IMMUNOTHERAPY FOR BRAIN METASTASIS

By Julia Boneder 7 meses ago
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Franziska Maria Ippen, MD

Postdoctoral Fellow
Divisions of Hematology/Oncology and Neuro-Oncology
Massachusetts General Hospital
Harvard Medical School

Priscilla Brastianos, MD

Director, Central Nervous System Metastasis Program
Divisions of Hematology/Oncology and Neuro-Oncology
Massachusetts General Hospital
Harvard Medical School
pbrastianos@partners.org

Brain metastasis represents one of the most devastating complications in
advanced systemic cancers. The treatment of patients with brain metastasis
remains an ongoing challenge. Historically, the major treatment approaches for
brain metastases included surgery, radiation therapy (as whole brain radiation
therapy and stereotactic radiosurgery) and chemotherapy. However, as genomic
studies have revealed a number of clinically actionable mutations and we gain
further insight in the molecular characteristics and the immune
microenvironment of brain metastases, more and more therapeutic agents
targeting molecular signaling pathways and immune responses in brain
metastases are emerging.
In recent years, immunotherapy has dramatically changed the landscape of
treatment of patients with brain metastases. To date, immune checkpoint
inhibitors such as ipilimumab targeting cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4) as well as pembrolizumab and nivolumab targeting
programmed cell death protein 1 (PD-1) are available for the treatment of
patients with brain metastases.
In a double-blinded phase-III trial in patients with unresectable stage III or IV
melanoma, the CTLA-4-inhibitor ipilimumab was shown to improve overall
survival (OS) (median 10.1 months), compared to treatment with the peptide
vaccine gp100 alone (median OS 6.4 months, hazard ratio, 0.66; p=0.003). No

difference in OS was observed between patients receiving ipilimumab alone and
a combination of ipilimumab and gp100 (median OS 10 months, hazard ratio for
death with ipilimumab plus gp100, 1.04; P=0.76).(1)
Studies following these promising results included an open-label phase-II trial
and two trials of the Italian Network for Tumor Biotherapy, NIBIT-1 and NIBIT2.
The open-label phase-II trial by Margolin et al. investigated the response to
treatment with ipilimumab in patients with neurologically asymptomatic
melanoma brain metastases without corticosteroid treatment (cohort A) and
neurologically symptomatic patients with melanoma brain metastases on a
stable dose of corticosteroids (cohort B). After 12 weeks, systemic disease
control was achieved in 18% of cohort A and in 5% of patients in cohort B.
Intracranial response to treatment was achieved in 24% patients of cohort A and
in 10% of cohort B.(2)
In the open-label, single-arm phase-II trial NIBIT-1, patients with measurable,
locally advanced, unresectable stage III or stage IV melanoma were included and
received a combination therapy of ipilimumab and fotemustine. Intracranial
disease control was achieved in 50% of participating patients with melanoma
brain metastases. Median brain progression-free survival (PFS) in these patients
was three months.(3) The authors subsequently published the three-year followup
results of this study, revealing that patients with brain metastases treated
with this combination had a median OS of 12.7 months.(4) These results set the
foundation for the open-label, triple arm phase-III trial NIBIT-2, which aims to
evaluate the OS of patients with melanoma brain metastases receiving either
fotemustine only, a combination of ipilimumab and fotemustine or the
combination of ipilimumab and nivolumab, which is currently recruiting
participants (NCT02460068).
The PD-1 inhibitors pembrolizumab and nivolumab are currently approved by
the U.S. Food and Drug Administration (FDA) for the treatment of advanced
nonsmall cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC). An
early analysis of an ongoing phase-II trial on pembrolizumab for patients with

untreated, asymptomatic brain metastases from melanoma or non-small-cell
lung cancer showed an intracranial response rate of 22% of patients with
melanoma and in 33% of patients with NSCLC with an acceptable safety
profile.(5)In regards to the combination of immune checkpoint inhibitors,
results of a recent randomized phase-III trial showed that the combination of
ipilimumab and nivolumab resulted in a significantly longer median PFS (11.5
months) in patients with metastatic melanoma as compared to nivolumab alone
(6.9 months) and ipilimumab alone (2.9 months). This study also demonstrated
that in patients with PD-L1-negative tumors, combination therapy of ipilimumab
and nivolumab resulted in a longer median PFS (11.2 months) than with
nivolumab alone (5.3 months). However, no difference in median PFS was
observed in patients with PD-L1-positive tumors between these two treatment
arms (14 months in both groups).(6)
On the basis of these promising results for CTLA-4 and PD-1 inhibitors, larger
studies investigating the role of several immune checkpoint inhibitors alone
(NCT02374242), in combination (NCT02320058, NCT02621515) and trials
investigating the combination of immune checkpoint inhibitors with
radiotherapy (NCT01703507, NCT01950195, NCT02107755) for the treatment
of patients with brain metastasis are currently ongoing.
Taken together, immune checkpoint inhibitors targeting CTLA-4 and PD-1 have
shown remarkable promise in patients with brain metastases from melanoma
and NSCLC thus far. Whether checkpoint inhibitors will lead to responses in
other histologic subtypes remains to be seen. Furthermore, there is still an
urgent need for a more detailed insight into potential resistance mechanisms
within the immune microenvironment in brain metastases. Biomarkers
predicting sensitivity or resistance to immune checkpoint inhibitors need to be
identified to further refine therapeutic regimens for patients with brain
metastases. Improved therapies are urgently needed, and immunotherapy is
now part of our armamentarium of therapies for this terrible and common
complication of cancer.

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