On March 1, 2019 Nektar Therapeutics (Nasdaq: NKTR) reported early results from the ongoing dose-escalation stage of the first-in-human REVEAL Phase 1/2 clinical study evaluating the safety and efficacy of NKTR-262, a novel toll-like receptor (TLR) 7/8 agonist, in combination with bempegaldesleukin* (NKTR-214 or bempeg), a CD122-preferential IL-2 pathway agonist (Press release, Nektar Therapeutics, MAR 1, 2019, View Source [SID1234533879]). The results were presented today in an oral session at the 2019 ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology Symposium by Dr. Adi Diab, Assistant Professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center (Oral Abstract Session B, Abstract #28, 1:00 p.m. – 2:15 p.m. PT).

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NKTR-262 is designed to induce the body’s innate immune response to prime antigen-specific cytotoxic T cells to fight cancer. Bempegaldesleukin is designed to activate the adaptive immune system to expand and proliferate these specific cancer-fighting T cells in the tumor microenvironment.

"We’re excited by the preliminary data from the REVEAL study which demonstrate desirable changes in the tumor micro-environment consistent with the activation of both the innate and adaptive immune responses induced by NKTR-262 and bempeg," said Dr. Jonathan Zalevsky, Chief Scientific Officer at Nektar. "The early data from REVEAL demonstrate that a comprehensive approach to activating the body’s immune system can drive abscopal anti-tumor responses even in the absence of a checkpoint inhibitor. We are looking forward to the ongoing dose-escalation and planned expansion of the study."

The dose-escalation phase of REVEAL is ongoing. As of January 23, 2019, 13 patients were enrolled that were refractory to all prior therapies known to confer clinical benefit. Key highlights of the data presentation are:

Maximum tolerated dose has not been reached and the dose escalation stage of the study is continuing.
Initial dose cohorts of NKTR-262 intra-tumoral injection combined with fixed dose of bempeg IV Q3W were well tolerated. Treatment-related adverse events were transient, characterized by Grade 1-2 flu-like symptoms (69.2%), rash (46.2%), fatigue (46.2%), pruritus (46.2%) and nausea (30.8%). There were no immune-mediated adverse events or study discontinuations due to TRAEs.
Local gene expression analysis of the injected tumor along with analysis of blood cells in system circulation demonstrated comprehensive activation of the immune system, including increases in the Type I interferon pathway and induction of CD4+, CD8+ and NK cell proliferation.
Early evidence of clinical benefit including abscopal responses in non-injected lesions was observed in the dose-escalation cohort. 11 of 13 patients in dose-escalation were evaluable for efficacy with at least one on treatment scan. 2 out of 5 evaluable patients with relapsed/refractory (R/R) melanoma who progressed on more than one prior checkpoint or I-O therapy experienced confirmed partial responses with 100% and 50% reductions in target lesions per RECIST 1.1, respectively. 2 out of 2 heavily pre-treated Stage IV leiomyosarcoma patients and 1 heavily pre-treated triple negative breast cancer patient experienced stable disease as best response.
A copy of the full data presentation made by Dr. Diab is available on Nektar’s corporate website at View Source

Analyst Call
Nektar will host an analyst conference call featuring Dr. Adi Diab and company management on Friday, March 1, 2019 at 3:00 p.m. PT during the 2019 ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology Symposium. The conference call may be accessed by dialing 877-881-2183 (toll-free) or 970-315-0453 (international) with the conference call passcode 6970019. The webcast and slides for the conference call can be accessed through a link posted on the Investors section of the Nektar website at View Source The webcast of the conference call will be available for replay through April 1, 2019.

About Nektar Phase 1/2 REVEAL Study
REVEAL is a Nektar-sponsored, open-label, multicenter, dose escalation and dose expansion study evaluating the combination of NKTR-262 administered as an initial intratumoral injection followed by bempeg administered as an IV infusion systemically (doublet). In the Phase 2 expansion, the study also may evaluate the doublet combination with nivolumab (triplet). During the dose escalation phases, recommended Phase 2 dose (RP2D) regimens of the doublet and/or triplet combinations will be established. Following dose escalation, the dose expansion phase will evaluate the doublet and/or triplet combinations in up to 350 patients who have been diagnosed with a range of locally advanced or metastatic cancers including: melanoma, Merkel cell carcinoma, triple-negative breast cancer, ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, or sarcoma. For more information, please visit View Source and search NCT03435640.

About Bempegaldesleukin (NKTR-214)
Bempegaldesleukin is an investigational, first-in-class, CD122-preferential IL-2 pathway agonist designed to provide rapid activation and proliferation of cancer-killing immune cells, known as CD8+ effector T cells and natural killer (NK) cells, without over activating the immune system. Bempegaldesleukin stimulates these cancer-killing immune cells in the body by targeting CD122 specific receptors found on the surface of these immune cells. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these effector T cells.1 In clinical and preclinical studies, treatment with bempegaldesleukin resulted in expansion of these cells and mobilization into the tumor micro-environment.2,3 Bempegaldesleukin has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

About NKTR-262
Cancer treatments that couple pharmacological activation of tumor antigen presentation with activation and expansion of CD8+ T and natural killer (NK) cells in the tumor environment have the potential to induce an effective anti-tumor immune response in patients. NKTR-262 is a novel small molecule agonist designed to activate toll-like receptors (TLRs). Intratumoral delivery of NKTR-262 promotes TLR activation to induce the development of antigen-specific immunity by initiating the process by which the immune system generates antigen-specific cytotoxic T cells to the patient’s specific tumor.4 Bempeg targets CD122 specific receptors found on the surface of these cancer-killing immune cells, known as CD8+ effector T cells. By first generating antigen-specific cytotoxic T cells with NKTR-262 and then growing these CD8+ effector T cells with bempeg, the patient’s entire immunity cycle can potentially be engaged to fight cancer. In preclinical studies, a single intratumoral dose of NKTR-262, administered in combination with bempeg, resulted in complete abscopal tumor regressions in multiple mouse syngeneic tumor models.5