Shots:
- Evorpacept emerges as the only CD47-blocking therapy with strong clinical activity and a highly manageable safety profile, thanks to its unique inactive Fc design that enables targeted tumor destruction while sparing healthy cells.
- Updated ASPEN-06 data highlights CD47 overexpression as a powerful predictive biomarker, showing dramatic improvements in ORR, DOR, PFS, and OS for patients with CD47-high and retained HER2+ gastric cancer, reinforcing evorpacept’s potential across multiple tumor types
- Jason Lettmann, CEO at ALX Oncology joins PharmaShots for a deeper conversation on biomarker-driven development, evolving HER2+ treatment paradigms, and the future of evorpacept in oncology
Saurabh: Could you provide a brief summary of your CD47 therapy, evorpacept, and what distinguishes it from previous CD47 therapies?
Jason: Evorpacept is the leading CD47 program in development with the potential to be the next targeted immune-oncology drug. It is the only CD47-blocking agent that has demonstrated activity when combined with anti-cancer antibodies in multiple clinical trials and has a manageable safety profile, a key distinguishing characteristic of ALX Oncology’s design.
CD47 is a protein that is broadly overexpressed on cancer cells as a means to evade detection by the immune system. It sends a “don’t eat me” signal that prevents destruction by phagocytosis from the innate immune system. Phagocytosis occurs when the innate system has the “don’t eat me” signal removed and receives a “do eat me” signal from the active Fc region of an antibody.
Evorpacept is a fusion protein that blocks the CD47 “don’t eat me” signal, allowing the innate immune system to detect the cancer. Evorpacept has a unique design with an inactive Fc region meaning the “do eat me” signal needs to come from a second anti-cancer antibody such as trastuzumab, rituximab, or other drugs. This one-two punch is designed to result in the targeted destruction of CD47 expressing cancer cells while avoiding the destruction of healthy cells.
Importantly, CD47 is also expressed on healthy cells like red blood cells. Former attempts to target C47 had active Fc regions, and these led to significant toxicities in some patients and prevented other molecules from moving forward in development. In contrast, the evorpacept approach, using an inactive Fc, spares normal cells. Our safety database of more than 750 evorpacept treated patients confirms its manageable toxicity profile.
We are currently developing evorpacept in combination with anti-cancer antibodies, like trastuzumab, in HER2+ breast cancer based on benefit demonstrated to date across our ASPEN-06 gastric cancer clinical trial in combination with trastuzumab and standard-of- care. In addition, activity has been demonstrated when evorpacept is combined with other anti-cancer antibodies such as zanidatamab in HER2+ breast cancer, rituximab in non-Hodgkin lymphoma, and we are currently partnering with Sanofi investigating the combination of evorpacept with SARCLISA®(isatuximab-irfc) in patients with multiple myeloma.
Saurabh: Could you summarize your results from the ASPEN-06 clinical trial which demonstrated that CD47 expression is a good biomarker for evorpacept use in HER2+ gastric/gastroesophageal (GE) cancers.
Jason: During our recent poster presentation at the Society for Immunotherapy of Cancer (SITC) Annual Meeting, we presented compelling findings from a pre-planned exploratory analysis of the ASPEN-06 clinical trial in gastric cancer, which highlighted CD47 overexpression as a key predictive biomarker for response and durable benefit in patients with retained HER2 expression.
As a reminder, ASPEN-06 is a randomized Phase 2 trial of evorpacept plus HERCEPTIN® (trastuzumab), CYRAMZA® (ramucirumab) and paclitaxel (TRP), we refer to this arm as evo + TRP, versus TRP, in patients with 2nd or 3rd line HER2+ gastric cancer that had previously been treated with a HER2-targeted therapy. Full data from this trial was presented at ASCO GI earlier this year. At SITC, we presented updated data from a pre-planned exploratory analysis of ASPEN-06 that identified CD47 overexpression as a key predictive biomarker for response and durable benefit in patients with retained HER2 expression. We defined retained HER2 expression as patients who are HER2-positive on a tumor biopsy after receiving a HER2-targeted treatment or by HER2 amplification by circulating tumor DNA (ctDNA).
Our findings demonstrated that in patients with retained HER2+ and CD47-high gastric cancer (n=43), evorpacept + TRP had a 65.0% objective response rate (ORR) versus 26.1% ORR for TRP, while patients with HER2+ and CD47-low gastric cancer (n=47), evorpacept + TRP had a 37.5% ORR compared to 26.1% ORR for TRP. Additionally, the duration of response (DOR) was three times longer in the evorpacept + TRP arm relative to TRP in these patients that had retained HER2 expression and high CD47 expression, with a median DOR of 25.5 months versus 8.4 months, respectively. Patients with HER2+ and CD47-low gastric cancer, had a median DOR of 11.2 months for evorpacept + TRP compared to 12 months for TRP. We also found that that the addition of evorpacept to TPR reduced the risk of disease progression or death by 61% for these patients with HER2+ and CD47-high tumors, as shown by the median progression free survival of 18.4 months for the evo + TRP arm versus 7.0 months for TRP, with a hazard ratio of0.39. Treatment with evorpacept + TRP resulted in an OS of 17 months versus 9.9 months for TRP, with a hazard ratio of 0.63.
