CD47 Blocker ALX148 Safe to Combine With Antibody Regimens, Chemotherapy in Gastric/GEJ and HNSCC

The high affinity CD47 myeloid checkpoint inhibitor ALX148 showcased favorable safety and elicited objective responses when combined with trastuzumab (Herceptin), pembrolizumab (Keytruda), and multiagent chemotherapy regimens in patients with gastric/gastroesophageal junction (GC/GEJ) cancer and head and neck squamous cell carcinoma (HNSCC), according to preliminary data from the ASPEN-01 trial (NCT03013218) presented during the 2020 SITC Annual Meeting.¹

Results showed that at a median follow-up of 5.3 months, patients with GC/GEJ cancer who were treated with a second-line combination comprised of ALX148, trastuzumab, ramucirumab (Cyramza), and paclitaxel (n = 14) experienced a median objective response rate of 64.3% (95% CI, 38.8-83.7). Patients with GC/GEJ cancer who received a 15mg/kg dose of ALX148 (n = 11) experienced an ORR of 63.6% (95% CI, 35.4-84.8) after a median follow-up of 4.2 months (95% CI, 2.4-6.2), while patients who were given a 10 mg/kg dose (n = 3) had an ORR of 66.7% (95% CI, 20.8-93.9) after a median follow-up of 8.9 months (95% CI, 5.1-9.6).

Additionally, patients with HNSCC who were given first-line treatment with ALX148 plus pembrolizumab, 5-fluorouracil (5-FU), and platinum-based chemotherapy (n = 4) achieved an ORR of 75% (95% CI, 30.0-95.0) after a median follow-up of 5 months (95% CI, 1.3-8.8). The 15-mg/kg dose of ALX148 yielded an ORR of 100% (n =1; 95% CI, 20.5-100) after a median follow-up of 1.6 months (95% CI, 1.3-1.9). Additionally, those who received the 10 mg/kg dose (n = 3) had an ORR of 66.7% (95% CI, 20.8-93.9) after a median follow-up of 5.3 months (95% CI, 5.0-8.8).

“[ALX148 has] a favorable safety profile [and] demonstrates compelling objective responses [when used] in combination with trastuzumab, pembrolizumab, and multiagent chemotherapies in patients with GC/GEJ cancer and HNSCC,” Keun-Wook Lee, MD, PhD, an associate professor at Seoul National University Bundang Hospital, Seoul National University College of Medicine, said in a virtual poster presentation during the meeting. “To our knowledge, this is the only CD47 targeted agent that has shown this kind of activity in the solid-tumor setting.”

ALX148 is a CD47 blocker fusion protein with an inactive human immunoglobulin Fc region.² The experimental agent was designed to boost the activity of targeted antibodies and checkpoint inhibitors, while decreasing the incidence of hematologic toxicities.

ALX148 bridges innate and adaptive immunity in that it is designed to safely maximize phagocytosis of cancer cells, increase the ratio of inflammatory M1 to suppressive M2 within the tumor microenvironment, activate dendritic cells, and enhance the cross-priming of T cells, explained Lee. CD47 is a myeloid checkpoint and marker that signals macrophages to ignore the cell that CD47 is expressed on.³

In the phase 1, 2-part, first-in-human ASPEN-01 trial, ALX148 was examined as a single agent and in combination with established anticancer antibodies. In part 1 of the study, ALX148 was examined as a single agent. Here, patients were administered escalating doses of intravenous ALX148, ranging from 0.3 mg/kg-10 mg/kg once weekly or 30 mg/kg every other week.

In the second part of the study, ALX148 combinations were examined. Patients received ALX148 at 10 mg/kg or 15 mg/kg once weekly in combination with several agents, including intravenous (IV) pembrolizumab (200 mg every 3 weeks), IV trastuzumab (8 mg/kg to 6 mg/kg every 3 weeks), ramucirumab (8 mg/kg on days 1 and 15 every 4 weeks), paclitaxel (80 mg/m2 on days 1, 8, and 15 every 4 weeks), cisplatin (100 mg/m2 every 3 weeks for 6 cycles), carboplatin (AUC 5 mg/mL/min on day 1 every 3 weeks for 6 cycles), and 5-FU (1000 mg/m2 on days 1, 2, 3, and 4 every 3 weeks for 6 cycles).

The combination dose expansion cohort specifically examined ALX148 plus trastuzumab, ramucirumab, and paclitaxel in the second-line or later treatment of patients with HER2-positive GC (n = 14) who had progressed on trastuzumab, fluoropyrimidine, or a platinum-based chemotherapy. Another cohort of patients with HER2-positive GC were given ALX148 plus trastuzumab in the second-line or later setting (n = 20) and all had progressed on fluoropyrimidine.

Moreover, a cohort of patients with HNSCC (n = 5) were administered first-line treatment with ALX148 plus pembrolizumab, 5-FU, and a platinum-based chemotherapy; none of these patients had received prior treatment for their disease. Lastly, a cohort of patients with HNSCC who had progressed on a prior platinum-based chemotherapy (n = 20) were given ALX148 plus pembrolizumab in the second line or later.

In order to be enrolled on the trial, patients needed to demonstrate adequate organ function and have hemoglobin of 9 g/dL or greater. Patients could not have not received prior treatment with an anti-CD47 or anti-SIRPα agent. CD47 target occupancy in peripheral blood T lymphocytes and erythrocytes were measured via flow cytometry.

