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Replies to post #218582 on Biotech Values
"Based upon highly compelling preclinical data, we are looking forward to combining Nektar's unique CD122-biased agonist with TAK-659, which is a dual inhibitor of both SYK and FLT-3," said Phil Rowlands, PhD, Head, Oncology Therapeutic Area Unit, Takeda. "NKTR-214 is unique in that it can stimulate tumor-killing T-cells in the tumor micro-environment itself. By combining with TAK-659, we hope to target different stages of the cancer immunity cycle in a combination regimen. This collaboration is aimed at achieving our goal of allowing more patients with different types of cancer to benefit from immunotherapies."
TAK-659 is an orally-available investigational reversible dual SYK/FLT-3 inhibitor. SYK is a non-receptor cytoplasmic kinase that binds to phosphorylated immuno-receptor tyrosine-based activating motifs and mediates cellular proliferation and survival. Mutations in FLT-3 genes can result in the constitutive activation of the FLT-3 receptor and result in acute myeloid leukemia and acute lymphoblastic leukemia. TAK-659 demonstrates both direct- and immune-mediated tumor cell kill mechanisms. It is currently being explored in clinical studies as a single agent and in combination in solid and hematological malignancies.
Hi, Corey, it's a very good question. And as you can imagine, partnering with BMS, we're able to leverage a lot of experience that they've had with the FDA on these topics. But in general, what you need to prove is that you can, with your 95% confidence interval for your objective response rate, that your lower bound of that 95% confidence interval rules out the point estimate for standard of care. So just to give you, like a specific example in terms of relapsed/refractory melanoma population, where those patients have been treated with a prior checkpoint inhibitor, a second-line treatment could be ipilimumab, which has about 13% objective response rate. So you would want to see an objective response rate somewhere around 20% or above 20%, where your 95% confidence interval, the lower bound would be above 13%. In terms of non-small cell lung cancer, post-I-O plus chemo or post-I-O, docetaxel is a very reasonable comparator in the second-line setting. And there's been a number of large Phase III trials that show that the objective response rate for docetaxel is roughly 9%. And so in the non-small cell lung cancer population that has been previously treated with an I/O agent, the doublet of NKTR-214 plus nivo, we had estimated has to have an objective response rate around 18% or higher to rule out the lower bound of the 95% confidence interval that's above 9%. Just to give you some ideas, when we do our statistical calculations, those cohorts need to be around 100 patients to be able to demonstrate that level of efficacy. I hope that helps.
Yes. We've shown an update from our dose escalation patients for first-line melanoma, first-line RCC and non-small cell lung cancer. And this pattern, we've actually seen to be consistent across all 3 of these solid tumor types. And from a biological perspective, it makes sense that NKTR-214 would have this robust effect in all tumor types because the mechanism provides for new antigen-specific T cells to be generated every 21 days, and that's why we see this effect over time in contrast to CAR-T cells, where you see a very high rate of relapse after 6 months of treatment because all those T cells are now gone. In contrast, NKTR-214 generates this new replenishment of these antigen-specific T cells every 21 days, which is why we see this ongoing tumor regression and tumor reduction with ongoing treatment.
