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ESMO Congress 2019 Spotlight on Leptomeningeal Metastases

Presentations cover a new classification strategy that may be prognostic of outcome and a new treatment option for leptomeningeal metastases in NSCLC patients
27 Sep 2019
Central nervous system malignancies

Patients with ALK-positive non-small cell lung cancer (NSCLC) and leptomeningeal metastases (LM) showed promising rates of response and intracranial anti-tumour activity following treatment with ceritinib, according to phase II study findings presented during the ESMO Congress 2019 in Barcelona, Spain. 

Approximately 5% of patients with ALK-positive NSCLC develop LM, which associates with a poor prognosis with current standard treatments. Since ceritinib is highly active in ALK-positive NSCLC and has demonstrated intracranial and central nervous system activity (results in patients with brain metastasis reported in a separate presentation, 1478O), Fabrice Barlesi, Department of Multidisciplinary Oncology and Therapeutic Innovations, Aix Marseille University, CNRS, INSERM, CRCM, APHM in Marseille, France and colleagues evaluated the efficacy and safety of ceritinib in the phase II ASCEND-7 trial (NCT02336451).

Eligible patients had ALK-positive NSCLC that was confirmed by FISH, demonstrated cerebrospinal fluid (CSF) invasiveness, and radiologically or cytologically confirmed LM. The patients were also required to have one or more extracranial measurable lesion by RECIST v1.1 criteria.

Median age of the 18 patients with LM enrolled in the study was 46.0 (37-74) years. The majority, (77.8%) of patients also had brain metastases; of these, 8 (44.4%) patients had measurable brain metastases at baseline. Sixteen (88.9%) patients had received prior crizotinib treatment and 7 (38.9%) patients had received prior brain radiotherapy.

The study objectives included evaluation of anti-tumour activity based on overall response rate (ORR) by investigator assessment, disease control rate (DCR), and progression-free survival (PFS).

Ceritinib shows meaningful anti-tumour activity in the largest series of patients with LM reported to date

At data cut-off for final analysis on 6 February 2019, the patients had received ceritinib for a median 18.1 weeks (range, 1.7 to 125.9 weeks). At this time, the ORR was 16.7% (95% confidence interval [CI], 3.6-41.4). The median duration of response (DoR) was 5.5 months (95% CI, 3.7-9.9) and the DCR was 66.7% (95% CI, 41.0-86.7).

Regarding the intracranial response in the 8 patients with measurable brain metastases at baseline, the intracranial ORR was 12.5% (95% CI, 0.3-52.7) and the intracranial DCR was 62.5% (95% CI, 24.5-91.5).

At a median follow-up of 3.84 months (range, 0.5 to 13 months) clinically significant PFS was observed. Median PFS was 5.2 months (95% CI, 1.6-7.2).

The median overall survival (OS) was 7.2 months (95% CI, 1.6-16.9).

All grade adverse events (AEs) occurred in all 18 patients and were similar to earlier reported results. Grade 3/4 AEs that were reported in at least 2 (≥10%) patients included increased alanine aminotransferase (22.2%), hyperglycaemia (16.7%), vomiting (16.7%), hypokalaemia (11.1%), increased gamma‑glutamyl transferase (11.1%), nausea (11.1%) and pneumonia (11.1%).

Prognostic role of the EANO-ESMO classification of leptomeningeal metastases

During the same session at ESMO 2019 Congress, Emilie Le Rhun of the Neuro-oncology, Neurosurgery Department, Roger Salengro Hospital in Lille, France, discussed the guidelines formulated by ESMO and the European Association of Neuro Oncology (EANO), which propose a classification of LM.

The classification is based on clinical and cytological presentation, which are rated as typical versus atypical and positive versus negative versus equivocal, respectively, as well as MRI data expressed as A linear, B nodular, C linear plus nodular, D normal or hydrocephalus only. Type I LM is defined by the presence of tumour cells in the CSF (confirmed LM), whereas type II LM is defined by typical clinical and MRI signs and classed as probable or possible LM.

The EANO-ESMO classification of LM can be used across a variety of primary tumour types

The utility of this classification system was evaluated by Dr Le Rhun and colleagues by investigating the association between the EANO-ESMO subtypes of LM and outcome. Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. The researchers acquired data from 254 patients with newly diagnosed LM. The patients’ median age at LM diagnosis was 56.5 years (range, 20 to 82 years). LM derived from different primary solid tumours, mainly breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%).

Of the 254 patients in the cohort, 225 (88.5%) patients demonstrated typical clinical LM symptoms or signs; only 13 (5%) patients were clinically asymptomatic. The most commonly occurring MRI subtype was A, which was present in 117 (46%) patients. Type B occurred in 33 (13%) patients, type C in 54 (21%), and type D was noted in 50 (19.5%) patients.

The CSF analysis was equivocal in only 24 (9.5%) patients; 186 (73%) patients had tumour cells in their CSF and 44 (17.5%) patients’ CSF was negative for tumour cells. The diagnosis of LM was confirmed in 189 (74.5%) patients, deemed probable in 51 (20%), and possible in 14 (5.5%) patients.

The presence of tumour cells in the cerebrospinal fluid was indicative of poorer survival

Regarding the EANO-ESMO classes, 86 (34%) patients were assigned to IA, 19 (7.5%) to IB, 39 (15.5%) to IC, and 45 (17.5%) patients were classified ID on the basis of tumour cells in the CSF. In addition, based on clinical symptoms and MRI data, 28 (11%) patients were assigned to IIA, 13 (5%) to IIB, 16 (6.5%) to IIC, and 8 (3%) patients to were classified IID.

In the entire cohort, median OS was 2.75 months (range, 0.09 to 220 months); however, OS was significantly poorer in type I LM patients with tumour cells present in the CSF compared to patients with type II LM (p = 0.0024). Patients with the EANO-ESMO subtype IIA classification had the longest survival compared to the other subtypes (p = 0.0103).

An analysis of pooled data showed that type I patients with tumour cells in the CSF and pooled MRI patterns A and D had poorer survival than patients with pooled MRI B and C patterns (p = 0.0402); however, longer survival was observed type II patients with no tumour cells in the CSF (p = 0.0273).

Conclusions

The ASCEND-7 investigators concluded that ceritinib demonstrated clinically meaningful efficacy and a safety profile similar to earlier reported results. To their knowledge, this study represents the largest set of ALK-positive NSCLC patients with LM reported to date.

The EANO-ESMO LM subtypes are prognostic, according to the study authors who recommend that this classification should be considered in the design of clinical trials. Furthermore, they concluded that the presence of tumour cells in the CSF played a greater prognostic role than the neuroimaging presentation in this cohort.

Disclosure

The ASCEND-7 trial was sponsored by Novartis Pharmaceuticals. The evaluation of the EANO-ESMO classification reported no external funding.

References

390O – Barlesi F, Kim DW, Bertino EM, et al. Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study.

1478O – Chow LQM, Barlesi F, Bertino E, et al. Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain.

391O – Le Rhun E, Devos P, Weller J, et al. Prognostic role of the EANO ESMO classification of leptomeningeal metastases.

Last update: 27 Sep 2019

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