Encouraging data from preclinical studies presented at the 2016 IASLC 17th World Conference on Lung Cancer, in Vienna, Austria, suggests that Mersana Therapeutics‘ immunoconjugate XMT-1536 induces durable complete tumor regressions in patient-derived xenograft models of non-small cell lung cancer (NSCLC). Results demonstrating outstanding pharmacokinetics and tolerability in non-human primates was also presented.[1]
…Based on these data, we plan to move rapidly into studies in patients that will help us develop new therapeutic options to treat this devastating disease…
Non-small cell lung cancer is the most common type of lung cancer. About 85% of lung cancers are non-small cell lung cancers. Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma are all subtypes of non-small cell lung cancer. Both small cell and non-small cell lung cancer combined are, according to American Cancer Society, the second most common cancers in both men and women. In men, prostate cancer is more common, while in women breast cancer is more common. About 14% of all new cancers are lung cancers. [2]
The American Cancer Society’s estimates that there will be about 224,390 new cases of lung cancer in the United States in 2016 (117,920 in men and 106,470 in women) and that about 158,080 deaths people will die of the disease (85,920 in men and 72,160 in women). [2]
Lung cancer mainly occurs in older people, on average 2 out of 3 people diagnosed with lung cancer are 65 or older while less than 2% are younger than 45. Statistically, each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. [2]
Early results
“We are encouraged by these early results that demonstrate XMT-1536’s potential in treating patients who have limited treatment options for their lung cancer,” noted Donald A. Bergstrom, M.D., Ph.D., Chief Medical Officer of Mersana.
“The data we presented at the conference suggest that XMT-1536 can induce complete and durable regressions in patient-derived lung cancer models. Based on these data, we plan to move rapidly into studies in patients that will help us develop new therapeutic options to treat this devastating disease.”
The study confirms that NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug development in this disease.
Highly potent immunoconjugate
XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein 2b (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin™ antibody-drug conjugate (ADC) platform. Dolaflexin is one of Mersana’s proprietary multivalent hydrophilic polymer (Fleximer®) immunoconjugate platforms.
Mersana’s technology platforms allows for significantly higher drug loads, providing greater efficacy while simultaneously increasing tolerability. The anti-tumor activity of XMT-1536 was evaluated in eight patient-derived xenograft models of NSCLC adenocarcinoma representing a spectrum of oncogenic driver mutations prevalent in NSCLC, including tumors without oncogenic drivers.
Trial design
The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. At the 3 mg/kg dose, XMT-1536 was active in 7/8 models: complete tumor regression in 4 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 4 of the 5 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60.
Non-human primates
XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study, in which there was no body weight loss, no clinical observations attributable to XMT-1536, and limited clinical pathology findings, including no evidence of neutropenia. Target organ toxicity was minimal to mild and generally reversible. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.
