Dose optimisation of immune checkpoint inhibitors may help address current healthcare resource constraints and improve treatment access
Immunotherapy, for all its success, may be like the so-called unfinished works of the Italian sculptor Michelangelo, whose impact on humanity lies not only in what has been revealed, but in what remains to be refined. Asking ourselves, as medical oncologists, whether less might sometimes be enough does not mean downgrading immunotherapy’s achievements; rather it reflects a continuous commitment to taking them seriously enough to interrogate its foundations to further advance the field in a sustainable and more equal way.
Immunotherapy has impacted the ethical dimension of cancer care as much as it has transformed clinical outcomes. Yet, the success of immune checkpoint inhibitors nurtures a paradox: therapies that are biologically powerful and clinically transformative remain inaccessible to most of the world’s patients with cancer (Ann Oncol. 2025 Mar;36(3):247-262 ).
The inclusion of immunotherapy for melanoma, non-small cell lung cancer, colorectal cancer and cervical cancer in the World Health Organization’s Essential Medicines List (WHO EML) in 2025 should act as a wake-up call for the oncology community: treatment dosing is no longer a technical detail but rather a central ethical-clinical issue that is instrumental in shaping access-oriented strategies for the sustainability of healthcare systems (EClinicalMedicine. 2025 May 24:84:103261 ).
The idea that immune checkpoint inhibitors might be effective at doses far lower than those currently approved is not new, but it has remained marginal in academic discourse. Administering doses that clearly exceed biological target saturation has been considered acceptable so far, as long as no additional clinical toxicity are observed. However, in the current scenario of constrained healthcare budgets and enduring disparities in access to high-quality cancer care, the oncology community is pushed to confront an uncomfortable possibility: has systematic overdosing been accidentally normalised?
Immunotherapy hardly fits the dose-escalation logic established for cytotoxic chemotherapy. Early-phase studies of anti-PD(L)1 agents demonstrated clinical activity at remarkably low doses, with no clear monotonic relationship between dose and either efficacy or toxicity. Pharmacodynamic analyses showed rapid and sustained saturation of the PD(L)-1 receptor at doses far below those eventually selected for phase III trials. Target occupancy persisted for weeks, despite relatively shorter serum half-lives (Nat Med. 2022 Nov;28(11):2236-2237 ).
Based on this evidence, the decision to advance substantially higher doses into late-phase development does not appear to be data-driven but rather rooted in the drug development paradigm of the chemotherapy era. In immunotherapy registrational trials, flat dosing replaced weight-based dosing for reasons of convenience, rather than because higher drug exposure translated into greater clinical benefit. The result, in clinical practice, is that immune checkpoint inhibitors may be administered at levels above their biologically effective dose. Whereas systemic immunotherapy overdosing can be absorbed - albeit uneasily - by healthcare systems and payers in high-income countries, in other areas it exacerbates barriers to medicine access. Therefore, dose-optimised immunotherapy emerges as a pragmatic response to real-world constraints: over the past decade, clinicians working in resource-limited settings have explored reduced-dose strategies out of necessity, demonstrating drug efficacy consistent with biological predictions.
Moreover, a recent systematic review evaluating post-commercialisation use of low-dose anti–PD-(L)1 therapies showed that across more than 30 studies and over 2,000 patients, radiological responses were reported even when doses were a fraction of those approved by regulatory agencies (Eur J Cancer. 2025 Jul 25:225:115564 ). In certain malignancies, including lymphoma, lung cancer, renal cell carcinoma, response patterns appeared broadly comparable to those seen in pivotal trials. Importantly, these outcomes were frequently achieved alongside dramatic reductions in drug expenditure, sometimes exceeding 80% compared with list prices.
More compelling evidence is provided by randomised data. In advanced head and neck squamous cell carcinoma, a randomised phase III study conducted in India demonstrated that adding very low-dose nivolumab (at the flat dose of 20 mg every three weeks) to metronomic chemotherapy, significantly improved overall survival compared with chemotherapy alone, without increasing toxicity (J Clin Oncol. 2023 Jan 10;41(2):222-232 ). This was not a non-inferiority comparison against standard-dose immunotherapy, but it addressed an ethically salient question, namely, whether any immunotherapy is meaningfully better than none in settings where standard dosing is simply unattainable. The answer, at least in this context, was unequivocally yes.
Similarly, in early triple-negative breast cancer, the phase II randomised PLANeT study presented at the ESMO Congress 2025, evaluated low-dose pembrolizumab (50 mg every 6 weeks) added to neoadjuvant chemotherapy, reporting a statistically significant increase in pathological complete response rates (Ann Oncol. 2025 Dec 22:S0923-7534(25)06335-5 ). The magnitude of benefit was numerically close to that observed in global registrational trials, but was achieved with a markedly reduced drug dose and, therefore, reduced costs. While longer follow-up and confirmatory studies are needed, these findings challenge the assumption that maximal dosing is a prerequisite for maximal benefit, even in potentially curative settings and in those tumours that are not traditionally considered highly immunogenic and where the highest dose is deemed preferable.
The idea of dose-optimised immunotherapy should come with a broader rethinking of pharmacology and its related clinical benefit and societal responsibility. Legitimising the scientific exploration of alternative dosing strategies, supporting rigorous non-inferiority and near-equivalence trials, and engaging constructively with regulators and policymakers are now fundamental to reshape the future of immunotherapy on sustainability and ethical implications.
