Immunotherapy Combo Clinically Beneficial in Patients with Melanoma Brain Metastases

A combination immunotherapy effectively shrank melanoma brain metastases in patients with stage 4 disease, according to a phase 2 study published in the New England Journal of Medicine.

Led by an investigator from The University of Texas MD Anderson Cancer Center, the study evaluated the efficacy and safety of the checkpoint inhibitor ipilimumab plus nivolumab in patients with stage 4 melanoma who had untreated brain metastases. The clinical trial was sponsored by Bristol-Myers Squibb.

With a median overall survival rate of 4 to 5 months, patients with brain metastases are in critical need of improved therapies. Currently, approximately 40% of patients with stage 4 melanoma have brain metastases at diagnosis and 75% eventually develop the condition.

Ninety-four patients were treated in the study with combined ipilimumab and nivolumab at a minimum follow-up of 9 months and a median of 14 months. Of the treated patients, 26% had a complete response to the therapy, 30% had a partial response, and 2% had stable disease, according to the data. The rate of intracranial clinical benefit was 57%. At the 9-month follow-up, 59.5% of patients with brain tumors had not progressed.

“The absence of progression for that long with brain metastases is huge,” lead author Hussein Tawbi, MD, PhD, associate professor of Melanoma Medical Oncology at MD Anderson, said in a press release. “Historically, the overall 1-year survival rate for patients with brain metastases is less than 20%, with the immunotherapy combination in this study, it’s 82%.”

Additionally, 56.4% of patients experienced shrinkage of non-brain tumors or remained stable. Nine-month progression-free survival (PFS) was 56.6% and median PFS and overall survival have not been reached.

Patients enrolled in the trial did not have neurological symptoms due to their untreated brain metastases. The researchers added a second arm to the study to investigate 20 patients who had neurological symptoms, but the trial arm had not been open long enough to analyze results.

Overall, 36.2% of patients had some type of central nervous system adverse effect, with headache being the most prominent, experienced by 21 patients. Seven of the 34 patients had more serious grade 3 or 4 toxicities: 3 headaches, 2 with brain swelling, 1 with brain hemorrhage, and 1 with syncope.

“We were quite concerned going into the study about immunotherapy causing inflammation and swelling in the brain, so this was closely monitored,” Dr Tawbi said in a statement. “In the end, only 5% of patients had swelling in the brain.”

The researchers indicated that the findings should elicit reconsideration of the current standard of care for brain metastases. Although stereotactic radiation can be an effective therapy for destroying small metastases, there is a 4-week wait between treatments in which new metastases can form.

“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,” Dr Tawbi said.

The study results add to building evidence of the clinical benefits of combination immunotherapy for patients with melanoma. A previous study published in Journal of Neuro-Oncology found that a combination of radiosurgery and immunotherapy, particularly PD-1 inhibitors, increased survival outcomes in patients with melanoma. The authors of the study concluded that anti-PD-1 immunotherapy produced more successful results, which indicates an advantage to anti-PD-1 or combination therapy with anti-CTLA4.

References

Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. NEJM. 2018. Doi: 10.1056/NEJMoa1805453

Combination immunotherapy shrinks melanoma brain metastases [news release]. MD Anderson’s website. https://www.mdanderson.org/newsroom/2018/08/combination-immunotherapy-shrinks-melanoma-brain-metastases.html. Accessed August 23, 2018.