Imagine a patient with metastatic melanoma who achieves complete remission after 18 months of pembrolizumab, only to hear from family members: “Don’t stop you’ll relapse.” This fear is widespread. Patient-reported surveys and real-world observations suggest that many individuals believe immune checkpoint inhibitors (ICIs) must be continued indefinitely to maintain disease control.
In reality, for a substantial proportion of responders, fixed-duration immunotherapy most commonly up to two years has been shown to be safe and effective, with durable clinical benefit persisting after treatment discontinuation. Long-term follow-up from landmark KEYNOTE and CheckMate trials, supported by real-world data and professional society guidance, directly challenges the assumption that lifelong immunotherapy is necessary to maintain disease control.
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This article examines where the “never stop immunotherapy” myth originated, reviews the clinical evidence supporting treatment discontinuation, and discusses the risks, benefits, and guideline-based considerations surrounding prolonged therapy.
Where Did the Idea of “Never Stopping Immunotherapy” Come From?
The belief that immunotherapy must be continued indefinitely did not emerge from strong biological evidence, but rather from trial design, regulatory language, and survivorship anxiety.
Many pivotal ICI trials and drug labels describe treatment as continuing “until disease progression or unacceptable toxicity.” While practical for regulatory approval, this wording fostered the impression that ongoing exposure is necessary to maintain benefit. This perception was further reinforced by parallels with chronic targeted therapies, where discontinuation often leads to rapid disease progression.
Importantly, this misconception is not rooted in early ipilimumab trials, which actually used fixed induction dosing. Instead, it reflects the broader evolution of immunotherapy into routine practice, combined with media narratives portraying ICIs as “miracle drugs” that must not be interrupted. In real-world settings, concerns about relapse are amplified by financial toxicity, cumulative adverse effects, and uncertainty about what happens once treatment stops.
However, accumulating clinical evidence now shows that durable immune-mediated tumor control can persist after treatment discontinuation in selected patients, directly challenging the need for indefinite therapy (Czarnecka et al., Targeted Oncology, 2025).
Why Immunotherapy Does Not Have to Be Forever
As ICIs transitioned from experimental therapies to standards of care, the central clinical question shifted from whether they work to how long they should be continued. While prolonged exposure was initially favored out of caution, long-term randomized and observational data now support fixed-duration strategies in appropriately selected patients particularly those with deep and sustained responses.
Crucially, many of the most influential trials in melanoma and lung cancer were designed with an upper treatment limit, providing real-world evidence that stopping therapy does not automatically negate benefit.
Pembrolizumab and the KEYNOTE Trials: Proof of Principle
In KEYNOTE-006 (Advanced Melanoma), pembrolizumab was administered for a maximum of approximately two years (35 cycles) or until progression or unacceptable toxicity. Long-term follow-up extending beyond a decade demonstrated that many patients who completed planned therapy maintained durable responses years after treatment cessation, including a high proportion of complete responders who remained progression-free without additional systemic therapy. These results established that continued drug exposure is not always required to sustain immune-mediated tumor control in melanoma.
KEYNOTE-024 (PD-L1–Positive Metastatic NSCLC)
Similarly, KEYNOTE-024 capped pembrolizumab treatment at 35 cycles. Among patients who completed the full two-year course while remaining progression-free, long-term analyses showed sustained survival benefits well beyond treatment discontinuation and superior overall survival compared with chemotherapy.
Together, these trials support the principle that clinical benefit from pembrolizumab can persist after elective discontinuation, validating fixed-duration therapy as a reasonable strategy in responders.
Nivolumab-Based Regimens: Lessons from CheckMate Trials
CheckMate-067 (Melanoma) demonstrated unprecedented long-term survival with nivolumab-based therapy in advanced melanoma. Although treatment was generally administered until progression or toxicity rather than a strict fixed duration, long-term follow-up revealed that many long-term survivors were no longer receiving active therapy yet maintained disease control. This underscores a key concept: durable benefit can persist after immunotherapy cessation, even when discontinuation was not protocol-mandated.
CheckMate-214 (Renal Cell Carcinoma)
In metastatic renal cell carcinoma, nivolumab plus ipilimumab achieved high rates of durable response, including complete remissions. Long-term analyses emphasized treatment-free intervals, with a substantial proportion of responders remaining off therapy for extended periods without loss of disease control. While this trial did not prescribe stopping therapy solely based on response confirmation, it clearly demonstrated that ongoing treatment is not always required to maintain benefit.
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Real-World Evidence and Meta-Analyses
Observational studies have reinforced these trial findings. In non–small cell lung cancer, large real-world cohorts comparing patients who stopped immunotherapy after approximately two years with those who continued longer found no statistically significant disadvantage in progression-free or overall survival among patients who discontinued while progression-free (Rousseau et al., The Lancet Regional Health – Europe, 2024).
