ASCO GU 2019: PIVOT-02 Study of NKTR-214 with Nivolumab in Metastatic Urothelial Carcinoma

San Francisco, CA (UroToday.com) Immune checkpoint inhibitors are approved both in the first line and second line for patients with metastatic urothelial carcinoma. In the first line, KEYNOTE 052 showed that pembrolizumab has significant anti-tumor activity for cisplatin ineligible patients with UC1, for a 38% objective response rate for patients with a combined positive score of 10% or more (PD-L1 positive). Further analysis last year found that the benefit to checkpoint inhibition in the first line was restricted to patients with a high PD-L1 expression, as defined by CPS≥10 or PD-L1 IC ≥5%. In the second line, KEYNOTE 045 improved median overall survival compared with chemo (10.3 v 7.4 months; HR, 0.70; P < 0.001)2.

Unfortunately, the majority of patients with UC do not have an elevated PD-L1 expression, and many patients in the front line are also cisplatin in-eligible due to renal impairment, hearing loss, peripheral neuropathy, or poor performance status. Thus, additional therapies are necessary for this vulnerable population of patients. This study evaluates NKTR-214, a CD122-preferential IL-2 pathway agonist for patients with mUC. 

This is an interim analysis of PIVOT-2, a multicenter phase 1/2 study of NKTR-214 for patients with locally advanced or metastatic UC who are either cisplatin-ineligible or have declined cisplatin based chemotherapy. The data cutoff point at the time of this analysis is December 3rd, which provides a median duration of follow up of 5.1 months.
PIVOT 02 picture1

A total of 41 patients with UC have been enrolled and 27 patients are available for follow up at this time. The median age of this population was 70. 75% of patients were ineligible due to poor renal function. Most patients had not had cystectomy (93%). 41% of patients were classified as PD-L1 negative based on a TC<1%.  56% of patients had visceral disease.

PIVOT 02 table1

In terms of safety, 88% of patients had a treatment related adverse event. The most common low grade (1/2) events were flu like symptoms, fatigue, rash, and pruritus. The most common grade 3 or 4 events were also flu like symptoms and hypotension. One patient developed complete AV block and one patient developed myocarditis. No patients had grade 4 or 5 toxicity. 10% of patients discontinued treatment due to adverse events. 

PIVOT 02 table2
In terms of efficacy, the objective response rate was 48%, with 19% complete responses and 30% partial responses. There was no significant difference in the objective response rate between PD-L1 negative and PD-L1 positive tumors. There are also 4 additional unconfirmed responses and 1 additional unconfirmed complete response. 10 patients are still pending their first scan. 85% of patients have ongoing responses and amongst patients who have a response, no patients have discontinued due to relapse. 

PIVOT 02 table3

PIVOT 02 figure2
There was one dramatic case of pseudoprogression where a patient had a 23% increase in target lesions at a 9 week scan and subsequently a 58.9% decrease during the week 20 scan. That patient continues on therapy with a 64% decrease from baseline at week 40.

PIVOT 02 figure4

In terms of biomarker analysis, 13 patients had pre treatment and post treatment biopsies. 70% of PD-L1 negative tumors had been converted to PD-L1 positive tumors. Responses were also seen independent of baseline CD8 T cell infiltration. 

This phase I/II study shows that NKTR-214 in combination with nivolumab is highly active for cisplatin ineligible patients with urothelial carcinoma. NKTR-214 successfully converted 7/10 PD-L1 negative tumors to PD-L1 positive based on the PharmDx 28-8 assay. A recent study examine the concordance of PD-L1 expression between primary and metastatic UC lesions and found that PD-L1 expression is temporally and spatially discordant so this may confound some of the PD-L1 data (CITE). Nonetheless, this abstract provides very exciting efficacy data, especially with the 20% complete response rate which is unheard of in this space. The main limitations of this study is the size and limited follow up but a larger phase II study is underway. 

Presented by: Arlene O. Siefker-Radtke, MD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine MD Anderson Cancer Center 

Written by: Jason Zhu,MD, Fellow, Division of Hematology and Oncology, Duke University. Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

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