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Case Reports
. 2024 Nov 22;6(3):100773.
doi: 10.1016/j.jtocrr.2024.100773. eCollection 2025 Mar.

Personalized Therapy in a Patient With EGFR-Mutated NSCLC Developing Sequential CCDC6-RET Fusion and BRAF V600E Mutation as Bypass Resistance Mechanisms

Arianna Marinello  1   2 , Claudia Parisi  1   3 , Damien Vasseur  4 , David Combarel  5 , Juliette Bihoreau  1 , Pernelle Lavaud  1 , Rémy Ezzedine  6 , Lodovica Zullo  1 , Luc Friboulet  7 , Gerard Zalcman  8 , Antoine Italiano  9 , Benjamin Besse  1   3 , Mihaela Aldea  1   3
Affiliations
Case Reports

Personalized Therapy in a Patient With EGFR-Mutated NSCLC Developing Sequential CCDC6-RET Fusion and BRAF V600E Mutation as Bypass Resistance Mechanisms

Arianna Marinello et al. JTO Clin Res Rep. .

Abstract

In this case report, we describe a case of sequential acquired CCDC6 -RET fusion and BRAF V600E mutation observed in a patient with EGFR-mutated NSCLC treated with osimertinib and with combined selpercatinib and osimertinib. The discovery of genomic resistance mechanisms was facilitated by serial liquid and tissue biopsies and molecular tumor board discussion. After the identification of CCDC6-RET fusion, the patient received a combination of selpercatinib and osimertinib with prolonged benefit and manageable toxicity. When a novel BRAF V600E mutation was detected at progression, the molecular tumor board suggested the administration of triple therapy, adding trametinib (anti-MEK). Nevertheless, treatment was discontinued for toxicity, highlighting the challenges of using multiple drug combinations to address complex resistance.

Keywords: BRAF V600E; Case report; EGFR-mutated NSCLC; RET fusion; Selpercatinib; Trametinib.

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Conflict of interest statement

Dr. Lavaud declares receiving grants from Servier, consulting fees from Astellas, Astra Zeneca, Sanofi, and BMS, and support for attending meetings/travels from IPSEN, JANSSEN, Astellas, Pfizer, Chugai, and Sanofi. Dr. Friboulet declares receiving grants from Debiopharm, Incyte, Relay Therapeutics, Sanofi, and Nuvalent. Dr. Zalcman declares receiving honoraria from AstraZeneca, Inventiva, BMS, and Pfizer, and support for attending meetings/travels from Roche, BMS, Pfizer, Abbvie, Pharmamar, and AstraZeneca. Dr. Italiano declares receiving grants from Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono, consulting fees from Roche, Daiichi Sankyo, Immune Design, Epizyme, Bayer, Lilly, honoraria from Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche, IPSEN, other intellectual property interests from BMS. Dr. Besse declares receiving funding for sponsored Research from Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, Nerviano, GSK, Pfizer, Roche-Genentech, Lilly, OSE Pharma, MSD, Celgene, Stemcentrx, Ignyta, Abbvie, Loxo Oncology, AstraZeneca, and Blueprint Medicines. Dr. Aldea declares receiving grants from Amgen, AstraZeneca, and Sandoz, and consulting fees from Viatris. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Timeline of molecular alterations identified through tissue and liquid biopsies, along with the corresponding therapies administered. Molecular findings from serial biopsies at various time points are displayed at the top, while systemic therapies received by the patient are shown at the bottom. Molecular data from tissue biopsies are indicated in green, and data from liquid biopsies are shown in red. Panels: ∗in-house DNA-based panel; ∗∗FoundationOne Liquid; ∗∗∗WES/RNAseq. RNAseq, RNA sequencing; WES, whole exome sequencing.
Figure 2
Figure 2
Hepatic function and abdominal computed tomography showing response to treatment. (A) Changes in ALP and GGT; (B) changes in ASAT and ALAT concentrations over time after the start of osimertinib plus selpercatinib; (C) Abdominal computed tomography with contrast enhancement performed before starting osimertinib plus selpercatinib; (D) Abdominal computer tomography with contrast enhancement after two months of treatment. ALAT, alanine transaminase; ALP, alkaline phosphatase; ASAT, aspartate transaminase; C, cycle; D, day; GGT, gamma-GT.
See this image and copyright information in PMC

References

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