Time toxicity in previously untreated metastatic or unresectable epidermal growth factor receptor-mutant non-small cell lung cancer: a clinical practice review

Introduction

Globally, lung cancer is the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) being the most common type of lung cancer (1,2). Many newer therapeutics have been available for patients with NSCLC, specifically emerging targeted therapy options for patients with key oncogenic driver mutations such as epidermal growth factor receptor (EGFR) mutations. For untreated locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation, osimertinib, an oral EGFR tyrosine kinase inhibitor (TKI), has been the standard of care for many years up until 2023 with the Food and Drug Administration (FDA) approval of amivantamab plus lazertinib, a combination regimen of an EGFR-MET bispecific antibody and EGFR-TKI, respectively, and osimertinib plus chemotherapy (3-5).

Overall, while these developments regarding single-agent EGFR-TKIs are exciting and likely to benefit survival, they have also led to conversations about health-related quality of life (HRQOL) and the toxicities of these treatment regimens. This is especially true since osimertinib has been considered a model TKI, which is relatively safe and tolerable to patients. Currently, three options are available for the frontline treatment of metastatic NSCLC with classical EGFR mutations. For patients who need aggressive management, the choice between osimertinib-chemotherapy or amivantamab-lazertinib is still unclear.

Among recent models and estimates of HRQOL, time toxicity is a concept that focuses on healthcare-related toxicity and adverse events. In addition to conventional toxicity, we believe that the idea of time toxicity should be incorporated into conversations with patients and their families about the benefits and risks of receiving palliative-intent treatment. Time toxicity, or treatment-related time toxicity, refers to the contact with healthcare required due to treatment schedules, adverse events/effects (AEs) of treatments, including additional clinic visits or hospitalizations, and monitoring parameters, including laboratory testing and images (6,7). Though there is a strong emphasis on grades and types of AEs in arising and existing treatment regimens, toxicities such as time and financial toxicity are seldom considered.

Here, we estimate the time toxicity of the three approved regimens for patients with unresectable or metastatic NSCLC with classical EGFR mutations. This study aims to calculate the healthcare contact time spent on these targeted therapies to measure time toxicity.

Methods

The trial protocols were analyzed in detail. To calculate the time toxicity of the frontline options for locally advanced, metastatic EGFR-mutant NSCLC, we analyzed the phase III clinical trials- FLAURA (NCT02296125), FLAURA2 (NCT04035486), and MARIPOSA (NCT04487080). The time cutoffs for analysis were the median duration of treatment (DOT) in each trial. Time toxicity was methodologically estimated by estimating hospitalization days by assessing the time invested in healthcare-related visits and grade 3+ treatment-associated AEs. Healthcare contact days were calculated using descriptive statistics, and the days attributed to AEs from each trial were incorporated into the final estimation of time toxicity.

Data from each published trial, including study design, population characteristics, treatment schedules, number of outpatient clinic visit frequency, surveillance imaging and laboratory schedules, treatment exposure duration, survival outcomes, and AE incidence and grades, were extracted from the respective study protocols. Two authors independently collected and calculated data using the predefined rubrics to minimize the observer, information, and misclassification bias. Based on trial protocols, a standardized point system was assigned for every 30 minutes invested in treatment-related health care visits: 1 point was assigned for every clinic visit for history and physical examinations (H&P), baseline and interval imaging such as computed tomography (CT) scans or magnetic resonance imaging (MRI) of the brain for tumor assessment and laboratory tests. The scoring system for treatment administration time was formulated based on the infusion time in the drugs’ FDA (the Federal Drug and Administration) label and as stated in trial protocols. No infusion time was used for oral options like osimertinib and lazertinib.

AEs described as “serious adverse events” in published trial data and seen in more than 1% of patients were analyzed to calculate time toxicity from AEs. Coronavirus disease 2019 (COVID-19) as an AE was removed from the calculation. The National Inpatient Sample (NIS) database (2016–2021), a publicly available resource from the Agency for Healthcare Research and Quality (AHRQ), was used to calculate the average hospital length of stay (LOS) for these AEs, specifically in NSCLC patients. Each AE’s average LOS (in days) was multiplied by its incidence in the respective clinical trial to quantify its contribution to time toxicity.

Results

As of the time of writing the manuscript, overall survival from FLAURA2 and MARIPOSA was unavailable, so we used progression-free survival (PFS) as the survival metric to compare with the time toxicity of each regimen. The median PFS in the osimertinib arm between FLAURA, FLAURA2, and MARIPOSA was similar. The estimated total time toxicity, based on time spent in the healthcare setting and average inpatient stay from serious AEs, was calculated as 1.03 days for the osimertinib-only group, 3.635 days for the osimertinib combined with platinum-based chemotherapy and pemetrexed group, and 6.425 days for the amivantamab plus lazertinib group (see Figure 1). Details of the calculation can be seen in Appendix 1.

