Can Keytruda (pembrolizumab) be combined with other cancer treatments?

Can Keytruda (Pembrolizumab) Be Combined with Other Cancer Treatments?

Yes, Keytruda (pembrolizumab) is extensively approved and recommended for use in combination with multiple other cancer treatments, including chemotherapy, targeted therapies, and other immunotherapies across numerous cancer types. 1

FDA-Approved Combination Regimens

Chemotherapy Combinations

Pembrolizumab is FDA-approved in combination with chemotherapy for:

• Non-small cell lung cancer (NSCLC): Combined with platinum-based chemotherapy for metastatic disease 2, 1
• Head and neck squamous cell carcinoma (HNSCC): Combined with platinum and 5-fluorouracil for first-line treatment of recurrent/metastatic disease 2, 1
• Gastric/gastroesophageal junction (GEJ) cancer: Combined with fluoropyrimidine and platinum-based chemotherapy for HER2-negative disease (Category 1 when PD-L1 CPS ≥5) 2, 1
• Esophageal cancer: Combined with platinum and fluoropyrimidine-based chemotherapy 2, 1
• Biliary tract cancer: Combined with gemcitabine and cisplatin 1
• Cervical cancer: Combined with chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic disease (when PD-L1 CPS ≥1) 1
• Triple-negative breast cancer (TNBC): Combined with neoadjuvant chemotherapy followed by adjuvant pembrolizumab monotherapy 2, 3
• Endometrial carcinoma: Combined with carboplatin and paclitaxel, followed by pembrolizumab as a single agent 1

Targeted Therapy Combinations

Pembrolizumab is FDA-approved in combination with targeted agents:

• Renal cell carcinoma (RCC): Combined with axitinib (5 mg orally twice daily) or lenvatinib (20 mg orally once daily) for first-line treatment of advanced disease 2, 4, 1
• HER2-positive gastric/GEJ cancer: Combined with trastuzumab plus fluoropyrimidine and platinum-based chemotherapy for locally advanced unresectable or metastatic disease (when PD-L1 CPS ≥1) 2, 1, 5
• Urothelial cancer: Combined with enfortumab vedotin for locally advanced or metastatic disease 2, 1
• Endometrial carcinoma (pMMR/not MSI-H): Combined with lenvatinib for advanced disease after prior systemic therapy 1

Chemoradiotherapy Combinations

• Cervical cancer: Combined with chemoradiotherapy for FIGO 2014 Stage III-IVA disease 1
• Resectable NSCLC: Neoadjuvant treatment in combination with chemotherapy for 12 weeks, followed by adjuvant pembrolizumab as a single agent after surgery for 39 weeks 1

Key Clinical Trial Evidence

Lung Cancer Combinations

The KEYNOTE-407 trial demonstrated that pembrolizumab plus chemotherapy in squamous NSCLC achieved a 5-year OS rate of 18.4% versus 9.7% with chemotherapy alone (HR 0.71) 2. The CheckMate 9LA trial showed that nivolumab plus ipilimumab with two cycles of chemotherapy doubled 4-year survival rates in squamous histology (20% vs 10%) 2.

Gastric Cancer Combinations

The KEYNOTE-811 trial showed that pembrolizumab combined with trastuzumab and chemotherapy in HER2-positive gastric cancer achieved an ORR of 72.6% versus 59.8% with chemotherapy alone, with improved complete response rates (14% vs 11%) 2. The KEYNOTE-859 trial demonstrated that pembrolizumab plus chemotherapy in HER2-negative gastric cancer with PD-L1 CPS ≥10 achieved median OS of 15.7 months versus 11.8 months with chemotherapy alone (HR 0.65) 2.

Renal Cell Carcinoma Combinations

The CheckMate 214 trial established nivolumab plus ipilimumab for intermediate- and poor-risk RCC 2. Multiple trials have demonstrated efficacy of pembrolizumab combined with VEGFR TKIs, with the CLEAR trial showing lenvatinib plus pembrolizumab achieved median PFS of 23.9 months versus 9.2 months with sunitinib 4.

Breast Cancer Combinations

The KEYNOTE-522 trial demonstrated that pembrolizumab plus neoadjuvant chemotherapy in triple-negative breast cancer achieved a pathological complete response rate of 64.8% versus 51.2% with chemotherapy alone (P<0.001) 3. If pembrolizumab was given in the preoperative setting, adjuvant pembrolizumab is recommended based on this trial 2.

Dosing When Combined with Other Treatments

Pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks when used in combination therapy 1. When given on the same day as chemotherapy, pembrolizumab should be administered prior to chemotherapy 1. When combined with enfortumab vedotin, pembrolizumab is administered after enfortumab vedotin 1.

Important Safety Considerations

Adverse Event Management

Grade 3-5 treatment-related adverse events occur in approximately 74-82% of patients receiving pembrolizumab plus chemotherapy combinations, compared to 70-72% with chemotherapy alone 2. The most common severe adverse events with pembrolizumab combinations include:

• Lymphocytopenia and neutropenia 6
• Anemia 2
• Immune-mediated adverse events (colitis, hepatitis, endocrinopathies, pneumonitis, nephritis) 2, 1

Dose Modifications

When combined with targeted therapies like axitinib or lenvatinib, dose reductions of the targeted agent are frequently required. In the CLEAR trial, lenvatinib dose reductions were required in 68.8% of patients receiving lenvatinib plus pembrolizumab 4. When axitinib is combined with pembrolizumab, dose escalation above the initial 5 mg dose may be considered at intervals of six weeks or longer 1.

Clinical Pitfalls to Avoid

• Do not discontinue pembrolizumab prematurely when combined with chemotherapy—continue until disease progression, unacceptable toxicity, or up to 24 months 1
• Do not use pembrolizumab combinations in patients who have progressed on prior ICI therapy for gastric cancer indications 2
• Do not combine pembrolizumab with trastuzumab in HER2-positive gastric cancer unless PD-L1 CPS ≥1 2, 1
• Monitor for immune-mediated toxicities which may be more severe when pembrolizumab is combined with other agents 5