A Historical Guide to ICIs: Lessons Learned

While immune checkpoint inhibitors (ICIs) have reshaped treatment paradigms across oncology, concerns regarding treatment resistance and safety persist. Insights learned from the use of ICIs across tumor types may help inform care in high-risk CSCC.

Interest in immune checkpoint inhibitors (ICIs) has expanded rapidly over the past decades. Ipilimumab, a cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) inhibitor, was the first FDA-approved ICI in 2011 for unresectable or metastatic melanoma.^1,2 In 2014, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved in the same disease space.^3-6 Since then, additional ICIs have been approved across a broad range of indications.⁷ The targets for most ICIs are CTLA-4, PD-1, and programmed death-ligand 1 (PD-L1),⁸ although next-generation ICIs include new targets such as lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin-3 (TIM-3).⁹ However, despite the success of ICIs in cancer treatment, important limitations in both efficacy and tolerability remain. Understanding the evolution of ICIs is increasingly relevant as their use expands beyond advanced disease into earlier-stage settings, including high-risk cutaneous squamous cell carcinoma (CSCC). 

Early Success in Advanced Disease 

Early successes in advanced melanoma demonstrated that ICIs could produce durable responses, reshaping expectations for long-term disease control.^1,3,5 These findings provided the rationale for evaluating ICIs in earlier-stage disease, including adjuvant and neoadjuvant settings, where the goal shifts to eliminating micrometastatic disease and reducing recurrence risk.¹⁰ Numerous phase 2 and phase 3 trials have been conducted to evaluate ICIs in adjuvant and neoadjuvant settings across multiple tumor types.¹¹ In 2025, cemiplimab, a PD-1 inhibitor, was FDA approved for the adjuvant treatment of high-risk CSCC.^12-13 

Efficacy Challenges 

Despite expanding approvals in both adjuvant and neoadjuvant settings,¹¹ efficacy challenges remain. Pseudoprogression can occur in a small subset of patients treated with ICIs. Tumors may initially appear larger on imaging studies despite true tumor regression over time; the initial size increase can be attributed to inflammatory effects of immune infiltration.⁷ Hyperprogressive disease is a rarer but clinically more consequential pattern, defined as an accelerated pace of progression after ICI treatment. This effect is not universally characterized, and criteria for hyperprogression include time-to-treatment failure <2 months, >50% increase in tumor burden, and >2-fold acceleration in progression rate. Patients can experience 35- to 40-fold accelerated progression, with an estimated survival of approximately 3 months. Early distinction between pseudoprogression and hyperprogression is critical, but methods for distinguishing between these clinical presentations are not well established.⁷ Furthermore, patients can develop resistance to ICIs even after initial positive response, and mechanisms of acquired resistance are not fully understood.^7,14 These response patterns highlight the importance of careful clinical interpretation when assessing treatment response, particularly in earlier-stage settings. 

Safety Considerations 

ICIs can disrupt the immune system balance and lead to a wide variety of immune-related adverse events (irAEs) across multiple organ systems and areas of the body.^7,11,15 While many irAEs can be managed with corticosteroids or additional immunosuppressive agents in the short-term, some irAEs may result in chronic conditions requiring lifelong management. In rare cases, irAEs can be fatal (0.3% to 1.3%).⁷ Currently, there are no reliable predictors to identify patients at risk for severe or life-threatening toxicities. Frequent patient monitoring is important, and temporarily pausing treatment or adjusting ICI dosage may be required.⁷ In the adjuvant setting, where patients may be clinically disease free, the potential for long-term or irreversible toxicities underscores the importance of careful patient selection and monitoring.

Implications for the Management of CSCC

The expansion of ICIs into earlier-stage disease represents a shift from treating advanced cancer to preventing recurrence in patients who may be clinically disease free following surgery. In this context, lessons learned from advanced disease, particularly around response patterns, resistance, and toxicity, remain highly relevant but must be applied within a different risk-benefit framework. Use of ICIs in the adjuvant setting requires careful patient selection, as the potential for durable benefit must be balanced against the risk of irAEs, some of which may be long-lasting or irreversible.¹¹   

Early identification of patients with high-risk CSCC is important for thoughtful integration of systemic therapy (ie, adjuvant cemiplimab) into broader treatment planning.^12,13,16 Multidisciplinary coordination is critical to safe and effective use, particularly to support monitoring, early recognition of adverse events, and alignment across specialties. As the role of ICIs continues to evolve in high-risk CSCC, clinicians must apply clinical judgment to navigate areas where evidence and guidelines are still emerging.

