Tirabrutinib (brand name Velexbru) is a drug used for the treatment of autoimmune diseases and hematological malignancies.

Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

In addition, tirabrutinib is in clinical development by Ono Pharmaceutical and Gilead Sciences in the United States, Europe, and Japan for autoimmune disorders, chronic lymphocytic leukemia, B cell lymphoma, Sjogren’s syndrome, pemphigus, and rheumatoid arthritis.

Tirabrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase.

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).

Methods: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.

Results: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.

Conclusion: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL 1).

Yoshioka et al. reported that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient’s level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia 2)

A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646 3).

Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone 4).


Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, Kitagawa J, Aoi A, Nishikawa R. Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol. 2021 Jan 30;23(1):122-133. doi: 10.1093/neuonc/noaa145. PMID: 32583848; PMCID: PMC7850159.

Yoshioka H, Okuda T, Nakao T, Fujita M, Takahashi JC. Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma. Int Cancer Conf J. 2021 Jun 5;10(4):290-293. doi: 10.1007/s13691-021-00491-1. PMID: 34567940; PMCID: PMC8421486.

Okita Y, Kano-Fujiwara R, Nakatsuka SI, Honma K, Kinoshita M. Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Exp Hematol Oncol. 2021 Apr 26;10(1):29. doi: 10.1186/s40164-021-00222-5. PMID: 33902692; PMCID: PMC8077707.

Satow T, Horiguchi S, Komuro T. Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone. Neurooncol Adv. 2020 Nov 27;2(1):vdaa164. doi: 10.1093/noajnl/vdaa164. PMID: 33409497; PMCID: PMC7770517.



Melphalan (trade name Alkeran, in former USSR also known as Sarcolysin) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.

Otherwise known as L-phenylalanine mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine.

Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis 1).

All patients with retinoblastoma treated by selective ophthalmic artery infusion chemotherapy at a single center during a 9-year period were reviewed. Only first-cycle treatments for previously untreated eyes were studied. Adjunctive factors (intra-arterial verapamil, intranasal oxymetazoline external carotid balloon occlusion) and technical factors (chemotherapy infusion time, fluoroscopy time) were documented by medical record review. Quantitative tumor reduction was determined by blinded comparison of retinal imaging acquired during examination under anesthesia before and 3-4 weeks after treatment. The dichotomous therapeutic response was classified according to quantitative tumor reduction as satisfactory (≥ 50%) or poor (<50%).

Results: Twenty-one eyes met the inclusion criteria. Patients ranged from 2 to 59 months of age. Adjuncts included intra-arterial verapamil in 15, intranasal oxymetazoline in 14, and external carotid balloon occlusion in 14. Quantitative tumor reduction ranged from 15% to 95%. Six showed poor dichotomous therapeutic response. A satisfactory dichotomous therapeutic response was correlated with intra-arterial verapamil (P = .03) in the aggregate cohort and in a subgroup undergoing treatment with single-agent melphalan at a dose of <5 mg (P = .02). In the latter, higher average quantitative tumor reduction correlated with intra-arterial verapamil (P < .01).

Conclusions: Intra-arterial verapamil during selective ophthalmic artery infusion chemotherapy is correlated with an improved therapeutic response, particularly when treating with lower doses of single-agent melphalan 2).

A phase II study explored the therapeutic gain obtained when exposing these patients to a combination of intra-arterially administered carboplatin and melphalan at first or second relapse as a salvage treatment in recurrent glioblastoma. Fifty-one consecutive patients diagnosed with glioblastoma were accrued and offered this treatment at first or second relapse. A Karnofsky score of ≥ 60 was required, and when appropriate, patients were first reoperated prior to accrual. Patients enrolled were treated every 4 weeks (1 cycle) for up to 12 cycles. Progression was evaluated by Macdonald criteria. Primary end point surrogates were overall survival from diagnosis and study entry. Median survival from diagnosis and study entry was 23 and 11 months, respectively. The median time to progression was 5.2 months. All patients enrolled were treated for a minimum of 2 cycles. Hematologic toxicity was manageable, with an 8 % of grade II neutropenia, 12 % of grade II thrombocytopenia and 7 % of grade III thrombocytopenia. This therapeutic strategy represents an adequate option in the second-line treatment of recurrent glioblastoma. The adjunction of an osmotic permeabilization could be considered to further expand delivery, and hopefully improve survival in these patients 3).

Patsalides et al describe their initial experience with a novel therapeutic approach that consists of intraarterial (IA) infusion of chemotherapy to treat progressive spinal metastases.

The main inclusion criterion was the presence of progressive, metastatic epidural disease to the spine causing spinal canal compromise in patients who were not candidates for the standard treatments of radiation therapy and/or surgery.

All tumor histological types were eligible for this trial. Using the transfemoral arterial approach and standard neurointerventional techniques, all patients were treated with IA infusion of melphalan in the arteries supplying the epidural tumor. The protocol allowed for up to 3 procedures repeated at 3- to 6-week intervals. Outcome measures included physiological measures:

1) Periprocedural complications according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events

2) MRI to assess for tumor response.

