Treatment in the index LOT was fragmented, suggesting a lack of an established standard of care after osimertinib discontinuation. Although approximately half of the patients who discontinued osimertinib received a platinum-based chemotherapy ± IO in the subsequent LOT, nearly one-quarter of patients were re-treated with EGFR TKI monotherapy or combination therapy, and more than one-third were treated with IO either alone or in combination. The use of platinum-based chemotherapy in this population is in line with NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®); however, a considerable number of patients were treated with platinum in combination with IO even though the benefit may be unclear. Given recent results from the CHECKMATE-722 and KEYNOTE-789 trials which showed no efficacy benefit when adding IO to chemotherapy in EGFR TKI-resistant patients, it is possible that these agents will be prescribed less frequently in the future [19, 20].

NCCN Guidelines® do suggest continuing or restarting EGFR TKIs beyond progression in some circumstances (i.e., if a flare phenomenon should occur upon discontinuation of these agents or continuing/restarting treatment with osimertinib for patients with progressive central nervous system disease). In our study, reutilization of EGFR TKIs as monotherapy after osimertinib discontinuation occurred in 16% (n = 21) of patients. Of these, six patients continued osimertinib after a gap in treatment, and 15 patients were treated with afatinib, erlotinib, or gefitinib.

Rechallenge with EGFR TKIs has been noted in published reports [21,22,23,24,25,26]. One review highlighted that several mutations promoting resistance to osimertinib remain sensitive to earlier-generation EGFR inhibitors, suggesting that rechallenging patients with these agents could be an effective approach [21]. Furthermore, due to their improved tolerability when compared with IO or cytotoxic therapies, retreatment with EGFR TKIs might also be considered [16, 27]. A few published case studies and small cohort studies have also touched upon rechallenging with EGFR TKIs, showing some potential as effective treatment [21, 23, 24]. However, rechallenge may also reflect a lack of alternative treatments in later LOTs as well as the limited knowledge of the optimal EGFR TKI sequence among patients with metastatic EGFR-mNSCLC [28]. Research is currently ongoing to further understand mechanisms of resistance to osimertinib, optimal treatment sequencing based on genomic testing at the time of disease progression, and the potential for improvement in patient outcomes [29].

To the best of our knowledge, only one previous study has examined real-world treatment patterns after discontinuation of osimertinib [15]. In a retrospective analysis using Flatiron electronic health records, Winfree et al. [15] reported findings from a cohort of patients with EGFR-mutated mNSCLC treated with first-line osimertinib between December 2017 and July 2019. Similar to our study, the majority of patients with a second-line treatment received platinum-based chemotherapy (± IO) (32%), and there was considerable use of EGFR TKI monotherapy (20%) and IO monotherapy (19%). The use of EGFR TKI and IO monotherapies following osimertinib suggests that clinicians and patients may prefer to try other treatment options first and delay the use of platinum chemotherapy for later LOTs where possible. Future studies are needed to further explore reasons for clinical decision-making, as these data are not available in the claims.

The duration of treatment in the LOT following osimertinib was short, underscoring the limited clinical benefit of existing treatment options for patients with EGFR TKI resistance. For nearly half of the patients who received a platinum-based chemotherapy ± IO, the mean duration of treatment was only 2.7 months. In the AURA3 trial, patients with a T790M mutation and disease advancement after first-line EGFR TKI were randomized to either osimertinib or platinum chemotherapy + pemetrexed [30]. The mean duration of treatment was 4.8 months for the chemotherapy arm. This difference may be attributable to the timing of treatment and the composition of the therapeutic regimens. In the AURA3 trial, treatment duration was assessed in the second LOT. In our study, 28.2% of patients had received three or more LOTs prior to the index LOT, suggesting more advanced disease in this population that may have reduced time on treatment. Further, patients in the AURA3 trial were treated with platinum + pemetrexed only, whereas in our study 40.3% of patients received IO in combination with a platinum-based chemotherapy regimen. It is possible that toxicities from this combination contributed to shorter time on treatment for some patients [30].

