What are some recent developments in cancer medications, such as pembrolizumab (pembrolizumab) and nivolumab (nivolumab)?

Recent Developments in Cancer Immunotherapy: Pembrolizumab and Nivolumab

Breakthrough Tissue-Agnostic Approvals

Both pembrolizumab and nivolumab have achieved landmark FDA approvals for mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) cancers across all tumor types—the first biomarker-driven, tissue-agnostic approvals in oncology history. 1

• Pembrolizumab demonstrated a 39.6% objective response rate across 15 different cancer types in patients with dMMR/MSI-H tumors, with 78% of responders maintaining responses for ≥6 months 1
• This represents a paradigm shift from site-specific to biomarker-specific cancer treatment 1

Optimal Dosing Evolution

FDA-approved dosing for both agents has evolved to simplified flat-dose regimens that differ from original pivotal trial protocols, based on pharmacokinetic modeling across large patient populations. 1

Current FDA-Approved Dosing:

• Pembrolizumab: 200 mg every 3 weeks (versus original weight-based 2-10 mg/kg regimens) 1
• Nivolumab: 240 mg every 2 weeks or 480 mg every 4 weeks (versus original 3 mg/kg every 2 weeks) 1
• Pharmacokinetic analyses confirmed no clinically meaningful differences in response rate, progression-free survival, or overall survival across different pembrolizumab dose levels (2 mg/kg vs 10 mg/kg, every 2 weeks vs every 3 weeks) 1

Treatment Duration Insights

Responses to anti-PD-1 therapy are remarkably durable and often persist for years beyond treatment discontinuation, challenging traditional continuous-until-progression paradigms. 1

• Most responses develop within 6 months, but a notable fraction take considerably longer 1
• Some patients experience initial RECIST-defined progression before ultimately responding (pseudoprogression) 1
• Long-term follow-up demonstrates that responses frequently persist after stopping therapy, with systemic accumulation reaching steady-state by 16 weeks 1, 2

Comparative Efficacy Across Indications

First-Line Non-Small Cell Lung Cancer:

Pembrolizumab monotherapy is FDA-approved for first-line metastatic NSCLC with PD-L1 ≥50%, while nivolumab monotherapy failed to demonstrate benefit in this setting. 1

• Pembrolizumab (KEYNOTE-024): Median PFS 10.3 vs 6.0 months (HR 0.50), median OS not reached vs 14.5 months (HR 0.63) compared to platinum chemotherapy 1
• Nivolumab (CheckMate 026): Failed to improve PFS (4.2 vs 5.9 months, HR 1.15) or OS (14.4 vs 13.2 months, HR 1.02) compared to platinum chemotherapy, despite broader PD-L1 inclusion criteria (≥5%) 1
• The squamous cell lung cancer subgroup showed particularly pronounced benefit with pembrolizumab (HR 0.35) 1

Second-Line NSCLC:

Both nivolumab and pembrolizumab demonstrate superior efficacy compared to docetaxel in previously-treated NSCLC, with comparable real-world outcomes. 1, 3, 4

• Nivolumab (CheckMate 017): OS 9.2 vs 6.0 months (HR 0.59), response rate 20% vs 9% in squamous NSCLC 1
• Real-world propensity-matched analysis showed no significant differences between nivolumab and pembrolizumab in previously-treated patients (median PFS 3.7 vs 4.6 months, HR 1.02; median OS 27.4 vs 19.6 months, HR 0.78) 4

Melanoma:

Both agents improve outcomes compared to ipilimumab or chemotherapy, with pembrolizumab demonstrating improved overall survival versus ipilimumab in head-to-head comparison. 1

• Pembrolizumab (KEYNOTE-006) improved OS compared to ipilimumab in treatment-naive patients 1
• Nivolumab (CheckMate 066,067) improved response rate, PFS, and OS compared to chemotherapy or ipilimumab monotherapy 1
• Cross-trial comparisons suggest pembrolizumab is more effective as first-line versus second-line therapy, even without prior checkpoint inhibitor exposure 1

