Combination Immunotherapy the New Standard for Patients with Metastatic Melanoma

June 2016, Vol 7, No 5

The key arguments supporting the use of combination therapy with checkpoint blockade immunotherapies as the standard of care for treating metastatic melanoma arise from the combination’s high disease control rates; rapid deep responses; improved response rates; longer progression-free survival (PFS); and good estimated overall survival (OS), approaching 70% at 3 years, said Steven J. O’Day, MD, Professor of Medical Oncology, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, at the recent HemOnc Today Melanoma and Cutaneous Malignancies meeting.

The new systemic immunotherapies produce durable tumor responses, early disease control, and symptom management. In addition, they offer patients time without symptoms or treatment and often long-term survival. Conversely, traditional cell-directed therapies are characterized by short responses with little impact on survival, Dr O’Day noted.

The newer PD-1–blocking antibodies, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), have demonstrated higher response rates than ipilimumab (Yervoy), the cytotoxic T-lymphocyte antigen-4 blockade agent that was the first in decades to show an OS benefit in patients with advanced melanoma.


The objective response rates in the phase 3 clinical trial CheckMate-067 were 19% with ipilimumab, 44% with nivolumab, and 58% with nivolumab plus ipilimumab. Complete responses were 2.2% with ipilimumab, 8.9% with nivolumab, and 11.5% with nivolumab plus ipilimumab. Similarly, the median PFS was 2.9 months with ipilimumab, 6.9 months with nivolumab, and 11.5 months with nivolumab plus ipilimumab.

However, the favorable response rates and survival data associated with nivolumab plus ipilimumab come with increased grade 3 or 4 adverse events, with 27.3% and 16.3% rates for ipilimumab and nivolumab, respectively, compared with 55% for nivolumab plus ipilimumab. No treatment-related deaths were reported with nivolumab plus ipilimumab.

“If patients are educated and prepared for side effects and communicate about them rapidly, early intervention reverses almost all of them,” Dr O’Day said. Although adverse events led to treatment discontinuation in 29.4% of patients who received nivolumab plus ipilimumab, the objective response rate was nearly 70% in patients who discontinued the combination therapy. “Those responses are still durable, so with coming off therapy, while it shortens treatment, the opportunity for long-term survival is still there,” Dr O’Day said.

High Toxicity Remains a Concern

Jeffrey S. Weber, MD, PhD, Deputy Director, Perlmutter Cancer Center, NYU Langone Medical Center, focused on the high toxicities associated with the combination of nivolumab plus ipilimumab. “You can talk about a zero death rate in a very tightly controlled, well put together randomized phase 3 trial, but when it comes to treatment in the community, where physicians have less experience, it’s going to be a different scenario.”

Dr Weber also said that roughly 40% of patients with melanoma with PD-1 ligand 1 tumors with an “inflammatory signature” are likely to benefit from PD-1 abrogation alone, with little need for adding ipilimumab.

“The toxicity of combination therapy suggests that those over 75-80 years of age or with significant comorbidities should be treated with single-agent PD-1 or a PD-1 combination other than ipilimumab,” he added.

Dr Weber noted that among patients who cannot tolerate combination therapy, but who can receive single-agent nivolumab or pembrolizumab, are patients with previous grade 3 or 4 ipilimumab-related adverse events, and patients with previous allografts or with a history of hepatitis or controlled HIV infection.

Dr Weber suggested that patients with BRAF mutation melanoma with low-to-normal lactate dehydrogenase (LDH) levels will likely respond as well to targeted BRAF plus MEK inhibitors, such as dabrafenib and trametinib, as they will to ipilimumab plus nivolumab, with a 30% plateau in OS. Combination therapy with BRAF plus MEK inhibitors is considerably less toxic than ipilimumab plus nivolumab combined.

For patients with BRAF mutation melanoma and with high LDH levels, a brief induction with BRAF plus MEK inhibitors followed by ipilimumab plus nivolumab may be preferred, because the BRAF plus MEK combination induces a T-cell influx into tumors, and converts a “cold” tumor to a responsive “warm” tumor.

Dr Weber said that an early-phase study with pembrolizumab and an indoleamine 2,3-dioxygenase inhibitor demonstrated a 53% objective response rate, similar to nivolumab plus ipilimumab, but with significantly less tox­icity. “Therefore, ipilimumab plus nivolumab combination therapy is not indicated for all metastatic melanoma patients,” he concluded.

“I completely agree with Dr Weber that the combinations with ipilimumab should be given through experienced hands. There needs to be a big commitment from the patient and the family to communicate information about side effects,” Dr O’Day said in an interview.

Although the pituitary cases (hypophysitis) typically require lifelong replacement therapy, which is a hassle for patients, the more important colitis and liver toxicities are generally reversible.

Combinations of a PD-1 agent with ipilimumab at lower doses, or with a third intralesional therapy, such as tal­imogene laherparepvec (Imlygic), may also prove successful for patients with metastatic melanoma, Dr O’Day said.

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