5:33 AM
Nov 06, 2018
 |  BC Extra  |  Company News

Pfizer's PARP, androgen inhibitors next combo partners for NKTR-214

Pfizer Inc. (NYSE:PFE) will combine NKTR-214 from Nektar Therapeutics Inc. (NASDAQ:NKTR) with the pharma's marketed drugs Xtandi enzalutamide, Talzenna talazoparib and Bavencio avelumab to treat prostate cancer, testing the biotech's hypothesis that stimulation of IL-2 alongside these other MOAs in tumors with a high mutational burden could provide synergistic benefits.

Financial terms for the clinical collaboration are not disclosed, but Pfizer will test triplet combinations of NKTR-214 with anti-PD-L1 drug Bavencio and either Talzenna or Xtandi in metastatic castration-resistant prostate cancer (mCRPC).

The rationale behind the triplet combinations is to build upon the immune response initiated by monotherapy with Talzenna, a PARP inhibitor, or Xtandi, an androgen receptor inhibitor.

NKTR-214 is an IL-2 that contains six conjugated PEG moieties that biases it to signal through the intermediate IL-2 receptor CD122, triggering proliferation and activation of CD8+ T cells and NK cells, which kill cancer cells. While prostate cancer is generally considered a "cold" tumor with respect to immune activity, PARP inhibitors such as Talzenna induce DNA damage, which can trigger neoantigen formation, resulting in the potential for a "classic immuno-oncology response," said Nektar SVP, Research and CSO Jonathan Zalevsky.

NKTR-214 has never been tested in mCRPC.

In preclinical models of BRCA-mutated ovarian cancer, combinations of NKTR-214 with PARP inhibitors resulted in "enormous synergy," Zalevsky told BioCentury.

With Xtandi, the expectation is that the addition of Bavencio and NKTR-214 will stimulate the immune response in the tumor microenvironment while Xtandi targets the tumor itself. "We know that with Xtandi on board, it will target the tumor itself and the underlying biology but with the doublet also on board, it's an opportunity to elevate the efficacy," Zalevsky said.

Pfizer will be responsible for the trials. The pharma will first run a Phase Ib study to establish the appropriate combination doses to take forward. Details of the study have not been disclosed.

Pfizer will also test NKTR-214 plus Bavencio in a Phase II trial to treat first-line metastatic squamous cell carcinoma of the head and neck (SCCHN), where patients have a high mutational burden but "cold" tumors.

"We really think it provides a treasure trove for NKTR-214 to act upon," said Zalevsky.

Nektar partnered with Bristol-Myers Squibb Co. (NYSE:BMY) in February to test NKTR-214 plus Opdivo nivolumab in multiple tumor types. The deal left open the opportunity for Nektar to test its program in other tumor types not covered by the BMS deal and with other combination agents (see "BMS, Nektar Partner on NKTR-214 Combos in $3.6B Deal").

"That partnership envisioned that we could collaborate with other anti-PD-1/PD-L1 inhibitors in other tumor types and with other mechanisms. The Pfizer collaboration accomplishes both," said Nektar spokesperson Jennifer Ruddock.

Pfizer and Merck KGaA (Xetra:MRK) co-market and develop Bavencio, which is approved to treat metastatic Merkel cell carcinoma and patients with locally advanced metastatic urothelial carcinoma.

Xtandi is partnered with Astellas Pharma Inc. (Tokyo:4503) and is approved to treat castration-resistant prostate cancer. Talzenna was approved in the U.S. last month to treat germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Pfizer is also running a Phase II trial of Talzenna to treat men with mCRPC with DNA-repair defects (see "After Three Deals, FDA Approval, Talazoparib Joins PARP Party").

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