A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib

Camidge, D. Ross; Morán, Teresa; Demedts, Ingel; Grosch, Heidrun; Mileham, Kathryn F.; Molina, Julian R.; Juan, Óscar; Bepler, Gerold; Goldman, Jonathan W.; Park, Keunchil; Wallin, Johan; Wijayawardana, Sameera R.; Wang, Xuejing Aimee; Wacheck, Volker; Smit, Egbert F.

doi:10.1016/j.cllc.2022.03.003

Cited by 16 publications

(15 citation statements)

References 39 publications

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“…Reduced MCL1 and BCL-XL expression predict for greater levels of mitochondrial dysfunction which also cannot be a survival mechanism. In addition to ERBB receptors, other receptor tyrosine kinases, such as c-MET are known to be evolutionary resistance mechanisms against drugs that target ERBB receptors [16,17]. However, neither c-MET, c-KIT nor PDGFRβ became activated after exposure to neratinib and pemetrexed.…”

Section: Discussionmentioning

confidence: 99%

Cellular responses after (neratinib plus pemetrexed) exposure in NSCLC cells

Booth,

Poklepovic,

Hancock

et al. 2023

Anti-Cancer Drugs

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We previously demonstrated that neratinib interacted with pemetrexed to kill non-small cell lung cancer (NSCLC) cells. From developing other drug combinations, we observed that several days following exposure, cells activated survival mechanisms to counteract drug toxicity. The present studies attempted to define mechanisms that evolve to reduce the efficacy of neratinib and pemetrexed. Neratinib and pemetrexed synergized to kill NSCLC cells expressing wild-type RAS proteins, mutant KRAS (G12S; Q61H; G12A and G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M and exon 19 deletion). Neratinib and pemetrexed interacted in a greater than additive fashion to kill after 24 h, and after a further 24 h culture in the absence of drugs. Mutant KRAS G12V was more cytoprotective than either activated MEK1 or activated AKT. Knockdown of mutant KRAS reduced drug combination killing at the 48 h timepoint. Despite culture for 24 h in the absence of the drugs, the expression and activities of ERBB1, ERBB2 and ERBB4 remained significantly lower as did the activities of mammalian target of rapamycin (mTOR) C1 and mTORC2. The drug combination reduced KRAS and NRAS levels for 24 h, however, in the absence of the drugs, RAS levels had normalized by 48 h. Expression of Beclin1 and ATG5 remained elevated and of MCL1 and BCL-XL lower. No evolutionary activations of survival signaling by ERBB3, c-KIT, c-MET or PDGFRβ or in intracellular signaling pathways were observed. These findings argue against the development of ‘early’ resistance mechanisms after neratinib and pemetrexed exposure. Future studies will be required to understand how NSCLC cells become resistant to neratinib and pemetrexed.

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Section: Discussionmentioning

confidence: 99%

Cellular responses after (neratinib plus pemetrexed) exposure in NSCLC cells

Booth,

Poklepovic,

Hancock

et al. 2023

Anti-Cancer Drugs

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“…Moreover, missing data points in RCTs may impact the validity of results; for example, median PFS (HR ratio of PFS at 95% CI), OS (HR ratio of OS at 95% CI), ORR, and DCR were not discussed in several papers. [33][34][35][36] Other parameters, such as the incidence of grade ≥3 AEs like fatigue and diarrhea, were also not discussed in each RCT. 31 Heterogeneity was significant in the analysis of PFS, ORR, and DCR.…”

Section: Discussionmentioning

confidence: 99%

“…However, the efficacy and side effects of these trials have yielded inconsistent results. [28][29][30][31][32][33][34][35] Therefore, we conducted this meta-analysis to systematically study the effect of the combination of various therapeutic regimens versus monotherapy for the treatment of patients with advanced NSCLC who failed first-line EGFR-TKIs treatment.…”

mentioning

confidence: 99%

“…Several clinical trials have evaluated the effectiveness of osimertinib and the combination of osimertinib with chemotherapy and other anticancer drugs/chemotherapeutic agents, as well as a combination of different therapeutic regimens for patients with advanced NSCLC as second-line therapy. However, the efficacy and side effects of these trials have yielded inconsistent results 28–35 . Therefore, we conducted this meta-analysis to systematically study the effect of the combination of various therapeutic regimens versus monotherapy for the treatment of patients with advanced NSCLC who failed first-line EGFR-TKIs treatment.…”

mentioning

confidence: 99%

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A Meta-analysis of Randomised Controlled Trials Comparing Combination Therapy as Second-line Treatment With Monotherapy in Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutation

Zhao,

Zhang,

Zheng

et al. 2023

American Journal of Clinical Oncology

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Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are standard therapy for patients with non-small cell lung cancer (NSCLC) with EGFR mutation; however, resistance is common. Combinatorial strategies have been explored to improve survival. This meta-analysis assesses the efficacy and safety of combination therapy versus monotherapy in patients with advanced NSCLC who failed first-line EGFR-tyrosine kinase inhibitor treatment. Methods: We searched randomized controlled trials from PubMed, Web of Science, Google Scholar, Cochrane Library, and ClinicalTrial.gov. The efficacy and toxicity of combination treatment groups were assessed in terms of progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: This meta-analysis included 6 randomized controlled trials covering 785 participants. The results showed that the combined regimen arm had no significant improvement of PFS (log hazard ratio = −0.228, 95% CI: −0.543 to 0.087, P = 0.157), ORR (odds ratio = 1.147 [95% CI: 0.577, 2.281], P = 0.695), DCR (odds ratio = 1.578 [95% CI: 0.428, 5.821], P = 0.493), and AEs, including fatigue and diarrhea (odds ratio = 0.833 [95% CI: 0.297, 2.333], P = 0.728 for fatigue and odds ratio = 2.268 [95% CI: 0.544, 9.448], P = 0.261 for diarrhea). Conclusions: Combination therapy may not provide a significant improvement in PFS, ORR, DCR, and incidence of AEs compared with monotherapy in patients with advanced NSCLC with EGFR mutations. Further research is needed to investigate the optimal sequencing of combination therapy in patients with NSCLC with different molecular targets to determine the most effective treatment strategy that can improve outcomes and quality of life for these patients.

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“…Osimertinib combined with savolitinib is also a potential treatment approach ( 67 ). In addition to the above combination of treatments, telisotuzumab-vedotin combined with erlotinib ( 68 ), capmatinib combined with erlotinib ( 69 ), and emibetuzumab combined with erlotinib ( 70 ) also achieved certain benefits.…”

Section: Drug Resistance Mechanisms and Progress In The Use Of First-...mentioning

confidence: 99%

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

et al. 2022

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According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

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A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib

Cited by 16 publications

References 39 publications

Cellular responses after (neratinib plus pemetrexed) exposure in NSCLC cells

Cellular responses after (neratinib plus pemetrexed) exposure in NSCLC cells

A Meta-analysis of Randomised Controlled Trials Comparing Combination Therapy as Second-line Treatment With Monotherapy in Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutation

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

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