The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions

Christopoulos, Petros; Kluck, Klaus; Kirchner, Martina; Lüders, H; Roeper, J.; Falkenstern-Ge, R; Szewczyk, Marlen; Sticht, Florian; Saalfeld, Felix C.; Wesseler, Claas; Hackanson, Björn; Dintner, Sebastian; Faehling, Martin; Kuon, Jonas; Janning, Melanie; Kauffmann-Guerrero, Diego; Kazdal, Daniel; Kurz, S; Eichhorn, Florian; Bozorgmehr, Farastuk; Shah, Rajiv; Tufman, Amanda; Wermke, Martin; Loges, Sonja; Brückl, W.; Schulz, Christian; Misch, Daniel; Frost, Nikolaj; Kollmeier, Jens; Reck, Martin; Griesinger, Frank; Grohé, Christian; Hong, Jisu; Lin, Huamao Mark; Budczies, Jan; Thomas, Michael

doi:10.1016/j.ejca.2022.04.020

Cited by 16 publications

(8 citation statements)

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“…[ 18 ] TP53, the most frequently mutated gene in lung cancer, leads to enhanced carcinogenic functions and is associated with shorter survival. [ 21 ] Our study revealed a positive correlation between high-KIFC1 expression and TP53 mutations, suggesting a potential link between these mutations and increased KIFC1 expression. This association may be attributed to the involvement of KIFC1 in the cell cycle signaling pathways.…”

Section: Discussionmentioning

confidence: 61%

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer

Li,

Wang,

Ruan

et al. 2024

Medicine

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The Kinesin Family Member C1 (KIFC1) is highly expressed in a variety of tumors. Since it is linked with tumorigenesis and progression, KIFC1 has emerged as a promising candidate for targeted chemotherapies. Thus, this study aims to find out the association between KIFC1 and lung cancer. The original data were assessed from The Cancer Genome Atlas and Gene Expression Omnibus databases. Compared to normal lung tissues, both mRNA and protein levels of KIFC1 were significantly increased in lung cancer tissues. The upregulation of KIFC1 was significantly correlated with sex, pathological stage, and TMN stage. Survival analysis revealed that increased KIFC1 expression was associated with poor overall survival, first-progression survival and post-progression survival in lung cancer. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, we observed that KIFC1 upregulation was linked to enrichment of the cell cycle and TP53 signaling pathway. Additionally, the overexpression of KIFC1 was positively correlated with TP53 mutations in lung cancer. Based on real-world cohort results, western blotting and RT-qPCR showed high-KIFC1 expression in lung cancer, which may be related to the malignancy of lung cancer. Finally, experiments in vitro showed that KIFC1 inhibitor could significantly inhibit the proliferation and invasion of lung cancer cells. In conclusion, KIFC1 is a poor prognostic biomarker, and patients with high-KIFC1 levels may benefit from targeted therapy.

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Section: Discussionmentioning

confidence: 61%

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer

Li,

Wang,

Ruan

et al. 2024

Medicine

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“…Thus, use of mobocertinib in patients with brain metastases will require complementary use of radiotherapy in order to extend the intracranial PFS, as is also standard for patients with other oncogene-driven NSCLC beyond the first line ( 22 ). At the same time the ORR under mobocertinib was clearly superior to that of current alternatives, such as monochemotherapy and EGFR inhibitors, which both showed ORR of 0-10% in real-world studies of pretreated patients with EGFR exon20ins ( 21 ).…”

Section: Discussionmentioning

confidence: 89%

“…However, it should be noted that a worse outcome for NSCLC with EGFR exon20 insertions and brain metastases has also been described under conventional therapies, i.e. platinum-based chemotherapy and EGFR inhibitors ( 21 ), therefore brain involvement appears to be an adverse prognostic factor for this patient group under several different therapies. Thus, use of mobocertinib in patients with brain metastases will require complementary use of radiotherapy in order to extend the intracranial PFS, as is also standard for patients with other oncogene-driven NSCLC beyond the first line ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer

Kian

Christopoulos²,

Remilah³

et al. 2022

Front. Oncol.

