What is the recommended chemotherapy and immunotherapy regimen for patients with advanced or metastatic cancer?

Choosing Chemotherapy and Immunotherapy for Advanced Cancer

Cancer-Specific Treatment Selection

The choice of chemotherapy and immunotherapy depends critically on the specific cancer type and biomarker profile, with recent guidelines establishing distinct treatment algorithms for each malignancy.

Gastroesophageal Cancer (Most Recent Evidence)

For advanced gastroesophageal adenocarcinoma or squamous cell carcinoma, treatment selection is driven by PD-L1 combined positive score (CPS) and HER2 status 1:

First-Line Treatment Algorithm

• PD-L1 CPS ≥5: Nivolumab combined with fluoropyrimidine- and platinum-based chemotherapy is the standard approach 1
• PD-L1 CPS 1-5: Consider nivolumab with fluoropyrimidine- and platinum-based chemotherapy on a case-by-case basis, weighing patient fitness and disease burden 1
• PD-L1 CPS 0: Use fluoropyrimidine- and platinum-based chemotherapy alone without adding nivolumab 1
• HER2-positive gastric/GEJ adenocarcinoma: Trastuzumab plus pembrolizumab combined with fluoropyrimidine- and oxaliplatin-based chemotherapy 1
• Esophageal squamous cell carcinoma with PD-L1 CPS ≥10: Nivolumab plus ipilimumab is an alternative option 1

Second-Line Treatment

• After first-line progression in gastroesophageal/GEJ adenocarcinoma: Ramucirumab plus paclitaxel 1
• HER2-positive disease progression: Trastuzumab deruxtecan 1

Urothelial Carcinoma (Most Recent High-Quality Evidence)

Enfortumab vedotin plus pembrolizumab is now the preferred first-line treatment for metastatic urothelial carcinoma, demonstrating superior overall survival of 31.5 months versus 16.1 months with platinum-based chemotherapy (HR 0.47) 2, 3:

First-Line Treatment Algorithm

• All eligible patients: Enfortumab vedotin plus pembrolizumab achieves objective response rate of 67.7% versus 44.4% with chemotherapy, with lower grade 3+ adverse events (55.9% vs 69.5%) 2, 3
• Cisplatin-eligible patients (if enfortumab vedotin unavailable): Gemcitabine plus cisplatin, followed by maintenance avelumab for patients achieving stable disease or better 2, 3
• Cisplatin-ineligible but carboplatin-eligible: Carboplatin plus gemcitabine, followed by maintenance avelumab 2, 3

Cisplatin ineligibility criteria include: creatinine clearance <60 mL/min, ECOG performance status ≥2, grade ≥2 hearing loss, grade ≥2 neuropathy, or NYHA Class III heart failure 3

Maintenance Therapy

• Avelumab maintenance is mandatory for patients achieving stable disease or better after platinum-based chemotherapy, providing overall survival of 21.4 months versus 14.3 months with best supportive care (HR 0.69), initiated within 4-10 weeks after completing chemotherapy 2, 3, 4

Second-Line Treatment

• Enfortumab vedotin: Overall survival gain of 3.97 months (HR 0.70 vs chemotherapy) 3
• Erdafitinib for FGFR2/3 alterations: Overall survival gain of 4.3 months (HR 0.64 vs chemotherapy) 3
• Sacituzumab govitecan or pembrolizumab: Alternative second-line options 3

Melanoma

For advanced melanoma, immunotherapy has replaced chemotherapy as the primary treatment modality 1:

• First-line treatment: Immune checkpoint inhibitors (anti-PD-1 or anti-CTLA-4 agents) are preferred over chemotherapy based on superior survival outcomes 1
• Chemotherapy role: Reserved for patients who have exhausted immunotherapy and targeted therapy options or have contraindications to these agents 1

Colorectal Cancer

For metastatic colorectal cancer, treatment selection depends on microsatellite instability status and KRAS mutation status 1, 4:

MSI-High or dMMR Metastatic CRC

• After progression on fluoropyrimidine, oxaliplatin, and irinotecan: Nivolumab as single agent or in combination with ipilimumab 4

