NKTR-214/Nivolumab Efficacy Sustained in Phase II Findings

Adi Diab, MD

Combining the CD122-biased cytokine NKTR-214 with the PD-1 inhibitor nivolumab (Opdivo) showed promising antitumor activity, particularly in PD-L1—negative patients, according to updated data from the phase I/II PIVOT-02 trial presented at the 2018 ASCO Annual Meeting.

Data were presented from the phase II dose expansion part of the study demonstrating an overall response rate (ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1—negative patients. The overall ORR and PD-L1–negative ORR were 46% and 53%, respectively, in previously untreated patients with renal cell carcinoma (RCC). Among cisplatin-ineligible patients with urothelial carcinoma receiving frontline treatment, the ORR was 60% both overall and in PD-L1–negative patients.

“Prespecified efficacy criteria were achieved [in the frontline setting] in melanoma, renal cell carcinoma, and cisplatin-ineligible urothelial carcinoma, which support the evaluation of NKTR-214 plus nivolumab in registrational trials,” lead investigator Adi Diab, MD, from the MD Anderson Cancer Center, said during his presentation of the results.

“Robust translational data confirm the rational for activation of the immune system in the tumor microenvironment with a conversion of PD-L1—negative tumors to PD-L1 positive on treatment,” Adi added.

Phase I data for the dose escalation cohort of PIVOT-02 were previously presented at the 2017 SITC Annual Meeting. At the time of that analysis, 38 total patients with melanoma (n = 11), RCC (n = 22), and non—small cell lung cancer (NSCLC; n = 5) had received treatment with the combination.

In the dose-escalation portion of trial, patients received nivolumab at 240 mg every 2 weeks (Q2W) or at 360 mg every 3 weeks (Q3W) with NKTR-214 at 0.003 or 0.006 mg/kg Q2W or Q3W. The identified recommended phase II dose for NKTR-214 was 0.006 mg/kg Q3W with nivolumab at 360 mg Q3W.

At ASCO, Diab first presented updated data on these cohorts, which had a cutoff of November 2, 2017, for the SITC results, and May 29, 2018, for the ASCO findings.

For the frontline cohort of patients with stage IV melanoma, the ORR was sustained between the SITC and ASCO results at 64% (7 of 11 patients). The disease control rate (DCR) was 91% (n = 10). The ORR among PD-L1—negative patients (expression <1%) was 60% (3 of 5 patients) and 67% among PD-L1–positive patients (expression ≥1%; 4 of 6 patients).

Among the frontline cohort of patients with stage IV RCC, the ORR at SITC was 46% (6 of 13 patients) and the DCR was 85% (11 of 13 patients). At the ASCO update, there was an additional patient, and the ORR was 71% (10 of 14 patients), with a DCR of 79% (n = 11). Five of 8 (63%) PD-L1—negative patients had a response and the ORR was 80% (4 of 5 patients) in the PD-L1–positive group. The PD-L1 status was unknown for 1 patient.

The phase II dose expansion cohort of the trial has a target enrollment of approximately 330 patients. The cohorts include melanoma (first through third line), RCC (first through third line), NSCLC (first and second line, as well as second line immune-relapsed/refractory), urothelial carcinoma (first line cisplatin ineligible, as well as second and third line), and triple-negative breast cancer (first and second line).

At ASCO, Diab presented data for the 3 cohorts that have met the trial’s prespecified efficacy criteria: frontline melanoma, frontline RCC, and frontline cisplatin-ineligible urothelial carcinoma.

“The other tumor types continue to be at various stages of enrollment and the data has not yet met the prespecified stopping criteria either for futility or efficacy,” explained Diab.

Forty-one patients have been enrolled in the frontline melanoma cohort, 24 are male and 17 are female. The median patient age was 63 years (range, 22-80). Three-fourths of patients had an ECOG performance score of 0. Twenty patients were PD-L1 positive, 14 were PD-L1 negative, and the status was unknown for 7. Regarding BRAF status, 36.6% were positive, 61.0% were wild-type, and 2.4% were unknown.

Diab reported data for 28 of these patients, among whom 14 responded, for an ORR of 50%. The DCR was 71% (n = 20). The median time on study for these patients was 4.6 months. The ORR was 42% (5/12) among PD-L1—negative patients and 62% (8/13) among PD-L1–positive patients. PD-L1 status was unknown for 3 patients.

The frontline RCC cohort had enrolled 48 patients, comprising 10 females and 38 males. The median age was 61 years (range, 40-78). The ECOG performance score was 0 for 60.4% of the patients and 1 for 39.6%. The PD-L1 status was unknown for 4 patients, 30 were negative, and 14 were positive.

At ASCO, Diab shared findings for 26 patients from this cohort. The ORR was 46% (n = 12) and the DCR was 77% (n = 20). The median time on study was 5.6 months. The ORR was 53% (9/17) for PD-L1—negative patients and 29% (2/7) for PD-L1–positive patients. PD-L1 status was unknown for 2 patients.

Sixteen patients had been enrolled in the frontline cisplatin-ineligible urothelial carcinoma group, comprising 5 females and 11 males. The median patient age was 70 years (range, 54-83). Six patients had an ECOG performance score of 0 and 10 had a score of 1. There were 7 PD-L1—positive patients, 7 PD-L1–negative, and 2 whose status was unknown.

Diab reported data for 10 of these patients. The ORR was 60% (n = 6) and the DCR was 70% (n = 7). The median time on study was 3.9 months. The ORR was 60% (3 each) among the 5 PD-L1—negative patients and the 5 PD-L1–positive patients.

Safety data were available for 283 patients treated at the recommended phase II dose. Grade ≥3 treatment-related adverse events (AEs) occurred in 14.1% of patients, including hypotension (n = 5), syncope (n = 5), increased lipase (n = 4), rash (n = 4), and dehydration (n = 3).

Immune-mediated grade ≥3 AEs occurred in 3.5% of patients. One patients died of grade 5 pneumonitis related to nivolumab. The patients had NSCLC previously treated with carboplatin/pemetrexed and a history of brain metastases.

Diab A, Hurwitz ME, Cho DC, et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. J Clin Oncol. 2018;36 (suppl; abstr 3006).

<<< 2018 ASCO Annual Meeting

For the patients with stage IV NSCLC, the ORR and DCR at SITC were both 75% (n = 3) among 4 patients receiving second-line therapy. The ASCO data included 1 extra patient receiving frontline treatment and the updated ORR was 60% (n = 3), with a DCR of 80% (n = 4). All 3 responders were PD-L1 negative, with 2 achieving a complete response.