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BackgroundNon-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertions (EGFRex20ins) is relatively resistant to the existing EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is a novel TKI that selectively targets EGFRex20ins and has demonstrated therapeutic efficacy in pretreated patients with tumors harboring these mutations.MethodsThis is a retrospective, non-interventional, multicenter real-world study aimed at assessing the efficacy and safety of mobocertinib in patients with EGFRexon20ins who received 160 mg QD monotherapy as part of expanded access. Data collection was based on patients’ records. PET-CT or CT scans were used to measure systemic response, while brain MRIs were used to examine intracranial response as part of the follow-up.Results16 patients were included in this report. Mobocertinib was administered to 31.3% (5) of patients as first-line, 50% (8) as second-line, and 18.7% (3) as a later-line therapy. The median age was 65 years (range, 38-83), 75% (12/16) were female, and 50% (8/16) had brain metastases at baseline before mobocertinib treatment. The objective response rate (ORR) to mobocertinib was 25% (4/16) (1/5 for first line and 3/11 for other lines), disease control rate (DCR) was 75% (12/16) with a follow-up period of 11 months. The median duration of treatment (mDoT) was 5.6 months across all patients, and 8.6 months in responders. Based on the presence or absence of brain metastasis, the mDoT was 14.8 and 5.4 months (p=0.01), respectively. Mobocertinib Grade ≥3 treatment-related adverse events (TRAEs) included diarrhea (19%), nausea (6%) and renal failure (6%). Dose reduction was reported in 25% of cases to 80 mg.ConclusionMobocertinib in compassionate use exhibited an ORR of 25%, which is very similar to that of the phase 2 EXCLAIM study and clearly better than historical data of monochemotherapy or conventional EGFR inhibitors. The greatest benefit was noted in patients without brain metastases, who showed durable effects with mDoT 14.8 months, while intracranial activity was limited. These findings may assist therapeutic considerations, inasmuch as results from the EXCLAIM cohort-3 dedicated to brain lesions are not available yet.

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“…Different regulatory authorities will interpret the same evidence divergently, for example the tyrosine kinase inhibitor (TKI) erdafitinib was approved by the FDA in April 2019 for pretreated metastatic urothelial carcinoma with susceptible FGFR2/ FGFR3 alterations based on results from the phase 2 single-arm study BLC2001 (NCT02365597) along with control RWD, but the same drug has not been approved by the EMA yet. Another example is the first-inclass EGFR exon 20 TKI mobocertinib, which was approved by the FDA in September 2021 based on single-arm evidence from the phase 2 EXCLAIM study (NCT02716116) combined with a real-world reference population, whereas the application of similar data, including a RWD control from Germany, 23,24 to the EMA had to be withdrawn by the company in July 2022 due to a very low likelihood of success. Yet other examples are the MET inhibitors tepotinib and capmatinib, which were approved by the EMA for advanced non-small-cell lung cancer (NSCLC) with MET exon 14 skipping after platinum chemotherapy and/or immunotherapy based on single-arm studies only in February 2022 and June 2022, respectively, whereas the FDA had approved the same drugs for even first-line use much earlier, already in May 2020 and February 2021, respectively.…”

Section: Harmonizing the Regulatory Frameworkmentioning

confidence: 99%

Real‐world data for precision cancer medicine—A European perspective

Christopoulos

Schlenk

Kazdal

et al. 2023

Genes Chromosomes & Cancer

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Leveraging real‐world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low‐prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or “best” supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan‐European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient‐reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient‐level data) suitable for approval and pricing with minimal effort. For an EU‐wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off‐label use could potentially also be harmonized across EU‐states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.

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The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions

Cited by 16 publications

References 40 publications

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer

Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer

Real‐world data for precision cancer medicine—A European perspective

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