References

1. Bristol-Myers Squibb. FDA approves Yervoy™ (ipilimumab) for unresectable or metastatic melanoma. March 25, 2011. Accessed April 21, 2026. https://news.bms.com/news/details/2011/FDA-Approves-YERVOY-ipilimumab-for-the-Treatment-of-Patients-with-Newly-Diagnosed-or-Previously-Treated-Unresectable-or-Metastatic-Melanoma-the-Deadliest-Form-of-Skin-Cancer/default.aspx
2. Yervoy. U.S. prescribing information. Bristol-Myers Squibb Company; revised May 2025. Accessed April 22, 2026. https://packageinserts.bms.com/pi/pi_yervoy.pdf 
3. Merck. Merck receives accelerated approval of Keytruda^® (pembrolizumab), the first FDA-approved anti–PD-1 therapy. September 4, 2014. Accessed April 21, 2026. https://www.merck.com/news/merck-receives-accelerated-approval-of-keytruda-pembrolizumab-the-first-fda-approved-anti-pd-1-therapy/ 
4. Keytruda. Prescribing information. Merck Sharp & Dohme LLC; revised April 2026. Accessed April 22, 2026. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 
5. Bristol-Myers Squibb. Bristol-Myers Squibb receives accelerated approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration. December 22, 2014. Accessed April 21, 2026. https://news.bms.com/news/details/2014/Bristol-Myers-Squibb-Receives-Accelerated-Approval-of-Opdivo-nivolumab-from-the-US-Food-and-Drug-Administration/default.aspx 
6. Opdivo. U.S. prescribing information. Bristol-Myers Squibb Company; revised March 2026. Accessed April 22, 2026. https://packageinserts.bms.com/pi/pi_opdivo.pdf 
7. Adashek JJ, Moran JA, Le DT, Kurzrock R. Lessons learned from a decade of immune checkpoint inhibition: the good, the bad, and the ugly. Cancer Metastasis Rev. 2025;44(2):43. doi:10.1007/s10555-025-10260-8 
8. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17(8):807-821. doi:10.1038/s41423-020-0488-6 
9. Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol. 2021;14(1):45. doi:10.1186/s13045-021-01056-8 
10. Janjigian YY, Wolchok JD, Ariyan CE. Eradicating micrometastases with immune checkpoint blockade: strike while the iron is hot. Cancer Cell. 2021;39(6):738-740. doi:10.1016/j.ccell.2021.05.013 
11. Björkström K, Matikas A, Svedman FC, et al. Perioperative immune checkpoint inhibitor therapy across tumors: insights and shared lessons from a rapidly evolving field. J Intern Med. 2026;299(5):538-569. doi:10.1111/joim.70073 
12. Regeneron Pharmaceuticals, Inc. Libtayo^® (cemiplimab-rwlc) approved in the U.S. as adjuvant treatment for CSCC. October 8, 2025. Accessed April 22, 2026. https://investor.regeneron.com/news-releases/news-release-details/libtayor-cemiplimab-rwlc-approved-us-first-and-only/ 
13. Libtayo. Prescribing information. Regeneron Pharmaceuticals, Inc.; revised October 2025. Accessed April 22, 2026. https://www.regeneron.com/downloads/libtayo_fpi.pdf 
14. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118(1):9-16. doi:10.1038/bjc.2017.434 
15. Köylü B, Esen BH, Bektaş ŞN, et al. Pharmacovigilance analysis of immune checkpoint inhibitor-related reproductive adverse effects based on the FDA adverse event reporting system. Sci Rep. 2025;15(1):7770. doi:10.1038/s41598-025-91476-0 
16. Rischin D, Porceddu S, Day F, et al. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449