NKTR-214/Nivolumab Combination Shows Promise in Early Study

Adi Diab, MD

The combination of the CD122-biased cytokine NKTR-214 and the PD-1 inhibitor nivolumab (Opdivo) demonstrated target lesion reductions of 72% for patients with advanced cancers, according to findings from the phase Ib PIVOT-02 trial presented at the 2017 SITC Annual Meeting.

The dose escalation trial enrolled patients in the first- or second-line setting with advanced non—small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and melanoma. The objective response rates (ORR) by RECIST criteria ranged from 46% to 75% across tumor types. Additionally, the combination was tolerable, with no discontinuations attributed to adverse events (AEs).

"NKTR-214 plus nivolumab is a novel combination of immuno-oncology agents with differentiated and complementary mechanisms of immune activation," lead investigator Adi Diab, MD, from the MD Anderson Cancer Center, said during his presentation of the results. "Efficacy results demonstrate important clinical activity in both PD-L1—negative and –positive patients."

The multi-cohort study enrolled patients with melanoma, NSCLC, and RCC. In a dose escalation portion of the study, 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 the time of the analysis, 38 total patients with melanoma (n = 11), RCC (n = 22), and NSCLC (n = 5) had received treatment with the combination in the dose escalation portion of the study. Across all cohorts, the median age of patients was 61 years and most were males (78.9%). Two-thirds of patients were treated in the frontline setting for metastatic disease (68.4%) and the most common ECOG performance status was 0 (65.8%).

In the melanoma group, half of patients were BRAF-positive and the remainder were wild-type. The most common disease stage was M1c and 45.5% tested positive for PD-L1 on ≥5% of cells. In the RCC group, 28.6% of patents were PD-L1—positive in the frontline setting (N = 14) and 62.5% were PD-L1–positive in the second-line setting (N = 8). All patients in the NSCLC cohort were PD-L1–negative and were immuno-oncology agent-naive.

In efficacy-evaluable treatment-naive patients with melanoma (n = 11), the ORR by RECIST was 64% and by irRECIST it was 73%. There was 1 complete response (CR) and 1 unconfirmed CR. The disease control rate (DCR; ORR plus stable disease) was 91% by both measurement criteria. The median time to response was 1.7 months and 100% of RECIST responses were ongoing at the time of the analysis.

In the treatment-naive RCC group (N = 13), the ORR by RECIST was 46% in those with ≥1 post baseline scan (n = 13) and it was 60% for those with ≥2 post baseline scans (n = 10). There was 1 unconfirmed CR. The DCR was 85% and 80% in the ≥1 and ≥2 scan groups, respectively. The median time to response was 1.9 months with all responses ongoing at the time of the analysis. In the second-line setting for those with RCC (n = 7), the ORR was 14% and the DCR was 100%.

In the NSCLC group (n = 4), the ORR and DCR were both 75%, with 1 unconfirmed CR. The median time to response was 1.7 months. One patients with NSCLC was treated in the frontline setting and had stable disease as the best response.

Of those treated with the recommended phase II dose (n = 25), just 1 experienced grade 3 or 4 treatment-related AEs (TRAE; 4%). The most common grade 1 and 2 TRAEs were fatigue (68%), flu like symptoms (60%), rash (52%), pruritus (32%), headache (32%), diarrhea (32%), arthralgia (24%), and decreased appetite (12%).

"NKTR-214 plus nivolumab is safe and tolerable and can be administered as a convenient, outpatient regimen," said Diab. "NKTR-214 did not increase the risk for immune-related AEs associated with nivolumab."

The phase II portion of the study continues to enroll patients across 13 expansion cohorts. In addition to RCC, NSCLC, and melanoma, the study is now also enrolling those with urothelial carcinoma and triple-negative break cancer. The estimated completion date is October 2018 (NCT02983045).

Diab A. Pivot-02: Preliminary safety, efficacy and biomarker results from dose escalation of the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. Presented at: SITC 32nd Annual Meeting; National Harbor, MD; November 8-12, 2017. Session 207.7.