Should dexamethasone be administered for nausea in a patient receiving pembrolizumab, and what dosing regimen is recommended?

Dexamethasone for Nausea in Patients Receiving Pembrolizumab

Dexamethasone should be administered for chemotherapy-induced nausea and vomiting (CINV) in patients receiving pembrolizumab, but only when pembrolizumab is combined with highly or moderately emetogenic chemotherapy agents—pembrolizumab itself is not emetogenic and does not require antiemetic prophylaxis. 1

Understanding the Clinical Context

The critical distinction here is that pembrolizumab as a single agent does not cause nausea or vomiting and therefore does not require antiemetic prophylaxis. 1 However, when pembrolizumab is combined with chemotherapy regimens (as in some treatment protocols), the antiemetic strategy should be based on the emetogenic potential of the chemotherapy agents, not the pembrolizumab. 1

Important Safety Consideration

Two major trials (KEYNOTE-183 and KEYNOTE-185) demonstrated that combining pembrolizumab with dexamethasone-containing regimens in multiple myeloma resulted in increased mortality and an unfavorable benefit-risk profile. 2, 3 However, these findings are specific to the multiple myeloma population receiving immunomodulatory drugs (lenalidomide or pomalidomide) and do not contraindicate dexamethasone use for CINV prophylaxis in other cancer types receiving pembrolizumab with emetogenic chemotherapy. 2, 3

Dosing Regimens Based on Chemotherapy Emetogenicity

For Highly Emetogenic Chemotherapy (HEC)

When pembrolizumab is combined with highly emetogenic chemotherapy, administer a three-drug regimen:

• 5-HT3 receptor antagonist (e.g., ondansetron 8-16 mg IV or palonosetron 0.25 mg IV) on day 1 1
• Dexamethasone 12 mg IV/PO on day 1 (note: reduced from 20 mg when combined with NK1 antagonist) 1
• NK1 receptor antagonist (aprepitant 125 mg PO day 1, then 80 mg PO days 2-3; or fosaprepitant 150 mg IV day 1 only) 1

For delayed phase (days 2-3):

• Aprepitant 80 mg PO daily on days 2-3 (if using oral regimen) 1
• Dexamethasone 8 mg PO daily on days 2-4 1

For Moderately Emetogenic Chemotherapy (MEC)

When pembrolizumab is combined with moderately emetogenic chemotherapy:

Acute phase (day 1):

• Palonosetron 0.25 mg IV plus dexamethasone 8 mg IV/PO is the preferred two-drug regimen 1
• Alternatively, for anthracycline-cyclophosphamide (AC) regimens: add aprepitant 125 mg PO to the above (three-drug regimen) 1

Delayed phase (days 2-5):

• Dexamethasone 8 mg PO daily on days 2-3 for MEC regimens 1, 4
• For AC regimens with aprepitant: continue aprepitant 80 mg PO on days 2-3 1

Evidence Supporting Dexamethasone Dosing

Dexamethasone 4-5 mg has similar efficacy to 8-10 mg for postoperative nausea and vomiting, but chemotherapy-induced nausea guidelines consistently recommend 8 mg for MEC and 12 mg (reduced to account for NK1 antagonist interaction) for HEC. 5 The higher doses in CINV reflect the more severe and prolonged emetogenic stimulus compared to surgical procedures. 1

For delayed CINV after MEC, dexamethasone alone (without a 5-HT3 antagonist) is effective: 87.4% of patients achieved complete protection versus 76.8% with placebo. 6 Adding ondansetron to dexamethasone provided only marginal additional benefit (91.8%) with increased constipation. 6

Clinical Algorithm for Decision-Making

1. Identify if pembrolizumab is given as monotherapy or with chemotherapy:

   • Monotherapy → No antiemetics needed 1
   • With chemotherapy → Proceed to step 2

2. Classify the emetogenic risk of the chemotherapy regimen:

   • High risk (e.g., cisplatin ≥50 mg/m²) → Three-drug regimen with dexamethasone 12 mg 1
   • Moderate risk, AC-based → Three-drug regimen with dexamethasone 8 mg 1
   • Moderate risk, non-AC → Two-drug regimen (palonosetron + dexamethasone 8 mg) 1

3. Administer acute prophylaxis before chemotherapy on day 1 1

4. Continue delayed prophylaxis on days 2-3 (or 2-4 for HEC):

   • Dexamethasone 8 mg PO daily 1
   • Plus aprepitant 80 mg PO daily if used in acute phase 1

Common Pitfalls and How to Avoid Them

Pitfall #1: Assuming pembrolizumab itself requires antiemetic prophylaxis.

• Solution: Only provide antiemetics when pembrolizumab is combined with emetogenic chemotherapy; base the regimen on the chemotherapy's emetogenic potential. 1

Pitfall #2: Extrapolating the multiple myeloma safety concerns to all pembrolizumab + dexamethasone combinations.

• Solution: The increased mortality seen in KEYNOTE-183 and KEYNOTE-185 was specific to the combination with immunomodulatory drugs (lenalidomide/pomalidomide) in multiple myeloma. 2, 3 This does not contraindicate standard CINV prophylaxis with dexamethasone in other cancer types.

Pitfall #3: Using inadequate dexamethasone doses or durations for delayed CINV.

• Solution: Ensure dexamethasone is continued for at least 2-3 days after MEC (days 2-3) and 3-4 days after HEC (days 2-4). 1

Pitfall #4: Confusing dexamethasone dosing when NK1 antagonists are used.

• Solution: Reduce dexamethasone to 12 mg on day 1 (from 20 mg) when aprepitant is added, due to CYP3A4 interactions that increase dexamethasone exposure. 1 On days 2-4, use dexamethasone 8 mg daily. 1

Pitfall #5: Failing to address breakthrough nausea despite prophylaxis.

• Solution: If nausea occurs despite optimal prophylaxis, add olanzapine 5-10 mg daily (if not already given prophylactically) or consider a different drug class such as metoclopramide, lorazepam, or a cannabinoid. 1

Route of Administration

Oral and intravenous dexamethasone are bioequivalent on a 1:1 basis, so oral administration is preferred for patient convenience and equivalent efficacy. 7, 8 Use IV dexamethasone only when oral intake is not feasible. 7