In the AURA3 trial, the proportion of patients with grade 3 or higher AEs was lower with osimertinib (23%) than with platinum-based chemotherapy (47%) [30]. Similarly, the overall rate of AEs associated with hospitalization in our study was considerably lower for patients treated with EGFR TKI monotherapy versus other treatments. Only nausea/vomiting and hepatic toxicity were identified as being associated with an inpatient stay among patients treated with EGFR TKI monotherapy. Although skin disorders and diarrhea are quite common in some EGFR TKI-treated patients, they may not necessitate visits to a tertiary care facility. The overall rates of AEs associated with hospitalization were similarly high across platinum chemotherapy ± IO and IO alone treatment groups. However, platinum chemotherapy ± IO appeared to have a less tolerable AE profile, including nausea/vomiting, hepatic and renal toxicities, and neutropenia, which may have contributed to longer inpatient stays and more frequent hospital readmissions versus IO alone. As IO therapy is associated with an increased risk of immune-related AEs, pneumonia/pneumonitis was more frequent in the group of patients treated with IO alone than in those treated with platinum chemotherapy, which had fewer patients receiving IO.

Similarly, we found that patients treated with platinum-based chemotherapy ± IO and/or IO alone had higher rates of all-cause HCRU than patients who received EGFR TKI monotherapy in the LOT after osimertinib discontinuation [13]. Although the proportions of patients with ≥ 1 IP admission and ≥ 1 ED visit were similar across platinum chemotherapy ± IO and IO alone treatment groups, patients who received platinum chemotherapy ± IO had numerically higher mean rates of IP admissions, IP days, and ED visits, suggesting more frequent and lengthier HCRU on a per-patient basis compared with those treated with IO alone. This finding is in line with previous studies reporting that IO was associated with lower HCRU and AEs compared with chemotherapy [31, 32].

Although current treatment options after progression on EGFR TKI therapy offer limited clinical benefit, promising new treatments are under investigation in this setting. HERTHENA-Lung02 is a phase III study comparing patritumab deruxtecan (an antibody–drug conjugate) with a platinum-based chemotherapy in patients with EGFR-mutated locally advanced or mNSCLC after progression on a third-generation EGFR TKI [33]. Likewise, MARIPOSA-2 is a phase III trial assessing the safety and efficacy of the EGFR-MET bispecific antibody amivantamab + platinum-based chemotherapy and amivantamab + lazertinib + platinum-based chemotherapy versus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC who progressed on or after osimertinib monotherapy [34]. These agents may offer improved treatment options for patients with EGFR TKI resistance.

This study has several strengths and limitations. Results from this study fill a gap in the literature by characterizing the subsequent LOT and real-world outcomes among patients with mNSCLC harboring an EGFR-sensitizing mutation who were previously treated with osimertinib monotherapy. The study was conducted using medical and pharmacy claims data from a patient sample representing commercial plans across diverse US geographic regions. For purposes of interpretation, it should be noted that this study examined the post-osimertinib LOT between November 2015 and September 2019; because osimertinib was initially approved to address first- and second-generation EGFR TKI resistance (November 2015) and then was subsequently approved for first-line treatment of EGFR mNSCLC (April 2018), patients included in the study may have used osimertinib as either first- or later-line treatment. Although claims data allow for a large and representative patient sample, detailed clinical information is not recorded. For example, because histology and biomarker information could not be identified via medical claims, patients treated with an EGFR TKI were assumed to have non-small cell histology and a common EGFR-sensitizing mutation. Further, reasons for treatment discontinuation were not available, and therefore it cannot be determined whether patients discontinued due to disease progression, tolerability issues, personal choice, or other reasons. AE rates may have been underestimated, as this study presented only those that were associated with hospital admissions. Due to the small sample size, results for specific treatment regimens should be interpreted with caution. Additionally, claims data are subject to inaccuracies in coding and may lead to misclassification of diagnoses, treatment, and outcomes. Moreover, complete mortality information is not available in claims data. In February of 2024, the Food and Drug Administration approved the use of first-line osimertinib combined with a platinum doublet based on improved progression-free survival versus osimertinib alone [35]. As this approval may change the current treatment paradigm, future studies are warranted to further characterize real-world treatment sequencing and outcomes among patients with EGFR TKI resistance.