NEW YORK – ALX Oncology is aiming to make its lead candidate, the CD47 inhibitor evorpacept, a key agent in multiple combination therapies that it hopes will improve outcomes compared to standard treatments across tumor types.
The firm is involved with nine clinical trials exploring evorpacept in seven different tumor types. Over the next year, ALX expects to report Phase II data from several of these studies. There was a top-line data readout in July from one of these trials, dubbed ASPEN-06, comparing evorpacept plus Genentech's HER2 inhibitor Herceptin (trastuzumab), Eli Lilly's VEGFR2 agonist Cyramza (ramucirumab), and paclitaxel versus the standard treatment for HER2-positive gastric and gastroesophageal junction cancer without evorpacept. The data from 127 patients showed that adding evorpacept improved the objective response rate and median duration of response versus the standard treatment alone.
According to ALX CEO Jason Lettmann, this is the first readout from a randomized trial of a CD47 inhibitor in solid tumors. "We're pioneering a new mechanism and new approach, both within CD47 blockage and more broadly within immuno-oncology," he said. "This is the first randomized study in the CD47 space to show a positive signal as well as a safety profile like what we've demonstrated. Having randomized data out there in a tough tumor type like gastric cancer is really of high interest."
Although the Herceptin-Cyramza-chemo combination is the standard treatment for gastric cancer patients in many countries, the options are rapidly changing. For example, in the US, Europe, and China, AstraZeneca and Daiichi Sankyo's HER2-targeted antibody-drug conjugate Enhertu (trastuzumab deruxtecan) is also approved as a second-line monotherapy option for HER2-positive gastric cancer. Even with newer options like Enhertu, Lettmann believes there's still a need for better treatments in this setting. The median overall survival seen with Enhertu in the registrational DESTINY-Gastric01 trial was around a year, he pointed out.
"[The benefits are] still pretty modest for patients that have progressed after first-line HER2-directed therapy," Lettmann said. "Our control arm [in the ASPEN-06 trial] supports that need, as well."
In ASPEN-06, 40.3 percent of patients in the evorpacept arm responded compared to 26.6 percent in the control arm. Adding evorpacept to Herceptin-Cyramza-chemo also doubled the median duration of response from 7.6 months to 15.7 months. "To see a durable response in a gastric patient for well over a year like this is really exciting," Lettmann said.
The addition of evorpacept to this combination was also well tolerated with adverse events "largely balanced" across the two treatment arms, Lettmann said. For example, the most frequent adverse event observed in both arms was decreased neutrophil count with 28.6 percent of patients experiencing this in the evorpacept arm compared to 25.4 percent in the control arm. The researchers noted that there were no on-study treatment-related deaths in either arm.
The researchers also explored the importance of HER2 overexpression in driving response. Patients in the study needed to have confirmed HER2 overexpression by scoring an IHC 3+ result or an IHC 2+ result with a positive result for HER2 gene amplification by in situ hybridization (ISH). Patients responded to the evorpacept combination similarly regardless of whether they scored IHC 3+ or 2+.
While the study determined HER2 status mostly using archival tumor samples, the outcomes were better when considering HER2 expression in a subset of patients with fresh tumor biopsies. Among 48 patients with HER2-positive tumors based on a fresh biopsy, adding evorpacept to Herceptin-Cyramza-chemo led to a 54.8 percent response rate compared to a 23.1 percent response rate on Herceptin-Cyramza-chemo alone.
"In gastric cancer, having a fresh HER2-positive biopsy can allow for the identification of a population enriched for HER2 expression, and this is certainly consistent with the data we've seen in [the ASPEN-06] study," ALX Chief Medical Officer Sophia Randolph noted on a webcast about the ASPEN-06 results in July.
However, HER2 expression can also be variable in gastric cancer patients, for example, if they developed resistance to prior anti-HER2 treatment or due to intratumor heterogeneity. That variability can also make repeat treatment with an anti-HER2 therapy less effective over time. While the subset of patients with fresh biopsies had better outcomes with the addition of evorpacept, the researchers noted there was little difference in how patients responded to the standard control treatment when they considered the fresh and archival biopsy groups.
This suggests that these patients may experience resistance to Herceptin after progressing on a prior HER2 inhibitor. But evorpacept's mechanism of action changes how immune cells detect and kill HER2-positive cancer cells, Randolph said, by also blocking the CD47 receptor on these cells that would normally tell immune cells not to attack the cancer cell. "We feel this [approach] translates across other cancer types, too," Lettmann noted. "For patients where HER2-directed therapy has failed, we can provide a novel approach and potentially deliver some benefit."
ALX is also exploring evorpacept's activity when combined with other agents, including with Jazz Pharmaceuticals' engineered immunoglobulin G1 bispecific monoclonal antibody zanidatamab in HER2-expressing tumors; with Enhertu in HER2-positive breast cancer; and with Merck's checkpoint inhibitor Keytruda with or without chemo in PD-L1-positive head and neck cancer. He also highlighted other upcoming trial readouts in the first half of next year for its two Phase II trials in combination with Keytruda with or without chemo in head and neck cancer.
"What's beautiful about the CD47 mechanism is it is active across almost every tumor type, and it's a primary way in which cancer is evading the immune system," Lettmann said.
As for ASPEN-06, the company will report full data at a future medical meeting, but the data at present are too early to inform larger studies or regulatory submissions, in Lettmann's view. Many patients in the trial are "still in early days" of treatment in ASPEN-06, which is designed to measure two-year overall survival, he noted.
"Across all three of our big shots on goal here, we have a ton of data coming," Lettmann said. "What's exciting for us is to be at that stage where [our data] is going to illuminate a new mechanism in immuno-oncology."