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Taking Out the Tregs by Inhibiting IDO1

Immune checkpoint inhibitors (e.g. anti-PD1/PDL1, anti-CTLA4) have revolutionized the treatment of multiple tumor types, including urothelial and renal cell carcinomas.1, 2 Unfortunately, response rates to anti-PD1/PDL1 therapy are still generally low, although those who do respond or who have stable disease may have long-term durable clinical benefit.  It is likely that combination immunotherapy strategies targeting multiple negative regulators of tumor immune responses will be more effective than anti-PD1/PDL1 monotherapy.

A very promising immunotherapy target is IDO1.  IDO1 is an enzyme that promotes the metabolism of tryptophan, and plays a role in down-regulating T-cell responses – blocking T-cell activation and inducing T-cell apoptosis.3  It is also able to promote naïve T-cell differentiation to T regulatory cells, which play an immunosuppressive role.4  The IDO1 inhibitor epacadostat is able to block IDO1 enzymatic activity, thus enhancing anti-tumor T-cell activity.  Preclinical models have shown that epacadostat is able to synergize with immune checkpoint inhibitors.5, 6 

In urothelial bladder cancer patients, epacadostat was added to pembrolizumab in the ECHO-202/KEYNOTE-037 open-label, phase I/II trial.7 Patients with advanced urothelial carcinoma, prior platinum chemotherapy and no prior checkpoint inhibitor therapy were eligible to participate.  A total of 40 patients were evaluated with an impressive overall response rate of 35%, with all being partial responses.  The treatment was well tolerated with rash being the most common toxicity other than fatigue.  Rash occurred in 18% of patients, reaching grade 3 status in 7.5% of patients.  As a result, two ongoing phase 3 trials have been launched.  One is the KEYNOTE-672/ECHO-307 trial for patients with advanced urothelial carcinoma who are ineligible for cisplatin chemotherapy.  The other is the KEYNOTE-698/ECHO-303 trial for patients with recurrent or progressive urothelial carcinoma after receipt of prior platinum-based chemotherapy.

In renal cell carcinoma, epacadostat with pembrolizumab also achieved impressive response rates in the ECHO-202/KEYNOTE-037 trial cohort.  Eligible patients had advanced clear cell renal cell carcinoma after prior antiangiogenic therapy and no prior checkpoint inhibitor therapy.  A total of 33 patients were enrolled and 30 were efficacy evaluable.  Overall response rates were 47% for those with 0-1 prior treatments but 0% for those with 2 or more prior treatments.  Fatigue and rash were the most common adverse events.  Due to the impressive response rates in the 0-1 prior treatment group, the phase 3 KEYNOTE-679/ECHO-302 trial has been launched in the first-line metastatic setting, pitting the combination of epacadostat plus pembrolizumab vs. standard of care antiangiogenic therapy, either sunitinib or pazopanib.

Please see below for brief summaries and access to the ongoing phase 3 trials in both urothelial and renal cell carcinoma.

  • Pembrolizumab +/- Epacadostat for cisplatin-ineligible urothelial carcinoma patients - NCT03361865
  • Pembrolizumab +/- Epacadostat for urothelial carcinoma patients previously treated with platinum chemotherapy – NCT03374488
  • Pembrolizumab + Epacadostat vs. Sunitinib or Pazopanib for advanced renal clear cell carcinoma in the first line – NCT03260894

References

  1. Bellmunt J, de Wit R, Vaughn DJ, et al.  Pembrolizumab as second-line therapy for advanced urothelial carcinoma.  N Engl J Med 2017; 376:1015-26. 
  2. Motzer RJ, Escudier B, McDermott DF, et al.  Nivolumab versus everolimus in advanced renal-cell carcinoma.  N Engl J Med 2015; 373:1803-13.
  3. Mellor AL, Baban B, Chandler P, et al.  Cutting edge: induced indoleamine 2, 3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion.  J Immunol 2003; 171:1652-5.
  4. Fallarino F, Grohman U, You S, et al.  The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulator phenotype in naïve T cells.  J Immunol 2006; 176:6752-61.
  5. Holmgaard RB, Zamarin D, Munn DH, et al.  Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4.  J Exp Med 2013; 210:1389-402.
  6. Spranger S, Koblish HK, Horton B, et al.  Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment.  J Immunother Cancer 2014; 2:3.
  7. Smith DC, Gajewski T, Hamid O, et al.  Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.  J Clin Oncol 2017; 35: suppl; abstr 4503.
  8. Lara P, Bauer TM, Hamid O, et al.  Epacadostat plus pembrolizumab in patients with advanced RCC: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.  J Clin Oncol 2017; 35: suppl; abstr 4515.