What is the recommended plan for a patient on Pembrolizumab with an initial biopsy result showing fibrous tissue without clear cell morphology and a final biopsy result pending in 2 weeks?

Management Plan for Patient on Pembrolizumab with Inconclusive Initial Biopsy

Hold pembrolizumab immediately and do not resume until definitive histologic diagnosis is confirmed in 2 weeks, as continuing immunotherapy without tissue confirmation of malignancy risks unnecessary toxicity and precludes accurate treatment planning. 1, 2

Immediate Actions (Week 0)

Suspend Pembrolizumab Treatment

• Stop all pembrolizumab doses until final biopsy results are available 2
• The finding of "fibrous tissue without clear cell morphology" is insufficient to guide immunotherapy decisions and may represent:
  • Sampling error from necrotic or fibrotic tumor areas
  • Non-malignant reactive tissue
  • Inadequate tissue for diagnosis 1

Document Current Disease Status

• Obtain baseline imaging (CT chest/abdomen/pelvis with contrast or PET-CT) to establish current disease burden before final pathology results 1
• Record any treatment-related adverse events from prior pembrolizumab cycles to assess cumulative toxicity risk 1
• Document performance status (ECOG) and baseline organ function 1

Week 2: Final Biopsy Results Review

If Final Biopsy Confirms Malignancy with Clear Histology

Resume pembrolizumab only if the confirmed diagnosis has established benefit from anti-PD-1 therapy 1

For PD-L1 Positive NSCLC (≥50% expression):

• Resume pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks per modeling data) 1, 3
• Continue for maximum 2 years in metastatic disease based on KEYNOTE-024 data showing 80.2% OS at 6 months 1, 2
• Plan restaging scans every 6-9 weeks 1

For Clear Cell Renal Cell Carcinoma:

• Resume pembrolizumab 200 mg IV every 3 weeks, ideally combined with lenvatinib 20 mg daily (HR 0.66 for OS vs sunitinib) 1
• Alternative: pembrolizumab with axitinib or cabozantinib-nivolumab if lenvatinib contraindicated 1

For Melanoma (Stage III/IV):

• Resume pembrolizumab 200 mg IV every 3 weeks for up to 1 year in adjuvant setting or 2 years in metastatic disease 1, 2
• Consider nivolumab plus relatlimab as alternative if progression occurs 1

If Final Biopsy Shows Non-Malignant Tissue or Remains Inconclusive

Discontinue pembrolizumab permanently and pursue additional diagnostic workup 1

Diagnostic Algorithm for Persistent Uncertainty:

1. Review adequacy of biopsy specimen with pathologist - confirm sufficient tissue, appropriate fixation, and absence of sampling error 1
2. Consider repeat biopsy of different site if multiple lesions present - target most metabolically active area on PET or largest accessible lesion 1
3. If ulcer or sinus tract present, obtain wound culture but recognize poor correlation with deep tissue (30% concordance) - only Staphylococcus aureus from sinus tract has reasonable predictive value for bone involvement 1
4. Ensure 2-week antibiotic washout before repeat biopsy to optimize culture yield if infection suspected 1

Critical Decision Points

Timing Considerations

• Do not delay final biopsy results beyond 2 weeks - if pathology is delayed, contact laboratory directly to expedite 1
• Maximum acceptable treatment interruption is 3-4 weeks - longer delays risk disease progression in truly malignant disease 2
• If final biopsy delayed beyond 2 weeks, obtain interval imaging to assess for progression 1

Node Biopsy Reconsideration

Despite patient preference against node biopsy, strongly reconsider if:

• Final tissue biopsy remains non-diagnostic 1
• Nodes are the only site of measurable disease 1
• Nodes show high SUV uptake on PET (>2.5) suggesting malignancy 1
• Image-guided core needle biopsy of node is feasible with acceptable risk 1

The rationale: continuing systemic immunotherapy without tissue diagnosis exposes the patient to 17% risk of grade 3-5 adverse events (including pneumonitis, colitis, hepatitis) without confirmed benefit 1

Monitoring During Treatment Hold

Weekly Assessment

• Monitor for disease-related symptoms (pain, dyspnea, weight loss) that might indicate progression 1
• No routine labs needed during 2-week hold unless symptomatic 1

If Symptomatic Progression During Hold

• Obtain urgent imaging 1
• Consider empiric resumption of pembrolizumab if life-threatening progression and high clinical suspicion of immunotherapy-responsive malignancy 2
• This represents treatment beyond standard guidelines and requires informed consent discussion 2

Common Pitfalls to Avoid

1. Do not continue pembrolizumab based solely on radiographic findings without histologic confirmation - fibrous tissue may represent post-treatment fibrosis, not active malignancy 1, 2

2. Do not assume PD-L1 status from initial biopsy if tissue was inadequate - repeat PD-L1 testing on final specimen is mandatory for NSCLC 1

3. Do not treat beyond 2 years in metastatic disease - CheckMate 153 showed benefit of continuous therapy only up to 2 years, with rechallenge possible if progression occurs ≥1 year after stopping 2

4. Do not ignore pseudo-progression - if resuming therapy and scans worsen initially, confirm true progression with repeat imaging in 4-6 weeks before discontinuing 2