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Sutro Biopharma Advancing STRO-002 in Phase I Trial With Eye on Biomarker Strategies

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NEW YORK – Sutro Biopharma, a San Francisco-based biotech, is using the proceeds from a recently closed public stock offering to advance its lead antibody drug conjugate, STRO-002, in ovarian and endometrial cancer and exploring the role of folate receptor alpha expression on patients' ability to respond to the drug.

This week, the company provided a progress update on the development of STRO-002, which comprises an anti-folate receptor alpha (FolRα) antibody bound to a tumor growth-inhibiting payload. Sutro said on Thursday that it had dosed the first patient in the expansion stage of a Phase I trial evaluating STRO-002 for ovarian and endometrial cancer.

The announcement comes roughly a month and a half after the company reported out interim data from the initial dose-escalation portion of the trial, in which roughly 32 percent of 31 heavily pretreated ovarian cancer patients experienced tumor shrinkage on STRO-002. Now, within the dose-expansion portion of the trial, patients will be randomized to receive intravenous doses of either 4.3 mg/kg of the drug or 5.2 mg/kg every 3 weeks.

Shortly after announcing these interim results in December, Sutro announced the closing of an upsized public offering of 6.9 million shares of its common stock, resulting in gross proceeds totaling $144.9 million. The firm said it would funnel a significant portion of the net proceeds toward the clinical development of STRO-002, which it discovered internally using its cell-free protein synthesis platform, XpressCF, and site-specific conjugation platform, XpressCF+, and is developing on its own.

STRO-002 is designed to target FolRα, a protein which, according to Sutro Chief Medical Officer Arturo Molina, is overexpressed in ovarian and endometrial cancers. In targeting FolRα, STRO-002 is able to deliver its payload — the tubulin inhibitor, hemiasterlin, which blocks cell growth — specifically to cancer cells. The design of the molecule is very particular thanks to the XpressCF+ system, Molina said. "The site-specific conjugation allows us to position the payload in a way that it leads to the best properties of the antibody-drug conjugate, and one of the properties that we want is specificity for the target, folate receptor alpha."

It is still unclear, however, just how much folate receptor alpha an ovarian or endometrial cancer tumor must express to derive benefit from the drug. This is one of the questions that Molina and the team at Sutro are hoping to address in this next stage of the Phase I trial.

The initial portions of the study allowed patients to enroll regardless of their biomarker status. In the ovarian cancer arm of the dose-expansion portion of the study, which is now enrolling, researchers will collect fresh or archival tumor samples and retrospectively analyze them using immunohistochemistry to assess whether there is a folate receptor alpha expression cutoff that is associated with differential STRO-002 response. In the endometrial cancer arm, however, patients will be selected based on their folate receptor alpha expression levels once the dose expansion phase begins enrolling later this year, though the cutoff has not yet been determined.

The company's differing biomarker approaches in studying STRO-002 in these two tumor types has to do with risk mitigation, according to Molina. "Even though we have compelling preclinical data in endometrial cancer, there is a lot less clinical experience treating patients with endometrial cancer," he said. "We're trying to spare them from the potential side effects of a medication that will not help them … if there is some folate receptor alpha expression, there is some better likelihood of a benefit."

In contrast, Molina noted there are data suggesting that ovarian tumors generally tend to have more FolRα expression, which increases the likelihood that all patients with this cancer type may benefit from STRO-002.

That said, he expects the retrospective biomarker analysis will help the company better define its biomarker strategy in this setting. "For the ovarian cancer patients, of the 13 samples we have out of the [initial] 31 [patients], we see [STRO-002's] activity across a whole broad range [of folate receptor alpha expression]," Molina said. "We're going to continue taking all comers for now and get more information to inform us of what would be a cutoff to start enrichment strategies and take those discussions to the US Food and Drug Administration."

Sutro CEO Bill Newell echoed this plan in a statement in December when the company announced interim results, saying, "additional data from the dose-expansion will inform regulatory discussions, accelerate registration strategy, and identify the broadest population that may benefit from STRO-002."

While the data are still emerging in this regard, there has been some indication that folate receptor alpha expression may be predictive of response. Molina shared that in the initial group of ovarian cancer patients from the dose-escalation portion of the trial, for which 13 tumor samples were available for IHC assessment, one patient whose tumor had an H-score of only seven out of 300 did not respond to STRO-002 at all. The patients who responded or had stable disease, on the other hand, tended to have H-scores starting around 100. "With more samples analyzed, we'll be able to finetune what would be a good cutoff," Molina said. "But the preliminary data suggest the H score cutoff of somewhere around 100 would allow a lot of patients to enroll in the trial."

To analyze the tissue samples for FolRα expression, Sutro will use an established IHC assay from Roche subsidiary Ventana Medical Systems.

Beyond homing in on a predictive biomarker approach, Sutro's longer-term strategy for STRO-002 includes advancing the drug into earlier lines of treatment. In the dose-escalation portion of the Phase I study, patients had already received a median of six prior lines of therapy, including standard-of-care platinum-based regimens, bevacizumab (Genentech's Avastin), PARP inhibitors, and checkpoint inhibitors. In the dose-expansion portion, ovarian cancer patients with platinum-resistant disease have received an average of one to three prior treatments and patients who have platinum-sensitive disease have received two to three prior treatments. In their decision to expand eligibility criteria to include patients with platinum-sensitive tumors, Sutro took into consideration the fact that, even when patients are able to respond to platinum-containing regimens, receiving several of these regimens back-to-back can become difficult to tolerate.

"Once we establish the efficacy of [STRO-002] in these more advanced patients, the obvious strategy would be to bring it up to earlier lines of treatment, or maybe it can be combined with other agents and try to maximize the response earlier on," Molina said.

In the meantime, Molina said he is encouraged by the preliminary results Sutro has seen with the agent, albeit in a very small group of patients. "What's very encouraging about our preliminary data is that we're seeing some patients deriving clinical benefit for over a year," he pointed out.

Indeed, of the first 31 patients evaluated, over half achieved disease control at 16 weeks, and 13 percent remained on treatment for over a year. "For some of these patients, our investigators have told us that the only other option would have been hospice," Molina said. "To have a patient be on treatment for over a year … that's very clinically meaningful."