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CNS metastases in NSCLC

Introduction

While much progress has been made in treating advanced NSCLC, the 16-20% of NSCLC patients who develop CNS metastases continue to have a poor prognosis.  However, with the development of therapies specifically targeted against driver mutations, as well as exciting immunotherapies, there is hope that the outlook for these patients may get brighter in the future. This collection collates some of the most important published literature in this area to help HCPs keep up to date with the latest developments in this area, as well as consolidate knowledge of the risk factors and treatment options for CNS metastases arising from NSCLC.

This collection was made possible by educational funding provided by AstraZeneca.


General

Review

Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion

Preusser M et al. ESMO Open 2018; 3(1): e000262. doi:10.1136/esmoopen-2017-000262. eCollection 2018.

Summary points

  • Overall survival of patients with NSCLC brain metastases (BM) remains poor, partly due to difficulties associated with therapies crossing the blood brain barrier (BBB).
  • While the naïve brain environment can eliminate some tumor cells, others can avoid these mechanisms and are able to co-opt pre-existing blood vessels, or grow by angiogenesis. Molecular features of these successful cells may become novel therapeutic targets.
  • Though the BBB remains a significant obstacle to delivery of drugs to the CNS, there is evidence that most BM show signs of disturbing the BBB, which could potentially allow drug delivery.
  • Treatment of NSCLC BM includes:
    • Surgical resection
    • Radiotherapy
    • Chemotherapy
    • Targeted drugs – e.g. third-generation TKIs
    • Multi-modal approaches – e.g. a combination of radiotherapy and TKIs or immunotherapy
  • Window-of-opportunity studies, in which the concentrations of antineoplastic agents in BM are measured, may allow for information around inter-individual variation of drug concentrations to be collected.
  • The move towards personalized cancer treatment may lead to an increased demand for tissue analysis of BM, even when there is a known primary lesion.


Epidemiology and risk

Review

Risk factors for brain metastases in patients with non–small‐cell lung cancer

An N et al. Cancer Med 2018; 7(12): 6357-6364. doi:10.1002/cam4.1865.

Summary points

  • Nonsquamous cell carcinoma, especially adenocarcinoma, may be an independent risk factor for metastasis of NSCLC, but some studies have failed to show any correlation between pathology and brain metastases (BM).
  • Gender may have some role as a predictor of BM in NSCLC, with evidence that women with completely resected early-stage NSCLC may have increased risk of BM. However, several other studies have shown that gender has limited effects.
  • Lymph node metastases have been shown to be an independent risk factor, especially with multiple metastatic mediastinal lymph nodes.
  • Younger age and better performance status have also been reported to be risk factors for brain metastases in NSCLC in many studies.
  • Levels of tumor markers may also be predictive of BM risk in NSCLC:
    • In locally advanced NSCLC, neuron-specific enolase has been shown to be an independent risk factor for BM
    • Elevated serum levels of carcinoembryonic antigen in NSCLC patients are an independent predictive factor for BM.
  • Mutations in oncogenes that may influence brain metastases risk include EGFR, ALK, and KRAS mutations. Expression of PD-1/ PD-L1 and TMB may also have some relationship with brain metastases.
Original research

Epidermal growth factor receptor mutational status and brain metastases in non-small-cell lung cancer

Bhatt VR et al. J Glob Oncol 2016; 3(3): 208–217. doi:10.1200/JGO.2016.00339.

Summary points

  • The analysis included a total of 1522 NSCLC patients, of whom 87% had adenocarcinoma histology.
  • Overall, on multivariate analysis, ethnicity, smoking status, alcohol consumption, adenocarcinoma, and metastatic disease were all found to be significant predictors of having a tumor with an EGFR mutation.
  • Median overall survival was 19.8 months, with shorter survival seen in patients with brain metastases (BM) versus those without (15.0 vs 20.6 months; p=0.02).
  • The study found that patients with tumors harboring an EGFR mutation had an almost twofold increase in risk of BM, but EGFR status was not predictive of survival in patients with BM.
Original research

CNS Metastases in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: Impact on Health Resource Utilization

Chooback N, Lefresne S, Lau SC, Ho C. J Oncol Pract 2018; 14(10): e612–e620. doi:10.1200/JOP.18.00054.