The primary objective of part 1 of the study was to characterize the safety profile of ALX148 monotherapy, while the goal of part 2 will be to determine the safety of the agent when used in combination with established anticancer antibodies with or without chemotherapy.

A total of 59 patients with solid tumors were enrolled to part 2 of the study examining the agent in combination. The median age across the cohort was 61 years. There were 10 men and 4 women received ALX148 plus trastuzumab, ramucirumab, and paclitaxel; 15 men and 5 women were given ALX148 plus trastuzumab; 4 men and 1 woman received ALX148 plus pembrolizumab, 5-FU, and platinum-based chemotherapy; and 15 men and 5 women were administered ALX148 in combination with pembrolizumab.

Additional data pertaining to the clinical activity of these combination regimens in response-evaluable patients revealed that those with GC who were given ALX148 plus trastuzumab as a second-line or later treatment (n = 19) after a median follow-up of 19.8 months (11.7-19.8) experienced an ORR of 21.1% (95% CI, 8.5-43.3), a median duration of response (DOR) of 8.7 months (95% CI, 5.6-9.4), a median progression-free survival (PFS) of 2.2 months (95% CI, 1.9-5.5), and a median overall survival of 8.1 months (95% CI, 3.4-12.6).

Patients with HNSCC who hadn't received a prior checkpoint inhibitor and received ALX148 plus pembrolizumab as a second-line or later treatment (n = 10) had an ORR of 40% (95% CI, 16.8-68.7) after a median follow-up of 25.1 months (95% CI, 15.3-25.6); these patients experienced a median DOR of 4.3 months (1.9–not calculable [NC]), a median PFS of 4.6 months (95% CI, 0.5-7.5), and a median OS of 22.1 months (95% CI, 3.1-NC). Patients with HNSCC who had progressed on a prior checkpoint inhibitor and received ALX148 plus pembrolizumab (n = 10) did not respond to treatment (0%; 95% CI, 0-27.8) after a median follow-up of 24.4 months (95% CI, 1-24.4); they had a median PFS of 2 months (95% 0.9-3.6), and a median OS of 7.4 months (95% CI, 3.1-15.4).

"Initial response data for patients with HNSCC [who were administered] ALX148 plus pembrolizumab, 5-FU, and platinum chemotherapy were encouraging, with 3 of the 4 evaluable patients reporting an objective response, including 1 complete response,” Lee explained.

Investigators reported that the combination of ALX148 plus trastuzumab, ramucirumab, and paclitaxel, as well as pembrolizumab, 5-FU, and platinum-based chemotherapy were well tolerated. The majority of treatment-related adverse effects (TRAEs) were low in both grade and frequency. Patients who were enrolled in cohorts that received chemotherapy experienced at least 1 AE, with 57% (n = 8) of patients who received ALX148 plus trastuzumab, ramucirumab, and paclitaxel experiencing 1 TRAE. Patients who were administered ALX148 plus 5-FU and a platinum-based chemotherapy did not experience a TRAE.

“No dose-limiting toxicities were reported in patients with GC who were treated with ALX148 and trastuzumab plus ramucirumab and paclitaxel,” said Lee. “Patients with HNSCC who received ALX148 and pembrolizumab plus 5-FU and platinum chemotherapy [didn't experience serious toxicities]."

The most common TRAEs experienced by patients who were given ALX148 plus trastuzumab, ramucirumab, and paclitaxel were low-grade diarrhea (21%; n =3), rash (21%; n = 3), and urticaria (21%; n = 3).

Notably, only 1 patient experienced a TRAE in the ALX148 plus trastuzumab, ramucirumab, and paclitaxel arm; the patient reportedly experienced grade 3 decreased lymphocyte count associated with treatment. This cohort additionally had several grade 3 all-causality AEs, the most common of which were decreased neutrophil count (36%; n = 5) and hypertension (36%; n = 5), as well as 1 case of grade 4 decreased neutrophil count. Patients who received ALX148 plus pembrolizumab, 5-FU, and platinum-based chemotherapy had several grade 3 all-causality AEs, including decreased neutrophil count (20%; n =1), anemia (20%; n = 1), dysphagia (20%; n = 1), pericarditis constrictive (20%; n = 1), and supraventricular tachycardia (20%; n = 1), with 1 case of grade 4 cardiac tamponade (20%).

Patients who are enrolled on the combination cohorts are still being followed, as of October 1, 2020.

References

1. Lee KW, Chung HC, Kim WS, et al. ALX148, a CD47 blocker, in combination with standard chemotherapy and antibody regimens in patients with gastric/gastroesophageal junction (GC) cancer and head and neck squamous cell carcinoma (HNSCC); ASPEN-01. Poster presented at: 2020 Virtual Immunotherapy of Cancer Annual Meeting; November 8-14, 2020; Virtual. Accessed November 12, 2020. Poster 404.

2. Kauder SE Kauder SE, Kuo TC, Harrabi O, et al. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. Plos ONE. 2018;13(8):e0201832 doi:10.1371/journal.pone.0201832

3. Weiskopf K. Cancer immunotherapy targeting the CD47/SIRPα axis. Eur J Cancer. 2017;76:100-109. doi:10.1016/j.ejca.2017.02.013