Summary
New therapies are showing significant promise for patients diagnosed with advanced metastatic melanoma—a disease with a historically poor prognosis. For example, the overall survival (OS) of patients treated with nivolumab in combination with ipilimumab remained steady at 57 percent, even after more than 4 years, new long-term data presented at the 2019 ASCO Annual Meeting suggests (Abstract 9533). Added to that, patient-reported quality-of-life (QoL) measures indicate the majority patients maintain their QoL during therapy and beyond (ASCO Abstracts 9568 and 9551).
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Original Article
Patient Survival, QoL Hold Steady With Nivolumab & Ipilimumab Therapy
Oncology Times
By Rebecca Hepp
New therapies are showing significant promise for patients diagnosed with advanced metastatic melanoma—a disease with a historically poor prognosis. For example, the overall survival (OS) of patients treated with nivolumab in combination with ipilimumab remained steady at 57 percent, even after more than 4 years, new long-term data presented at the 2019 ASCO Annual Meeting suggests (Abstract 9533). Added to that, patient-reported quality-of-life (QoL) measures indicate the majority patients maintain their QoL during therapy and beyond (ASCO Abstracts 9568 and 9551).
Survival Stats
In the combination’s initial phase I dose-escalation study, patients with previously treated or untreated unresectable stage III or IV melanoma and an ECOG performance status of 0 or 1 were randomized to one of five cohorts, each with a different dosing scale of nivolumab and ipilimumab. The longest maintenance regimen reached 96 weeks. The data showed patients could expect an OS of 63 percent at 3 years. This 4-5 year follow-up was just as reassuring, according to lead author Michael B. Atkins, MD, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center and the Scholl Professor and Vice Chair of the Department of Oncology at Georgetown University Medical Center.
For 94 patients receiving the combination, the researchers found an OS of 57 percent between 4 and 4.5 years of follow-up.
“Although this population is not identical to the population in the phase III trial that led to the combination’s approval (some had previous therapies or different regimens), it still gives us a good sense of anti-tumor activity,” Atkins explained. “We saw that at 4 years, 57 percent of the patients with advanced melanoma were alive, and this appeared be a plateau of the survival curve. Before 2011, the median survival was 6-9 months, and less than 10 percent were alive at 4-5 years. Other studies with either ipilimumab or nivolumab monotherapy produced overall survival plateaus in the 30 percent to 45 percent range.”
The team also noted patients in all subgroups experienced durable benefit ranging from an OS plateau of 49 percent in patients with elevated LDH to 71 percent in patients whose disease was PDL-1 positive.
“When we looked at which subgroups did the best, we couldn’t identify any one group that didn’t do well on the therapy—even those with poor prognostic factors such as elevated LDH had an overall survival of at least 49 percent,” he noted. “So, it works well across the board for patients with advanced melanoma. If you responded, and you had a reasonable chance of responding, you were likely to have a durable benefit.”
Once patients discontinued treatment, Atkins and his team looked at the OS for the next 3 years to see if the reason for therapy cessation affected their outcome. For those who discontinued treatment for any reason, the 1-, 2- and 3-year OS after stopping treatment came in at 74 percent, 65 percent, and 56 percent, respectively. Patients who completed the treatment course experienced an OS of 86 percent 3 years after stopping treatment. If patients discontinued due to treatment toxicity, 65 percent were alive 3 years after stopping treatment. Not surprisingly, discontinuation due to disease progression led to lower OS rates of 52 percent, 34 percent and 24 percent at 1, 2 and 3 years post-treatment. Such patients who experienced progressive disease were more likely to exhibit poor prognostic characteristics such as elevated LDH levels and prior treatment.
“No matter what the risk factors were for a particular subgroup at the start of treatment, those that made it through treatment or experienced toxicity requiring treatment cessation were highly likely to do well long-term,” Atkins claimed. “These data provide some support for stopping treatment earlier for patients experiencing benefit or significant toxicity. Stopping treatment in such patients can achieve an ultimate goal for these patients: to have their cancer controlled and treatment stopped so that they can get back to their pre-cancer lives.”
The next step is identifying exactly when patients experiencing a good response can stop treatment and still gain maximal benefit, Atkins added.
Quality Is Key
In addition to better survival rates, the combination therapy provides patients with a good QoL, even 4 years post-treatment. Researchers already knew patients treated with nivolumab with or without ipilimumab maintained their QoL at least 1 year after therapy, but little was known after that. But new long-term data from the CheckMate 067 investigation show a similar trend.
The researchers first randomized 945 patients to one of three treatment arms: nivolumab with placebo, nivolumab with ipilimumab followed by a different dosing regimen of nivolumab, or ipilimumab with placebo.
They assessed the patient-reported QoL outcomes at baseline, weeks 1 and 5 of each 6-week treatment cycle, and the treatment-free interval—after study treatment and without subsequent therapy—for up to 4 years using two different scales, the EORTC QLQ-C30 and the EQ-5D-3L. While the EORTC QLQ-C30 helped assess the patient’s global health status, the EQ-5D-3L revealed general QoL.
During treatment, the researchers found patients reported no deterioration of QoL, regardless of the treatment arm, leading them to believe extended treatment doesn’t affect patients’ QoL.
“The quality of life was not negatively impacted by the fact that there was more toxicity with the combination,” Atkins explained. “The toxicities, while potentially severe, occur in only about half of patients, and the symptoms can often be quickly controlled. This is different than toxicities typically associated with chemotherapy or more chronic therapies, which are more universal and often prevalent throughout treatment. Further, as the toxicity of immunotherapy is associated with a better chance of response, its impact on quality of life was further mitigated.”
As for the treatment-free interval, the researchers assessed patients 30 and 84 days after the last treatment dose, and then every 3 months for the first year and every 6 months thereafter. They found patient-reported QoL measures remained steady at both 30 and 84 days post-treatment, no matter the reason for treatment discontinuation. They noted that patients who stopped treatment due to toxicity reported a clinically significant decline in QoL in some questionnaire subscales at day 30, but all but one of those subscales improved to baseline by the second, 84-day, follow-up.
The researchers noted the study was limited by small sample sizes at subsequent follow-up, which hampered their ability to assess QoL beyond the first two data points. Of the patients initially enrolled in the study, fewer than 50 receiving treatment remained after three years. However, what data they have suggests QoL remained stable beyond the 84-day check.
All of this is good news for patients with advanced melanoma, and the next research efforts are already looking at ways of maximizing not only the benefit of treatment, but also potentially the survival free of treatment, according to Atkins.
Rebecca Hepp is a contributing writer.