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Data emerge on new immunotherapeutic targets for melanoma
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NEW YORK — Several trials either have been completed or are underway to evaluate new immunotherapeutic targets for patients with melanoma, according to a presenter at HemOnc Today New York.
“When we think about where we’re going with immune therapy, it’s important to realize where we are and where have we been,” Michael A. Postow, MD, assistant attending physician on the melanoma-sarcoma service at Memorial Sloan Kettering Cancer Center, said during his presentation. “What are the targets we have been using, and how do we modify what we know and explore totally new territory to try to improve outcomes?”
Use of immune checkpoint inhibitors that target CTLA-4 and PD-1 have been “the really big treatment advance” in immune therapy in the past 5 to 7 years, Postow said.
“These strategies get T cells to fight tumors more strongly, but in the tumor microenvironment, there are other immunosuppressive molecules — like stop signs — that prevent T cells from getting into the tumor and killing it the in the appropriate way.”
One of them is indoleamine 2,3 dioxygenase (IDO), which inhibits T cell responses in the tumor microenvironment through a number of complex mechanisms. For example, it depletes tryptophan, an essential amino acid for T cells, and also produces a toxic metabolite of tryptophan called kynurenine.
“The idea is that if you block IDO, that would hopefully increase tryptophan levels and decrease this toxic metabolite kynurenine,” Postow said.
Several IDO inhibitors are in development, including epacadostat (Incyte), indoximod (NewLink Genetics) and BMS-986205 (Bristol-Myers Squibb).
Results of nonrandomized phase 2 trials that evaluated these agents in combination with PD-1 inhibitors — such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) — showed promising response rates that exceeded 50% and even reached 61%.
Single-arm data of the combination of epacadostat plus pembrolizumab showed median PFS of 12.4 months for all 39 patients, and 22.8 months for treatment-naive patients.
“That is fantastic,” Postow said. “That is much better than we have with PD-1 therapy alone, or with ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab together. ... This is very promising single-arm data, and these outcomes are enough to justify and launch a number of randomized clinical trials with primary endpoints including PFS.”
In addition, studies of IDO inhibitors in combination PD-1 inhibitors have not shown obvious increases in side effects, Postow said.
“We are eagerly awaiting the randomized data from ongoing phase 3 studies,” he said.
The question arises whether IDO inhibition plus PD-1 therapy will be the next first-line immunotherapy approach for all patients.
“I don’t quite know the answer,” Postow said. “Of course, we would need to see that PFS benefit in a randomized context. Also, it would be nice to absolutely know the median PFS with IDO plus PD-1 looks comparable to the ipilimumab-nivolumab combination, which is 11.5 months.”
In addition, the efficacy of IDO and PD-1 inhibition is unclear for patients who progressed on adjuvant nivolumab, Postow said.
Other new targets are being developed in PD-1 refractory melanoma.
One of them is LAG-3.
A study presented at last year’s European Society for Medical Oncology Congress examined the LAG-3 inhibitor relatlimab (Bristol-Myers Squibb) plus nivolumab for 68 patients with melanoma that progressed on prior PD-1-based treatment.
Seven patients (11.5%; 95% CI, 4.7-22) responded to treatment, including one (1.6%) who achieved a complete response and six (9.8%) who achieved partial response.
Postow emphasized several of the patients enrolled on this study had responded to prior anti-PD-1/PD-L1 therapy, including one (1.5%) who achieved complete response and 12 (18%) who achieved partial response.
“I’d like to know if the patients who received relatlimab and nivolumab are different from or similar to the patients who previously responded,” he said. “Is there something about reinduction with PD-1 that may account for some of these responses, or is this all being driven by LAG-3? These answers remain unknown, and hopefully with more time and more data, we’ll get those answers.”
The response rates observed with the LAG-3-nivolumab combination approximate those seen with ipilimumab and chemotherapy in PD-1-refractory melanoma. However, the LAG-3-nivolumab combination appeared better tolerated, Postow said.
“As long as we get response rates that are less than 20%, it leaves the field open to other combinations,” Postow said. “That is somewhat of an arbitrary threshold, but if we can really push responses over that 20% threshold, I think that’s when we’re going to start getting excited.” – by Mark Leiser
Reference:
Postow M. New immunotherapeutic targets in melanoma: What does the future hold? Presented at: HemOnc Today New York; March 8-10, 2018; New York.
Disclosure: Postow reports advisory board roles with Array BioPharma, Bristol-Myers Squibb, Incyte, Merck, NewLink and Novartis, as well as honoraria from Bristol-Myers Squibb and Merck.