Author of

• 36336

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  P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Targeted Therapy - Clinically Focused
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 36446

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    P76.90 - Molecular Characteristics of BRAF Mutations in EGFR Mutant NSCLC after Progression on EGFR TKIs and Response to Combination Targeted Therapy (ID 3653)

    00:00 - 00:00  |  Presenting Author(s): Wenfeng Fang
    • Abstract
    • Slides

    Introduction
    

    Large studies on molecular characteristics of BRAF mutations in EGFR-mutant NSCLC patients after progression on EGFR TKIs are limited. And how to overcome BRAF-induced resistance remains unknown. Herein, we analyzed the distribution of BRAF activating aberrations in EGFR mutated patients after progression on EGFR TKIs and evaluated their response to combined targeted inhibitors.

    Methods
    

    Next-generation sequencing (NGS) tests (Geneseeq) were performed in 1637 EGFR mutated NSCLC patients after resistance to EGFR TKIs, with 1074 patients receiving first-and/or second-generation EGFR TKIs and 563 patients receiving osimertinib. The emergence of BRAF aberrations covering BRAF missense mutations, BRAF fusions and copy number variations, as well as other resistant mechanisms were recorded. A real-world cohort with fourteen patients was collected to evaluate the clinical response to combined BRAF/MEK inhibitors and EGFR TKIs in NSCLC harboring both EGFR and BRAF mutations.

    Results
    

    BRAF mutations were identified in 71 (4.3%, 71/1637) EGFR-TKI treated NSCLC patients, among which 34% were BRAF V600E, 24% were copy number variations, 20% were non-BRAF V600E missense mutations and 14% were BRAF fusions. In patients treated with first-and/or second-generation TKIs, BARF mutations resulted in 3% of the resistant events while in osimertinib cohort, the proportion is 6.9%. As for EGFR-TKI resistant patients receiving combined BRAF/MEK inhibitors and EGFR TKIs, all patients with BRAF V600E achieved disease control (4 Partial response and 5 stable disease). None of 3 patients with non-BRAF V600E missense mutations achieved disease control. One patient with AGAP3-BRAF achieved stable disease after treatment with sorafenib and osimertinib. (Detailed information of responses was shown in Table 1)

    Conclusion
    

    BRAF mutations represented roughly 4.3% of EGFR mutant cases after progression on EGFR TKIs. Combination therapy of BRAF/MEK inhibitors and EGFR TKIs showed preliminary antitumor activity in EGFR-TKI treated patients with BRAF V600E. Combined Pan-RAF inhibitors like sorafenib with EGFR TKIs might exert tumor inhibitory effect in patients with BRAF fusion.

    Table 1. clinical characteristics and response to EGFR TKI with BRAF/MEK inhibitors in BRAF-mutated lung cancer patients after progression on EGFR TKIs. PR, partial response; SD, stable disease; PD, progressive disease; amp, amplification.

    Patient	Age	gender	Mutation before EGFR TKI	Previous EGFR TKIs	Mutation after progression	Combination therapy	Line of therapy	Best response
    1	66Y	Male	EGFR 19del/T790M	Osimertinib	EGF19del/T790M, BRAF V600E	Osimertinib +Dabrafenib + Trametinib	3	PR
    2	68Y	Female	EGFR L858R/T790M	Osimertinib	EGFR L858R, BRAF V600E	Osimertinib +Vemurafenib	3	PR
    3	56Y	Female	EGFR 19del/T790M	Osimertinib	EGFR 19del, BRAF V600E	Osimertinib +Vemurafenib	3	SD
    4	68Y	Female	EGFR 19del/T790M	Osimertinib	EGFR 19del, BRAF V600E	Icotinib +Vemurafenib	4	SD
    5	74Y	Male	EGFR L858R/L861Q	Icotinib	EGFR L858R/L861Q, BRAF V600E	Icotinib +Vemurafenib	2	SD
    6	84Y	Female	EGFR 19del	Erlotinib	EGFR 19del, BRAF V600E	Gefitinib + Vemurafenib	2	PR
    7	78Y	Female	EGFR L858R	Gefitinib	EGFR L858R/A871G, BRAF V600E	Erlotinib + Vemurafenib	4	PR
    8	76Y	Male	EGFR 19del/amp	Gefitinib	EGFR 19del/amp, BRAF V600E	Gefitinib + Dabrafenib	2	SD
    9	46Y	Female	EGFR L858R	Gefitinib	EGFR L858R/T790M, BRAF V600E	Osimertinib +Vemurafenib	2	SD
    10	57Y	Male	EGFR S768I/G719C/T790M	Osimertinib	EGFR S768I/G719C/T790M, BRAF K601E	Osimertinib + Trametinib	3	PD
    11	53Y	Female	EGFR 19del/T790M/amp	Osimertinib	EGFR 19del/T790M/amp, BRAF K601E	Osimertinib +Vemurafenib	3	PD
    12	65Y	Female	EGFR G719C/G719A	Icotinib	EGFR G719C/G719A, BRAF D469A	Icotinib +Vemurafenib	2	PD
    13	54Y	Male	EGFR 19del/T790M/amp	Osimertinib	EGFR 19del, AGAP3-BRAF	Osimertinib + Sorafenib	4	SD
    14	40Y	Male	EGFR 19del/T790M	Osimertinib	EGFR 19del, TRIM24-BRAF	Osimertinib + Vemurafenib	5	PD

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