Nine patients with progressive spinal metastatic disease and cord compression were enrolled in a Phase I clinical trial of selective IA chemotherapy. All patients had metastatic disease from solid organs and were not candidates for further radiation therapy or surgery. A total of 19 spinal intraarterial chemotherapy (SIAC) procedures were performed, and the follow-up period ranged from 1 to 7 months (median 3 months). There was 1 serious adverse event (febrile neutropenia). Local tumor control was seen in 8 of 9 patients, whereas tumor progression at the treated level was seen in 1 patient.

These preliminary results support the hypothesis that SIAC is feasible and safe 4)


Francis JH, Gobin YP, Nasany RA, Knopman J, Ulaner GA, Panageas K, Hatzoglou V, Salvaggio K, Abramson DH, Patsalides A, Diamond EL. Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis. Neurology. 2021 May 12:10.1212/WNL.0000000000012070. doi: 10.1212/WNL.0000000000012070. Epub ahead of print. PMID: 33980709.

Abruzzo T, Abraham K, Karani KB, Geller JI, Vadivelu S, Racadio JM, Zhang B, Correa ZM. Correlation of Technical and Adjunctive Factors with Quantitative Tumor Reduction in Children Undergoing Selective Ophthalmic Artery Infusion Chemotherapy for Retinoblastoma. AJNR Am J Neuroradiol. 2021 Jan;42(2):354-361. doi: 10.3174/ajnr.A6905. Epub 2020 Dec 24. PMID: 33361377; PMCID: PMC7872184.

Fortin D, Morin PA, Belzile F, Mathieu D, Paré FM. Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J Neurooncol. 2014 Sep;119(2):397-403. doi: 10.1007/s11060-014-1504-4. Epub 2014 Jun 20. PubMed PMID: 24947313.

Patsalides A, Yamada Y, Bilsky M, Lis E, Laufer I, Gobin YP. Spinal intraarterial chemotherapy: interim results of a Phase I clinical trial. J Neurosurg Spine. 2015 Oct 23:1-6. [Epub ahead of print] PubMed PMID: 26496162.

Non-small cell lung cancer intracranial metastases treatment

Non-small cell lung cancer intracranial metastases treatment

Brain metastases are common in patients with non-small cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients 1).

EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression free survival compared to standard chemotherapy in the molecularly defined Non-small cell lung cancer (NSCLC) subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies 2).

The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPKAKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway stimulates the proliferation of tumor cells and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases 3).

KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non-small cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 4).

A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 5).

PUBMEDEMBASE, the Cochrane LibraryWeb of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastasis (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).

A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.

There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis 6).

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 7).

Response rates after platinum based antineoplastics, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10-25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown 8).

see Non small cell lung cancer intracranial metastases whole brain radiotherapy

see Non small cell lung cancer intracranial metastases radiosurgery

see Non small cell lung cancer intracranial metastases surgery.


Bulbul A, Forde PM, Murtuza A, Woodward B, Yang H, Bastian I, Ferguson PK, Lopez-Diaz F, Ettinger DS, Husain H. Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer. Oncology (Williston Park). 2018 Apr 15;32(4):156-63. Review. PubMed PMID: 29684234.

Wrona A, Dziadziuszko R, Jassem J. Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors. Cancer Treat Rev. 2018 Dec;71:59-67. doi: 10.1016/j.ctrv.2018.10.011. Epub 2018 Oct 21. Review. PubMed PMID: 30366200.

Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K. Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma. Int J Mol Sci. 2021 Jan 8;22(2):593. doi: 10.3390/ijms22020593. PMID: 33435596; PMCID: PMC7826874.

She C, Wang R, Lu C, Sun Z, Li P, Yin Q, Liu Q, Wang P, Li W. Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. Thorac Cancer. 2018 Nov 28. doi: 10.1111/1759-7714.12913. [Epub ahead of print] PubMed PMID: 30485664.

Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO Open. 2018 Jan 26;3(1):e000262. doi: 10.1136/esmoopen-2017-000262. eCollection 2018. Review. PubMed PMID: 29387475; PubMed Central PMCID: PMC5786916.

Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review. Med Sci Monit. 2015 Jan 12;21:144-52. doi: 10.12659/MSM.892405. PubMed PMID: 25579245.

Kim SY, Hong CK, Kim TH, Hong JB, Park CH, Chang YS, Kim HJ, Ahn CM, Byun MK. Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. Yonsei Med J. 2015 Jan 1;56(1):103-11. doi: 10.3349/ymj.2015.56.1.103. PubMed PMID: 25510753; PubMed Central PMCID: PMC4276743.

Cedrych I, Kruczała MA, Walasek T, Jakubowicz J, Blecharz P, Reinfuss M. Systemic treatment of non-small cell lung cancer brain metastases. Contemp Oncol (Pozn). 2016;20(5):352-357. doi: 10.5114/wo.2016.64593. Epub 2016 Dec 20. Review. PubMed PMID: 28373815; PubMed Central PMCID: PMC5371701.
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