What are the next steps for a patient with malignant melanoma of the vault who has progressive disease after 4 cycles of nivolumab (Opdivo) and 3 cycles of pembrolizumab (Keytruda) post-operatively?

Treatment Options After Progression on Nivolumab and Pembrolizumab in Malignant Melanoma

For a patient with malignant melanoma of the vault showing progressive disease after 4 cycles of nivolumab and 3 cycles of pembrolizumab post-operatively, ipilimumab should be offered as the next line of therapy. 1

Assessment of Current Situation

The patient has:

• Malignant melanoma of the vault
• Post-operative status
• Failed treatment with two PD-1 inhibitors:
  • 4 cycles of nivolumab
  • 3 cycles of pembrolizumab
• Progressive disease despite these therapies

Treatment Algorithm Based on BRAF Status

Step 1: Determine BRAF Mutation Status

The next treatment approach depends critically on whether the patient has a BRAF mutation:

If BRAF Wild-Type:

• First option: Ipilimumab (3 mg/kg every 3 weeks for a maximum of 4 doses) 1
• This is supported by ESMO and ASCO guidelines for patients who have failed PD-1 inhibitor therapy

If BRAF V600 Mutation Positive:

• First option: BRAF/MEK inhibitor combination therapy 1
  • Dabrafenib plus trametinib
  • Vemurafenib plus cobimetinib
  • Encorafenib plus binimetinib

Step 2: Consider Clinical Trial Enrollment

• Clinical trial participation should be prioritized if available 1
• This is particularly important as the patient has already progressed on two lines of immunotherapy

Rationale for Ipilimumab After PD-1 Inhibitor Failure

Ipilimumab works through a different mechanism than PD-1 inhibitors:

• Targets CTLA-4 rather than PD-1 pathway
• Can be effective even after PD-1 inhibitor failure 1
• ESMO guidelines specifically recommend ipilimumab if not given previously after IO (immuno-oncology) failure 1

Important Considerations

• Toxicity management: Ipilimumab has a higher rate of grade 3-4 immune-related adverse events (approximately 20%) compared to PD-1 inhibitors 1, 2
• Response assessment: Responses to ipilimumab may take longer to develop and can occur after initial progression
• Duration of therapy: Unlike PD-1 inhibitors which can be given until progression, ipilimumab is given for a maximum of 4 doses 3

Special Considerations

For BRAF-Mutated Melanoma

• If BRAF-mutated, targeted therapy offers rapid responses in patients with high disease burden or rapidly progressing disease 1
• The combination of BRAF/MEK inhibitors is superior to single-agent BRAF inhibitors in terms of response rates, PFS, and OS 1

For Patients with Brain Metastases

• If brain metastases are present, the ipilimumab/nivolumab combination might be considered despite prior PD-1 failure, as it has shown >50% response rates in brain metastases 1

Common Pitfalls to Avoid

1. Not testing for BRAF mutation: Always confirm BRAF status before deciding on next-line therapy
2. Continuing same class of therapy: Switching to a different PD-1 inhibitor after failure of two PD-1 inhibitors is unlikely to be effective
3. Overlooking clinical trials: Clinical trials should always be considered, especially after failure of standard therapies
4. Inadequate monitoring: More frequent monitoring is needed when switching to ipilimumab due to its different toxicity profile

In conclusion, for this patient with progressive melanoma after PD-1 inhibitor therapy, ipilimumab is the most appropriate next-line therapy if BRAF wild-type, while BRAF/MEK inhibitor combination would be indicated if BRAF-mutated.