treatment for stage IV melanoma has improved
greatly in recent years, our patients with metastases to the brain have
remained the group most in need, they've had the worst prognosis, so we are
very excited about these results," said the national study's principal
investigator and lead author, M.D., Ph.D., associate professor of Melanoma
Medical Oncology at MD Anderson.
‘Hard-to-cure stage IV melanomas due to their spread into lymph nodes and brain regions can now be treated in patients with brain tumors.’
percent of patients with stage IV melanoma have tumors that
have already spread to the brain (brain metastases) at the time of diagnosis,
and 75 percent eventually developed the condition. This condition was earlier
so unmanageable by the treatment that these patients were routinely excluded
from clinical trials of new drugs.
One reason to omit these patients from clinical trials is that the
blood-brain barrier (BBB), tight vascular construction, prevents drugs from
reaching tumors in the brain.
are a common cause of the
disabling neurologic complications such as impaired
thinking, vision or memory, and death seen in patients with metastatic
overall median survival of patients with brain metastases is meager at around
four to five months.
Previous studies of the checkpoint inhibitors nivolumab
metastatic melanoma as mentioned before have excluded patients with untreated
brain metastases. However, immunotherapy used in the clinical trials does
not treat the tumors directly -instead, it empowers immune system cells, the T
cells, that can then defeat the barrier.
Drawbacks include immune-related side
Hence, in the current
study, the scientists conducted efficacy and safety evaluations of nivolumab
plus ipilimumab in patients with melanoma who had untreated brain metastases.
Study Design and Results
The study was an open-label, multicenter, phase 2 study conducted on
patients with metastatic
melanoma who had no neurologic symptoms and had at least one measurable, brain
metastasis with a tumor of 0.5 to 3 cm that had not been treated by radiation.
All patients received nivolumab
(1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks
for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks
until progression of the disease or the presence of unacceptable toxic effects.
Ipilimumab works by blocking a particular checkpoint on T cells and
nivolumab inhibits activation of another checkpoint. If unchecked, both
checkpoints shut down T cells and thus block the anti-tumor immune response.
minimum follow-up period of the trial was nine months and the result determined
was the rate of intracranial (inside the brain) clinical benefit, defined as
the percentage of patients who had stable disease for at least 6 months,
complete response, or partial response.
Among 94 patients with a median
of 14 months, the overall rate of intracranial clinical benefit was 57 %
- Twenty-four patients (26 %) showed a complete
- Twenty-eight patients (30 %) showed a partial
- Two patients (2 %) had stable disease
"This practice-changing study proved that you can start with
immunotherapy first with these patients, tackling both brain and extracranial
disease at the same time," Tawbi said. "And it opens up new
opportunities for development of systemic therapies for metastatic
At nine months, 59.5 percent of patients with brain tumors had not
progressed,making the overall one-year survival rate for patients with brain metastases with
the immunotherapy combination a whopping 82 percent.
Comparing this to patients (at less than 20 percent) with the same
condition but who are not in the study, Tawbi considers the absence of
progression for that long with brain metastases as huge.
Tawbi and colleagues go as far as to say that that the results shown
with the immunotherapy combination are valid enough to reconsider the current
standard of care for brain metastases: surgery or targeted radiation for a
small number of tumors and whole-brain radiation for more extensive disease.
Small metastases are usually treated with stereotactic radiation
which is quite effective
followed by a four-week wait and then treated with immunotherapy
. However, while the
radiation kills the original metastases, new ones crop up during the four
weeks, further delaying systemic treatment.
Tawbi says that in the current study "We've shown you don't have to
wait for radiation, you can initiate immunotherapy early for all patients and
expect the tumors in the brain to respond as well as those outside the brain.
Current efforts focus on adding radiation at the right time for lesions that
have not responded or progress. Neurosurgeons, radiation oncologists and
medical oncologists will continue to work together to recommend the best
initial approach for our patients and the best timing for subsequent treatments
For extracranial or outside-the-brain tumors -
- The tumors shrank or remained stable for 56.4
percent of study patients
- The nine-month progression-free survival was 56.6
At the time of data analysis, median progression-free and overall
survival had not been reached.
Brain-related side effects
Tawbi says, "We were quite concerned going into the study about
immunotherapy causing inflammation and swelling in the brain, so this was
closely monitored. In the end, only 5 percent of patients had swelling in the
Overall, the safety profile was similar to those caused by the
combination immunotherapy in patients with melanoma and without brain
The side effects noted were as follows -
- Around 34 patients or roughly 36 percent had some central nervous
system side effect - with the most prominent one being headache
experienced by 21of the patients More severe grade 3 or 4 toxicities -
three headaches, two with brain swelling, one with a brain hemorrhage and
one with loss of consciousness was experienced by 7 of the 34 patients
- Grade 3 or 4 adverse events were experienced by
fifty-two patients (55 percent), with 19 patients (20 percent) having to
leave the trial - the most common side effects in these grades were
probably signs of potential liver damage depicted by increased
alanine aminotransferase in 15 patients and increased aspartate
aminotransferase in 16 patients. One patient died from immune-related
inflammation of the heart.
Earlier studies have shown that ipilimumab alone had a response rate of
around 20 percent in brain metastases, and the combination had demonstrated
high response rates for brain metastases but at shorter durations.
Tawbi says that including melanoma patients with brain metastases in
clinical trials will accelerate progress for this patient population.
- Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain - (https://www.nejm.org/doi/full/10.1056/NEJMoa1805453?query=featured_home)