bempegaldesleukin (NKTR-214)

BEMPEG plus NIVO did not meet the efficacy threshold for ORR in patients with previously untreated locally advanced or metastatic urothelial carcinoma and low PD-L1 expression.

Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.

P3, N=783, Completed, Bristol-Myers Squibb | Trial completion date: Sep 2023 --> Mar 2024

First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.

P2, N=88, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P1, N=30, Completed, Nektar Therapeutics | Phase classification: P1b --> P1

P1, N=30, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed

Anti-CCR8 and the IL-2Rβγ agonist Bempegaldesleukin selectively target intra-tumoral Treg population, with the former approved to not elicit autoimmunity...Blimp-1 inhibitors and glucocorticoid-induced TNFR-related protein agonists are example approaches that can be used for diverting Treg differentiation into Th1-like CD4+ T cells, thereby powering immunogenicity against cancer. Finally, selective target of intra-tumoral Tregs and their reprogramming into effector T cells is applicable using low-dose chemotherapy, and high-salt and high-tryptophan diet.

The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

P3, N=783, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Sep 2023

P3, N=114, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | Trial completion date: Sep 2023 --> Jun 2023

P2, N=5, Terminated, University of Wisconsin, Madison | Trial completion date: Nov 2024 --> Oct 2022 | Active, not recruiting --> Terminated; study closed by the sponsor

So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy.

FCγR polymorphisms did not influence OR/PFS/TS.These data show that clinical response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial may be associated with the repertoire of KIR/KIR-ligands an individual inherits. Further investigation and validation of these results may enable KIR/KIR-ligand genotyping to be utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens.

Bempegaldesleukin, the first of the modified IL-2 agents to reach phase 3 evaluation in combination with an anti-PD-1, did not improve outcome for patients with metastatic melanoma and renal carcinoma. The disappointing data raise important questions about the potential efficacy of other interleukin-2 variants, however, several of the other variants appear to be sufficiently differentiated in anticipated pharmacokinetic properties and immune modulatory effects to warrant continued clinical development.

Although five immune-oncologic-drug-based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined...Moreover, novel drugs, such as the hypoxia-inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin-2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment-naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required.

P3, N=775, Terminated, Nektar Therapeutics | Trial completion date: Jul 2027 --> Sep 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2027 --> Sep 2022; (Sponsor decision)

P3; Trial completion date: Jun 2024 --> Oct 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2022 --> Jan 2022; Sponsor decision

NKTR-214, the most advanced IL-2 pathway-targeted agent in clinical development for oncology, shows exciting results in treatment of melanoma in combination with nivolumab. At the same time, many more other modified molecules against cancer and autoimmune diseases are being tested in clinical research, an exciting future lying ahead for IL-2 therapeutics.

P1/2, N=127, Terminated, Nektar Therapeutics | N=240 --> 127 | Trial completion date: Jan 2024 --> Aug 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Jul 2022; Sponsor decision

P1, N=30, Active, not recruiting, Bristol-Myers Squibb | Phase classification: P1/2 --> P1 | N=251 --> 30 | Trial completion date: Jan 2026 --> Feb 2024 | Trial primary completion date: Dec 2024 --> Feb 2024

Moreover, we discuss the currently available data regarding the mechanism of action of immune checkpoint inhibitors and IL-2 analogs in the treatment of COVID-19. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in an elderly melanoma patient.

P2, N=192, Completed, Nektar Therapeutics | Active, not recruiting --> Completed | Trial completion date: Oct 2022 --> Jun 2022

P1/2, N=64, Terminated, Nektar Therapeutics | Trial completion date: Oct 2022 --> May 2022 | Active, not recruiting --> Terminated; Based on the overall results from the Phase 1 part of the study the sponsor decided to end the study. The decision was not due to safety reasons.

BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC.

P2/3, N=2, Terminated, Nektar Therapeutics | SFJ Pharmaceuticals, Inc. and Nektar Therapeutics, in consultation with the study IDMC, have decided to discontinue PROPEL-36.

P1/2, N=251, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P2, N=5, Active, not recruiting, University of Wisconsin, Madison | Recruiting --> Active, not recruiting | N=24 --> 5 | Trial completion date: Jun 2026 --> Nov 2024 | Trial primary completion date: Jun 2024 --> Nov 2022

P1/2, N=240, Active, not recruiting, Nektar Therapeutics | Recruiting --> Active, not recruiting

P2/3, N=2, Active, not recruiting, Nektar Therapeutics | Recruiting --> Active, not recruiting | N=500 --> 2

BEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.

BEMPEG+NKTR-262 therapy elicited more robust expansion of activated CD8 T cells compared with BEMPEG+RT, suggesting that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared with RT. A clinical trial of BEMPEG+NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

P3, N=775, Active, not recruiting, Nektar Therapeutics | Recruiting --> Active, not recruiting

PIVOT-12 is a randomized, Phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

TBD

In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

P1, N=826, Recruiting, Exelixis

P3; Trial primary completion date: Dec 2021 --> Jun 2022

P2/3; N=500; Ongoing; Sponsor:Nektar Therapeutics

P1/2, N=64, Active, not recruiting, Nektar Therapeutics | Trial completion date: Dec 2021 --> Oct 2022 | Trial primary completion date: Sep 2021 --> Jul 2022

P2/3, N=500, Recruiting, Nektar Therapeutics | Not yet recruiting --> Recruiting

Enhancement of the activated CD8+ T cell response in mice treated with NKTR-262 in combination with BEMPEG suggests that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared to RT. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).