Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.

Jänne, Pasi A.; Neal, Joel W.; Camidge, D. Ross; Spira, Alexander I.; Piotrowska, Zofia; Horn, Leora; Costa, Daniel B.; Tsao, Anne S.; Patel, Jyoti D.; Gadgeel, Shirish M.; Bazhenova, Lyudmila; Zhu, Viola W.; West, Howard; Vincent, Sylvie; Zhu, Ji‐Min; Li, Shuanglian; Riely, Gregory J.

doi:10.1200/jco.2019.37.15_suppl.9007

Cited by 55 publications

(25 citation statements)

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“…Early data for TAK‐788 in EGFR exon20ins NSCLC showed a confirmed overall response rate of 43%. Grade III adverse events have been observed in >50% of patients in trials of either inhibitor . The hope is that the benefit observed for patients with EGFR exon20ins NSCLC can translate to EGFR exon20ins UC, but this must be tested via UC‐focused clinical trials as lead by medical oncologists focusing on genitourinary cancers or via a basket trial with sufficient enrolment of UC to test this therapeutic hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

Madison¹,

Gupta

Elamin

et al. 2020

BJU International

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ObjectiveTo review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. Materials and MethodsTumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. ConclusionEGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFR exon20ins and ERBB2 exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

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Section: Discussionmentioning

confidence: 99%

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

Madison¹,

Gupta

Elamin

et al. 2020

BJU International

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“…In a phase I/II trial, the objective response rate associated with TAK-788 also has decreased over time, from an initially reported 54% to a confirmed rate of 43%. 153 Early evidence of clinical activity has been seen with the EGFR-cMET bispecific antibody, JNJ-372, in an ongoing phase I trial. 129…”

Section: Exon 20 Insertionsmentioning

confidence: 99%

Targeted Therapy for Non-Small Cell Lung Cancer

Noor

Cummings

Johnson

et al. 2020

Semin Respir Crit Care Med

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Lung cancer is a heterogeneous disease, and the availability of comprehensive genomic profiling has allowed for the characterization of its molecular subtypes. This has increased the ability to deliver “personalized medicines” by tailoring therapies to target driver mutations in a patient's cancer. The development of targeted therapies for non-small cell lung cancer (NSCLC) has helped define the era of precision medicine throughout oncology. This article aims to contextualize recent research and provide an updated summary of targeted therapies available for patients with NSCLC. With practitioners and clinical researchers in mind, we note standard of care therapies, important approvals, practice guidelines, and treatments in development. The first section discusses mutations in the epidermal growth factor receptor (EGFR) gene, and the second section examines rearrangements in the anaplastic lymphoma kinase (ALK) and ROS1 fusions. Finally, we explore the rarer molecular alterations in BRAF, RET, MET, HER2, and KRAS. Given the many available therapies, it is important to understand the molecular alterations in NSCLC, and how to target them.

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“…1,3,4,33,34 While the latter are sensitive to third-generation EGFR-TKIs, EGFR exon 20 insertions can be targeted with the specific inhibitor TAK-788. 35 Initial results from a phase I/II trial (NCT02716116) showed a disease control rate (DCR) of 89% with 54% of the patients achieving a partial response (confirmed + unconfirmed) and 35% stable disease. Overall, 23 of 24 evaluable patients (93%) showed a reduction in the tumor volume; side effects were consistent with other EGFR-TKIs.…”

Section: Egfr Mutations and Outcomes With Egfr-tkismentioning

confidence: 99%

“…Therefore, a phase III trial (n=318, 1:1 randomization) comparing TAK-788 with platinum/pemetrexed combination chemotherapy was initiated with enrolment starting in late 2019 (NCT04129502). 35…”

Section: Egfr Mutations and Outcomes With Egfr-tkismentioning

confidence: 99%

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

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Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

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Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.

Cited by 55 publications

References 0 publications

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

Targeted Therapy for Non-Small Cell Lung Cancer

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

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