The PIVOT-02 Trial: NKTR-214 With Nivolumab

Adi Diab, MD:The PIVOT-02 trial is a phase I/II study combining NKTR-214 together with nivolumab in patients with solid tumor malignancies. The initial data were as a phase I trial to identify the recommended phase II. And in the phase I dose escalations, we tested 5 different doses and different scheduling. And ultimately, we recognized that recommended phase II as NKTR-214 0.006 mg/kg and nivolumab 360 mg, both given IV as outpatient regimens every 3 weeks.

And the initial data from that were presented last year at SITC. We had very promising responses. We had a 64% response in the melanoma cohorts, and initially, we had a 46% response rate into the renal cell carcinoma. And only in patients who we enrolled into the lung cancer, we have 3 out of 6 patients who are responding.

What was interesting in the NKTR-214 combination with nivolumab, and what we picked up early on, is that we’d see activity not only in the PD-L1—positive cohort where you really expect single-agent nivolumab or single-agent anti–PD-1 to do well, but we’ve seen very good responses and deep responses into the PD-L1–negative group where anti-PD-1 is not necessarily doing a great job in those patient populations.

And furthermore, the data were presented at this ASCO. We have seen that as the data mature, many patients who had a stable disease continued to have a good response and they transform from a stable disease to partial response. And some patients who already were partial responders continued to deepen their response, even including patients who are PD-L1 negative and achieving very deep responses.

The same thing with non—small cell lung cancer. And those 5 patients, all who were PD-L1 negative, 3 out of those were responders, and 2 out of these PD-L1–negative responders converted to be complete responders. And that’s the encouraging part. Obviously, the data have to be matured more. These are preliminary safety and efficacy data, so we’ll have to see how these data mature and translate into the final form. But the encouragement, and why we call it promising, is because of the results that we really see in the PD-L1–negative population.

And to further encourage us to see that, we also reported at this meeting about 10 patients of urothelial cancer who had 6 out of 10 responders, and 3 out of these responders are PD-L1 negative. And 2 out of these 3 PD-L1—negative responders also achieved complete response. I think some of them were unconfirmed complete response. But nonetheless, this patient population in urothelial cancer who are PD-L1 negative carry poor response rates to single-agent immunotherapy.

And recently, the FDA alerted us that they stopped enrolling single-agent anti—PD-1 because it was inferior to chemotherapy. So, that’s indicating that these patients are really an unmet need. And when you see responses, this is encouraging. Very early preliminary data, but when you talk about the promise, that is the source of the promise: the deep responses and PD-L1 negativity.

The data presented at ASCO demonstrated that NKTR-214 in combination with nivolumab achieved the prespecified efficacy criteria for first-line metastatic melanoma, first-line renal cell carcinoma, and first-line urothelial cancer. So, at the moment, I think the plan is to go to registrational randomized trials to test the true efficacy, which is the ultimate test to see if these drugs truly demonstrate superiority over single agents and on the standard of care.

So, in melanoma, the randomized trials will be NKTR-214 plus nivolumab against nivolumab alone. And if this trial demonstrates superiority, then I think this regimen could be the first standard of care. Obviously, we have to wait for this trial to start and mature before we see the results.

Transcript edited for clarity.