Background and Rationale

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but present significant challenges including high costs limiting global access, substantial toxicity profiles, and mounting evidence that current approved doses exceed therapeutic necessity.^1,2   The fundamental principle supporting dose reduction lies in pharmacokinetic properties showing full target engagement at lower doses than currently approved.³   

Pharmacological Evidence

Target Saturation: Pembrolizumab shows full PD-1 receptor engagement at 1 mg/kg every 3 weeks, with peripheral receptor occupancy saturated at 0.3 mg/kg for nivolumab and >90% with 0.5 mg/kg pembrolizumab.¹ Dose-Response Plateau: For most ICIs except ipilimumab, dose-response curves show obvious plateaus, with exposure-response relationships reaching saturation at nivolumab doses ≥1 mg/kg, suggesting lower doses could achieve equivalent efficacy.⁴   

Clinical Evidence

NVALT-30 Trial: The most robust prospective evidence comes from this ongoing non-inferiority trial comparing reduced-dose pembrolizumab (300mg Q6W or 100mg Q3W) versus standard dosing in stage IV NSCLC. Interim analysis of 250 patients showed 1-year overall survival rates of 55.0% (reduced-dose) versus 57.7% (standard-dose), meeting pre-specified non-inferiority criteria for continued enrollment.⁵   

Real-World Evidence: A Singapore study of 114 NSCLC patients demonstrated that pembrolizumab 100mg Q3W achieved superior progression-free survival (6.8 vs 4.2 months, HR 0.60) compared to standard 200mg dosing, with equivalent overall survival and significant cost savings of SGD 39,942 per patient.³ European analysis of 391 patients revealed higher toxicity rates in patients.

Safety Profile

Lower doses consistently demonstrate improved safety profiles. In the Singapore study, grade ≥3 immune-related adverse events occurred in 17% versus 22% for reduced versus standard dosing respectively.³ Gynecologic cancer studies showed irAEs in 33.3% of patients receiving low-dose pembrolizumab, with only 7.7% experiencing grade 3-4 events.¹

Economic Impact and Global Access

The economic implications are profound: 95% of patients while reducing healthcare burden.⁶   

Practical Recommendations

Evidence supports several optimization strategies: Lower Fixed Dosing – pembrolizumab 100mg Q3W for patients ≤70kg; Extended Intervals – 200mg Q6W instead of Q3W maintains therapeutic levels; Weight-Based Dosing – 2mg/kg Q3W provides personalized optimization.⁷   Current standard doses of 200mg Q3W, 400mg Q6W, and 150mg Q3W could potentially be optimized without compromising efficacy.^8,9   

Conclusion

Compelling evidence from pharmacokinetic studies, real-world data, and prospective trials demonstrates that lower ICI doses maintain therapeutic efficacy while improving safety profiles and dramatically reducing costs. The current “one-dose-fits-all maximalist regimens” appear based on historical precedent rather than optimal biological activity.¹⁰    Implementation of evidence-based dose optimization represents a critical opportunity to improve global cancer care accessibility while maintaining therapeutic excellence.

Pembrolizumab Enables Treatment De-escalation in Cutaneous Squamous Cell Carcinoma

A response-adapted approach using neoadjuvant pembrolizumab allowed many patients with resectable cutaneous squamous cell carcinoma to avoid surgery and/or radiotherapy.

The De-Squamate study, published in the Journal of Clinical Oncology, showed that many patients achieved complete responses from pembrolizumab alone, without surgical or radiotherapy intervention.¹

“The De-Squamate study provides a rationale for using multimodal response assessment with 18F-FDG-PET imaging and targeted biopsy to guide management of patients with resectable cutaneous squamous cell carcinoma after pembrolizumab,” wrote study lead Rahul Ladwa, MBChB, MPhil, of Princess Alexandra Hospital in Brisbane, Australia. “It supports using pembrolizumab to avoid major surgery and radiotherapy without compromising disease-free survival in patients achieving a complete response.”

