Commenting for The ASCO Post, ­melanoma expert Vernon K. Sondak, MD, Chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, Tampa, maintained that the association between immuno­therapy-related toxicity and better outcomes is not yet clear.

Vernon K. Sondak, MD

He first noted the impact of novel agents on melanoma mortality—a 29% reduction in deaths in just 3 years. But with more than 7,000 deaths predicted for 2019, “we still have a long way to go,” according to Dr. Sondak. “Adjuvant therapy using the drugs that have shown so much benefit in unresectable disease is a logical next step.”

Outcomes and Tolerability

“Recent randomized phase III trials have shown that ipilimumab, pembrolizumab, nivolumab, and the combination of dabrafenib plus trametinib can all decrease the risk of melanoma recurrence in patients with high-risk node-positive melanoma. As the long-term follow-up of the EORTC 18071 trial shows, the use of adjuvant therapy (with ipilimumab at a dose of 10 mg/kg, which is higher than the dose typically used for metastatic disease) can also be associated with a significant survival benefit,” he noted. “We are awaiting mature results of trials involving the other agents mentioned here to see how much, if any, survival benefit they provide compared with placebo-treated or ipilimumab-treated control subjects.”

Dr. Sondak emphasized that in the adjuvant setting, high-dose ipilimumab has substantial toxicity, but the anti–PD-1 (programmed cell death protein 1) agents pembrolizumab or nivolumab clearly have much less, with potentially greater efficacy. Because the toxicity of these immunomodulatory drugs is a reflection of the degree of immune stimulation and the abrogation of “tolerance” to self-antigens, he said, “It is certainly logical to ask whether patients who get more toxicity get more benefit as well. This seems to be the case, at least according to the analysis of EORTC 1325/KEYNOTE-054.”

Words of Caution

However, establishing cause and effect for such associations is not always straightforward, Dr. Sondak pointed out. “That’s because people who are doing well on a treatment take it for longer and hence have a higher risk of experiencing side effects, whereas people whose tumor comes back quickly stop treatment and hence have fewer side effects,” he explained. “Even in a large clinical trial, this time-on-treatment bias can be a difficult thing to adjust for in analyzing associations between toxicity and efficacy.”

“We already know that the less toxic anti–PD-1 drugs are better than the more toxic ipilimumab, and another ASCO presentation describing the results of the E1609 trial¹ showed that the more toxic high-dose ipilimumab regimen was not more effective than the somewhat less toxic standard-dose ipilimumab regimen in a head-to-head comparison in the adjuvant setting,” he noted. “So, it is appropriate to be skeptical about whether more toxicity is better in patients with melanoma who are undergoing adjuvant ­immunotherapy.”

“At the same time, it’s also logical to investigate whether combinations of anti–PD-1 and anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibodies—which are known to be more toxic than either one alone—might be more effective in the adjuvant setting. Such studies are ongoing, but no results have yet been reported. It is far too premature to consider using combination immunotherapy in the adjuvant setting, and the possibility that adding drugs just because a patient is not experiencing toxicity must be considered purely investigational,” Dr. Sondak maintained. ■

DISCLOSURE: Dr. Sondak has served as a consultant or advisor to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck/Schering Plough, Novartis, and Provectus Biopharmaceuticals; and served on the data safety monitoring boards of Array, Bristol-Myers Squibb, Novartis, Pfizer, and Polynoma.

REFERENCE

1. Tarhini AA, Lee SJ, Hodi FS, et al: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms. 2017 ASCO Annual Meeting. Abstract 9500. Presented June 4, 2017.