Merck and Bristol-Myers Squibb extend partnerships with Incyte on the eve of the American Association for Cancer Research (AACR) Meeting in Washington D.C., where IDO1 inhibitors took center stage on Tuesday.

On March 31st, on the eve of the 2017 American Association for Cancer Research (AACR) annual meeting in Washington D.C., Merck & Co. and Bristol-Myers Squibb (BMS) both announced extensions of their ongoing partnerships with Incyte, Corp., whose targeted therapy and immuno-oncology portfolio was featured in over 20 abstracts.

The extension of the 2015 Incyte and Merck Phase III clinical collaboration for the first-line combinational treatment for advanced melanoma using Incyte’s IDO1 inhibitor epacadostat and Merck’s anti-PD-1 Keytruda (pembrolizumab), adds four new tumor types: non-small cell lung cancer (NSCLC), bladder cancer, renal cell carcinoma (RCC), and squamous cell carcinoma of the head and neck (SCCHN).

The extension of the partnership between BMS and Incyte includes a cohort expansion of the ECHO-204 study established in 2014. This collaboration included a Phase I/II clinical investigation of epacadostat in combination with BMS’s anti-PD-1 Opdivo (nivolumab) as the first-line treatment for melanoma. The partnership will also include new Phase III registrational studies of this combination therapy as the first-line treatment for NSCLC (across the spectrum of PD-L1 expression) and the first-line treatment for head and neck cancer.

In addition to their anti-PD-1 partnerships, Incyte is also investigating possible combinational therapies with Roche’s anti-PD-L1 Tecentriq (atezolizumab) and AstraZeneca’s yet-to-be-approved anti-PD-L1 durvalumab.

IDO1 inhibitors were on display Tuesday at AACR in Washington. Both Incyte and NewLink Genetics — which produces epacadostat’s biggest competitor, indoximod — presented the efficacy of their IDO1 inhibitors taken in combination with immune system checkpoint inhibitors (ICI). NewLink Genetics’ indoximod showed pronounced success rate when combined with Keytruda, with a 52%-59% Overall Response Rate (ORR) when treating melanoma — whereas Keytruda treatment alone hovered in the low 30s. However, people took to Twitter immediately after the presentation to question the significance of these findings, especially when compared to the more robust results from Incyte. 

Incyte and NewLink Genetics are not the only two IDO1s currently being investigated. BMS presented data on their own IDO1, BMS-986205, which Faoud Namouni, BMS’s oncology development chief, thinks has the potential to be “one of the most potent in the class.” 

IDO1 inhibitors are an attractive option because, unlike systemic inhibitors like PD-1 and CTLA-4, they target the tumor microenvironment, which raises fewer safety concerns. Yet it is still too early to tell whether they will replace anti-CTLA-4s such as Yervoy (ipilimumab), which have shown extremely pronounced efficacy when combined with PD-1 inhibitors like Opdivo. The combination of these two ICIs has shown a 61% objective response rate (ORR) for patients with metastatic melanoma. However, this combination therapy also exhibits increased adverse events when compared to either drug alone. 

IDO1 inhibitors promote an increased immune cells response, which can be used to target cancer cells. Inhibiting IDO1 decreases kynurenine, a metabolite of tryptophan known to quell immune response by deactivating dendritic cells, NK cells, and T-lymphocytes. IDO1 inhibitors appear to have a more far-reaching promotion of an immune response compared to anti-CTLA-4, as well as being easier for patients to handle due to decreased adverse effects. 

Opdivo, which had to overcome several hurdles this year—one of which being results that showed little to no improvement over chemotherapy treatment—found a bright note this year at AACR, as it showed a 5-year survival rate of 16% for patients with advanced NSCLC taking Opdivo alone. Historically, the survival rate for NSCLC is 5%.

The forecast for the oncological immunotherapy continues to be one of the most erratic in the pharmaceutical sector as companies continue to spread their arms between therapeutics. Six months ago saw forecasts at $34b by 2024, but now the estimates vary from $75.8b in 2022 to $119b in 2021, depending on the source.