How should clinicians manage metastatic non-small cell lung cancer patients with BRAF non-V600E mutations?

In the current era of broad molecular testing clinical management of non-small cell lung cancer (NSCLC) patients with BRAF non-V600E mutations may be a challenge as no effective targeted therapies are available. Abuali and colleagues have successfully tried to create a handy oversight of treatment approaches together with highlighting several distinctions between NSCLC with BRAF V6000E and BRAF non-V600E (1).

All BRAF mutations in NSCLC are estimated to 2–4% and the incidence of BRAF non-V600E mutations is higher than BRAF V600E (2,3). Some distinctions between BRAF V600E and BRAF non-V600E have been determined leading to develop three classes of BRAF mutations defined by kinase activity, potency to dimerization and depending on RAS-signaling. Basically, class I, II and III are corresponding to different BRAF non-V600E mutations, precluding only BRAF V600E mutation in class I. However, BRAF non-V600E seems to be a heterogenous disease with a lot of undetermined mutational variants, including also variants of unknown significance (VUS) (4). BRAF non-V600E mutations are rare coexisting with other mutations like PIK3A, KRAS or TP53 (5). BRAF V600E mutations, however, may emerge as an acquired tyrosine kinase receptor (TKI)-resistance mechanism in patients with oncogene-addicted NSCLC, while acquired BRAF non-V600E are reported sporadically (6-8).

As the value for clinical prognostication of BRAF mutations is not established, we can practically use the distinction between BRAF V600E and BRAF non-V600E taking possibility of targeted treatment for BRAF V600E as a proxy for better outcome. However, median time-to-treatment-failure with BRAF-targeting agents seems to be shorter as compared to approved targeted therapy of other oncogenic drivers. NSCLC patients with BRAF non-V600E are prone to get poorer outcome than the patients with BRAF V600E, but some BRAF non-V600E variants may also respond to Vemurafenib or Dabrafenib/Trametinib or Sorafenib. Abuali et al. also discuss the role of check point inhibitors (CPIs) and show that patients with BRAF non-V600E are prone to respond slightly better to CPIs than the patients with BRAF V600E. Furthermore, class I appear to be less susceptible to immunotherapy than BRAF class II/III mutations. Regarding effect of chemotherapy for the whole BRAF NSCLC population, the better outcome is observed in BRAF-wild type NSCLC, and BRAF non-V600E NSCLC patients seem to respond slightly better than for BRAF V600E NSCLC patients.

Reassuming, the keynote of this article is to enable BRAF non-V600E NSCLC patients for early enrollment into currently ongoing trials, followed by standard immunotherapy with or without chemotherapy according to guidelines for non-oncogene-addicted NSCLC. Every BRAF non-V600E variant should be carefully assessed to find a feasible option for targeted therapy in second line or further. Despite of the fact that many aspects of BRAF non-V600E NSCLC remain unclear, we can use this compact review to get an idea how to manage this group of patients before clinical trials reveal effective treatment options.

Acknowledgments

Funding: None.

Footnote

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

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://pcm.amegroups.com/article/view/10.21037/pcm-22-24/coif). The author reports receiving honoraria from Takeda, Amgen, Roche, Astra Zeneca, and Novartis in the last 36 months for lectures and presentations, and from Pfizer for advisory board; support from MSD for attending IASLC WCLC 2022, Vienna, Austria, September 6-9. 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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