Weighing Efficacy and Tolerability for Adjuvant Ipilimumab in Advanced Melanoma

Jean Jacques Grob, MD, PhD

Treatment with ipilimumab (Yervoy) has been shown to improve overall survival (OS), and the FDA approved the anticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody for use in patients with unresectable or metastatic melanoma in 2011. However, improved OS often comes with toxicity, and while those adverse events (AEs) are often mild to moderate, they are common, appearing in 70% to 88% of patients.

Jean Jacque Grob, MD, PhD, professor of Dermatology at the Hospital de la Timone, discussed the challenge of balancing safety and efficacy in his presentation at the 7^th European Post-Chicago Melanoma/Skin Cancer Meeting. The choice, he said, depends on the setting. In the curative setting, providers need to prioritize efficacy especially if there is an immediate threat to the patient, such as brain metastases.

Grob summarized results from four key studies of patients with advanced melanoma, CA184169, CheckMate 067, CheckMate 204, and KEYNOTE-029.

In the CA184169 study, median OS was significantly longer in patients with metastatic melanoma who received the higher ipilimumab dose of 10 mg/kg versus those patients receiving the lower dose of 3 mg/kg but the rate of grade 3-5 adverse events was markedly higher, 34% versus 19%.

In CheckMate 067, investigators saw only a modest OS benefit with ipilimumab 3 mg/kg plus nivolumab (Opdivo), compared with nivolumab or ipilimumab alone in patients with advanced melanoma.

“If improvement in intracranial progression-free survival (PFS) is confirmed at the 1- and 2-year time points then severe toxicity would be more acceptable,” said Grob.

In the KEYNOTE-029 trial, treatment with very-low-dose ipilimumab, 1 mg/kg, appeared to be efficacious in combination with pembrolizumab, and was associated with lower toxicity than ipilimumab 3 mg/kg.

“Overall, the toxicity:efficacy ratio appears to be better with lower ipilimumab doses in the curative setting,” Grob said. However, he noted that there isn’t enough data to draw strong conclusions.

In contrast, Grob said tolerability is more important in the adjuvant setting where recurrence is low and quality of life concerns are high. Tolerability is even more important for the patient groups considered to be “lower risk” but who account for the majority of deaths from melanoma, said Grob.

Duration and reversibility of adverse events also need to be taken into consideration, he said, and there is some risk administering treatment in this setting could decrease the efficacy of the same drugs when administered later for metastatic disease.

That said, there are clear survival advantages associated with adjuvant ipilimumab. Results from EORTC 18071 showed that 10 mg/kg ipilimumab produced a significantly higher 5-year OS compared with placebo in patients with high-risk stage III melanoma (65% vs 54%; HR, 0.72; 95% CI, 0.58-0.88; P = .001). However, 54.1% of patients in the ipilimumab group experienced a grade 3-5 AE.

That incidence rate for grade ≥3 AEs is similar to what investigators have observed in ECOG 1609. In that study, patients with resected stage IIIB, IIIC, M1a and M1b melanoma are randomly assigned to 3 mg/k then 10 mg/kg in a 2-step fashion or high-dose interferon alfa-2b.

Preliminary efficacy and toxicity results show that the relapse-free survival (RFS) rates at 3 years were similar between the two doses of ipilimumab whereas toxicity was substantially higher in the ipilimumab 10 mg/kg arm, 56.5% versus 36.6%.

Grob said that 3 mg/kg ipilimumab appears to be better tolerated than 10 mg/kg ipilimumab, but this trial was not designed to test this comparison.

“The high toxicities associated with ipilimumab 10 mg/kg are not acceptable in the adjuvant setting, and even the toxicity observed with ipilimumab 3 mg/kg is still not that low,” he said. He noted that 3 mg/kg ipilimumab is associated with acceptable toxicity, but efficacy has yet to be established. “If you look at all the trials we have in the adjuvant setting with IPI 3 and IPI 10, the toxicity is much lower with the IPI 3 dose. This makes ipilimumab a difficult drug to administer in the adjuvant setting.

“Ipilimumab 3 mg/kg plus nivolumab is still the reference immunotherapy regimen in the adjuvant setting but may become obsolete if not repositioned in a relevant subgroup, such as very aggressive melanoma.”

Grob said the balance between safety and efficacy for 10 mg/kg ipilimumab is barely acceptable for stage III melanoma patients, and debatable for stage III C-D patients.

He added that the balance between efficacy and tolerability of different regimens containing ipilimumab need to be assessed in light of other combinations with potentially better risk/benefit ratios.

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