XMT-1536 as a Game-Changer for NSCLC and Ovarian Cancer

Donald Bergstrom, MD, PhD

Donald Bergstrom, MD, PhD

The antibody drug conjugate XMT-1536 could change the treatment paradigm for both non-small cell lung cancer (NSCLC) and ovarian cancer, according to Donald Bergstrom, MD, PhD.

In an interview withTargeted Oncology, Bergstrom, Chief Medical Officer at Mersana Therapeutics, discusses the pre-clinical trials in mice and monkey models that XMT-1536 has undergone, how the drug differs from its peers, how phase I trials may be constructed for the drug, and what the future potentially holds for the treatment.

TARGETED ONCOLOGY:Can you tell us about the recent data with XMT-1536?

Bergstrom:

Despite recent advancements in the treatment of ovarian cancer and NSCLC, there still remains a significant need for therapies in these diseases. We've identified a tumor-associated antigen that is highly overexpressed in these two tumor types — it's called NaPi2b, and it's a transporter expressed from the cell surface that is really broadly expressed in both NSCLC and ovarian cancer. It's hardly expressed on any normal tissues. Because of this, we've used our Fleximer technology at Mersana to design an antibody drug conjugate. We used an antibody that specifically recognizes the NaPi2b protein on the surface of cells, the antibody drug conjugate binds to the antigen, is then internalized into the cell, and when it makes it into the cell then it released a potent payload that's able to kill tumor cells.

We recently presented the first data we generated from pre-clinical models of XMT-1536, which is our Fleximer antibody drug conjugate against the NaPi2b antigen. What we're showing is that in ovarian cancer tumor models, after we give either one dose or three repeated doses of XMT-1536, we get complete tumor regressions. We've also tested XMT-1536 in what are called "patient-derived xenograft models" of NSCLC. These are tumors that are taken directly from a patient, and implanted into a mouse. They're found to better recreate the human disease in a pre-clinical model. We've tested a number of models with XMT-1536, and similarly we've seen complete tumor regressions in these very aggressive NSCLC tumors.

We've also tested XMT-1536 in safety models. As I mentioned, this is a tumor antigen that has very low expression on normal tissue. Consequently, when we take it into a monkey where the antibody recognizes the monkey protein, what we see is very good tolerability. We've dosed up to doses that are about sevenfold higher than we would need to see for regressions in the mouse models, and it's still very well tolerated in the monkey with limited toxicities that's fully reversible. So we're very encouraged by these data, that this may represent a new therapeutic approach for the treatment of ovarian cancer and NSCLC. We're targeting to bring this molecule to patients in 2017, and we're actively working to develop this promising new therapy.

TARGETED ONCOLOGY:Can you go into detail about some of the steps for bringing it into trials?

Bergstrom:

We'll target the patient population who express this tumor antigen, and again there are two populations of patients where NaPi2b is a relevant target. One is an epithelial ovarian cancer, and the other is a non-squamous, NSCLC. Starting in phase I, we will target those two patient populations. It'll be a standard oncology phase I trial where we'll initially find the right dose through a dose escalation part of the trial, but then we'll really focus on expanding into approximately 20 patients of each indication of each ovarian cancer and NSCLC to get an initial idea of what the activity of the drug is, and to get an initial idea of if we need to use a molecular tool to select the right patients that have the right expression levels for treatment with our drug. We anticipate those data will be available roughly in the 2018 or early 2019 timeframe.

TARGETED ONCOLOGY:How does XMT-1536's mechanism of action make it unique?

Bergstrom:

At Mersana, we build antibody drug conjugates, which are a very effective way of targeting the delivery of potent cytotoxic molecules to tumor cells. What really differentiates the Mersana technology is that we use a water-soluble to conjugate the drug to an antibody. What this allows us to do is to conjugate much higher drug loads to an antibody. Traditional approaches where the drugs are conjugated directly to an antibody have really been pioneered and translated into important therapies for patients. Those can only load about four drugs onto an antibody before the antibody is no longer soluble and you run into issues with the properties of the molecule. Because of our polymer, we target drug loads of typically about 15. We can go as high as 20 drugs per antibody, and as you can imagine, that translates into more efficient payload deliveries into the tumor.

We also have a proprietary payload molecule, which is a potent anti-microtubule drug, but we've designed it in such a way that when it's released in the tumor environment, it's very potent and capable of killing cells in the tumor environment. In the tumor, it's actually metabolically detoxified. So any drug that leaks out of the tumor is relatively non-toxic, which means that we're able to dose to much higher doses than can be achieved with traditional payloads that remain toxic, even when they leave the tumor. Consequently, what we recently showed is that we can dose up to at least sixfold higher than can be achieved with other technologies. So we have better efficacy and we have better tolerability because of the advances we've engineered into the technology.

TARGETED ONCOLOGY:What is the future for XMT-1536?

Bergstrom: