It Takes Two

PAIRING TWO IMMUNOTHERAPIES COULD bring multiple benefits for some people with advanced melanoma — a longer respite from the disease, and from some of the health and financial costs it generates.

By interfering with proteins that normally keep the immune system from going into overdrive, checkpoint inhibitors free up the body’s disease-fighting mechanism to better recognize and attack cancer. Two drugs in this class, Opdivo (nivolumab) and Yervoy (ipilimumab), are standard options for melanoma that has spread within the body.

Now, a team of investigators collaborating across several cancer centers has found promise in the combination of Opdivo and Yervoy after studying its cost-effectiveness compared with each drug alone. Their large retrospective study explored the length of the treatment-free interval between the completion of immunotherapy and the need for a subsequent therapy due to progression of disease. The team investigated the use of health care resources and their associated costs accrued by patients during that interval and determined which regimen led to the least amount of intervention for the longest time.

The result? The combination brought somewhat better outcomes than Opdivo alone, and both of those regimens by far bested single-agent Yervoy, particularly in melanoma that does not carry any BRAF gene mutations. Ahmad Tarhini, M.D., Ph.D., director of the Melanoma and Skin Cancer Program and the Center for Immuno-Oncology Research at the Cleveland Clinic Taussig Cancer Institute in Ohio and one of the study’s authors, presented those findings during the Society for Immunotherapy of Cancer conference in November 2017.

WEIGHING SIDE EFFECTS

“Immunotherapies for advanced melanoma, particularly (Opdivo plus Yervoy), may lead to a long treatment-free interval before starting second‐line therapy,” Tarhini and his co-authors concluded in their abstract. “The estimated annual cost of managing advanced melanoma is relatively low in the treatment-free interval prior to disease progression, especially with (Opdivo) and (Opdivo plus Yervoy).”

The study included 882 patients who had participated in the phase 3 CheckMate 067 and phase 2 CheckMate 069 trials, which tested various regimens of Opdivo and/or Yervoy in patients with advanced melanoma. The researchers found that, after immunotherapy treatment that lasted a median of about half a year, the mean treatment-free interval was 5.3 years with the drug combination, 3.4 years with Opdivo alone and 2.3 years with Yervoy alone.

But how was patients’ quality of life during the time off treatment? To determine “quality-adjusted time without symptoms or toxicity” (Q-TWiST), the researchers used a formula that factored in the time after immunotherapy that patients lived with burdensome side effects; the length of time with no symptoms, toxicities or progression; and the interval between disease progression and death or the end of the trial’s measurement period. They divided patients into groups based on which immunotherapies they had taken.

CONSIDERING THE ECONOMICS

At 23.5 months, the Q-TWiST was highest for Opdivo plus Yervoy compared with the monotherapies: 21.8 months for Opdivo and 15.3 months for Yervoy. That meant that compared with Yervoy, the combination regimen and Opdivo represented a relative gain in quality-adjusted time of 36.81 and 29.18 percent, respectively. Adding Yervoy to Opdivo brought a smaller gain of 6.35 percent compared with Opdivo alone. For all three comparisons, the relative gains increased continually with follow-up from three to 40 months.

Looked at in dollars and cents, Opdivo and the combination also outperformed Yervoy. When patients were off treatment and progression-free, their mean annual use of health care resources was $2,198 after Opdivo alone; $3,055 after the combination; and $8,679 after Yervoy by itself. When patients were off treatment and experiencing disease progression, those who’d taken the combination used $15,541 in health care resources, whereas those who’d taken either drug alone accrued more than $19,000 per year each in costs.

The calculations of health care resources included medications, laboratory tests, procedures, consultations, hospitalizations and surgeries. The researchers estimated prices for each service by applying unit costs from publicly available sources in the United States.

Hospitalizations for side effect management accounted for 34 to 62 percent of total costs in the progression‐free phase, and hospitalizations and surgeries made up about 94 percent of total costs in the progression phase.

The combination of Opdivo and Yervoy “has the longest treatment-free interval and a higher proportion of progression-free patients; therefore, the lower annual costs associated with the off-treatment phase and progressionfree phase are accrued for a longer time,” Tarhini said in his presentation.

The researchers also calculated cost per quality-adjusted life year, a measurement that incorporates both longevity and quality of life. The combination regimen still proved the least costly, at $95,464, if the treatments given upon first and second progressions were chemotherapies. The most expensive studied regimen, costing $168,614 per quality-adjusted life year, relied on Yervoy as an initial immunotherapy, followed upon progression by Opdivo and then chemotherapy.

“Treatment sequences starting with (Opdivo plus Yervoy) are cost-effective, driven by a long treatment-free interval, and provide important qualityadjusted survival gains to patients (who have advanced melanoma without BRAF gene mutations),” Tarhini concluded.

The study’s lead author, Michael B. Atkins, M.D., deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., discussed the importance of those findings with CURE®. “As shown with our melanoma research, immunotherapy has the potential to control disease for long periods of time even after treatment stops. This provides patients with treatment-free survival, which allows them the opportunity to return to their cancer-free lives,” he said.

The goal of combination immunotherapy regimens should be to gain control of the disease faster, enabling treatment to end sooner and maximizing the time until disease progression, according to Atkins. “(Although) such approaches may result in more up-front toxicity and cost to the health care system, if they achieve this goal, they may ultimately prove cheaper and more tolerable when measured over the longer horizon,” he said. “These principles should be kept in mind in drug development for all immunotherapy-sensitive cancer, and this information may ultimately help physicians and patients choose the treatment approach that is best for them.”