Figure 1 Progression-free survival and time toxicity across regimens. (A) Comparison of median progression-free survival data in months; (B) comparison of total calculated time toxicity in days. FLAURA: the osimertinib-only group; FLAURA2: the osimertinib plus chemotherapy group; MARIPOSA: the amivantamab plus lazertinib group.

Discussion

Our study demonstrates a way to calculate time toxicity in cancer patients that includes time spent in healthcare settings due to the administration of drugs and safety around them. In addition, we include an estimate of the time that could be added from the toxicity of the drug. This method of time toxicity can be used to inform patients of the time commitment from a trial, especially in the case of EGFR-mutated NSCLC, where multiple frontline options exist.

In our estimate, amivantamab plus lazertinib had the highest time toxicity of 2.79 days longer when compared to osimertinib plus platinum-based chemotherapy. This information might be necessary for patients to make decisions. Still, it informs that the added time of more extended amivantamab infusion does not add an immense amount of time toxicity to the patient’s treatment journey. Since the added time was mainly due to the need for amivantamab infusion, and as this space is currently evolving rapidly, it is worth noting that the amivantamab plus lazertinib combination might decrease their time toxicity with the availability of subcutaneous amivantamab. PALOMA-3 showed the efficacy of subcutaneous amivantamab being equivalent and much safer compared to intravenous formulation, which would most likely alter the toxicity associated with the amivantamab-lazertinib combination and decrease the infusion time for the drug (8).

We believe we are the first manuscript to propose this framework to calculate time toxicity until this metric is prospectively captured in clinical trials, and this variable will aid patients, especially in the metastatic setting, where there is a growing focus on QOL and HRQOL, especially given the palliative intent of treatments. Further, recent literature has highlighted the concern for time toxicity in various malignancies, including NSCLC—for example, Gupta et al., in a cohort study of patients with stage IV NSCLC, demonstrated that patients spent 1 in 3 days with healthcare contact, highlighting the significant time toxicity patients suffered as a result of treatments (9). In another cohort study of patients with newly diagnosed stage IV lung cancer, including NSCLC, patients were seen to spend about 22% of healthcare contact days of their days alive (10). Thus, time toxicity is a key factor that should be incorporated into guiding clinicians in choosing specific treatment regimens.

While we emphasize the importance of a metric like time toxicity calculated by us, the limitation here is that given the novelty of these trials and the lack of complete, mature overall survival data, the comparison of time toxicity is limited. In addition, we did not have lengths of hospitalization for AEs; as such, the estimated time toxicity arising from AEs was generalized from available data from the NIS.

Overall, the estimates for time toxicity are likely conservative given that there is expected underreported time toxicity to the patients and their caregivers from individual treatment outcomes and AEs, clinical factors including pre-medications and clinic logistics, including transportation, additional clinic visits, and outpatient management of AEs leading to time toxicity while at home.

Conclusions

As we await the overall survival results of the studies FLAURA, FLAURA2, and MARIPOSA—particularly with the potential positive overall survival findings in MARIPOSA—further investigation into time toxicity compared to regimens based on their differences in overall survival is warranted. Additionally, while our study assessed the experimental arms of each trial, it is encouraged to evaluate the control arms of the trials and to compare time toxicity differences within each study.

Our study provides several ways to address the time toxicity of the three FDA-approved regimes for NSCLC with EGFR mutation, which patients can discuss as they make their choices. The results demonstrate the need to weigh time toxicity arising from treatment schedules and time toxicity from AEs against the survival benefits associated with each treatment regimen, especially given the evolution of treatment regimens and supportive care offered after the trials were conducted.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-720/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-720/coif). A.D. reports consulting/advisory roles with Sanofi, Amgen, Foundation Medicine, AstraZeneca, Janssen Oncology, Merus, AbbVie, Catalyst Pharmaceuticals, Merck, Eli Lilly, Daiichi Sankyo, Regeneron, and Boehringer Ingelheim, and has received funding support from the Lung Cancer Research Foundation, LUNGevity Foundation, Novellia, and the Robert Winn Career Development Grant. E.C. has served in an advisory role for MDoutlook, and received research funding from Merck Sharp & Dohme LLC, G1 Therapeutics, Ipsen Bioscience Inc., Taiho Oncology, and Jazz Pharmaceuticals, accommodations from Daiichi Sankyo/AstraZeneca, and honorarium from Horizon CME. R.T. reports consulting fees from Catalyst Pharmaceuticals, Nuvation, Pfizer, Johnson & Johnson/Janssen, and Bristol Myers Squibb, honoraria from MJH Life Sciences, and support for attending meetings and/or travel from Black Diamond Therapeutics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ethical approval is not applicable as the study did not involve humans or animals directly.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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