Positive preclinical data for Mersana Therapeutics‘ lead product candidate, XMT-1522, demonstrates significant anti-cancer activity in both HER2-positive and HER2 low-expressing tumor models refractory to currently available therapies. The new data were presented today during a poster session at the 2015 San Antonio Breast Cancer Symposium (SABCS) being held December 8 – 12, 2015 in San Antonio, Texas.
XMT-1522 is an anti-HER2 antibody-drug conjugate or ADC comprised of a novel anti-HER2 antibody (HT-19) and the dolaflexin ADC platform. The technology allows for conjugation of 12-15 proprietary auristatin drug payload molecules per antibody without aggregation or detrimental impact on pharmacokinetics.
The anti-HER2 HT-19 antibody binds to a novel HER2 extracellular domain epitope. Studies have shown that the HT-19 antibody does not compete for HER2 binding with trastuzumab (Herceptin®; Genentech/Roche) or or pertuzumab (Perjeta®; Genentech/Roche). Consequently, the combination of XMT-1522 with trastuzumab does not block the ability of the ADC to bind HER2 or efficiently internalize. Researchers found that in vivo the combination of low dose XMT-1522 with a full dose trastuzumab and pertuzumab is synergistic in a HER2-driven model.
In in vitro researchers found that XMT-1522 has sub-nanomolar potency in cell lines expressing as few as 25,000 HER2 antigens per cell, and is ∼100X more potent than ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) across a panel of 25 cell lines representing a range of tumor indications and HER2 expression levels.
The drug candidate pairs Mersana’s Fleximer® immunoconjugate polymer backbone with the company’s custom linker chemistries to create ADC therapies armed with high doses of a proprietary derivative of the dolastatin family of cytotoxic agents.
The conjugate, optimized for payload delivery, utilizes a novel HER2-targeted antibody, which binds to a different epitope than existing anti-HER2 antibodies. XMT-1522 has the potential to address significant unmet needs and improve patient outcomes in multiple oncology indications.
Fleximer-based immunoconjugate molecules have been shown to have superior efficacy, including with targets previously considered not amenable to antibody-drug conjugate approaches. Mersana has collaborations utilizing Fleximer technology with Takeda, Merck KGaA, and Asana BioSciences.
The study evaluated XMT-1522 in models of HER2 low-expressing (IHC 1+/2+) advanced breast cancer, and HER2-positive breast cancer insensitive to ado-trastuzumab emtansine and other HER2-targeted therapies.
“These results demonstrate XMT-1522’s potential to expand the population of breast cancer patients for whom HER2-targeted therapy is appropriate, from the 20 percent currently diagnosed with HER2-positive breast cancer to the full range of patients with HER2 expression,” noted Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer of Mersana.
“The data strongly support moving XMT-1522 into clinical trials with breast cancer patients who have both HER2-positive and HER2 low-expressing tumors,” Bergstrom added.
The study showed significant efficacy of XMT-1522 in all eight xenograft models representative of the target patient populations. In three HER2-positive models, XMT-1522 dosed at 1 mg/kg or 3 mg/kg induced durable complete tumor regressions, while currently available HER2-targeted therapies, including ado-trastuzumab emtansine or lapatinib (Tykerb®; Novartis) /gemcitabine (Gemzar®; Eli Lilly and Company) were inactive.
In five patient-derived xenograft models of HER2 low-expressing breast cancer, a 1 mg/kg or 3 mg/kg XMT-1522 dose led to complete tumor regression in three of the five models, with tumor stasis in the remaining two models. All models achieving complete regression were refractory to gemcitabine, a standard agent for advanced breast cancer patients with HER2-negative disease. The doses of XMT-1522 associated with tumor regression in these models have previously been shown to be well-tolerated in non-human primate safety studies.
The exposure achieved with XMT-1522 at well-tolerated doses in cynomolgus monkey is several fold higher than the exposure needed in mice to achieve complete tumor regressions across models representing a range of HER2 expression and tumor indications. Based on these data, XMT-1522 will soon enter clinical testing in breast cancer patients with both HER2-positive tumors and HER2 low-expressing (IHC 1+ and 2+/FISH-) tumors.