Pembrolizumab and indoximod for melanoma

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Published: 13 Apr 2017
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Prof Yousef Nabih Zakharia - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, USA

Prof Zakharia speaks with ecancer at AACR 2017 about adding indoximod, an IDO inhibitor, to pembrolizumab to treat advanced melanoma.

In this interim report of results from 102 patients, he highlights that 52% of all patients respond, and that those figures increase when discounting patients with aggressive ocular melanoma.

Compared to phase III single agent studies of pembrolizumab, these results are a marked improvement in response with minimal added toxicity, though Dr Zakharia cautions against direct comparison before further trials conclude.

You can read more about these findings here.

This is our exciting phase II clinical trial combining IDO inhibitor indoximod with a standard of care checkpoint inhibitor in patients with advanced melanoma.

What were you focusing on?

This clinical trial is for unresectable and metastatic melanoma patients, including the ocular melanoma. It’s basically combining standard of care checkpoint inhibitor with IDO inhibitor indoximod in this patient population.

How many patients were involved?

As of March 2017 we enrolled 102 patients on this clinical trial. This is an interim analysis of 60 patients.
What are your findings thus far?

We are reporting the data on patients who got pembrolizumab with indoximod and the overall response rate in the whole patient population is 52% with a disease control rate of 73%. As we know the ocular melanoma is an aggressive disease and resistant to the available types of treatment so the overall response rate in the non-ocular melanoma patients was even higher at 59% with a disease control rate of 80%. In comparison to historical data in the KEYNOTE 006 with single agent pembrolizumab in phase III study the overall response rate in this patient population, the non-ocular melanoma patient was 33%. Obviously we need to practice caution in comparing this data since it’s not a head-to-head comparison.

Can you speculate on the mode of action?

Indoximod is an IDO pathway inhibitor; it’s a tryptophan mimetic so it restores the tryptophan sufficiency signal. It acts directly on the immune cells to reverse the IDO mediated immune suppression.

What are the implications?

This is a very exciting clinical trial because the overall response rate is impressive and more importantly the safety of this combination in comparison to prior clinical trials combining PD1 and anti-CTLA4 inhibitors, our study combination of indoximod and pembrolizumab was fairly well tolerated – minimal added toxicity on what we would expect from a single agent pembrolizumab, very few grade 3 toxicities, no grade 4 toxicities. In comparison to the PD1 and CTLA4 inhibitors the grade 3 and 4 toxicities were as high as 55% in prior published data. No treatment related deaths in our study population.

What is your take home message?

This is an exciting phase II trial; definitely the overall response rate in the range of 59% is encouraging. The safety of this combination is encouraging. Obviously this robust data supports the need for a phase III randomised study combining indoximod with a checkpoint inhibitor in comparison to a checkpoint inhibitor alone.