Urothelial Carcinoma:

Pembrolizumab is the only agent with Level A evidence demonstrating improved survival in platinum-refractory urothelial carcinoma, and is FDA-approved for cisplatin-ineligible patients in first-line. 1

• Five agents (atezolizumab, durvalumab, avelumab, pembrolizumab, nivolumab) are FDA-approved for platinum-refractory disease 1
• Pembrolizumab demonstrated improved survival and is the only agent with Level A evidence in this setting 1
• Pembrolizumab and atezolizumab are approved for first-line treatment in cisplatin-ineligible patients 1

Colorectal Cancer with dMMR:

Pembrolizumab and nivolumab represent breakthrough options for dMMR metastatic colorectal cancer, with dramatic efficacy in this chemotherapy-refractory population. 1

• Pembrolizumab: 40% immune-related objective response rate in dMMR CRC vs 0% in MMR-proficient CRC; median PFS and OS not reached vs 2.2 and 5.0 months (HR 0.10) 1
• Nivolumab: Median PFS 5.3 months in dMMR CRC with monotherapy, not reached with nivolumab plus ipilimumab, vs 1.4 months in MMR-proficient CRC 1
• Recommended as second- or third-line options for dMMR metastatic colorectal cancer; patients progressing on one should not receive the other 1

Novel Combination Strategies

Enfortumab Vedotin Plus Pembrolizumab:

The combination of enfortumab vedotin plus pembrolizumab represents the new standard of care for first-line metastatic urothelial carcinoma, with unprecedented survival benefit and no PD-L1 testing requirement. 5, 6

• Median OS 31.5 vs 16.1 months with platinum chemotherapy (HR 0.47) 5, 6
• Objective response rate 67.7% (29.1% complete response) vs 44.4% (12.5% complete response) 5, 6
• Median PFS 12.5 vs 6.3 months (HR 0.45) 5, 6
• Benefits demonstrated regardless of cisplatin eligibility or PD-L1 status 5, 6

Nivolumab Plus Ipilimumab:

Combination ipilimumab/nivolumab significantly improves response and PFS compared to ipilimumab monotherapy across multiple tumor types, though with increased toxicity. 1

• In metastatic urothelial carcinoma: Overall response rate 38.5% with nivolumab 1 mg/kg + ipilimumab 3 mg/kg 1
• In melanoma: Improved response rate and PFS versus ipilimumab monotherapy 1
• FDA-approved dosing: Ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab monotherapy 7

Safety Profile Distinctions

Anti-PD-1 agents (pembrolizumab, nivolumab) demonstrate more favorable toxicity profiles compared to anti-CTLA-4 therapy (ipilimumab), with immune-related adverse events occurring in ≤30% versus up to 75% of patients. 1

• Grade ≥3 immune-related adverse events: ≤20% with PD-1 inhibitors vs up to 43% with ipilimumab 1
• Pneumonitis occurs in approximately 3-7% of patients on pembrolizumab or nivolumab and represents one of the most serious toxicities 1
• Real-world data shows no significant difference in grade ≥3 immune-related adverse events between nivolumab (9.7%) and pembrolizumab (11.1%) 4
• Treatment-related deaths occur in up to 2% of patients receiving immune checkpoint inhibitors 1

Interchangeability Considerations

Pembrolizumab and nivolumab are mechanistically similar anti-PD-1 antibodies with comparable efficacy and safety profiles across most indications, though specific regulatory approvals and clinical trial data differ by tumor type. 8

• Both are IgG4 monoclonal antibodies engineered to minimize antibody-dependent cell-mediated cytotoxicity 1
• Real-world comparative effectiveness studies demonstrate similar outcomes in previously-treated NSCLC 4
• Pembrolizumab has broader first-line approvals (NSCLC with PD-L1 ≥50%, cisplatin-ineligible urothelial carcinoma) 1
• Treatment selection often depends on practical considerations including dosing convenience, specific FDA-approved indications, and institutional formulary decisions 1