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Patients with positive driver mutations in non-small cell lung cancer (NSCLC) have a higher incidence of brain metastases, and the rapid development of molecularly targeted drugs has provided more treatment methods for patients with brain metastases in NSCLC, and improved the survival and quality of life of patients with brain metastases in NSCLC to a certain extent. This article summarizes the research on targeted drugs for intracranial remission of brain metastases in NSCLC in recent years for readers.
9 recognized driver genes in the field of NSCLC
The IPASS study in Asian populations [1] kicked off targeted therapies for lung cancer and ushered in a new era of individualized treatment of tyrosine kinase inhibitor TKIs for epidermal growth factor receptor (EGFR) mutation-positive NSCLC. With the development of genetic testing technology, more and more NSCLC has been confirmed to have driver gene mutations, and the mutated genes drive normal cells to become cancer cells, so that cancer cells can survive for a long time, replicate rapidly, spread and evolve. These genetic mutations are therefore called driver mutations, and they are also called "targets", and some molecularly targeted drugs are specifically designed for them.
Figure 1 lists the types of driver mutations in NSCLC and their frequency [2]. Currently, there are 9 recognized driver genes in the NSCLC field, including EGFR, KRAS, ALK, MET, ROS1, HER2, BRAF, RET, and NTRK. In China, there are more NSCLC patients with positive driver mutations. Studies [3] have shown that about 73.9% of Chinese NSCLC patients have at least one treatment-related variant recommended by the National Comprehensive Cancer Network (NCCN) guidelines, among which the proportions of EGFR genomic alterations (including mutations and amplification) and ALK gene fusions are 50.1% and 7.8%, respectively, which are significantly higher than those in the Western population.
Figure 1: Incidence of targeted driver gene mutations in lung adenocarcinoma
Patients with NSCLC who are positive for driver mutations have a higher incidence of brain metastases
With the continuous exploration of targeted therapy and the successful development of related targeted drugs, more patients will benefit from targeted precision therapy. However, once brain metastases have developed in NSCLC patients, the prognosis remains poor. Approximately 20 to 40 percent of patients with NSCLC develop brain metastases [4]. The incidence of brain metastases is higher in NSCLC patients with oncogenic driver mutations such as EGFR, ALK, ROS1, BRAF, and KRAS, ranging from 30 to 40 percent at baseline [5] and up to 60 to 70 percent cumulatively [6].
Table 1: Baseline and cumulative incidence of brain metastases [6]
Treatment of brain metastases in NSCLC includes both local (surgery and radiotherapy) and systemic therapies (molecularly targeted agents, chemotherapy and immunotherapy). There are many factors that physicians need to consider when making clinical decisions. Assess the need for upfront topical therapy based on the presence of symptoms before initiating treatment, control the risk of toxicity, and the need for extracranial disease.
To assess how patients can benefit from systemic therapy, clinicians need to understand the rates of intracranial and extracranial remission of various treatments, the timing of initiation of treatment response, the risk of pseudoprogression after immunotherapy, and the risk of toxicity from delayed radiotherapy. The ultimate goal of treatment is to treat metastatic lesions, improve patient symptoms and quality of life, and maximize patient survival.
Targeted therapy prolongs survival and improves quality of life in patients with brain metastases
The treatment of brain metastases in NSCLC in the past was mostly limited to radiotherapy and chemotherapy, and only patients with a score of 3.5 or higher achieved a median overall survival (OS) of more than one year according to the Special Diagnostic Assessment Prognostic Grading System (DS-GPA) [7]; In a phase III clinical study comparing upfront radiotherapy with delayed whole-brain radiotherapy, there was no difference in efficacy and median OS was less than six months [8].
In recent years, the rapid development of molecular targeted therapy has provided more treatment methods for patients with brain metastases in NSCLC, and improved the survival and quality of life of patients with brain metastases in NSCLC to a certain extent.
1. EGFR
In a subgroup analysis of the FLAURA study, osimertinib significantly prolonged disease progression to 15.2 months in treatment-naïve patients with positive EGFR mutations and brain metastases, reducing the risk of intracranial disease progression by 53 percent compared with first-generation EGFR-TKIs [9].
2. ALK
In the CROWN study, the intracranial objective response rate (ORR) was as high as 83.3% in the lorlatinib group for ALK-positive NSCLC patients, with 72.2% of patients with measurable brain metastases at baseline achieving an intracranial complete response (CR) with lorlatinib, demonstrating the amazing brain-penetrating ability of lorlatinib [10].
3. MET exon 14 skipping mutations
In the post-hoc analysis of the Phase II study of savolitinib, the first MET-TKI approved in China, patients with intracranial lesions shrunk or remained stable after savolitinib treatment, with 3 patients achieving partial response (PR), 15 patients achieving an ORR of 46.7% for extracranial lesions, and a median OS of 17.7 months for patients with brain metastases in patients with brain metastases in NSCLC with MET14 exon 14 skipping mutations [11,12].