Meta-analyses and retrospective series across melanoma and NSCLC suggest that only a minority of patients relapse after elective discontinuation, particularly those who achieved complete or deep partial responses. Importantly, a proportion of patients who do experience progression can respond again to immunotherapy rechallenge, although response rates vary by tumor type, depth of initial response, and reason for stopping treatment (Czarnecka et al., Targeted Oncology, 2025).
When and Why to Stop Immunotherapy: Guideline-Based Practice
Professional society guidelines emphasize individualized decision-making rather than a one-size-fits-all approach. In clinical practice, elective discontinuation after sustained response—often around 18 to 24 months is commonly considered, reflecting the design of pivotal trials rather than an absolute biological threshold (NCCN Guidelines; ASCO Clinical Practice Updates, 2024–2025).
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Clear guidance exists for toxicity-driven discontinuation. Severe immune-related adverse events, particularly neurologic or cardiac toxicities, generally warrant permanent cessation, whereas controlled endocrinopathies may allow continued therapy with appropriate hormone replacement.
The Risks of Prolonged Immunotherapy
Continuing ICIs beyond durations supported by trial evidence offers uncertain additional survival benefit while increasing cumulative risks. These include chronic immune-related adverse events, financial toxicity, and long-term quality-of-life impairment. As survivorship becomes a central focus in oncology, balancing durable tumor control with patient safety and well-being is increasingly critical (Marron et al., Journal for ImmunoTherapy of Cancer, 2021; Czarnecka et al., Targeted Oncology, 2025).
The idea that immunotherapy must be continued forever is a myth not a mandate of the immune system. For many patients who achieve sustained responses, particularly complete remission, planned discontinuation after a fixed duration is supported by robust clinical evidence. The goal of immunotherapy is not endless treatment, but durable immune control sometimes achieved long after the last infusion.
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Written by Aharon Tsaturyan, MD, Editor at OncoDaily Intelligence Unit
FAQ
Is it safe to stop immunotherapy after 2 years if I’m in remission?
For some patients who remain progression-free after ~2 years of PD-1 therapy, stopping treatment can be a reasonable option especially when treatment duration mirrors trial design. In advanced NSCLC, real-world data and a large cohort analysis suggest stopping at 2 years may yield similar survival to continuing longer in selected patients.
What is the relapse risk after stopping pembrolizumab?
Relapse risk varies based on cancer type, depth of response (complete vs partial), and why treatment stopped. Studies consistently show that many deep responders remain disease-controlled after discontinuation, but relapse can still occur so stopping should be individualized and followed by close surveillance.
Can I stop Keytruda (pembrolizumab) after a complete response?
In several pivotal pembrolizumab studies, treatment was capped at ~2 years (35 cycles), and many patients who completed therapy maintained durable benefit after stopping. This supports the idea that continued exposure is not always required in selected responders.
What happens if cancer comes back after stopping immunotherapy?
Some trials and protocols allow re-treatment after progression following planned discontinuation, and real-world practice sometimes mirrors this (depending on prior benefit, toxicity history, and time off therapy). However, retreatment success rates vary and are not guaranteed.
How long should I stay on Opdivo (nivolumab) for melanoma?
There isn’t one universally “correct” duration for everyone. Many trials treated until progression/toxicity, while others used caps; long-term follow-up shows some patients maintain durable control after stopping for various reasons. This is a shared decision based on response, side effects, and preferences.
Do NCCN/ASCO guidelines say exactly when to stop immunotherapy?
Guidelines emphasize individualized decision-making and toxicity-based stopping rules more clearly than they mandate a single fixed treatment duration for all patients. In practice, many clinicians consider ~2 years in selected responders because that’s how several pivotal trials were designed.
Does stopping immunotherapy guarantee relapse?
No. In advanced NSCLC, analyses suggest patients who stop at 2 years while progression-free may have similar overall survival to those who continue longer—though observational studies can’t prove causality.
Should I stop immunotherapy early because of side effects?
Sometimes, yes especially with serious immune-related adverse events. The safest approach is to follow your oncology team’s toxicity management plan; severe neurologic or cardiac events often require permanent discontinuation, while controlled endocrinopathies may allow continuation with hormone replacement.
Is lifelong immunotherapy necessary for metastatic melanoma?
Not necessarily. Some patients achieve durable immune control after a finite period of therapy, and long-term follow-up from key studies supports that durable benefit can persist after treatment stops in selected responders.
How will I be monitored after stopping immunotherapy?
Most monitoring is imaging-based and individualized by cancer type, prior disease burden, and relapse risk. Be cautious about claiming ctDNA is standard everywhere its use is evolving and not universally embedded as routine follow-up across cancers.