Response assessment and outcome of combining immunotherapy and radiosurgery for brain metastasis from malignant melanoma

Abstract

BackgroundThe optimal sequence of stereotactic radiotherapy (SRT) and immune checkpoint inhibition (ICI) and assessment of response in patients with brain metastases from melanoma remain challenging.MethodsWe reviewed clinical and neuroimaging data of 62 patients with melanoma, including 26 patients with BRAF-mutant tumours, with newly diagnosed brain metastases treated with ICI alone (n=10, group 1), SRT alone or in combination with other systemic therapies (n=20, group 2) or ICI plus SRT (n=32, group 3). Response was assessed retrospectively using response evaluation criteria in solid tumours (RECIST) V.1.1, response assessment in neuro-oncology (RANO) and immunotherapy RANO (iRANO) criteria. MRI follow-up from 43 patients was available for central review.ResultsPatients treated with ICI alone showed no objective responses and had worse outcome than patients treated with SRT without or with ICI. RECIST, RANO and iRANO criteria were concordant for complete response (CR) and partial response (PR). RANO called progression earlier than RECIST for clinical deterioration without MRI progression in some patients. Progression was called later when using iRANO criteria because of the need for a confirmatory scan. Pseudoprogression was documented in seven patients: three patients in group 2 and four patients in group 3. Radionecrosis was documented in seven patients: two patients in group 2 and five patients in group 3. Regression of non-irradiated lesions was seen neither in two patients treated with SRT alone nor in five patients treated with SRT plus ICI, providing no evidence for rare abscopal effects.ConclusionsPseudoprogression is uncommon with ICI alone, suggesting that growing lesions in such patients should trigger an intervention. Pseudoprogression rates were similar after SRT alone or SRT in combination with ICI. Abscopal effects are rare or do not exist. Response assessment criteria should be considered carefully when designing clinical studies for patients with brain metastases who receive SRT.

EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours

“…The optimal timing of SRT in the multimodal therapeutic approach to BM from melanoma remains to be determined, although data from uncontrolled cohort studies also support early combination [82].…”

“…The rate of pseudoprogression with immunotherapy alone appears to be low. Further studies are required to determine how to distinguish treatment-related changes from progression after SRT with or without systemic therapy [82]. For BM patients, whose primary tumour is still unknown after a first work-up at diagnosis, whole-body FDG-PET in the follow-up may be useful.…”

The abscopal effect: systematic review in patients with brain and spine metastases

“… 21 In two case series comprising 68 patients with metastatic melanoma who received ICI and radiotherapy (36, 32 patients respectively), no evidence of abscopal effects were found (total n = 61, 62). 19 , 20 …”

“… 21 , 22 This is contradicted, however by two studies which found no evidence of the abscopal effect; conclusions from one of these studies, however, is limited as reduction in tumor size was primarily studied for CNS metastases which may be a significantly rarer phenomenon. 20 In addition, in one case report a patient experienced an initial abscopal effect (following irradiation of brain metastases) and subsequent progression of extracranial disease, with a second abscopal effect observed following irradiation of a spinal metastasis. 17 This suggests that there are systematic changes occurring which promote anti-tumor immunity and may be harnessed in future treatments.…”

The Role of the Immune Response in Brain Metastases: Novel Imaging Biomarkers for Immunotherapy

“…Further guidance on endpoints in immunotherapy trials in BM—particularly the issue of separating out the intracranial and extracranial response—has been provided by the FDA ( 20 ). Whilst criteria are dynamic ( 21 , 22 ), such guidance should reduce the over-reporting of progressive disease due to imaging immune responses and consensus guidelines—which are technically low-quality evidence—will invariably will be applied in trials going forward ( 23 ).…”