Time to Rethink Treating Brain Metastases in NSCLC?

H. Jack West, MD


August 15, 2019

We have long known that conventional chemotherapy has very limited activity in the central nervous system. And while whole brain radiation therapy and stereotactic radiosurgery have more consistent utility against brain metastases, physicians and patients are concerned about neurotoxicity and cognitive deficits.[1]

Fortunately, our therapeutic prospects are improving, at least for limited subsets of these patients. Osimertinib for epidermal growth factor receptor (EGFR) mutation–positive non–small cell lung cancer (NSCLC)[2] and multiple next-generation ALK inhibitors for ALK-positive NSCLC[3] have demonstrated intracranial response rates of 50% or higher in patients with untreated brain metastases, meaning that it is now appropriate to consider deferring radiation for even a very limited number of brain metastases that may be amenable to stereotactic radiosurgery, let alone whole brain radiation therapy.

Of note, however, this approach only applies to relatively small subgroups of patients with biomarker-driven advanced NSCLC.

With immunotherapies now playing an ever-increasing role in managing NSCLC (and other cancers), could these drugs also provide an effective strategy for treating brain metastases in a broader population of patients without a tumor harboring a driver mutation?

Harnessing Immunotherapy's Potential

This approach has been described in isolated case reports.[4] A retrospective assessment of the expanded-access program for nivolumab in Italy demonstrated some intracranial responses with an intracranial disease control rate of 39%.[5] Goldberg and colleagues[6] also documented intracranial responses to pembrolizumab in 6 of 18 patients (33%) with measurable brain metastases.

Most recently, Hendriks and colleagues[7] offered an important contribution to the field in the form of a multicenter, international study. They analyzed real-world data from 1025 consecutive patients with advanced NSCLC who received a PD-1 or PD-L1 inhibitor with or without a CTLA-4 inhibitor. Patients were excluded if they had leptomeningeal metastases or received chemotherapy. Among the total population, 255 (24.9%) had brain metastases at baseline, 100 (39.2% of those with brain metastases) of which were listed as being active untreated or as demonstrating progression after treatment with steroids.

Among patients with active brain metastases, the intracranial objective response rate was 27.3% (35.7% in those with tumor PD-L1 expression ≥ 1% vs 11.1% in those with PD-L1-negative tumors). In addition, 12.7% had a discordant intracranial vs extracranial response, and two patients (0.8% of those with brain metastases) demonstrated pseudoprogression. Patients with brain metastases had a median overall survival of 8.6 months, compared with 11.4 months for patients without brain metastases (P = .035). However, a subgroup analysis indicated that patients with brain metastases and on daily corticosteroids (> 10 mg of prednisolone equivalent/day) had a poorer prognosis (hazard ratio = 2.37).

What Does This Mean for Clinical Practice?

Although the overall survival in patients with brain metastases does not match that of those without them, the gap is closing. A much larger proportion of our patients with advanced NSCLC and brain metastases now have treatments available to them with meaningful intracranial activity.

Echoing the survival benefit that immunotherapy has ushered in elsewhere, emerging evidence now illustrates that PD-1/PD-L1 immune checkpoint inhibitors can provide good intracranial disease control to a broader population as well. Of note, the intracranial activity that we are observing with immunotherapy here is markedly lower than that seen with our more effective EGFR or ALK inhibitors.

This leaves open the question of whether it might be favorable to have more patients with brain metastases defer radiation in hopes of achieving a sustained response to immunotherapy, particularly if their tumor demonstrates high PD-L1 expression, high tumor mutational burden, or other emerging features that may be associated with greater probability of benefit. An alternative hypothesis that requires further exploration is whether radiation (such as stereotactic radiosurgery) prior to treatment with first-line immune checkpoint inhibitor therapy alone or with concurrent chemotherapy may facilitate the abscopal effect, in which responses to radiation may occur at distant sites from the radiated field.

Admittedly, we do not yet know the optimal first step in treating most patients with advanced NSCLC and brain metastases, but we have undoubtedly entered a new era in managing these patients. This is due to the growing array of systemic therapies that provide a realistic possibility, if not yet probability, of producing intracranial responses and effective control along with or potentially instead of the local therapies upon which we have relied historically. More important, targeted therapy and immunotherapy strategies can raise the low ceiling for overall survival that we have faced in these patients with brain metastases for far too long.

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