As the only difference between treatment arms was the addition of evorpacept, these results demonstrate the contribution of evorpacept to these outcomes. These data tell us that our drug worked best when both targets, CD47 and HER2, are expressed.
Saurabh: How might CD47 be used as biomarker in a clinical setting?
Jason: In our study, CD47 levels were measured by immunohistochemistry (IHC) in tissue biopsies. We saw consistent benefit across multiple CD47 expression cut points, starting from as little as 5% IHC3+ for CD47-high. The prevalence of CD47 high expression ranges from 40% to nearly 60% of HER2-positive patients in our study depending on the cut off point used.
It’s important to remember that CD47 is not a gastric-cancer specific biomarker. CD47 has been heavily studied for over a decade, and it is highly expressed in a range of tumors. In addition, it’s been identified in the literature as being a negative prognostic factor meaning it can lead to worse outcomes for patients. Because of this, the data we’ve presented is even more important as evorpacept has the potential to provide benefit to this patient population in need of new options.
It is possible that there are some indications where patients could be selected for treatment based on CD47 expression, like gastric cancer, and others where selection may not be required because CD47 expression is uniformly high.
Saurabh: Given the positive results from ASPEN-06, what are ALX Oncology’s plans for further development of evorpacept in HER2-positive cancers? Are there any other tumor types or combination therapies you’re considering for future trials?
Jason: We believe the positive results from ASPEN-06 demonstrating improved outcomes in patients with CD47-high expression in retained HER2+ gastric cancer support the hypothesis that CD47 expression could be a key predictive biomarker for evorpacept efficacy in other clinical settings. Specifically, the insights we have gained in gastric cancer are guiding our biomarker targeted clinical development strategy for evorpacept in combination with trastuzumab and chemotherapy in HER2+ breast cancer. We will be enrolling patients with HER2-positive tumors that have previously received ENHERTU® (fam-trastuzumab – deruxtecan-nxki) and we will evaluate efficacy measures by CD47-expression level and by HER2 amplification in ctDNA in our ongoing Phase 2 ASPEN-09-Breast Cancer trial.
There is a growing need for new agents that can overcome resistance to ENHERTU® and that bring an additional mechanistic approach to HER2-positive cancer. We believe the activity shown with evorpacept plus a trastuzumab-based regimen in HER2-positive gastric cancer, as well as data we have in breast cancer when combining evorpacept with zanidatamab (a HER2-targeted bispecific) provide clinical support for investigating evorpacept with trastuzumab in breast cancer HER2-positive breast cancer.
Saurabh: How do you envision that evorpacept could change the treatment paradigm for gastric cancer and a variety of other difficult to treat tumor types?
Jason: There are no approved therapies for patients with cancers that overexpress CD47, and we know that expression leads to worse outcomes. Evorpacept has the potential lead to better outcomes for these patients. The data from the ASPEN-06 analysis not only compares well to benchmark studies in HER2+ gastric cancer but also offer valuable insights as to how evorpacept could be used in other tumor types that also have CD47 overexpression, when combined with trastuzumab or other anti-cancer antibodies beyond HER2+ cancers. We have an ongoing collaboration with Sanofi who is combining evorpacept with SARCLISA® in patients with multiple myeloma. SARCLISA® is another antibody with an active Fc, where we believe evorpacept could drive additional benefit. We’ve also seen activity with evorpacept when combined with rituximab in an investigator-led trial from MD Anderson Cancer Center in non-hodgkin’s lymphoma, a disease that is known to have high CD47 expression. With activity across multiple tumor types and a manageable safety profile as documented across over 750 patients, we are confident in our approach to bring evorpacept to patients.
About the Author
Jason Lettmann
Chief Executive Officer, ALX Oncology
Jason Lettmann is a seasoned biotechnology investor and executive with a strong track record in building and scaling life-science companies. He currently serves as Chief Executive Officer and director at ALX Oncology, a position he assumed in September 2023. Previously, Jason served as General Partner at Lightstone Ventures and Partner at Morgenthaler Ventures, where he backed and advised numerous biopharma and med-tech firms. He also led Promedior Inc. as CEO until its acquisition by Roche, and earlier held a vice-presidential role at Split Rock Partners. Jason holds a B.A. in Psychology from the University of Iowa and an MBA from the Ross School of Business at the University of Michigan.
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