Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study

Cho, B.C.; Cheng, Ying; Zhou, Changdong; Ohe, Y.; Imamura, Fumio; Lin, Meng C.; Majem, Margarita; Shah, Riyaz; Rukazenkov, Yuri; Todd, Alexander; Markovets, Aleksandra; Barrett, Carl; Chmielecki, Juliann; Gray, Jhanelle E.; Ramalingam, S.

doi:10.1093/annonc/mdy483.007

Cited by 15 publications

(15 citation statements)

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“…EGFR C797S mutation was the most frequent resistance in EGFR-dependent resistance, accounting for 14-29% in second-line osimertinib [7,11,44,45]. When osimertinib is used as the first-line therapy, the frequency of C797S decreases but still exists in 0-7% of patients [46,47]. C797S, where the serine is substituted for cysteine at codon 797 within the ATPbinding site, results in the loss of the covalent bond between osimertinib and the conformational change, which is classified into EGFR-mutant/C797S, triple EGFR-mutant/T790M/C797S in trans, and in cis [10,44].…”

Section: Epidermal Growth Factor Receptor-dependent Resistancementioning

confidence: 99%

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Zeng

Tian

et al. 2021

Current Opinion in Oncology

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Purpose of reviewThis review aims to introduce the resistance mechanisms to osimertinib, discuss the therapeutic strategies, and make clinical updates in overcoming resistance to osimertinib. Recent findingsOsimertinib has shown favorable efficacy on second-line and first-line treatments in EGFR-mutant advanced nonsmall cell lung cancer (NSCLC). However, the presence of primary and acquired resistance to osimertinib restricts its clinical benefits. The primary resistance mainly consists of BIM deletion polymorphism and EGFR exon 20 insertions. Meanwhile, the heterogeneous mechanisms of acquired resistance include EGFR-dependent (on-target) and EGFR-independent (off-target) mechanisms. EGFR C797S mutation, MET amplification, HER2 amplification, and small cell lung cancer transformation were identified as frequent resistance mechanisms. Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. With the results of completed and on-going clinical trials, the emerging therapeutic strategies of postosimertinib progression are summarized.

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Section: Epidermal Growth Factor Receptor-dependent Resistancementioning

confidence: 99%

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Zeng

Tian

et al. 2021

Current Opinion in Oncology

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“…Amplification of MET and subsequent overexpression of the MET protein promotes resistance to TKIs by driving HER3-dependent activation of PI3K [44]. MET amplification is reported in approximately 5% of tumors resistant to first-line erlotinib, gefitinib, or afatinib, and approximately 15% to 20% of osimertinibresistant tumors [21,90,91], making it an attractive target for potential therapies. Several small-molecule MET inhibitors are being developed for approval in NSCLC; 2 approved agents include capmatinib and tepotinib, while tivantinib and savolitinib are still in development.…”

Section: Met-targeted Therapiesmentioning

confidence: 99%

“…HER2-amplification is observed in approximately 10% of tumors that progress after first-line erlotinib or gefitinib; less so following osimertinib resistance [21,90,91]. In addition, HER2 mutations are oncogenic drivers in NSCLC [100].…”

Section: Her2-targeted Therapiesmentioning

confidence: 99%

Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies

et al. 2022

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“…Unfortunately, resistance to osimertinib also develops through further acquired mutations in EGFR ( 61 ). Analysis of patient plasma samples collected in clinical trials that investigated osimertinib as a first-line ( 61 , 67 ) and a second-line therapy after failure of other first-line TKIs ( 67 ) identified an EGFR C797S mutation, which affects the critical site for osimertinib binding, in 7% and 14% of samples, respectively. The C797S mutation frequently occurs in the same allele as the T790M mutation, thus rendering osimertinib completely inactive ( 64 ).…”

Section: Therapeutic Agents Inhibiting Egfr Activation and Signalingmentioning

confidence: 99%

Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling

2022

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The epidermal growth factor receptor (EGFR) is a key player in the normal tissue physiology and the pathology of cancer. Therapeutic approaches have now been developed to target oncogenic genetic aberrations of EGFR, found in a subset of tumors, and to take advantage of overexpression of EGFR in tumors. The development of small-molecule inhibitors and anti-EGFR antibodies targeting EGFR activation have resulted in effective but limited treatment options for patients with mutated or wild-type EGFR-expressing cancers, while therapeutic approaches that deploy effectors of the adaptive or innate immune system are still undergoing development. This review discusses EGFR-targeting therapies acting through distinct molecular mechanisms to destroy EGFR-expressing cancer cells. The focus is on the successes and limitations of therapies targeting the activation of EGFR versus those that exploit the cytotoxic T cells and innate immune cells to target EGFR-expressing cancer cells. Moreover, we discuss alternative approaches that may have the potential to overcome limitations of current therapies; in particular the innate cell engagers are discussed. Furthermore, this review highlights the potential to combine innate cell engagers with immunotherapies, to maximize their effectiveness, or with unspecific cell therapies, to convert them into tumor-specific agents.

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Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study

Cited by 15 publications

References 0 publications

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies

Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling

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