Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer

Pan, Kelsey; Concannon, Kyle; Li, Jing; Zhang, Jianjun; Heymach, John V.; Le, Xiuning

doi:10.1038/s41571-023-00808-4

Cited by 5 publications

(4 citation statements)

References 187 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sequential, systemic therapy based on examinations of major genetic alterations and programmed cell death ligand 1 (PD-L1) can be another treatment option to enhance the anti-tumor efficacy without dose escalation [4]. If the BM of this case harbored a driver gene alteration, the combined use of a tyrosine-kinase inhibitor might have augmented anti-tumor efficacy [18].…”

Section: Discussionmentioning

confidence: 99%

“…Brain metastases (BMs) without locoregional or any other distant tumor seeding are a pattern of recurrence after definitive surgery of non-small cell lung cancer (NSCLC) [1]. Local treatment such as external-beam radiotherapy (EBRT) or surgical resection is generally preferred over systemic therapy for oligo-BMs [2][3][4]. A single isolated BM requires long-term control (local curability) and safety with localized treatment, which can significantly affect prognosis [1,3].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fifteen-Fraction Radiosurgery Followed by Reduced-Dose Whole-Brain Irradiation With a Total Biologically Effective Dose of >90-100 Gy for a Locally Invasive Brain Metastasis From Lung Adenocarcinoma With a High Dissemination Potential

Ohtakara,

Ohka,

Tanahashi

et al. 2023

Cureus

View full text Add to dashboard Cite

A deep-seated, locally infiltrative 5.8-cm brain metastasis (BM) involving the ventricular wall and optic radiation is deemed unamenable for a safe total resection, while preventing tumor seeding. Meanwhile, radiotherapeutic management alone for such a BM close to the brainstem is also challenging.We describe such a BM (gross tumor volume [GTV] 40.3 cm 3 ) from lung adenocarcinoma (LAC), located in the left temporo-occipital lobes, with extensive invasion to the tentorium cerebelli and a high potential for dissemination. The BM was treated with 15-fraction(s) (fr) stereotactic radiosurgery (SRS) followed by whole-brain irradiation (WBI) at 27 Gy/15 fr with a 19-day interval. During the SRS, the solid component away from the tentorium showed obvious shrinkage. The cumulative biologically effective doses (BEDs) of the minimum and D 99% of the GTV were ≥92.3 Gy and ≥102.6 Gy, respectively, where the BED was based on the linear-quadratic formula at an alpha/beta ratio of 10 (BED 10 ). Despite a maximum response with nearly complete regression at 7.5 months, local tumor regrowth near the tentorial incisura became gradually apparent from 11.2 to 19.3 months. Salvage re-SRS with 53 Gy/10 fr specific to these lesions resulted in obvious regression at 5.8 months. However, radiation injury concomitant with triventriculomegaly progressed from 7.9 to 13.9 months, eventually leading to meningeal dissemination and patient mortality at 34.6 months. This case demonstrates that a BED 10 ≥90-100 Gy in 30 fr to the GTV boundary with a more than two-week interval without combined systemic therapy is insufficient for achieving complete local tumor eradication of a 40-cc LAC-BM. Shorter treatment duration with a steeper dose gradient outside and inside the GTV in the SRS or a volumetric modulated arc-based SRS combined with simultaneously integrated WBI may improve efficacy and safety.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fifteen-Fraction Radiosurgery Followed by Reduced-Dose Whole-Brain Irradiation With a Total Biologically Effective Dose of >90-100 Gy for a Locally Invasive Brain Metastasis From Lung Adenocarcinoma With a High Dissemination Potential

Ohtakara,

Ohka,

Tanahashi

et al. 2023

Cureus

View full text Add to dashboard Cite

show abstract

“…The third-generation EGFR inhibitor osimertinib, the ALK inhibitor alectinib, the RET inhibitor selpercatinib, and ROS1 or NTRK inhibitors like entrectinib have shown a central nervous system (CNS) ORR of up to 80%. However, other targets, such as EGFR exon 20 insertions, C797S mutations, HER2 mutations, and MET exon 14 skipping, still require the development of CNS-active small-molecule inhibitors [204]. A promising strategy in this field involves combining next-generation ROS1 TKIs with selective MET TKIs like crizotinib or tepotinib, which have the ability to penetrate into the CNS.…”

Section: Crossing the Blood-brain Barriermentioning

confidence: 99%

“…This measure evaluates CNS penetration and drug efflux by transport proteins at the BBB. From a clinical standpoint, objective metrics such as the CNS ORR and median PFS should also be considered when evaluating the CNS activity of drugs [204]. These objective measures can offer valuable insights into the efficacy of kinase inhibitors in managing CNS metastases.…”

Section: Crossing the Blood-brain Barriermentioning

confidence: 99%

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Li,

Gong,

Zhou

et al. 2024

IJMS

View full text Add to dashboard Cite

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

show abstract

Brain metastases in clinical trial participants with KRAS-mutated advanced non-small cell lung cancer receiving docetaxel: Pooled data analysis

Aptekar,

Jain,

Korytowsky

et al. 2024

Lung Cancer

View full text Add to dashboard Cite

Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer

Cited by 5 publications

References 187 publications

Fifteen-Fraction Radiosurgery Followed by Reduced-Dose Whole-Brain Irradiation With a Total Biologically Effective Dose of >90-100 Gy for a Locally Invasive Brain Metastasis From Lung Adenocarcinoma With a High Dissemination Potential

Fifteen-Fraction Radiosurgery Followed by Reduced-Dose Whole-Brain Irradiation With a Total Biologically Effective Dose of >90-100 Gy for a Locally Invasive Brain Metastasis From Lung Adenocarcinoma With a High Dissemination Potential

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Brain metastases in clinical trial participants with KRAS-mutated advanced non-small cell lung cancer receiving docetaxel: Pooled data analysis

Contact Info

Product

Resources

About