Response to the Combination of Osimertinib and Trametinib in a Patient With EGFR-Mutant NSCLC Harboring an Acquired BRAF Fusion

Dagogo‐Jack, Ibiayi; Piotrowska, Zofia; Cobb, Rosemary; Banwait, Mandeep K.; Lennerz, Jochen K.; Hata, Aaron N.; Digumarthy, Subba R.; Sequist, Lecia V.

doi:10.1016/j.jtho.2019.05.046

Cited by 30 publications

(13 citation statements)

References 10 publications

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“…Our studies and others have demonstrated that targeting MEK/ERK signaling through either MEK or ERK inhibition can achieve impressive effects in overcoming acquired resistance to osimertinib in different preclinical models 8‐12 . A clinical case study reported that an osimertinib‐resistant patient with NSCLC with a B‐Raf mutation responded to the treatment with the osimertinib and trametinib combination 13 . Moreover, MEK inhibition using trametinib combined with WZ4002, another third‐generation EGFR TKI, was shown to delay the emergence of acquired resistance to WZ4002 in WZ4002‐sensitive models 14 .…”

Section: Introductionmentioning

confidence: 70%

MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor–mutant lung cancers

Yao

Shi

et al. 2020

Cancer

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BACKGROUND: The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib. METHODS: Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo. RESULTS: Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo. CONCLUSIONS: These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC.

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Section: Introductionmentioning

confidence: 70%

MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor–mutant lung cancers

Yao

Shi

et al. 2020

Cancer

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“…According to the authors, this reduced dose was prescribed owing to a grade 2 pyrexia, nausea, and vomiting under higher dabrafenib and trametinib doses. Dagogo-Jack and colleagues 19 also described a successful case of combined EGFR/MAP kinase pathway blockade with osimertinib 80 mg OD and trametinib 1 mg OD; as treatment-related AEs, their patient experienced grade 2 diarrhea and fatigue, along with grade 1 rash and gastrointestinal bleeding. Nevertheless, it is worth highlighting the rapid clinical improvement, the remarkable radiologically confirmed objective response, as well as the good tolerance observed in this case even using only half standard dose of dabrafenib and trametinib approved for NSCLCs harboring BRAF V600E mutations.…”

Section: Discussionmentioning

confidence: 99%

“…BRAF mutations and fusions (i.e. AGK-BRAF, ESYT2-BRAF) have recently emerged as additional mechanisms of AR to thirdgeneration EGFR TKI 2,[18][19][20] . Studies demonstrating the efficacy of concurrent inhibition of EGFR and BRAF 3 or MEK 21 in pre-clinical models have raised clinicians' expectations about overcoming AR by combining TT.…”

Section: Introductionmentioning

confidence: 99%

“…Studies demonstrating the efficacy of concurrent inhibition of EGFR and BRAF 3 or MEK 21 in pre-clinical models have raised clinicians' expectations about overcoming AR by combining TT. Nevertheless, reports of successful combinations of TT for patients harboring BRAF-driven AR to osimertinib are very limited 19,[22][23][24] and no prospective data regarding efficacy and safety of BRAF/MEK/EGFR concurrent inhibition are available, with chemotherapy-based regimens remaining the treatment of choice in this unfavorable scenario. Similarly, PIK3CA mutations may also mediate AR to second-line osimertinib in 4-11%, but no clinical reports suggesting potential benefits of blocking these alterations in NSCLC are available 6,9,[25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

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Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient

et al. 2021

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The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.

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“…In agreement with the preclinical findings, a clinical case study reported that an osimertinib-resistant patient with NSCLC carrying an EGFR 19del mutation and a B-RAF fusion (AGK-BRAF) partially responded to the combination of osimertinib and trametinib during a 5-month treatment period. 46 An NSCLC patient harboring EGFR L858R, T790M and B-RAF V600E mutations that received treatment of osimertinib and dabrafenib (a B-Raf inhibitor) plus trametinib showed significantly improved clinical symptoms after 3 weeks and could stay in the outpatient department (recovery from ECOG PS of 3 to 1). All treatment-related adverse events, including a grade II rash and decreased appetite, were tolerable.…”

Section: Introductionmentioning

confidence: 99%

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Yu¹,

Zhao²,

Vallega³

et al. 2021

LCTT

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Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.

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Response to the Combination of Osimertinib and Trametinib in a Patient With EGFR-Mutant NSCLC Harboring an Acquired BRAF Fusion

Abstract: Chiu C-H. Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.

Cited by 30 publications

References 10 publications

MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor–mutant lung cancers

MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor–mutant lung cancers

Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

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