CytomX Therapeutics 3rd Annual Guggenheim Healthcare Innovation Conference

Sean, welcome. Thanks, Paul. Thanks for having us.

Yeah, happy to. CytomX Therapeutics, we're an oncology-focused company based in the Bay Area, leveraging a very unique technology platform that we call the PROBODY therapeutic platform, which is a biologic masking strategy that allows us to engineer antibodies, cytokines, other biologics to be localized into the tumor microenvironment and less active in the periphery. The way we do that is through leveraging the protease-rich microenvironment of tumor tissue to cleave off peptide masks from the masked biologics. That creates a differential between normal and tumor tissue, which we are able to use to open therapeutic window, and either open therapeutic window where there hasn't been one previously, for example, with EpCAM that we'll talk about a lot in a moment, I'm sure, or improve and broaden therapeutic window where there's room for improvement. For example, our second program, which is a masked version of interferon alpha-2b.

This is a technology that we've really championed over more than a decade now, and it really just continues to allow us to do really interesting and unique things, which is really important at this moment in time where differentiation and staying ahead of the pack, I think, is particularly important.

Yeah, so EpCAM, epithelial cell adhesion molecule, it's a very highly expressed antigen that actually was first described as a colorectal cancer target many years ago. It's expressed also on most other solid tumors, so it's been of interest to the oncology field for many years. Many attempts have been made to try to drug EpCAM with different strategies, including antibodies, T-cell engaging bispecifics, but they've all run into challenges very early in development because of the expression of EpCAM in normal tissues. One of the typical toxicities that was seen early in development of EpCAM therapies was acute pancreatitis due to expression of EpCAM in pancreatic epithelium.

That said, we have known for a few years now that if you can locally target EpCAM with an empowered antibody, whether it's a T-cell engager or certain drug conjugates, local delivery can be effective, for example, in bladder cancer, or in the treatment of malignant ascites, for which there's actually an approved product in Europe called KORJUNY. With the evidence that if you can get the drug to the target and you can shrink tumors, but with the lack of ability of others to have systemically engaged EpCAM, we reasoned that masking could be an ideal way to unlock a therapeutic window for this high potential target, not just in CRC, but potentially in many other cancers as well. We set about making a masked ADC with a topoisomerase I payload, and that's what we call CX-2051, now varsetatug masetecan.

We've just made terrific progress over the last couple of years in the clinic, initially in CRC.

Absolutely. We decided a couple of years ago, as we entered the clinic with Varseta-M, to initially focus 100% in metastatic colorectal cancer for a number of reasons. First of all, that's where the target is most abundantly and most consistently expressed. It's also homogeneously expressed in every patient. We knew the target was there and that we wouldn't need to select patients into the study. We also, I mean, really had intentionally designed the drug to be active in late-line CRC. Thirdly, of course, there's just enormous unmet medical need. We felt that it was absolutely the right place to go first. A little bit risky, but certainly the right place to go first.

We've, as of our most recent update in March, our first update, first data disclosure was in May of 2025, where we showed that this appears to be an active drug. We showed significant evidence of anti-tumor reduction, and we clearly had opened a therapeutic window for EpCAM for the first time with an ADC. We updated that data in March this year. At that time, we were able to report response rates in fourth line or later colorectal of 20%-30%, progression-free survival of six to seven months. We didn't report OS at that time. That's something that's coming in our next update. But a really great start showing unequivocally that this is an active drug in late-line colorectal cancer, where the currently available therapies are highly inadequate.

Just to put our data into context, that 20%-30% response rate and six to seven months of PFS, that compares to. In the fourth-line setting, current standard of care drugs like fruquintinib or regorafenib have response rates of 1%-2%, progression-free survival of about three months. In fact, overall survival for those drugs is about five to six months. Our PFS in the most recent update actually exceeded overall survival in current standard of care in the fourth line. A very strong start for this ADC. Even in the third line, current standard of care is the combination of bevacizumab, the anti-VEGF antibody, with LONSURF, and their response rates are about 5%, PFS of about five months, and OS of about 9-10 months.

We think a really significant step forward, potentially, in the treatment of colorectal with VARSETA-M really functioning as designed. In terms of safety, I should comment on the safety profile as well, of course. First of all, one of the most notable things that we learned in our early clinical experience is no evidence of the classic EpCAM toxicities. We haven't seen any evidence of acute pancreatitis. In fact, we haven't seen any evidence of even elevation of pancreatic enzymes like amylase or lipase. The masking clearly seems to be working and opening therapeutic window. We've seen no ILD, so no interstitial lung disease. This is a novel topoisomerase I payload on VARSETA-M, so masetecan, it's a topoisomerase I inhibitor that we licensed from ImmunoGen, formerly known as CAMP59. So no ILD. Low rates of hematologic toxicity as well, which is really encouraging.