Does Keytruda (pembrolizumab) have to be given after Padcev (enfortumab vedotin) in an adult cancer patient with neuropathy?

Keytruda Does Not Have to Be Given After Padcev

Keytruda (pembrolizumab) and Padcev (enfortumab vedotin) are administered together as a combination regimen, not sequentially, for the treatment of locally advanced or metastatic urothelial cancer. 1

Standard Administration Protocol

The combination regimen is given concurrently on the same treatment schedule:

• Enfortumab vedotin is administered at 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle 2
• Pembrolizumab is administered at 200 mg intravenously on day 1 of each 21-day cycle 2
• Both drugs are given during the same treatment cycle, not one after the other 1, 2

Evidence Supporting Concurrent Administration

The phase III EV-302 trial established this combination as the preferred first-line regimen for locally advanced or metastatic urothelial cancer:

• Median overall survival was 31.5 months with the combination versus 16.1 months with chemotherapy (HR 0.47, P<.001) 1
• Median progression-free survival was 12.5 months versus 6.3 months with chemotherapy (HR 0.45, P<.001) 1
• Complete response rate was 29.1% with the combination versus 12.5% with chemotherapy 1
• The NCCN panel designated this combination as Category 1 (highest level of evidence and consensus) and the only preferred first-line regimen for both cisplatin-eligible and cisplatin-ineligible patients 1

Managing Neuropathy with This Combination

Since your patient has neuropathy, specific management considerations are critical:

Baseline Assessment:

• Evaluate pre-existing neuropathy severity before initiating treatment, as this is a risk factor for worsening chemotherapy-induced peripheral neuropathy (CIPN) 1
• Assess for other treatable causes: check TSH and vitamin B12 levels, as deficiencies can exacerbate neuropathy 3
• Document baseline neuropathy symptoms using a numeric scale (0-10) and functional impact 1

Monitoring During Treatment:

• Peripheral neuropathy occurs in approximately 50-55% of patients receiving enfortumab vedotin-containing regimens 4, 5
• Regular symptomatic assessments at each treatment visit are essential for early detection of worsening neuropathy 1, 5
• Early recognition allows for dose modifications before permanent damage occurs 1

Treatment Modifications for Neuropathy:

• Grade 2 neuropathy (moderate symptoms interfering with instrumental activities of daily living): Hold enfortumab vedotin until improvement to Grade ≤1, then resume at reduced dose 5
• Grade 3 neuropathy (severe symptoms limiting self-care activities): Permanently discontinue enfortumab vedotin 5
• Pembrolizumab can typically be continued during enfortumab vedotin dose holds for neuropathy management 5

Pharmacologic Management of Painful Neuropathy:

• Duloxetine is the only evidence-based treatment for painful CIPN: Start at 20 mg daily for one week, then increase to 40 mg daily 1, 6, 3
• Gabapentin or pregabalin may be considered if duloxetine is ineffective or not tolerated, though evidence is limited for CIPN specifically 1
• Avoid acetyl-L-carnitine, as it may worsen neuropathy 1, 3

Critical Pitfall to Avoid

Do not assume all neuropathy in this patient is from prior chemotherapy without excluding other treatable causes (B12 deficiency, hypothyroidism, diabetes) that could be corrected before starting this combination 3. Up to 50% of peripheral neuropathy may be asymptomatic on examination despite significant nerve damage, so functional assessment is essential 3.

Alternative Regimens Only If Combination Is Contraindicated

If the patient cannot tolerate the enfortumab vedotin plus pembrolizumab combination due to severe pre-existing neuropathy or other contraindications, alternative first-line options include:

• Cisplatin-based or carboplatin-based chemotherapy (followed by avelumab maintenance if appropriate) 1
• Gemcitabine/cisplatin plus nivolumab (with nivolumab maintenance) 1
• Pembrolizumab monotherapy (only for patients with PD-L1 CPS ≥10 who are cisplatin-ineligible) 1, 7

However, these alternatives have inferior survival outcomes compared to the enfortumab vedotin plus pembrolizumab combination 1.