Loading ...

Although targeted therapies and immunotherapy have improved survival outcomes in many patients with lung cancer, these therapies come at a cost, not only financially but also in terms of cumulative and long-term treatment toxicities. But could patients benefit from receiving less therapy rather than more? 

At the European Lung Cancer Congress (ELCC) 2025, Benjamin Besse, MD, PhD, presented a keynote talk on the rationale and strategies for treatment de-escalation in lung cancer, challenging the notion that “more is better” when it comes to cancer therapy. Other experts shared their answers to the question as well, during interviews with Medscape Medical News and another session at the meeting.

Why Consider De-escalation?

“De-escalation trials are mandatory, but not everywhere and not with every drug,” Besse emphasized during his keynote lecture. “It has to be based on strong biological and pharmacokinetic rationale.”

Besse explained that the concept of de-escalation is not merely academic; rather, it has profound real-world implications.

“In India, only 2.8% of the people can afford immunotherapy,” he said, during this presentation. This statistic underscores that although cutting-edge treatments are readily available in high-income countries, they remain inaccessible to most of the world’s population.

Suresh Ramalingam, MD, executive director of Winship Cancer Institute of Emory University, Atlanta, echoed this concern.

“The unfortunate reality is that patients in several countries cannot afford the most advanced therapies for lung cancer,” he said in an interview with Medscape Medical News. “The necessity to do more with less is prompting studies exploring lower doses.”

Besse argued that de-escalation strategies could save patients from unnecessary toxicity, reduce time spent in hospitals, and dramatically decrease healthcare costs, without compromising treatment effectiveness.

Dose reduction, which entails using lower doses of medications that maintain the drug’s efficacy; treatment interval extension, which involves extending times between treatments; and duration reduction, which entails shortening the overall treatment period, are methods for de-escalating treatment, Besse outlined during his talk.

The Biological Rationale for Dose Reduction

For immune checkpoint inhibitors, such as pembrolizumab and nivolumab, the biological rationale for dose reduction is that these monoclonal antibodies work by blocking the programmed cell death 1 (PD-1) receptor on T cells, and relatively low doses are needed to achieve saturation.

Besse pointed to data from research showing that even at a dose of 1 mg/kg administered every 3 weeks, pembrolizumab saturates the PD-1 receptor on peripheral T cells.

He also referenced data showing that a single infusion of nivolumab at 10 mg/kg is sufficient to occupy > 70% of PD-1 molecules on T cells for up to 80 days.

“One injection of pembrolizumab at 10 mg/kg saturates PD-1 on lymphocytes for 400 days, and yet we administer the drug every 21 days; it doesn’t make sense,” Besse noted.

Studies in patients with melanoma showed that nivolumab at 0.1 mg/kg (30 times less than the standard dose) achieved similar response rates to 10 mg/kg. However, standard dosing remains “much higher,” with “flat doses calculated based on the median weight of healthy people rather than cancer patients, who typically weigh less,” Besse said.

Real-World Evidence for Lower Doses

A real-world study from India demonstrated that ultralow-dose nivolumab (40 mg every 2 weeks) combined with chemotherapy showed promising results in non–small cell lung cancer (NSCLC). According to Besse, although these survival data are not directly comparable to those in standard dosing trials, the survival curves appeared remarkably similar.

“The hazard ratio seems to be similar, as if the biology was similar between the two doses,” Besse noted. “This approach reduced costs by 86% while maintaining efficacy.”

Ramalingam pointed to another study from India, saying, “The study in head and neck cancer from Tata Memorial Hospital could serve as a model for others to study similar approaches that will ultimately extend the use of these agents to broader groups of patients.”

The ongoing DEDICATION-1 trial in the Netherlands is formally testing reduced-dose (300 mg every 6 weeks or 100 mg every 3 weeks) pembrolizumab against standard dosing (400 mg every 6 weeks, 150 mg every 3 weeks, or 200 mg every 3 weeks) in patients with advanced NSCLC, with preliminary results showing comparable progression-free and overall survival rates.

When asked about these findings, Besse noted: “The data presented come from an interim analysis that did not indicate a reduced dose is valid. This interim analysis suggests that the trial can continue to accrue participants.”

However, Ramalingam urged that caution is needed when reducing the doses of cancer therapies.

“There is inadequate knowledge on what level of dose reduction is appropriate,” he said in an interview. “Of course, when patients experience toxicity, dose reduction or interruptions may be necessary.”

Extending Treatment Intervals

The PULSE trial, led by Besse, is investigating whether pembrolizumab can be administered every 6 weeks instead of every 3 weeks in maintenance therapy for nonsquamous NSCLC.

