Abstract
Background
The objective of this work was to characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy.
Materials and Methods
Patients from four medical centers were included if they presented with isolated brain metastases treated with local therapy and received adjuvant treatment with ICIs.
Results
Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n = 8) and/or stereotactic radiosurgery (SRS; n = 6), were included. Ipilimumab/nivolumab was the adjuvant ICI used in four patients, of whom one recurred (25%) and none died, compared with three of seven (43%) who recurred and two of seven (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial.
Conclusion
Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI therapy, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.
Short abstract
Optimal management for patients with isolated resected brain metastases remains unclear. This article describes a series of patients presenting with isolated brain metastases managed with definitive local therapy (surgery and/or stereotactic radiosurgery) followed by immune checkpoint inhibitor (ICI) treatment.
Introduction
Anti–programmed death‐1 (PD‐1) therapy has demonstrated improved clinical outcomes as adjuvant therapy for stage III melanoma [1]. The adjuvant treatment of resected stage IV (i.e., isolated metastases) remains less clear. Subgroup analyses of one study of nivolumab versus ipilimumab showed that nivolumab improved outcomes for the small number of stage IV patients [2]. More recently, one small study suggested that the combination of ipilimumab and nivolumab was superior to nivolumab or observation in this setting of resected stage IV disease [3]. However, no study, including these, had more than a small number of patients with isolated resected brain metastases, an uncommon but clinically relevant scenario; thus, the optimal management for these patients remains unclear. We herein describe a series of patients presenting with isolated brain metastases managed with definitive local therapy (surgery and/or stereotactic radiosurgery [SRS]) followed by immune checkpoint inhibitor (ICI) treatment.
Materials and Methods
Institutional review board approval was obtained, and data were collected from four international academic medical centers. Patients were included if they presented with isolated brain metastases that were treated with surgical resection and/or stereotactic radiosurgery and received subsequent treatment with an ICI. Patients with >1 metastasis, including intra‐ or extracranially, were included if every metastasis was treated with definitive local therapy (surgery and/or SRS). Patient demographics, histologic details of the primary lesion, brain metastases characteristics, and management and outcomes were tracked. Kaplan‐Meier curves were used to assess survival outcomes with overall survival (OS) and progression free survival (PFS). A p value <.05 was considered significant. All analyses were conducted using GraphPad Prism 8.2.1.
Results
Eleven patients were identified, and most were male (90.1%) with a median age of 51 years. The primary lesions were cutaneous and of unknown origin in six and five patients, respectively. At primary presentation, three patients had lymph node involvement and six had identifiable mutations (two BRAF V600K, two BRAF V600E, two NRAS). No patients received prior systemic or adjuvant therapies.
The median time between primary presentation and identification of brain metastases was 14.4 months. The parietal lobe (five patients) was the most common location, followed by the temporal (two patients), cerebellum (one patient), parieto‐occipital (one patient), frontal (one patient), and occipital (one patient). The median brain metastases size was 3.9 cm. Ten lesions had surrounding edema and five had a hemorrhagic component. Two patients had >1 metastases; one with a right parietal and left parietal lesions, and one with a colon metastasis that was also resected. Eight patients underwent surgical resection of the brain metastasis, with three patients receiving SRS after resection. Additionally, three patients underwent SRS alone.
Following surgery and/or radiation, patients received nivolumab monotherapy (five patients), ipilimumab with nivolumab (four patients), pembrolizumab (one patient), and ipilimumab (one patient). Whereas no patients had extracranial disease recurrence, four patients experienced intracranial recurrence (three at the same primary site) with a median size of 1.6 cm. After recurrence, four out of four patients received additional systemic therapy (two with nivolumab; two with BRAF and MEK inhibitors). Eight patients developed immune‐related adverse events (irAEs), with three being severe (grade III/IV). Of the severe irAEs, there were two cases of hepatitis (ipilimumab and ipilimumab + nivolumab treatment) and one case of colitis (nivolumab treatment). One patient also developed cerebral radiation necrosis (Table 1).
Table 1.