Study Design

Patients with locally advanced or metastatic cutaneous squamous cell carcinoma have shown significant responses to immunotherapy, including pembrolizumab and cemiplimab. A phase II trial of neoadjuvant cemiplimab showed a 51% pathologic complete response rate in patients with resectable stage II to IV disease.²

Investigators conducted the prospective, multicenter, phase II De-Squamate trial to determine if treatment could be de-escalated following immunotherapy. The study enrolled 27 patients with resectable stage II-IV nonmetastatic cutaneous squamous cell carcinoma in Australia who had not previously received radiotherapy.¹

Patients received 200 mg IV pembrolizumab every 3 weeks for up to four cycles, followed by 18F-FDG-PET imaging. Patients with a clinical complete response or complete metabolic response plus negative ultrasound-guided biopsies avoided surgery or radiotherapy. Others proceeded to surgical resection. Those with a pathologic complete or major response avoided adjuvant radiotherapy. Patients then received 13 additional maintenance pembrolizumab cycles and were followed for 3 years.

The primary endpoint was clinical or pathologic complete response rate after up to four initial cycles. The secondary endpoint was treatment de-escalation rate.

Key Findings

Of 27 patients, median age was 77 (range 59–90) and 89% were male. Most tumors (89%) were in the head and neck; 67% had stage IV disease without metastasis and 59% had nodal metastasis.

Seventeen patients (63%) achieved a clinical or pathologic complete response (95% CI = 42%–80%), including clinical complete response in 48% and pathologic complete response in 15%. All avoided surgical resection and/or adjuvant radiotherapy.

The objective response rate was 66% (95% CI = 50%–80%), with complete responses in 22% and partial responses in 44%. Complete metabolic responses occurred in 56% (95% CI = 40%–70%).

Four patients with pathologic complete response had achieved only partial response to pembrolizumab, but FDG-PET showed complete metabolic responses in two and partial metabolic responses in two.

Nineteen patients were recommended for maintenance pembrolizumab; 16 accepted and 14 completed all 13 cycles.

At 18 months, event-free survival was 74%. No recurrences occurred in patients who achieved complete response. In these patients, 1-year event-free survival was 94% (95% CI = 76%–99%) with median not yet reached, compared with 40% (95% CI = 15%–70%) and median of 7 months (95% CI = 0–14.7) in those without complete response.

Safety

Adverse events occurred in 89% of patients, most commonly fatigue (37%), pruritus (37%), diarrhea (26%), nausea (26%), and arthralgia (22%). Grade 3 events occurred in 26%, grade 4 in 4%, and grade 5 in 11%. No grade 5 events were treatment-related.

Treatment-related adverse events occurred in 74% and immune-related adverse events in 30%. One patient discontinued pembrolizumab due to a treatment-related event during maintenance.^11,12   

References

1. Jiang M, et al. Dosing Regimens of Immune Checkpoint Inhibitors. Front Oncol. 2022;12:906251.

2. Remon J, et al. De-Escalation Strategies With Immune Checkpoint Blockers in NSCLC. JCO. 2024. DOI:10.1200/JCO-24-02347

3. Jiang M, et al. Dosing Regimens of Immune Checkpoint Inhibitors. Front Oncol. 2022;12:906251.

4. Jiang M, Hu Y, Lin G, Chen C. Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course. Front Oncol. 2022;12:906251. doi: 10.3389/fonc.2022.906251

5. Agrawal S, Feng Y, Roy A, et al. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 2016;4:72. doi: 10.1186/s40425-016-0177-2

6. Jiang M, et al. Dosing Regimens of Immune Checkpoint Inhibitors. Front Oncol. 2022;12:906251.

7. Low JL, et al. Low-dose pembrolizumab in advanced non-small cell lung cancer. Int J Cancer. 2021;149:169-176.

8. Van den Heuvel M, et al. NVALT-30 clinical trial interim analysis. Ann Oncol. 2024. DOI:10.1016/j.annonc.2024.08.1315

9. Fortuna M, Kovačevič M. Fixed vs weight-based dosing of pembrolizumab for patients under 80 kg, based on observed ADRs in one cancer setting. Eur J Hosp Pharm. 2023;30:A123.

10. Remon J, et al. De-Escalation Strategies With Immune Checkpoint Blockers in NSCLC. JCO. 2024. DOI:10.1200/JCO-24-02347

11. Ladwa R, Lee JH, McGrath M, et al: Response-adapted surgical and radiotherapy de-escalation in resectable cutaneous squamous cell cancer using pembrolizumab: the De-Squamate study. J Clin Oncol. July 21, 2025 (early release online).

12. Gross ND, Miller DM, Khushalani NI, et al: Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med 387:1557-1568, 2022.