Should pembrolizumab (programmed death receptor-1 inhibitor) be continued as part of chemoradiation therapy (CRT) in a patient with buccal mucosa carcinoma who showed disease progression on PET (positron emission tomography) CT after receiving neoadjuvant pembrolizumab with DCF (docetaxel, cisplatin, and 5-fluorouracil) and has undergone surgery?

Do Not Continue Pembrolizumab After Progression on Neoadjuvant Pembrolizumab

You should not continue pembrolizumab as part of your postoperative chemoradiation regimen for this patient who progressed on neoadjuvant pembrolizumab with DCF. Instead, proceed with standard postoperative chemoradiation using cisplatin without pembrolizumab 1.

Rationale for Discontinuing Pembrolizumab

Evidence of Treatment Failure

• Your patient demonstrated disease progression on PET-CT while receiving neoadjuvant pembrolizumab combined with DCF, which represents clear evidence of pembrolizumab failure in the neoadjuvant setting 2, 3
• Continuing an immunotherapy agent that has already failed to control disease progression lacks biological rationale and clinical evidence 1
• The European Association of Urology guidelines for renal cell carcinoma explicitly recommend against ICI rechallenge after progression on adjuvant ICI therapy, a principle applicable to head and neck cancer given similar mechanisms of resistance 1

Lack of Evidence for ICI Rechallenge in Head and Neck Cancer

• Current EHNS-ESMO-ESTRO guidelines only support pembrolizumab use in the recurrent/metastatic setting for patients who have NOT received recent platinum-based chemotherapy or who progressed after prior platinum therapy—not for patients who progressed ON immunotherapy 1
• The guidelines specifically state that after progression on platinum-based chemotherapy AND anti-PD-1 inhibitors, "no standard of care exists" 1
• No prospective trial data support continuing pembrolizumab after documented progression on neoadjuvant pembrolizumab 2, 3

Recommended Treatment Approach

Standard Postoperative Chemoradiation

• Proceed with postoperative radiotherapy (66 Gy) with concurrent high-dose cisplatin (100 mg/m² every 3 weeks) if the patient has R1 resection and/or extracapsular spread 1
• Weekly cisplatin at 40 mg/m² plus radiotherapy is a non-inferior alternative if the patient cannot tolerate high-dose cisplatin 1
• Postoperative radiotherapy should be started within 6-7 weeks after surgery, with the entire treatment regimen (surgery plus postoperative RT) delivered within 11 weeks 1

Risk Stratification Determines Intensity

• High-risk features (positive margins, extracapsular spread) mandate concurrent chemoradiation with cisplatin at 66 Gy 1
• Intermediate-risk features (pT3-4, close margins 1-5mm, perineural infiltration, lymphovascular spread, >1 invaded lymph node) require postoperative radiotherapy to 58-64 Gy 1
• Your patient's progression on neoadjuvant therapy suggests aggressive biology, making adherence to high-risk protocols critical 2

Why Pembrolizumab Should Not Be Added to Adjuvant Treatment

Absence of Supporting Data

• The KEYNOTE-689 trial demonstrated benefit for neoadjuvant and adjuvant pembrolizumab in treatment-naive patients, but your patient already failed neoadjuvant pembrolizumab 3
• The KEYNOTE-412 trial (pembrolizumab with concurrent chemoradiation and maintenance) enrolled treatment-naive patients, not those who progressed on prior pembrolizumab 4
• The ADRISK trial is investigating adjuvant pembrolizumab plus chemoradiation versus chemoradiation alone, but only in patients who have NOT received prior immunotherapy 5

Mechanism of Resistance

• Progression on pembrolizumab indicates either primary resistance (tumor never responded) or acquired resistance mechanisms that will not be overcome by simply continuing the same agent 1
• PET-CT progression during neoadjuvant therapy represents the most definitive evidence of treatment failure, more reliable than biochemical or clinical assessment alone 1

Critical Timing Considerations

Avoid Treatment Delays

• Do not delay postoperative chemoradiation to pursue additional pembrolizumab cycles 1
• The 6-7 week window from surgery to start of radiotherapy is critical for outcomes 1
• The entire treatment sequence (surgery plus postoperative RT/CRT) must be completed within 11 weeks 1

Future Treatment Options If Disease Recurs

Salvage Therapy After Adjuvant Treatment Failure

• If the patient develops recurrent/metastatic disease after completing postoperative chemoradiation, treatment options depend on timing and PD-L1 status 1
• For recurrence >6 months after platinum-based therapy with PD-L1 CPS ≥1: Consider pembrolizumab monotherapy or pembrolizumab plus platinum/5-FU 1
• For recurrence <6 months after platinum-based therapy: Platinum/5-FU/cetuximab is preferred over immunotherapy rechallenge 1
• Nivolumab or pembrolizumab monotherapy is approved for patients who progress within 6 months of platinum therapy in the recurrent/metastatic setting, but this applies to patients who were immunotherapy-naive during their platinum treatment 1

Common Pitfalls to Avoid

Do Not Extrapolate from Metastatic Disease Guidelines

• Guidelines supporting pembrolizumab in recurrent/metastatic HNSCC apply to different clinical contexts than your patient's situation 1
• The KEYNOTE-048 trial that established pembrolizumab's role in recurrent/metastatic disease excluded patients with prior immunotherapy 6

Do Not Assume Neoadjuvant Failure Predicts Adjuvant Failure

• While your patient failed neoadjuvant pembrolizumab, this does not mean standard adjuvant chemoradiation will fail 1
• Cisplatin-based chemoradiation has robust Level I evidence for improving locoregional control and overall survival in the adjuvant setting, independent of prior immunotherapy exposure 1