Results from a Phase II clinical study evaluating single-agent NKTR-102 (Nektar Therapeutics) as a second- and third-line treatment in patients with metastatic breast cancer demonstrates sustained clinical benefit in 46% of them. The results of the study were presented today at the 47th annual meeting of the American Society of Clinical Oncology Meeting (ASCO).

NKTR-102, Nektar Therapeutics’s lead oncology drug candidate, is a next-generation topoisomerase I inhibitor with reduced peak concentrations and a continuous concentration profile being evaluated in multiple cancer indications. NKTR-102 is based on Nektar’s advanced polymer conjugate technology platform.

The randomized Simon two-stage study presented at ASCO evaluated two 145 mg/m2 dose schedules of single-agent NKTR-102, every two weeks (q14d) and every three weeks (q21d), in 70 metastatic breast cancer patients who failed a prior taxane therapy. Eighty-nine percent (62/70) of patients in the study received a prior anthracycline/taxane with or without capecitabine.

More than one million women worldwide are diagnosed with breast cancer every year and the disease is the leading cause of cancer-related death among women.[1] The chance of developing invasive breast cancer at some time in a woman’s life is a little less than one in eight (12%). There are approximately 200,000 new cases of breast cancer in the United States and 430,000 in Europe each year.[2] Metastatic breast cancer refers to cancer that has spread from the breast to distant sites in the body.

Current Thearpies
Anthracyclines and taxanes (AT) are the most active and widely used chemotherapeutic agents for breast cancer, but the increased use of these agents at an early stage of disease often renders tumors resistant to these drugs by the time the disease recurs, thereby reducing the number of treatment options for metastatic disease. Drugs used to treat patients who progress following AT treatment can have response rates as high as 20-30%; however, resistance develops rapidly and new agents with different mechanisms of action, such as topoisomerase I inhibitors, are needed to allow novel ways to overcome the problem of drug resistance. [3] There are currently no FDA-approved topoisomerase I inhibitors to treat breast cancer.

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Clinical Trial
A total of 66 of the 70 patients treated with single-agent NKTR-102 in the Phase II study were assessable for the primary endpoint of objective tumor response rate (ORR), including confirmed complete responses (CRs) and partial responses (PRs) per RECIST 1.0. As of May 9, 2011, for the q14d day schedule, the confirmed and unconfirmed ORR was 35 percent (11/31) and the confirmed ORR was 32 percent (10/31), including two confirmed CRs.

Clinical benefit rate for the 31 evaluable patients in the q14d schedule was 42% (13/31) (defined as confirmed CR+ PR+ Stable Disease (SD) >6 mos). For the q21d schedule, the confirmed and unconfirmed ORR was 31 percent (11/35) and the confirmed ORR was 26 percent (9/35). Clinical benefit rate for the 35 evaluable patients in the q21d schedule was 49% (17/35). Clinical benefit rate for the overall study population was 46%. An additional four patients in the study had near CRs, with 100% disappearance of all target lesions.

The first topoisomerase I-inhibitor in Breast Cancer
“NKTR-102 is emerging as a promising anti-cancer investigational treatment with the potential to become the first topoisomerase I-inhibitor to be used in the fight against breast cancer,” said Prof. Ahmad Awada, Head of the Medical Oncology Clinic at the Institut Jules Bordet in Brussels, Belgium. “The drug’s high confirmed objective response rate and clinical benefit is very interesting, particularly when one observes that this response rate was maintained in patients pre-treated with anthracyclines, taxanes with or without capecitabine, and also maintained in poor prognosis subsets within the study, such as triple-negative breast cancer and patients with visceral disease.”

The confirmed ORR in patients previously treated with anthracycline/taxane/capecitabine was 31% (5/16); confirmed ORR in patients with metastatic triple-negative breast cancer was 39% (7/18); and confirmed ORR in patients with visceral disease was 30% (17/57).

“The every three week dose schedule appears well-tolerated overall and demonstrates encouraging PFS and OS of 5.3 months and 13.1 months, respectively,” Awada continued. “We are in need of effective new therapeutic options whose mechanism of action is different from those already available for women with metastatic breast cancer and we look forward to NKTR-102 entering Phase III development.”

Patients treated in the single-agent NKTR-102 study had a median of two lines of prior cytotoxic treatments for metastatic disease. Seventy-four percent (52/70) of the patients received neoadjuvant and/or adjuvant therapy and 86% (60/70) had visceral disease.

“The clinical benefit we’ve observed in multiple tumor settings with NKTR-102, where a highly active topoisomerase 1 inhibitor could be extremely useful, makes us very excited about the future of this new anticancer drug candidate,” said Lorianne Masuoka, M.D., Nektar’s Senior Vice President and Chief Medical Officer.

Manageable side effects
Side effects were generally manageable with dose-limiting toxicity consisting primarily of Grade 3 diarrhea (20-23%) typically occurring after three months of therapy for both schedules. Neuropathy and alopecia were minimal with only one patient experiencing G2 alopecia in the study. Both neuropathy and alopecia are significant adverse events commonly associated with standard breast cancer therapies.

For more information:
Study Authors: Awada et. al.
Abstract Title: Antitumor activity in a randomized phase II study comparing two schedules of NKTR-102 in patients (Pts) with pretreated metastatic breast cancer (MBC).
Abstract: #1034, Poster Board #24Poster Discussion Session: Breast Cancer – Triple negative/Cytotoxics/Local Therapy
Session Date and Time: Saturday, June 4, 2011, 2:00 PM ? 6:00 PM

[1] American Cancer Society, 2007 Global Cancer Facts and Figures Report.
[2] American Cancer Society, 2009 Global Cancer Facts and Figures Report.
[3] Alvaro and Perez, Mayo Clin Proc. 2009; 84(6):533-545.

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