What are the next best treatment options for an elderly female patient with BRAF-mutated non-small cell lung cancer (NSCLC) who has progressed after treatment with pembrolizumab (anti-PD-1 therapy), dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor)?

Treatment Options After Progression on Pembrolizumab and Dabrafenib/Trametinib in BRAF-Mutated NSCLC

For an elderly female patient with BRAF V600E-mutated NSCLC who has progressed after both pembrolizumab monotherapy and dabrafenib/trametinib combination therapy, the recommended next-line treatment is platinum-based chemotherapy with or without immunotherapy, specifically regimens such as carboplatin/pemetrexed (for non-squamous histology) or carboplatin/gemcitabine (for squamous histology). 1

Rationale for Chemotherapy as Next-Line Treatment

The NCCN explicitly states that systemic therapy regimens (chemotherapy with or without immunotherapy) can be used as subsequent therapy options for patients whose disease progressed after receiving a first-line therapy that included a BRAF inhibitor. 1

Why Not Re-challenge with Targeted Therapy

• Encorafenib plus binimetinib is NOT recommended in this scenario because the NCCN guidelines specify these combinations (dabrafenib/trametinib or encorafenib/binimetinib) as subsequent therapy options "if the patient with BRAF V600E mutation did not previously receive a BRAF inhibitor" 1
• Since your patient has already progressed on dabrafenib/trametinib, switching to another BRAF/MEK inhibitor combination is not guideline-supported 1

Specific Chemotherapy Recommendations Based on Performance Status

For elderly patients with PS 0-1:

• Carboplatin-based doublet chemotherapy is the preferred option, with carboplatin being favored over cisplatin in elderly patients due to better tolerability 1, 2
• For non-squamous histology: carboplatin/pemetrexed is recommended 1, 2
• For squamous histology: carboplatin/gemcitabine is recommended 1

For elderly patients with PS 2:

• Single-agent chemotherapy with gemcitabine, vinorelbine, docetaxel, or pemetrexed (for non-squamous only) is appropriate 1, 2
• Carboplatin-based combination therapy can still be considered in carefully selected PS 2 patients with adequate organ function 1

For patients with PS 3-4:

• Best supportive care is recommended unless there are molecularly targetable alterations with minimal toxicity treatments 1

Role of Immunotherapy Re-challenge

The evidence regarding immunotherapy re-challenge after progression on pembrolizumab is limited but suggests caution:

• The NCCN and ESMO guidelines state that for patients with progression after first-line immunotherapy with pembrolizumab, platinum-based chemotherapy is recommended as the second-line treatment option 1
• Immunotherapy combinations with chemotherapy could be considered if the patient had not received them previously, though the guidelines do not strongly support re-challenging with immunotherapy alone after progression on pembrolizumab 1

Alternative Considerations

If the patient has not received docetaxel:

• Docetaxel with or without ramucirumab is an option for subsequent therapy in all histologic subtypes 1
• Ramucirumab/docetaxel showed median OS of 10.5 months versus 9.1 months with docetaxel alone 1

If the patient has non-squamous histology and has not received pemetrexed:

• Pemetrexed monotherapy is recommended with similar survival to docetaxel but less toxicity 1

Important Caveats for Elderly Patients

Toxicity monitoring must be more vigilant in elderly patients:

• The combination of dabrafenib and trametinib can cause relatively severe adverse events in "oldest old" elderly patients, including hypoalbuminemia, peripheral edema, and pneumonia 3
• Dose reductions may be necessary to maintain tolerability 3, 4
• Treatment decisions should be discussed within a multidisciplinary tumor board that includes specialists trained in geriatric care 2

Performance status assessment is critical:

• PS strongly correlates with treatment outcomes in elderly patients and should guide the intensity of therapy 2
• Carboplatin-based doublet chemotherapy should only be offered to elderly patients with PS 0-2 and adequate organ function 1, 2

Clinical Pitfalls to Avoid

• Do not attempt to re-challenge with dabrafenib/trametinib or switch to encorafenib/binimetinib after progression on BRAF/MEK inhibitor therapy, as this is not supported by guidelines 1
• Do not use single-agent BRAF inhibitors (dabrafenib or vemurafenib alone) unless the patient did not tolerate combination therapy initially 1
• Avoid aggressive combination regimens in patients with PS 3-4, as best supportive care is more appropriate 1
• Consider molecular re-testing at progression to identify any new actionable mutations, though this is not standard practice after BRAF inhibitor failure 1