Commenting on the financial implications of extending treatment intervals for immunotherapy, Besse said: “If this trial is positive, it will save €1 billion every 3 years in France alone.” He added that running the trial will save the health system money because the experimental arm receives half the dose of pembrolizumab.

Optimizing Treatment Duration

The question of how long to continue treatment also presents opportunities for de-escalation. Data from the French national healthcare database showed that patients who stopped pembrolizumab after 2 years had similar overall survival to those who continued treatment.

In addition, the phase 3 DICIPLE trial demonstrated that stopping immunotherapy at 6 months did not negatively affect progression-free or overall survival compared to continuing treatment. Stopping immunotherapy also reduced grade 3 or higher immune-related adverse events by nearly 10 times (2.9% vs 28.6%).

Regulatory Challenges

Besse explained that despite its potential benefits, de-escalation faces significant regulatory hurdles. Even if trials prove that lower doses or shorter durations are equally effective, drug labels may not change because pharmaceutical companies have little incentive to pursue such changes.

“We need to modify the clinical guidelines and lobby the FDA [US Food and Drug Administration] and other relevant regulatory agencies through academic incentives so that the label can be changed,” he added.

Ramalingam agreed on the importance of advocating for evidence-based approaches: “Any de-escalation approach should be based on evidence from well-conducted randomized trials. The onus is on the academic community to conduct such trials to inform clinical practice.”

The Counterargument: When More Is Better

Some are in favor of extending treatments durations. Hye Ryun Kim, MD, PhD, presented arguments for following this approach when using targeted therapies in EGFR-mutated NSCLC, during a debate session at the ELCC 2025.

“Patients still face the risk of recurrence after 3 years,” Kim noted, pointing to data from the ADAURA trial showing late relapses after discontinuation of osimertinib. She advocated for treatment “as long as possible” in high-risk patients.

Rafal Dziadziuszko, MD, PhD, who also presented during the debate, offered a different perspective, distinguishing between immunotherapies, which he described as “cytotoxic,” and targeted therapies, which are “cytostatic.”

He suggested that 1 year or less might be sufficient for immunotherapy in the adjuvant or perioperative setting. In contrast, targeted therapies might need to be continued until disease progression to suppress the remaining micrometastatic clones.

He noted, however, that prospective data are needed to support this hypothesis and confirm the optimal treatment duration.

The Path Forward

When asked in an interview which de-escalation strategy holds the most promise, Ramalingam noted that the optimal approach varies by context.

“With regards to the use of immunotherapy, there is evidence that lower doses and shorter duration of therapy may be just as effective. In the case of certain targeted therapies, dose reductions may result in preservation of efficacy with an improved tolerability,” he said.

Multiple experts Medscape Medical News interviewed for this story agree that personalization based on biomarkers is key when developing de-escalation strategies.

Kim and Dziadziuszko highlighted the potential of minimal residual disease monitoring to identify patients who truly need extended therapy, for example.

Besse also sees promise in this approach.

“Monitoring the response with circulating biomarkers could allow us to select the best responders and maybe stop treatment earlier, but this is only speculation and needs to be proven,” he said in an interview, noting that this will be tested in the PULSE trial.

When designing de-escalation trials, Besse emphasized that “patients come first, and these trials should aim for zero risk to decrease efficacy while hopefully being less toxic.”

The rationale for de-escalation should be very strong, based on pharmacokinetic data and biology, he added.

Besse reported receiving consultation or advisory fees from AbbVie, BioNTech SE, Beijing Avistone Pharmaceuticals Biotechnology, Bristol Myers Squibb (BMS), CureVac AG, PharmaMar, Regeneron, Sanofi Aventis, Eli Lilly, Ellipses Pharma Ltd, Hoffmann-La Roche Ltd, Foghorn Therapeutics, Genmab, Immunocore, and Owkin. Dziadziuszko reported having financial relationships with Roche, AstraZeneca, Novartis, Pfizer, GlaxoSmithKline (GSK), MSD, Boehringer Ingelheim, Illumina, and BioNTech. Kim reported receiving clinical trial support (to institution) from AstraZeneca, BMS, Genentech/Roche, Merck, Affimed, Immunocore, and GSK; consultation or advisory fees from MSD, AstraZeneca, and GSK; and research funding from the Yonsei Lee Youn Jae Fellowship. Ramalingam reported receiving research funding (to institution) from Amgen, AstraZeneca, BMS, Merck, and Pfizer and travel support from AstraZeneca and AbbVie.

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.