In two clinical trials, the CD122-preferential IL2 pathway agonist bempegaldesleukin increased proliferation and activation of tumor-infiltrating lymphocytes in patients with solid tumors. Despite the lack of response to the agent as a monotherapy in the first-in-human trial, patients with metastatic urothelial carcinoma in the subsequent PIVOT-02 trial did respond when the drug was combined with the PD-1 inhibitor nivolumab.

In a recently published first-in-human study, the CD122-preferential IL2 pathway agonist bempegaldesleukin (NKTR-214; Nektar Therapeutics), given alone, increased proliferation and activation of tumor-infiltrating lymphocytes (TIL) in patients with solid tumors. Although the agent showed modest activity, patients with metastatic urothelial carcinoma (mUC) in the subsequent PIVOT-02 trial, in which bempegaldesleukin was combined with a checkpoint inhibitor, had stronger responses, suggesting a potential new treatment.

Low levels of TILs predict a poor response to treatment with checkpoint inhibitors, but research has shown that stimulating the IL2 pathway can lead to robust expansion and activation of these immune cells. In preclinical work, bempegaldesleukin was shown to boost CD8+ T cells and natural killer (NK) cells, and increase T-cell clonality.

For the monotherapy trial, researchers recruited 28 patients with a variety of solid tumors, who had previously tried multiple therapies, to receive bempegaldesleukin alone. Based on RECIST criteria, no objective responses were observed: Nine of 26 evaluable patients (35%) experienced some tumor shrinkage and 14 experienced stable disease. However, the drug dramatically increased proliferation of CD4+ and CD8+ T cells and NK cells without expanding regulatory T cells. High expression of ICOS, PD-1, CTLA4, and OX40 confirmed immune-cell activation.

Building on those findings, another group of researchers initiated the phase I/II PIVOT-02 study to test bempegaldesleukin plus the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) in patients with mUC and other solid tumors. The mUC cohort included 41 patients with inoperable locally advanced or metastatic disease who weren't eligible for, or refused, first-line treatment with standard cisplatin–gemcitabine chemotherapy. According to Arlene Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center in Houston, about 70% of cisplatin-ineligible patients with mUC aren't likely to benefit from first-line checkpoint inhibitors due to low PD-L1 expression, demonstrating the need for new therapies.

At the 2019 Genitourinary Cancers Symposium in February, Siefker-Radtke presented data on 27 patients with mUC in PIVOT-02 who were evaluable for efficacy. She reported that of 11 patients who were PD-L1–negative, the overall response rate (ORR) was 45%, with a complete response rate of 19% and a disease control rate (DCR) of 73%. Of the 12 PD-L1–positive patients, the ORR was 50% and the DCR was 75%. Two of the four patients with an unknown PD-L1 level also responded.

Higher levels of CD8+ TILs at baseline predict improved response to single-agent checkpoint inhibition, with a poorer response observed in those with both low CD8+ TILs and PD-L1–negative tumors. Intriguingly, the addition of bempegaldesleukin appeared to overcome this limitation. Four of eight patients with low CD8+ TILs and no PD-L1 expression at baseline responded to the combination treatment, underscoring its “promising clinical benefit,” Siefker-Radtke noted.

“The response rates are very impressive,” said Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA. Although his enthusiasm for immunotherapy combinations waned after seeing lackluster data from other trials, “this data has reinvigorated my interest.”

As part of PIVOT-02, researchers obtained paired tissue samples from 13 patients to assess any changes in PD-L1 expression. Notably, of the 10 patients who were PD-L1–negative prior to starting bempegaldesleukin–nivolumab therapy, seven “converted” to PD-L1–positive after 3 weeks of treatment. The three who were PD-L1–positive at baseline remained PD-L1–positive. “This increase in PD-L1 expression suggests that immune activation is occurring,” says Siefker-Radtke. “However, obtaining the right immune cell response that effectively targets the cancer may be more important than PD-L1 expression alone.”

Pal noted that patients' PD-L1 status has changed during neoadjuvant studies of PD-1/PD-L1 blockade, “so it is not clear that NKTR-214 is necessarily responsible,” he said. “The results here speak to the dynamic nature of PD-L1 as a biomarker.” –Suzanne Rose

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.