Shrink Brain Tumors With Combination Immunotherapy

Highlights:

• Skin cancer or melanomas which have spread to the brain can now be treated effectively and safely by a combination of immunotherapy drugs
• Tumors that have spread to the brain (brain metastases) occur in advanced melanomas and have so far been difficult to treat due to non-enrollment of these patients in clinical trials
• The current study could change the present course of treatment for brain metastases

Stage IV melanomas are often the most difficult to cure. However, in a recent clinical trial, combination immunotherapy was given to Stage IV melanoma or skin cancer patients, where the tumor that had spread to the brain begain to shrink in more than half of the patients. The research was led by an investigator at The University of Texas MD Anderson Cancer Center. "As 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.

About 40 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.

Brain metastases are a common cause of the disabling neurologic complications such as impaired thinking, vision or memory, and death seen in patients with metastatic melanoma. The overall median survival of patients with brain metastases is meager at around four to five months.

Previous studies of the checkpoint inhibitors nivolumab combined with ipilimumab in 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 effects.

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.

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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.

The 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.

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Long-lasting responses

Among 94 patients with a median of 14 months, the overall rate of intracranial clinical benefit was 57 % among whom

• Twenty-four patients (26 %) showed a complete response
• Twenty-eight patients (30 %) showed a partial response
• 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 melanoma."

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 as needed."

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 percent

At the time of data analysis, median progression-free and overall survival had not been reached.

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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 brain."

Overall, the safety profile was similar to those caused by the combination immunotherapy in patients with melanoma and without brain metastases.

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.

Reference:

1. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain - (https://www.nejm.org/doi/full/10.1056/NEJMoa1805453?query=featured_home)

Source-Medindia