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Indoximod plus pembrolizumab prompts response in advanced melanoma
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The addition of investigational immunotherapy indoximod to pembrolizumab conferred superior response rates in patients with advanced melanoma, according to interim results of a phase 2 clinical trial presented at the American Association for Cancer Research Annual Meeting.
Pembrolizumab (Keytruda, Merck), a PD-1 inhibitor, was approved by the FDA in 2014 as an initial treatment for patients with advanced melanoma after showing an overall response rate of 33% in clinical trials.
“We demonstrated a robust response rate of 52% with indoximod [NLG-8189, NewLink Genetics] in combination with pembrolizumab for patients with advanced melanoma, including ocular melanoma,” Yousef N. Zakharia, MD, assistant professor in the department of internal medicine at University of Iowa, told HemOnc Today. “We also showed a 73% disease control rate without added toxicity.”
Zakharia and colleagues investigated whether they could improve response rate by adding an inhibitor of the [indoleamine 2,3-dioxygenase (IDO)] pathway to pembrolizumab.
The normal function of the IDO pathway is to keep the immune system in check and prevent it from responding inappropriately.
“However, some tumors hijack the pathway, using it to prevent the immune system from attacking and destroying the tumors, suggesting that it could be a good target for cancer immunotherapy,” Zakharia said.
Researchers evaluated 60 patients with advanced melanoma who received indoximod continuously in 21-day cycles (1,200 mg orally twice daily) concurrently with 3 mg/kg pembrolizumab every 21 days.
Objective, complete and partial response rates served as the primary endpoints.
As of January, six of 60 patients achieved complete response, and an additional 25 patients achieved partial response, for an overall response rate of 52%.
Fatigue, diarrhea, nausea, arthralgia, headache, cough, rash, pruritus and hypertension were the most common adverse events, occurring in more than 20% of patients. Anemia (17%) and hyperglycemia (17%) were the most frequently reported laboratory abnormalities.
The trial included nine patients with ocular melanoma, which is known to be more aggressive and less responsive to available systemic treatments, Zakharia noted.
“When the results are considered without the ocular melanoma patients, the response rate in cutaneous and nonocular melanoma is actually 59%, and the disease control rate is 80% in this patient population,” Zakharia said.
The initial results of the trial are “very promising,” Zakharia said, but added that the clinical benefit needs to be confirmed in a larger, randomized Phase 3 trial.
“Here’s an example of actually taking drugs that are designed to work together based upon an extensive body of literature that has been painstakingly accumulated over several decades, showing the relevance of IDO as a modulator of immune reactivity, and here’s a clinical trial that suggests this is a strategy for enhancing the likelihood of benefit in this disease,” Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, who was not associated with the study, said. “That would be a really important milestone in the development of strategies that would be akin to the combination of checkpoints like CTLA-4 plus anti–PD-1 antibody to treat melanoma.”
Indoximod is currently being tested in multiple types of malignancies, including breast cancer, brain tumors, glioblastoma and leukemia.
Following his presentation, Zakharia was asked if a triple combination of pembrolizumab, indoximod and ipilimumab (Yervoy, Bristol-Myers Squibb) might confer an even greater benefit in patients with melanoma.
“This is a very interesting question,” Zakharia said. “What worries me with that combination is the overall toxicity we are encountering with all three. Although I would expect based on these current data that it would not increase the toxicity with this combination, that would need to be tested. It’s an interesting concept, and one would expect it might increase the efficacy, but that needs to be tested.” – by Chuck Gormley
Reference:
Zakharia Y, et al. Abstract CT117. Presented at: AACR Annual Meeting; April 1-5, 2017; Washington, D.C.
Disclosure: NewLink Genetics funded this study. Zakharia reports travel expenses from NewLink Genetics.