Summary

  • A total of 499 patients with advanced EGFR-mutant NSCLC referred to a single center in Canada between March 2010 and December 2015 were included in this analysis, of whom 270 (54%) did not have or develop CNS disease and 229 (46%) had been diagnosed with CNS metastases.
  • Whole brain radiotherapy, with or without surgery, or stereotactic radiosurgery, was the main mode of treatment for most patients with CNS metastases.
  • Median overall survival for patients without CNS metastases was 33.2 months, compared with 24.7 months for those with CNS metastases; in the CNS-metastases group, median overall survival from time of diagnosis of CNS metastases was 9.1 months.
  • In the 9 months prior to death or last follow-up, the presence of CNS metastases increased HRU, with more clinic visits (12.71 vs 8.53; p<0.001), hospitalizations (0.76 vs 0.43; p<0.001), CNS-imaging investigations (2.65 vs 0.52; p<0.001), ER visits (0.14 vs 0.03; p=0.001), and hospice admissions (19% vs 3%; p<0.001) reported with patients with CNS metastases compared with those without.
  • Overall, the study revealed that the incidence of CNS disease in EGFR-mutant NSCLC patients is high and associated with increased use of healthcare resources.


Treatment landscape

Review

A Neuro-oncologist’s Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer

McGranahan T, Nagpal S. Curr Treat Options Oncol 2017; 18(4): 22. doi:10.1007/s11864-017-0466-0.

Summary points

  • TKIs are a first-line therapy option for patients with advanced NSCLC tumors with activating mutations in EGFR (EGFRact+), and should be offered to all patients with EGFRact+ NSCLC regardless of performance status, due to their tolerability and rapid action.
  • Use of TKIs in patients with brain metastases (BM) is increasing, despite a lack of evidence from randomized controlled trials. The most common first-line TKI in Asian countries is gefitinib, with erlotinib more commonly used in the US – retrospective analysis does not support significant survival differences between these two agents. In patients who develop resistance to first- or second-generation TKIs, usually due to the acquired point mutation T790M, osimertinib, a potent irreversible inhibitor of T790M, is favored.
  • Conventional chemotherapy has been thought to play a limited role in the treatment of BM due to concerns regarding penetration of the BBB, but available evidence suggests that the antifolate chemotherapy agent pemetrexed may improve survival.
  • There are three immune checkpoint inhibitors approved for use in NSCLC: nivolumab, pembrolizumab and atezolizumab. The use of these agents is reserved for after TKIs, and usually not until progression on conventional chemotherapy, except in instances where there is high expression of PD-L1.
  • Currently, use of bevacizumab in the treatment of BM is limited to the management of steroid-refractory vasogenic edema and of radiation necrosis.
  • Surgery is reserved for large (>3cm), symptomatic, accessible BM or when additional histologic diagnosis is required.
  • Whole-brain radiation therapy is reserved for patients with intracranial progression refractory to all systemic therapies who are not candidates for surgery or stereotactic radiosurgery when performance status allows. Stereotactic radiosurgery in combination with TKIs for brain metastases <3 cm is the currently favored approach.
Review

Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors

Wrona A et al. Cancer Treat Rev 2018; 71: 59–67. doi:10.1016/j.ctrv.2018.10.011.

