Written by Giannis Mountzios, MD PhD and Sandip Patel, MD.
Immune checkpoint inhibition has revolutionized lung cancer care. However, the question of optimal treatment duration is still unanswered. Can treatment benefits be maximized by prolonged immunotherapy in patients with lung cancer? Here are some pros and cons.
I would agree that maximizing the duration of immunotherapy in lung cancer care is the preferred strategy if at least one of the following arguments were correct: if it is associated with better biological activity or improved clinical outcomes, if it does not substantially increase toxicity or adversely affect quality of life, and if it is associated with a favorable cost-benefit ratio. Regarding biological efficacy, phase I trials consistently showed that receptor saturation is achieved with very low doses of immune checkpoint inhibitors (ICIs) in > 95 % of cases (1-3). This lasts for ≥ 2 months, even with doses that are significantly lower and further spaced apart than the ones we use in clinical practice.
A study using PET with 89Zr-labeled antibodies demonstrated no significant differences in target saturation using a wide spectrum of radioactive doses (4). Also, target occupancy after a single dose was comparable across two PET scans performed at least one month apart.
Giannis Mountzios MD, MSc, PhD
Henry Dunant Hospital Center, Athens, Greece
Taken together, pharmacokinetic and pharmacodynamic data do support continuous administration of ICIs, although in smaller doses and at larger intervals than approved in clinical practice. The available evidence certainly does not support the notion that indefinite administration of ICIs improves target saturation or occupancy over time.
Efficacy data from clinical studies
Regarding clinical outcomes, it is uncertain whether maximizing ICI therapy duration conveys improvement. In the three registrational phase III trials of first-line pembrolizumab, slightly more than half of patients who discontinued immunotherapy at two years per protocol showed disease relapse at five years (5-8). There is no compelling evidence from randomized controlled trials suggesting that prolonged immunotherapy beyond two years would have prevented these recurrences.
In CheckMate 153, progression-free survival and overall survival (OS) were improved by continuation of nivolumab therapy beyond one year (9). However, this was an exploratory analysis of a community-based trial that was not blinded and not stratified according to prior ICI response. The randomized patients included a large group with progressive disease. Benefits of continuing nivolumab were only observed in the subgroup that experienced complete or partial remission, but not in those with stable disease.
At the same time, two huge population-based cohort studies from France and the US consistently showed that continuation of ICI therapy beyond two years was not associated with better OS compared to fixed-duration treatment (10-11). The DICIPLE trial that assessed nivolumab plus ipilimumab beyond six months was prematurely terminated due to poor accrual, although at least it can be said that there was no detrimental effect of the “stop and go” strategy as compared to continuation (12).
Toxicity and cost/benefit ratio
Prolonged duration of ICI therapy clearly leads to higher rates of treatment-related adverse events (TRAEs) and especially immune-related AEs that tend to be chronic and impact patient quality of life. In the CheckMate 9LA trial testing nivolumab/ipilimumab plus chemotherapy, 62.5% patients who were alive at five years had discontinued ipilimumab due to toxicity (13). According to a Pearson’s correlation test, it appears that the duration of ipilimumab treatment did not affect long-term survival. At the same time, patients who discontinued ICI treatment due to TRAEs fared better even after stopping therapy compared to the control arms in both CheckMate 227 and CheckMate 9LA (13-14).
Finally, there is no doubt that prolonged ICI therapy does not have a favorable cost/benefit ratio. In Greece, for example, two years of first-line pembrolizumab instead of five years would result in cost savings of almost 200 million euros.
Maximizing benefit through prolonged therapy
In the second-line metastatic setting, the CheckMate 153 study has shown that one year of anti-PD-1 therapy is inferior to continuous nivolumab (9). This effect was independent of ECOG performance status and PD-L1 status. With its caveats, CheckMate 153 is still one of the few studies investigating treatment duration.
The fact remains that after fixed-duration therapy, retreatment does not work in substantial proportions of patients. In the KEYNOTE-010 study, 57 % did not respond to rechallenge with pembrolizumab after two years of second-line pembrolizumab therapy (15). KEYNOTE-024 showed similar results for the frontline setting; here, only one third of patients who had previously received two years of pembrolizumab experienced responses to pembrolizumab rechallenge (6). There is no way to predict in which patient the rechallenge strategy is going to work. Therefore, we should maximize treatment benefits because our options afterwards are quite limited.
Sandip Patel, MD
UC San Diego Moores Cancer Center, San Diego, USA
However, to my mind, the most relevant point is that treatment duration is arbitrary and independent of disease biology. Neither the cancer nor the immune system perceive time in a calendar format. Treatment duration in clinical studies is usually just related to factors such as drug supply. At a population level, cut-offs make sense, but they do not necessarily inform clinical decisions. These need to be made individually because there are some patients who do not need indefinite therapy. One potential future avenue will be minimal residual disease-guided treatment duration. This approach has been applied successfully in the field of GIST, some sarcomas, breast cancer and chronic myeloid leukemia (CML). Some patients may require six months of therapy, some two years. In fact, many patients with CML are treated indefinitely. Taken together, prolonged treatment is a reasonable approach for patients without immune-related adverse events who are motivated to maximize benefit from immunotherapy.
This article is based on the debate by Dr. Giannis Mountzios and Dr. Sandip Patel from the ILCS 2024. Explore more on the topic by watching their full presentation below.
References
- Aggarwal S et al: Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunoth Cancer 2016; 4: 72
- Elassaiss-Schaap J et al: Using model-based “learn and confirm” to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacom System Pharmacol 2017; 6(1): 21-28
- Weber JS et al: Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 2008; 26(36): 5950-5956
- Miedema IHC et al: 89Zr-immuno-PET with immune checkpoint inhibitors: Measuring target engagement in healthy organs. Cancers (Basel) 2023; 15(23): 5546
- Rodriguez-Abreu D et al: Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol 2021; 32(7): 881-895
- Reck M et al: Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol 2021; 39(21): 2339-2349
- Garassino MC et al: Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-Year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol 2023; 41(11): 1992-1998
- Novello S et al: Pembrolizumab plus chemotherapy in squamous non–small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol 2023; 41(11): 1999-2006
- Waterhouse DM et al: Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: CheckMate 153. J Clin Oncol 2020; 38(33): 3863-3873
- Rousseau A et al: Impact of pembrolizumab treatment duration on overall survival and prognostic factors in advanced non-small cell lung cancer: a nationwide retrospective cohort study. Lancet Reg Health Eur 2024; 43: 100970
- Sun L et al: Association between duration of immunotherapy and overall survival in advanced non-small cell lung cancer. JAMA Oncol 2023; 9(8): 1075-1082
- Zalcman G et al: Nivolumab plus ipilimumab 6-months treatment versus continuation in patients with advanced non-small cell lung cancer: Results of the randomized IFCT-1701 phase III trial. Ann Oncol 2022; 33 (suppl_7): S448-S554
- Reck M et al: Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer 2024; 211: 114296
- Brahmer J et al: Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol 2023; 41(6): 1200-1212
- Herbst RS et al: Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non‒small-cell lung cancer in the KEYNOTE-010 study. J Clin Oncol 2020; 38(14): 1580-1590
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