MSI-Stable Disease

• First-line: Fluoropyrimidine-based combination with oxaliplatin (FOLFOX/CAPOX) or irinotecan (FOLFIRI) 1
• Bevacizumab addition: Increases survival and progression-free survival when combined with fluoropyrimidine-based chemotherapy 1
• KRAS wild-type tumors: Add cetuximab or panitumumab to chemotherapy, as anti-EGFR antibodies are only active in KRAS wild-type disease 1

Non-Small Cell Lung Cancer

For metastatic NSCLC without targetable oncogenic drivers, treatment selection is based on PD-L1 expression level 5, 6, 7:

Treatment Algorithm

• PD-L1 ≥50%: Pembrolizumab monotherapy provides superior overall survival and response rates with less toxicity compared to platinum doublet chemotherapy 7
• PD-L1 <50% or any PD-L1 level: Combination of PD-1/PD-L1 inhibitors (pembrolizumab or atezolizumab) with platinum doublet chemotherapy demonstrates improved overall survival and response rates compared to chemotherapy alone 5, 6, 7

Critical caveat: Do not initiate immunotherapy until testing for EGFR mutations, ALK and ROS1 rearrangements is completed and negative, as targeted therapies remain superior for these oncogenic drivers 7

Essential Biomarker Testing Requirements

Before initiating treatment, specific biomarker testing must be completed to guide therapy selection:

Mandatory Testing by Cancer Type

• Gastroesophageal cancer: PD-L1 CPS, HER2 status (IHC and FISH), and MSI/dMMR status 1
• Urothelial carcinoma: FGFR2/3 genetic alterations for all patients with advanced disease to identify erdafitinib candidates 3
• Colorectal cancer: MSI/dMMR status and KRAS mutation status 1, 4
• NSCLC: PD-L1 expression, EGFR mutations, ALK and ROS1 rearrangements (preferably via broad next-generation sequencing) 7

Chemotherapy Backbone Selection

When chemotherapy is indicated, specific regimens are preferred based on cancer type and patient fitness:

Platinum-Based Combinations

• Gastroesophageal cancer: Fluoropyrimidine (5-FU or capecitabine) plus platinum (cisplatin or oxaliplatin) 1
• Urothelial carcinoma: Gemcitabine plus cisplatin for cisplatin-eligible patients; gemcitabine plus carboplatin for cisplatin-ineligible patients 1, 2, 3
• NSCLC: Platinum doublet with pemetrexed (non-squamous) or gemcitabine/paclitaxel (squamous) 7

Renal Function Considerations

• Creatinine clearance <60 mL/min: Substitute carboplatin for cisplatin, though carboplatin-based regimens have inferior efficacy 1, 3
• Severe renal impairment: Consider non-platinum regimens or dose-adjusted protocols 1

Immunotherapy-Related Adverse Events Management

Combining immunotherapy with chemotherapy increases treatment-related toxicities compared to either modality alone 6, 7, 8:

• Grade 3+ adverse events: Occur in 55.9% with enfortumab vedotin plus pembrolizumab versus 69.5% with chemotherapy alone in urothelial carcinoma 3
• Immune-related adverse events: Require prompt recognition and management with corticosteroids, with 9% of patients requiring oral prednisone ≥40 mg daily 2
• Monitoring requirements: Assess for immune-related toxicities affecting skin, gastrointestinal tract, endocrine organs, liver, and lungs at each visit 1, 2

Treatment Duration and Sequencing

Treatment continuation and sequencing strategies vary by cancer type:

Duration Guidelines

• Nivolumab in urothelial carcinoma: Continue for up to 2 years from first dose in absence of disease progression or unacceptable toxicity 4
• Avelumab maintenance: Start within 4-10 weeks after completing first-line chemotherapy and continue until progression 2, 3
• Chemotherapy duration: Fixed treatment period of 3-6 months is appropriate, with consideration for maintenance fluoropyrimidine alone if cumulative toxicity occurs and disease control is achieved 1

Sequencing After Progression

• After enfortumab vedotin plus pembrolizumab: Consider platinum-based chemotherapy, vinflunine, taxanes, or clinical trials with novel agents 3
• After first-line immunotherapy failure in NSCLC: Switch to chemotherapy-based regimens 7, 8