How to navigate an increasingly heterogeneous spectrum of resistance mechanisms in oncogene driven non-small cell lung cancer?

Osimertinib is currently standard of care for metastasized non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation (1). Recently, following the encouraging overall survival (OS) results of the ADAURA trial, osimertinib has moved into the adjuvant setting, as a 3-year treatment after complete surgical resection of a stage IB to IIIA NSCLC harboring an EGFR exon 21 L858R or EGFR exon 19 deletion (2). In metastatic disease, the occurrence of resistance to osimertinib is a certainty. Mutational analysis of tissue of patients in the FLAURA trial demonstrated a marked difference in resistance patterns that occurred under osimertinib versus earlier generation EGFR tyrosine kinase inhibitor (TKI). Whereas so-called on target or EGFR-dependent resistance mechanisms occurred in more than half of patients treated with early generation EGFR TKI, patients who were treated with osimertinib developed a more heterogeneous spectrum of resistance mechanisms including on and off target mechanisms and even histologic transformation (3). It is of interest whether the expansion of osimertinib into early-stage disease will have an effect on the resistance mechanisms that we encounter. At the time of writing this editorial, these analyses of the ADAURA trial have not yet been published.

With such a diverse range of possible resistance mechanisms, a one size fits all treatment approach is out of the question, but gathering randomized evidence on treatment is challenging. The relative rarity of driver mutations also hinders progress in this field. Re-biopsy at time of disease progression is paramount, and should consist of at least tissue, as with liquid biopsy alone, histologic transformation can be missed. Acquired resistance in the form of histologic transformation occurs in 4–15% of EGFR-mutated NSCLC treated with TKIs (4). Liquid biopsy is also not available/standardized in many countries (5).

Receptor tyrosine kinase (RTK) fusions constitute a possible escape mechanism for EGFR-mutated NSCLC treated with EGFR TKI. The development of a rearranged during transfection (RET) fusion as a way of acquired resistance was first reported in 2015 and this alteration is the most commonly seen RTK fusion in EGFR TKI resistant disease (6,7). Treatment of EGFR-mutated disease with an acquired RET mutation using combined osimertinib/pralsetinib, the other Food and Drug Administration (FDA) approved RET TKI, has been described as well, although not yet in such a large series (8).

This case series of Rotow et al. retrospectively analyzed combined osimertinib/selpercatinib treatment for patients with classic EGFR mutations that progressed on osimertinib and developed a RET fusion. Safety and efficacy was investigated, as well as the molecular findings prior to treatment with the experimental combination and after disease progression (9).

This case series revealed a number of interesting molecular findings, one of them being the predominance of EGFR exon 19 deletions in this cohort (12 patients, 86%). To our knowledge, an association between EGFR exon 19 deletions and the development of off target resistance mechanisms on osimertinib treatment, let alone RET fusions, has not been established. EGFR exon 19 deletions are known to be a heterogeneous group however, and differences in resistance patterns have been found between the different genotypes (10). It could be warranted to monitor patients with EGFR exon 19 deletions more closely for this type of acquired resistance. Compiling these resistance mechanisms in a database is of paramount importance to guide future treatment and follow-up.

In this case series, either next-generation sequencing (NGS) was performed on tissue, or plasma cell-free DNA was sequenced at baseline. At progression, there was only one out of 8 patients who had both tissue and plasma analyzed, and there was a discrepancy in the findings, with loss of the original RET fusion in tissue but still present in plasma. This incongruity underscores the importance of not relying solely on liquid biopsy results.

Another marked finding was that whereas KIF5B is the most common fusion partner in de novo RET fusions in NSCLC, in this cohort the KIF5B-RET fusion only occurred in two patients (14%) (11). This discrepancy supports the Lamarckian hypothesis, that states that cells undergo transformation as a result of treatment, as opposed to the Darwinian theory that argues that therapy resistant clones are selected under therapeutic pressure, and were thus already present at diagnosis (12).

The patients in this cohort were treated with standard dose osimertinib and reduced dose selpercatinib, in an effort to minimize toxicity. These drugs are generally well tolerated in monotherapy and the combination of osimertinib and selpercatinib did not result in treatment related serious adverse events. This is highly encouraging. However, recently awareness has been raised about the invalidating effect of even mild toxicities to TKIs (13,14). Combining TKIs, even selectively, will undoubtedly lead to accumulated adverse events which could impair quality of life. Dose reduction to mitigate toxicity on the other hand, might lead to decreased RTK inhibition, as was seen in this case with one patient developing a RET gatekeeper mutation as acquired resistance to the experimental combination. Publication of datasets such as these, as well as case evidence is vital not only from an efficacy standpoint but also with regards to safety, as in the future, combined TKI treatment will likely become more common (15).

Combined osimertinib and selpercatinib treatment proved to be efficacious in this cohort, with a disease control rate of 83% [95% confidence interval (CI): 55–95%]. Median duration of treatment was 10.6 months [95% CI: 7.9–not reached (NR)] in patients who showed an objective response (6 out of 14). At progression, rebiopsy results were available for 6 out of 8 patients. The mutational analysis of these samples showed a heterogeneous spectrum of new resistance mechanisms, both on and off target, both in EGFR and RET. A combination of new resistance mechanisms was seen in all but one of the six patients.

In this dataset, selpercatinib was provided through compassionate use protocols. It is important to underscore the necessity for such programs, as experimental combinations such as the one used here, would not be feasible without them. Similar datasets, also making use of compassionate use/expanded access programs have been reported in EGFR-mutated, osimertinib resistant disease harboring a mesenchymal-epithelial transition (MET) amplification, for patients that were ineligible for trial (16). The ongoing ORCHARD trial is a phase 2 study in which patients who progress on osimertinib will be treated depending on their resistance mechanism, with either a targeted osimertinib/TKI combination, a non-targeted EGFR TKI or chemotherapy approach, or lastly standard of care treatment (NCT03944772). Hopefully trials such as these, combined with datasets and case evidence, could make targeted treatments more available for off label use in this setting.

In summary, both systematic data collection and reporting of these rare cases, as well as improved off-label availability of targeted treatments, are required to overcome the difficulties we currently face in treating these complex resistance patterns.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-35/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-35/coif). P.V.S. received consulting fees and honoraria for lectures from AstraZeneca, Janssen (institutional fees), BMS, MSD and Roche (personal fees). He is president of IASLC (International Association for the Study of Lung Cancer) from 2023 to 2025 and treasurer of BACTS (Belgian Association for Cardiothoracic Surgery), both unpaid positions. The other author has 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.

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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