Summary points

  • Based on available data, stereotactic radiosurgery (SRS) is currently the preferred radiotherapy technique following surgical resection of 1–3 brain metastases (BM); compared with whole-brain radiotherapy, SRS offers sparing of adjacent healthy brain parenchyma and reduced neurotoxicity.
  • Targeted therapies for BM in a molecularly defined population of NSCLC patients include the first- and second-generation EGFR TKIs, with the preferred agent among, erlotinib, gefitinib and afatinib remaining unknown, owing to comparable median overall survival (22–26 months for all three) and no available direct comparisons.
  • While the combination of first-generation TKIs and radiotherapy could theoretically be expected to improve survival, this combination has not found a place in clinical practice, largely due to inconsistent available data.
  • The third-generation TKIs have better CNS permeability and challenge the concept of upfront whole brain radiotherapy, with better efficacy and tolerability.
  • Other potential treatment options include the first-generation ALK inhibitor crizotinib and next-generation agents, designed to more efficiently cross the BBB and achieve higher concentrations in the CNS.
  • These newer agents now fit into the management algorithm for BM in NSCLC patients with oncogenic mutations. In all instances, consolidation of local therapy with TKIs should be considered.


Radiotherapy

Systematic review

Upfront cranial radiotherapy vs. EGFR tyrosine kinase inhibitors alone for the treatment of brain metastases from non-small-cell lung cancer: a meta-analysis of 1465 patients

Du X-J et al. Front Oncol 2018; 8: 603. doi:10.3389/fonc.2018.00603.

Summary points

  • ​​​​​​​There were 13 studies selected for inclusion in this meta-analysis, of which 12 were retrospective and one was a randomized controlled trial. The studies included a total of 1456 patients with brain metastases from EGFR-mutated NSCLC.
  • Of the included studies, 11 used upfront radiotherapy plus a TKI in the treatment group, with the other two defining the treatment group as upfront radiotherapy only.
  • Upfront brain radiotherapy was associated with significantly higher overall survival (hazard ratio [HR] 0.78, 95% CI 0.65–0.93, p=0.005) than TKIs alone, with upfront radiotherapy plus TKIs associated with better overall survival (HR 0.71, 95% CI 0.58–0.86, p=0.0005) and intracranial progression-free survival (HR 0.69, 95% CI 0.49–0.99, p=0.04).
  • Upfront stereotactic radiosurgery was associated with better overall survival than TKIs alone (HR 0.37, 95% CI 0.26–0.54, p<0.00001).
  • The results of this study suggest that in NSCLC patients with brain metastases, treatment with only first-generation TKIs (erlotinib or gefitinib) is insufficient.


Surgery

Retrospective chart review

Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer

Kakusa B et al. J Neurooncol 2018; 140(3): 705–715. doi:10.1007/s11060-018-03002-0.

Summary points

  • A total of 18 patients with brain metastases who died within 3 months of stereotactic radiosurgery were identified, along with 29 patients who were alive at the 6-month follow-up and 9 patients who died between the 3- and 6-month follow ups.
  • In univariate analysis, older age, male gender, shorter time interval between primary cancer and first brain metastasis diagnoses, greater number of brain metastases, and lower Karnofsky performance status were associated with shorter overall survival following the most recent stereotactic radiosurgery.
  • Male gender, increased number of brain metastases, and lower Karnofsky performance status remained significant predictors of reduced overall survival on multivariate analyses.
  • Further research is necessary to develop predictive models of early death and long-term survival in these patients with NSCLC.


Immunotherapy

Original research

Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study

Gadgeel SM et al. Lung Cancer 2019; 128: 105-112. doi:10.1016/j.lungcan.2018.12.017

Summary points
  • Preliminary evidence has emerged suggesting that immune checkpoint inhibitors may be effective in brain metastases emerging from NSCLC.
  • In the previously reported phase III OAK study that compared atezolizumab and docetaxel in NSCLC patients, around 14% of patients in each arm had a history of asymptomatic brain metastases (61/425 in the atezolizumab arm and 62/425 in the docetaxel arm), identified by brain scans prior to enrollment and in follow up.
  • This subsequent exploratory analysis investigated the safety and efficacy of atezolizumab and docetaxel in this subpopulation.
  • The results showed a trend towards improved overall survival with atezolizumab compared with docetaxel in this population, with an acceptable neurologic safety profile.
  • There was also an increase in the time to radiographic identification of new symptomatic brain lesions in the patients treated with atezolizumab.
  • This analysis provide initial evidence for a role of immune checkpoint inhibitors in treating patients with brain metastases.

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