Summary of patients presenting with isolated brain metastases
| Characteristic | Number of patients (%) |
|---|---|
| Age, median, years | 51.0 |
| Gender (% male) | 10 (90.1) |
| Mutation present | 6 |
| BRAF | 4 (66.7) |
| NRAS | 2 (33.3) |
| History of cutaneous primary lesion | 6 (54.5) |
| Breslow depth, cm | 1.74 |
| Ulceration present | 2 (33.3) |
| History of unknown primary lesion | 5 (45.5) |
| Prior lymph node involvement | 3 (27.3) |
| Median time between primary lesion and brain metastases, months | 14.4 |
| Location of brain metastases | |
| Parietal | 5 (45.5) |
| Temporal | 2 (18.2) |
| Cerebellum | 1 (9.1) |
| Parieto‐occipital | 1 (9.1) |
| Frontal | 1 (9.1) |
| Occipital | 1 (9.1) |
| Median size of brain metastases, cm | 3.9 |
| Surrounding edema with metastases | 10 (91.0) |
| Hemorrhagic component of metastases | 5 (45.5) |
| Immune checkpoint inhibitor for brain metastases | |
| Nivolumab | 5 (45.5) |
| Nivolumab with ipilimumab | 4 (36.4) |
| Pembrolizumab | 1 (9.1) |
| Ipilimumab | 1 (9.1) |
| Surgical treatment | 8 (72.7) |
| Radiosurgery | 6 (54.5) |
| Surgery and radiosurgery | 3 (27.3) |
| Recurrent brain lesion | 4 (36.4) |
| Median size of recurrent brain lesion, cm | 1.6 |
After a median duration of follow‐up of 10.6 months, nine patients were alive. Median survival from the date of brain metastases diagnosis to last follow‐up was 12.7 months. Of patients treated with ipilimumab and nivolumab, one out of four experienced recurrence and none died. Comparatively, of the seven patients who received monotherapy, three (43%, two patients with nivolumab and one patient with ipilimumab) experienced recurrence and two patients died (29%, one patient with nivolumab and one patient with pembrolizumab). Patients treated with combination therapy trended toward improved OS (median not reached for either group, p = .27) and PFS (median not reached vs. 29.1 months, p = .43) compared with those treated with monotherapy but were not statistically significant (Fig. 1).
Figure 1.
Clinical outcomes for patients treated with combination therapy vs. monotherapy. (A): OS in patients treated with monotherapy versus combination therapy (nivolumab with ipilimumab). (B): PFS in patients treated with monotherapy versus combination therapy (nivolumab with ipilimumab).Abbreviations: OS, overall survival; PFS, progression‐free survival.
Discussion
Recent studies have demonstrated the efficacy of ICIs, particularly PD‐1 inhibitors, in the treatment of melanoma brain metastases [3, 4]. Although ICIs have displayed promising results, patients with stage IV presentations without evidence of disease were excluded from most major trials validating ICIs in this population [5, 6]. Therefore, the outcomes of stage IV disease with isolated brain involvement are largely unknown. This study described the management and outcomes of patients who presented with stage IV disease after local treatment of brain metastases. Interestingly, similar to the recent data from the phase II IMMUNED trial, our preliminary results suggest patients treated with combination therapy displayed more favorable survival outcomes when compared with treatment with monotherapy [3]. Examining results from the IMMUNED study further, patients with history of brain metastases had a 100% rate of recurrence (six of six) when treated with nivolumab, compared with only 25% (two of eight) when treated with ipilimumab and nivolumab. When pooling data (in a highly exploratory fashion) from the IMMUNED study with our results, we suggest a lower rate of relapse with combination treatment (3 of 12, 25%) compared with monotherapy (9 of 13, 69%; chi‐square p = .027) in patients with brain metastases treated with adjuvant therapy. Other studies have shown a higher response rate with ipilimumab and nivolumab in patients with active brain metastases compared with monotherapy, thus providing additional indirect support for our results [7, 8, 9].
Notably, all patients who recurred did so intracranially. Although multiple options are available, the optimal sequence of therapy for melanoma brain metastases is not established. As an example, radiation in the setting of melanoma brain metastases has demonstrated a potential increased risk of radiation necrosis when combined with ICIs [10]. With 82% of our study population alive at last follow‐up, these results further emphasize the importance of undertaking a multidisciplinary approach for these patients.
There are some limitations with this study. Given the small sample size, it is difficult to make definitive conclusions from these data and extrapolate the findings to all patients with brain involvement. With a median follow‐up time of <1 year from treatment initiation, the long‐term outcomes for these patients are not established.
Conclusion
We summarized a series of patients presenting with isolated brain metastases treated with ICIs following definitive local therapy. Patients treated with combination therapy demonstrated favorable outcomes, and recurrences appeared to occur most frequently intracranially. These results should help guide future study design to characterize management and outcomes of this rare presentation.
Disclosures
Suthee Rapisuwon: Bristol‐Myers Squibb (RF); Matteo Carlino: Bristol‐Myers Squibb, Merck Sharp & Dohme, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai (C/A), Bristol‐Myers Squibb, Merck Sharp & Dohme, Novartis (H); Douglas B. Johnson: Array Biopharma, Bristol‐Myers Squibb, Merck, Novartis, Jansen, Iovance (C/A), Bristol‐Myers Squibb, Incyte (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Acknowledgments
This work was supported by a National Comprehensive Cancer Network Young Investigators Award, American Cancer Society Institutional Research Grant, NIH K23 CA204726, and NIH R01CA227481 (all to D.B.J.).
Disclosures of potential conflicts of interest may be found at the end of this article.
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