According to Steven O’Day, MD, Professor of Medical Oncology, The John Wayne Cancer Institute, Santa Monica, CA, the essential arguments supporting combinations of checkpoint blockade immunotherapy as the standard for treating metastatic melanoma arise out of their high disease control rates, rapid deep responses, improved response rates, longer progression-free survival, and good estimated overall survival (approaching 70% at 3 years).
The new systemic immunotherapies, he pointed out, are distinct from the traditional cell-directed therapies characterized by short responses with little impact on survival. The new therapies produce durable tumor responses, early disease control and symptom management, and offer patients time without symptoms or treatment and often long-term survival.
The newer programmed death-1 (PD-1) inhibitors, such as nivolumab and pembrolizumab, have demonstrated higher response rates than ipilimumab, the cytotoxic T-lymphocyte protein 4 inhibitor that was the first in decades to show an overall survival benefit in advanced melanoma.
Objective response rates (ORRs) in phase 3 research (CheckMate 067) were 19% for ipilimumab, 44% for nivolumab, and 58% for the combination of nivolumab and ipilimumab. Complete responses were reported in 2.2% for ipilimumab, 8.9% for nivolumab, and 11.5% for the nivolumab/ipilimumab combination. Similarly, median progression-free survival was 2.9 months for ipilimumab, 6.9 months for nivolumab, and 11.5 months for the combination.
Increased grade 3/4 adverse events were the price, with rates for ipilimumab and nivolumab at 27.3% and 16.3%, respectively, compared with 55.0% for the combination. No treatment-related deaths were reported in the nivolumab/ipilimumab arm (0.3% each for the nivolumab and ipilimumab arms).
“If patients are educated and prepared for side effects and communicate about them rapidly, early intervention reverses almost all of them,” O’Day said. Although adverse events led to discontinuation of therapy in 29.4% of patients receiving the ipilimumab/nivolumab combination, the ORR among discontinuing patients was nearly 70%. “Those responses are still durable, so with coming off therapy, while it shortens treatment, the opportunity for long-term survival is still there,” O’Day said.
Resolved: Ipilimumab + Nivolumab Is Not Suitable for All Metastatic Melanoma Patients
Jeffrey Weber, MD, PhD, Perlmutter Cancer Center, NYU Langone Medical Center, New York City, focused on the high toxicities with combination therapy. “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.”
Weber also said that the roughly 40% of melanoma patients with “hot” PD-1 ligand 1–positive tumors with an “inflammatory signature” are likely to benefit from PD-1 abrogation alone, with little need for adding ipilimumab. He added, “The toxicity of combination therapy suggests that those over 75 to 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 continued, noting that among patient populations unlikely to tolerate combination therapy, but appropriate for single-agent nivolumab or pembrolizumab, are patients with prior grade 3/4 adverse events related to ipilimumab therapy and patients with prior allografts or a history of hepatitis or controlled HIV infection.
Weber suggested that BRAF-mutated melanoma patients with low to normal lactate dehydrogenase (LDH) will likely respond as well to targeted BRAF + MEK inhibitors such as dabrafenib and trametinib as they will to ipilimumab + nivolumab, with a 30% overall survival plateau. The BRAF + MEK combination is much less toxic. For high-LDH, BRAF-mutated patients, a brief induction with BRAF + MEK followed by ipilimumab + nivolumab might be preferred, because the BRAF + MEK combination induces a T-cell influx into tumors and converts a “cold” tumor to a responsive “warm” tumor.
Looking to future combinations, Weber said that an early-phase study with pembrolizumab and an IDO inhibitor has demonstrated a 53% ORR, similar to ipilimumab/nivolumab, but with significantly less toxicity. “Therefore, ipilimumab plus nivolumab combination therapy is not indicated for all metastatic melanoma patients,” he concluded.
In a postdebate interview, O’Day said, “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.” While the pituitary cases (hypophysitis) generally require lifelong replacement therapy, a “hassle” factor for the patient, 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 T-VEC or PV-10, may also prove successful, O’Day said.