On April 11, 2022 Sutro Biopharma reported that Phase I data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 8 showing that its lead compound, STRO-002, not only kills the tumor but also elicits immunogenic cell death (Press release, Sutro Biopharma, APR 11, 2022, View Source [SID1234611948]).
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"STRO-002 is in phase I trials for ovarian and endometrial cancer. It’s a fully targeting antibody-drug conjugate (ADC) that binds to the folate receptor alpha antigen that is specific to tumors to deliver its drug payload," Kristin Bedard, Ph.D., VP of discovery at Sutro, told BioSpace before her AACR (Free AACR Whitepaper) presentation.
"Not every tumor cell dies the same way," she explained. "Some tumor cells are unrecognized by the host immune system, and others cause other immune signals to appear as the tumor cells are dying." By recognizing those differences and designing therapies to leverage them, it’s possible to not only kill the tumor cells but also to activate immune responses that may fight any remaining tumors more effectively and thereby build protective immunity.
STRO-002 is showing the advantages of this approach in its effectiveness against advanced tumors. "ADCs kill tumors by binding to the tumor cells and causing them to die. But, to get a complete response you have to hit the majority of the tumor cells," Bedard explained. That requires also debulking the tumor. Therefore, activating the immune system response is like a second layer of defense.
A Phase I study of 33 patients with advanced ovarian cancer reported previously showed an objective response rate (ORR) of 47% in patients who received the optimal dosage. Patients with tumor proportion scores above 25% and who received the optimal dosage had an ORR of nearly 54%. For all evaluable patients on the trial, the disease control rate was 76% at the time of the data cut.
At the most recent interim reporting period (November 2021), the median duration of response had not been reached. At that time, 30 weeks was the longest period of treatment, and approximately half of the patients were continuing in the study. Treatment-emergent adverse events (TEAE) were manageable, with neutropenia being the most common side effect.
Based on nonclinical studies, it is likely that STRO-002 will pair well with other therapies, such as checkpoint inhibitors or other immune-modulating medicines. "Combination therapies are the direction in which oncology treatments are going," Bedard said.
Immune activation, like that enabled by STRO-002, will play an important role in many of those treatments, she predicted. "The immune system is equipped to fight off cancer. The tumors just do a very good job of hiding, so the more things we can do to alert the immune system to the tumor, the more meaningful the response will be."
To that point, Sutro is actively recruiting for a combination study with bevacizumab that is expected to begin in the next few months. That trial is particularly interesting, Bedard said, because it involves the vascular endothelial growth factor (VEGF) blockade mechanism. Therefore, the combination should have immune activation effects as well as anti-tumor properties. Essentially, STRO-002 primes the immune system and the VEGF blockade then releases its brakes.
STRO-002 also may be effective against triple-negative breast cancer and lung cancers, both of which are hard to treat because of the difficulty in getting complete responses. "As a monotherapy, it has shown good activity in non-clinical models of non-small cell lung cancer," Bedard said.
"STRO-002, our immunogenic cell death (ICD)-inducing ADC, is our most advanced clinical asset," Bedard said, but the company also is developing additional technologies. For example, the iADC technology can be used to deliver dual payloads that have different mechanisms of action directly to the tumor using one antibody.
STRO-002 is based on Sutro’s proprietary cell-free platform, which allows it to make any biologic in an in vitro system. As Bedard explained, "We make it in a cell lysate, which allows us to place non-natural amino acids anywhere we want in the antibody. "The position of where you put the drug matters," and affects the activity, stability and toxicity of the drug.
The cell-free aspect also is important, she said, because that ensures that "Every single drug molecule we make using our cell-free technology is exactly the same." In contrast, ADCs that are produced in cell-based manufacturing processes aren’t identical. "There’s a big mixture of variations," and those variations affect the performance of the drug.