In addition, the Phase II clinical studies of Capmatinib and tepotinib included 13 and 15 patients with brain metastases at baseline and evaluable intracranial efficacy, respectively. Capmatinib resulted in control of intracranial lesions in 12 patients, of whom 7 achieved intracranial remission, including 4 complete remission (CR) [13]; Of the 15 patients treated with tepotinib, 13 had intracranial lesions controlled, including 3 CR, 9 PR, and 1 stable (SD) [14]. The above data suggest that these two MET-TKIs also have certain efficacy in the use of intracranial lesions.
4. KRAS G12C
Targeted therapy has greatly improved the survival time of patients, and adverse effects can be controlled, and the new generation of targeted drugs has achieved encouraging results in the control of brain metastases. At the 2022 ASCO Annual Meeting, the results of a blockbuster study of targeted therapy for brain metastases in NSCLC were presented. The KRYSTAL-1 study was the first to show activity in active central nervous system (CNS) metastases to KRAS G12C-mutant NSCLC [15].
In the multi-cohort Phase I/II KRYSTAL-1 Phase I.b cohort study, Adagrasib achieved a 32% ORR and 84% disease control in patients with KRAS G12C-mutated solid tumors with untreated active central nervous system metastases. In addition, when assessed by lumbar puncture, Adagrasib exhibited excellent CNS concentrations with a mean concentration ratio of cerebral effusion to plasma (Kp, uu) of 0.47, which was higher than the concentration ratio observed in other drugs known to have intracranial activity. As we all know, KRAS is a difficult-to-treat target, and we hope that more R&D data will break through expectations in the future.
Limitations and future prospects of targeted therapy for brain metastases in NSCLC
The widespread use of targeted drugs has somewhat changed the treatment strategy for brain metastases in NSCLC with driver mutations, and the era of precision medicine requires a multidisciplinary team based on patient-specific factors and tumor-specific variables (performance status, prognosis, targeted mutations, symptomatic brain metastases, extracranial disease state, and molecular genomic characteristics and PD-L1 expression of NSCLC) [16,17]. However, one of its main limitations is that patients with NSCLC and untreated brain metastases are often excluded from randomized clinical studies evaluating systemic therapy. This is changing with the increasing incidence of brain metastases and the emergence of clinical studies that include or specifically target patients with brain metastases.
What is the future of NSCLC with positive driver mutation genes, Professor Lizza Hendriks of Maastricht University Medical Center in the Netherlands put forward the following views:
(1) Liquid biopsy techniques such as cerebrospinal fluid (CSF) were used to track the mechanism of EGFR-TKI drug resistance in the CNS;
(2) focus on ongoing dose-escalation studies evaluating TKIs;
(3) the data for osimertinib alone may be less than ideal, and chemotherapy combined with anti-angiogenic drugs may improve clinical outcomes in patients with brain metastases;
(4) co-mutations have been shown to be associated with a higher incidence of brain metastases, and systemic treatment regimens are adjusted according to co-mutations;
(5) "Should TKI therapy be continued to control CNS when systemic progression?" Can radiation therapy be given at the same time as TKI therapy when CNS progresses? "This remains a controversial topic and further work is needed to guide clinical decision-making in different response scenarios.
参考文献：[1]Mok TS, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3; 361(10):947-57. [2] Tan AC, Tan DSW. Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations. J Clin Oncol. 2022 Feb 20; 40(6):611-625. [3] Wen S, et al. Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer. Oncologist. 2019 Nov; 24(11):e1070-e1081. [4] Villano JL, et al. Incidence of brain metastasis at initial presentation of lung cancer. Neuro Oncol. 2015 Jan; 17(1):122-8. [5] Patil T, et al. The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib. J Thorac Oncol. 2018;13:1717-1726. [6] Schoenmaekers JJAO, et al. Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when? Transl Lung Cancer Res. 2020 Dec; 9(6):2599-2617. [7] Sperduto PW, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1; 77(3):655-61. [8]8 Robinet G, et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan; 12(1):59-67. [9] Ramalingam SS, et al; FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2; 382(1):41-50. [10] Benjamin J. Solomon, et al. Updated Efficacy and Safety From the Phase 3 CROWN Study of First-Line Lorlatinib vs Crizotinib in Advanced Anaplastic Lymphoma Kinase (ALK)–Positive Non-Small Cell Lung Cancer (NSCLC). AACR2022, Abstract #CT223. [11] Lu S, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations:a multicentre, single-arm, open-label, phase 2 study[J]. The Lancet Respiratory Medicine,2021,9(10):1154-1164. [12] Lu S, et al.2MO Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations(METex14+)NSCLC[J]. Annals of Oncology, 2022, 33(S2): S27. [13] Wolf J, Seto T, Han J Y, et al. Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer[J]. New England Journal of Medicine, 2020, 383(10): 944-957. [14] Le X, Sakai H, Felip E, et al. Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice[J]. Clinical Cancer Research, 2022, 28(6): 1117-1126. [15] Ou SI, et al. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Feb 15:JCO2102752. [16] Vogelbaum MA, et al. Treatment for brain metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol. 2022;40:492-516. [17] Le Rhun E, et al; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021;32:1332-1347.
This article was first published: Rare Targets Ecosystem in the Medical Community Responsible Editor: Sheep
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