Evorpacept Combo Shows Better Responses vs SOC in Advanced/HER2+ Gastric Cancer

Josep Tabernero, MD, PhD

Evorpacept (ALX148), a differentiated CD48 blocker, administered in combination with trastuzumab (Herceptin) plus ramucirumab (Cyramza; EVO-TRP) has achieved an objective response rate (ORR) of 52% in patients with advanced, HER2-positive gastric cancer. This result compares favorably to the use of trastuzumab plus ramucirumab, and paclitaxel, which showed a 22% ORR.¹

The results come from the interim analysis of the phase 2 ASPEN-06 clinical trial (NCT05002127), which were announced in a conference call by ALX Oncology on October 3, 2023. Fifty-four patients with advanced, HER2-positive gastric cancer in the second- or third-line setting were enrolled and randomized to receive the evorpacept 30 mg/kg every 2 weeks in combination with trastuzumab and ramucirumab or the chemotherapy combination.

The median duration of response (DOR) in the evorpacept combination arm was not reached at the interim analysis compared with 7.4 months in the control arm. Further, the efficacy in ASPEN-06 appeared to be better than data from the RAINBOW trial (NCT01170663), which established ramucirumab plus paclitaxel as a standard of care treatment for advanced, HER2-positive gastric cancer. The ORR in RAINBOW was 28%, and the median DOR was 4.4 months.

“Almost all evaluable ASPEN-06 patients administered evorpacept has some degree of tumor shrinkage as measured by the best percentage change in target lesion sum of diameters. This broad antitumor effect compared to that of TRP control arm and is consistent with best overall response rates reported from patient receiving Evo-TRP,” said Josep Tabernero, MD, PhD, during the conference call.

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Tabernero, chief of medical oncology, Vall d'Hebron University Hospital, also explained that robust tumor shrinkage was shown in the subgroup of patients with HER2-positive disease.

Safety results showed that the profile of evorpacept in ASPEN-06 was consistent with that shown in previous studies using evorpacept. Evorpacept, according to comments made by ALX Oncology’s chief executive officer, Jason Lettmann, during the conference, can selectively target CD47. The agent was design to work alongside anti-cancer therapies to specifically target cancer cells rather than targeted CD47 on healthy cells. It is a differentiated agent from other CD47 inhibitor, which tend to active Fc and target healthy cells in addition to cancer cells.

“These initial interim data support the potential for a standard of care in gastric cancer. The ASPEN-06 final analysis is anticipated in the second quarter of 2024,” said Lettmann.

ASPEN-06 was designed to fill a gap in treatment for advanced, HER2-positive gastric cancer, for which the 5-year survival can be as low a 7% for patients with distant metastases, and up to 75% in patients with localized disease.

“Advanced gastric cancer is a challenging disease to treat, and there is a global unmet need for novel and tolerable treatment options. While the rises in incidence are highest in Asia, it has a significant presence in Europe, the Americas, and regions,” explained Josep Tabernero, MD, PhD, chief of medical oncology, during the conference call.

Rationale for ASPEN-06

Multiple clinical trials have explored or continue to explore the efficacy and safety of evorpacept in combination with anti-cancer antibodies for the treatment of patients with solid tumors and hematologic malignancies. Lettmann highlighted a phase 1b study (NCT03013218) of evorpacept plus pembrolizumab (Keytruda) or trastuzumab, which showed preliminary activity and tolerable safety, leading to the launch of the phase 2 study (NCT04675294). In addition, evorpacept is being investigated in a phase 1b study of evorpacept administered in combination with rituximab (Rituxan).²

The current standard of care for this disease come from RAINBOW and DESTINY-Gastric01 (NCT03329690). Although both were large, randomized clinical trials, the therapies produced modest response in patients and the survival benefit was only about 1 year. The data from these studies underscore the need for new therapies to treat advanced, HER2-positive gastric cancer, according to Tabernero.¹

“There is a need for novel therapeutics for patients with gastric cancer and evorpacept has a novel mechanism of action in combination with HER2 antibodies,” said Tabernero.

Finalizing ASPEN-06

Based on the interim analysis results, the futility has been met for EVO-TRP. In the final analysis, 122 patients with advanced, HER2-positive gastric cancer will be randomized 1:1 to receive the experimental or control regimen. The final analysis is 80% powered to detect a 50% improvement in ORR with intravenous evorpacept 30 mg/kg plus trastuzumab (6 mg/kg or 4 mg/kg, ramucirumab 8 mg/kg over trastuzumab plus ramucirumab, and paclitaxel 80 mg/m².)

The study will continue to explore ORR as the primary end point, along with the key secondary end points of DOR, PFS, and overall survival.

To execute the final analysis, patients have been enrolled at study sites across 13 countries in North America, Europe, Asia, and Australia. The enrolled population has a median age of 65 years (range, 41-79 years) in the EVO-TRP arm and 57 years (range, 31-81 years) in the TRP arm. Patients in both treatment arms are predominantly male and Asian or White. All patients enrolled have a ECOG performance status of 0 or 1. Notably, 15% of patients in the EVO-TRP arm and 22% in the TRP arm have gastroesophageal carcinoma.

Sophia Randolph, MD, PhD, chief medical officer, ALX Oncology stated that these results from ASPEN-06 offer the first prospective, randomized clinical data of a CD47 blocker that supports combining myeloid checkpoint inhibition with anti-cancer antibodies.

_REFERENCES:

_{1. ASPEN-06 phase 2 interim gastric/GEJ cancer data conference call. Presented at ALX Oncology conference call. October 3, 2023; virtual.}

_{2. Lakhani NJ, Chow LQ, Gainor JF, et al. Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours (ASPEN-01): a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2021;22(12):1740-1751. doi:10.1016/S1470-2045(21)00584-2}