 expression status and is suitable for elderly patients with preserved performance status. 1

Alternative Second-Line Options

Single-Agent Chemotherapy

If ramucirumab is contraindicated or unavailable:

• Pemetrexed monotherapy may be offered for non-squamous histology, with a more favorable tolerability profile than docetaxel. 1
• Gemcitabine represents another alternative single-agent option. 1
• Docetaxel monotherapy can be used if ramucirumab cannot be added. 1

Emerging Option: Trastuzumab Deruxtecan

• Trastuzumab deruxtecan may be offered if HER2 testing demonstrates IHC 3+ overexpression (using gastric scoring criteria). 1 This represents a weak recommendation based on very low-quality evidence but provides an important targeted option if HER2 is overexpressed. 1

Critical Pre-Treatment Considerations

Performance Status Assessment

• The patient must have ECOG performance status 0-2 to be eligible for second-line therapy. 1, 3
• Age 73 alone should not exclude her from combination therapy if her performance status and organ function are adequate. 1

Molecular Testing Gaps

PD-L1 status should be obtained if not already done, though it does not change the second-line recommendation after immunotherapy failure. 1 More importantly:

• Confirm that comprehensive molecular profiling was completed to exclude actionable mutations (EGFR, ALK, ROS1, BRAF V600, MET exon 14 skipping, RET, NTRK). 1
• HER2 IHC testing should be performed to determine eligibility for trastuzumab deruxtecan. 1

Why Not Re-Challenge with Immunotherapy?

The 2019 Pan-Asian and ESMO guidelines explicitly state that platinum-based chemotherapy is recommended as the second-line treatment option for patients with progression after first-line immunotherapy with pembrolizumab. 1, 3

However, one case report suggests that switching from anti-PD-1 (pembrolizumab) to anti-PD-L1 (atezolizumab) achieved partial response in a patient who progressed on pembrolizumab. 4 This remains investigational and is not guideline-supported, but could be considered in highly selected cases where chemotherapy is contraindicated.

Common Pitfalls to Avoid

• Do not delay treatment to pursue additional immunotherapy options; chemotherapy-based regimens are the evidence-based standard after immunotherapy failure. 1, 3
• Do not use single-agent docetaxel when ramucirumab can be added, as the combination provides superior outcomes. 1, 2
• Do not assume the patient is too old for combination therapy; carboplatin-based doublet chemotherapy is recommended for eligible patients ≥70 years with PS 0-2 and adequate organ function. 1
• Do not overlook HER2 testing, as trastuzumab deruxtecan provides a targeted option if HER2 IHC 3+ is present. 1

Treatment Duration and Monitoring

• Treatment may be prolonged if disease is controlled and toxicity is acceptable. 1
• The median duration of response with docetaxel/ramucirumab after chemo-immunotherapy is 6.4 months. 2
• Monitor for ramucirumab-specific toxicities including hypertension, proteinuria, and bleeding risk. 1