Can we cure metastatic EGFR-mutated lung cancer today?

Ever since the availability of tyrosine kinase inhibitors (TKI) against the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and other oncoproteins with superior efficacy and tolerability than cytotoxic chemotherapy for non-small cell lung cancer (NSCLC), first priority of management has been the precise identification of patients able to benefit from targeted drugs (1). Upfront use of EGFR inhibitors has pushed the median overall survival (OS) for EGFR-mutant metastatic lung cancer beyond 3 years (2). However, the possibility and requisites for cure of these patients remain unclear.

In the this issue of Translational Cancer Research, Wan et al. describe a very interesting case of lung cancer with ongoing long-term benefit over 8 years under EGFR inhibitors and contribute valuable evidence about the potential circumstances of such extraordinarily favorable courses (3). Owing to the detailed profiling of this patient by the authors, several interesting characteristics can be noted: (I) the primary driver alteration was an EGFR exon 19 deletion (del19), which has been associated with higher TKI sensitivity, as well as longer progression-free (PFS) and OS than EGFR p.L858R or “rare” EGFR mutations (4); (II) female sex (5), Asian ethnicity (6), and secondary stage IV following relapse of an early-stage tumor after surgery (7) have all been described as favorable, as well; (III) she was a never-smoker, which is also linked to longer survival (8), possibly due to the correlation with a lower tumor mutational burden (9); (IV) she presented with brain-only oligometastatic disease, which is indicative of less aggressive NSCLC biology (10); (V) at the time of gefitinib failure in the first line, she developed oligoprogression in the brain, which is known to occur later and correlate with longer OS compared to diffuse disease progression in NSCLC under any systemic treatment, in particular when local ablative therapies are additionally applied (11,12); (VI) the authors managed to perform multiple rebiopsies and deliver 4 successive lines of treatment, which is an indication of very careful and close managements, since approximately 30–40% of patients are lost and die without subsequent systemic therapy after each disease progression in EGFR+ NSCLC according to retrospective studies (2). Simultaneous presence of multiple good prognostic features explains the long-lasting clinical benefit in the current patient despite the per se unfavorable brain involvement (4), and may help predict exceptional responses in other similar patients the future (Table 1). That being said, this case was diagnosed several years ago, in April 2014, which poses the important question: what else could have been done today?

One essential issue is the method and extent of molecular profiling: while the EGFR mutation in the described patient was detected using real-time PCR (ADx-ARMs) back in 2014 (3), combined DNA and RNA next-generation sequencing (NGS) is meanwhile the recommended standard at initial diagnosis of advanced NSCLC regardless of histology for the timely, i.e., within 10 working days, parallel testing of all potentially actionable genetic alterations (1,14). One special advantage from such a broader approach is the additional coverage of genes with prognostic and predictive importance, like TP53, the wild-type status of which has been linked to durable responses under EGFR and ALK inhibitors (4,15). While no TP53 sequencing was performed here, as TP53 was not included in the 23-gene NGS panel used in April 2022 (3), it is reasonable to assume that this particular patient with >62-month-long response to late-line osimertinib lacked TP53 mutations, since these are strongly associated with shorter PFS and OS in this situation, with a hazard ratio >2.5 compared to TP53 wild-type in retrospective analyses (16). One additional possibility to further refine patient stratification are longitudinal circulating tumor DNA (ctDNA) assays under treatment, as clearance under EGFR TKI (13) and/or undetectable ctDNA at the time of oligoprogression (17) are associated with better outcomes in oncogene-driven NSCLC (Table 1). In fact, the detectability of EGFR del19 in the last plasma analysis performed by the authors in April 2022, during the ongoing radiological response to osimertinib (3), suggests that the described patient is actually not cured, but destined to experience another disease progression, which highlights the need for additional and more potent therapies.

What can we offer today? Unfortunately, not much. The combination of osimertinib with bevacizumab given by the authors as fourth-line treatment for a “progressive” brain lesion under osimertinib may have facilitated a >40-month-long radiologic response here, but cannot be generally recommended: two randomized phase 2 trials have shown no benefit from the addition of bevacizumab to osimertinib, neither in the first-line setting, nor in T790M⁺ patients, despite the positive results of the erlotinib/bevacizumab and erlotinib/ramucirumab studies, as well as the preclinical evidence of VEGF induction by oncogenic signaling (18-20). Actually, it is quite possible that the growing lesion under osimertinib successfully treated by bevacizumab may in fact have been a manifestation of radionecrosis (RN), which is rare (1–2%), but possible after whole-brain radiotherapy and responds very well to angiogenics (21), contrary to what would be expected for osimertinib-resistant cancer cells. In case of further disease progression without actionable drivers, the first option would currently be the chemoimmunotherapy with carboplatin/paclitaxel/atezolizumab/bevacizumab (IMpower150 regime), which can achieve a response rate of approximately 80% and a median PFS of 10 months in TKI-resistant EGFR⁺ NSCLC patients (22). In the near future, recent progresses in deciphering the immunologic tumor microenvironment of EGFR+ NSCLC (23) may facilitate successful application of more effective, next-generation immunotherapies for these patients, such as multispecific antibodies and T-cell receptor transgenic T (TCR-T) cells (24,25), which currently hold a justified hope for the cure of lung cancer and other solid tumors (20).

Acknowledgments

Funding: This work was funded by the German Center for Lung Research (DZL).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2926/coif). The author declares research funding from AstraZeneca, Amgen, Merck, Novartis, Roche, and Takeda; speaker’s honoraria from AstraZeneca, Novartis, Pfizer, Roche, Takeda; support for attending meetings from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Janssen, Novartis, Takeda; and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer and Roche; all outside the submitted work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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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