PIVOT-02 for First-Line Stage IV Melanoma

Adi Diab, MD:PIVOT-02 has a dose-escalation strategy in a phase Ib/II trial. Earlier this year at ASCO [American Society of Clinical Oncology], we described and completed the dose-escalation data as well as preliminary efficacy and safety data of the phase II study. By completing the dose-escalation data in the PIVOT-02 trial, we identified the recommended phase II dose of NKTR-214 to be 6 μg/kg, given concurrently with nivolumab at a flat dosage of 360 mg every 3 weeks. At SITC [Society for Immunotherapy of Cancer], we reported on the complete safety, efficacy, and biomarker data of the completely enrolled cohort of patients treated with the combination NKTR-214 and nivolumab for first-line melanoma therapy.

The baseline patient demographics that were enrolled were similar to what we see in the pivotal trials like the CheckMate 067 and KEYNOTE-006, in terms of the percentage of patients who had elevated LDH [lactate dehydrogenase]. Usually that’s above 30%. That’s what we have in the PIVOT-02. A substantial percentage of the patients also had M1c, meaning patients had visceral involvement—more than just lung or subcutaneous. About 37% of the patients were PD-L1 [programmed death-ligand 1] negative. I think about 10% or less reported unknown status of their PD-L1. But in general, these are patient demographics that are similar to what you see in phase III trials, and that’s what you want to capture in single-arm phase II trials—how much the patient demographics resemble phase III pivotal trials.

In terms of efficacy, we have seen that the overall response rate as determined by independent radiology review was 53%, with 24% achieving complete response. The disease-control rate was 76%, which is very encouraging. When you look at the responses, you can see that patients who were PD-L1 negative at baseline achieved deep responses. The patients who were PD-L1 positive reported similar results. What’s also encouraging from the data is that we’ve seen some meaningful responses in patients who have what we call the negative clinical prognostic factors, such as elevated LDH and liver metastases. We’ve seen responses of 45% and 50%, respectively.

We’ve also seen some deep responses over time. The responses seem to occur early. The median time to response was 2 months. A lot of the responses are durable, and 85% of the patients who responded continue to respond. The median duration of response was not reached at the time of the presentation at SITC.

Again, we have seen overall responses obtained and assessed by the independent radiology review of 53% response rate. Among those, 24% achieved a complete response rate.

We’ve seen that in many of the patients who initially had partial responses, their partial responses continue to deepen and their target lesions continue to shrink. Some of these patients who enrolled in the trials have achieved a complete response. So we definitely see continuous immune response. Obviously it was really noticed in this trial with the combination of NKTR-214 and nivolumab [Opdivo]. This kind of deepening of response can sometimes be explained with a mechanism of action of NKTR-214.

The most common treatment-related adverse effects in this trial were flu-like symptoms. About 70% of the patients developed flu-like symptoms, which translate into fatigue, pruritis, and rash. But most of the toxicities were grade 1 and 2. These toxicities are usually predictable. They occur 24 hours after the first administration of the drug and usually last for 3 to 5 days. Generally, they’re treated with conservative treatments like NSAIDs [nonsteroidal anti-inflammatory drugs] or over-the-counter options. The frequency and intensity of these symptoms decrease. We notice that they decrease over time after the first dose. Some of that is physiological adaptation of the body to these toxicities, and some of it is psychological adaptation, where the patient is really embracing these and knows what they’re expecting.

On the positive side, the toxicity is predictable. We know when they’re going to start, and we know roughly when they’re going to end. That gives assurance to the patients and physicians on how to prepare patients for treatment. If these symptoms linger in a patient, we can interfere and monitor them more closely. About 5% of the patients had immune-mediated adverse effects that required immunosuppressive treatment. Two patients reported treatment-related discontinuation.

Transcript edited for clarity.