ALX Oncology’s Innovations in CD47 Inhibition Are Changing the Landscape of Cancer Therapy

After nearly two decades in venture capital, Jason Lettmann made a bold move—from investing in biotech breakthroughs to leading one. As CEO of ALX Oncology, he brings a unique perspective on what it takes to turn promising science into life-changing therapies. Having served on ALX’s board since its early days, Jason had a front-row seat to the company’s mission: harnessing the innate immune system to fight cancer by targeting the CD47 checkpoint pathway. Now at the helm, he’s guiding ALX through the next phase of clinical development, with their lead therapy, evorpacept, showing exciting potential across multiple tumor types. Jason shares what drew him to this role, the lessons he’s carried from venture capital and how ALX is working to push the boundaries of immunotherapy.

You spent a significant portion of your career in venture capital. What motivated your transition to leading a life science company, and how has your experience in investment shaped your approach to building and scaling ALX Oncology?

Through my nearly 20 years of experience on the venture side of the industry, I was exposed to a breadth of companies big and small at various stages of development. I find that having spent time on both sides of the industry, I have a much fuller picture of all of the challenges biotech companies face at any given time. Experience in VC can often be truly humbling to see firsthand just how hard it is to bring a new therapeutic to patients. Additionally, my time on the investor side taught me how impactful it is to stick with an investment thesis when it remains viable—even in tough times. I learned how it’s a rare case when the big wins are a straight line to success, and how maintaining conviction in the science and data are key.

I was fortunate to have been involved with ALX since its founding and had been a member of the ALX Oncology board since 2015, so when the opportunity to transition into the role of CEO arose, I couldn’t pass it up. ALX has an incredibly hard-working, passionate team and board of directors, it presented the perfect moment for me to join and continue taking the company to its next stage of development. I’ve always firmly believed the scientific foundation at ALX was incredibly strong and continue to be excited and energized by our emerging clinical data as it clearly validates what we had hoped to see in patients.

ALX Oncology takes a synergistic approach to cancer treatment. Can you elaborate on how this strategy enhances patient outcomes and differentiates your immunotherapies from others available?

The advent of immunotherapy has enabled tremendous progress in cancer treatment, offering the potential to bring the powerful disease-fighting capabilities of the body’s natural defenses to bear against cancer. Despite their promise, the full potential of immunotherapies has not yet been realized; further innovation is essential to ensure that more patients can benefit meaningfully from them.

This is the premise upon which we founded ALX Oncology—that by better optimizing the ability of the immune system to fight cancer, we have the potential to fully deliver on the promise of innovative cancer therapies. Our lead asset evorpacept, is designed to do just this.

Evorpacept is a potential best- and first-in-class CD47 checkpoint inhibitor and one of the most advanced checkpoint inhibitors to target and activate the innate immune system. It does this through removing a shield—the CD47 protein—that cancer cells often adopt to evade immune detection and avoid destruction. As a result, evorpacept uniquely reveals these cells to the innate immune system, helping to unleash the full power of the body’s natural defenses against cancer and potentially boosting responses to other important cancer therapies.

Further, evorpacept’s highly differentiated design allows for its potential to offer a more targeted impact with significantly fewer dose-limiting toxicities than seen with previous CD47-blocking approaches.

In short, we are incredibly proud of the rigor of our scientific approach, the tremendous potential for our lead investigational therapy, evorpacept, which is currently being studied across multiple ongoing clinical trials in a wide range of cancer indications, and the tenacity of our team to meaningfully advance the treatment paradigm for people with cancer—initially through our efforts to finally deliver on the promise of CD47 inhibition with evorpacept.

The ASPEN-06 Phase 2 trial is generating valuable insights into evorpacept’s potential in treating HER2-positive gastric cancer. What are the most significant findings so far, and how do they shape your next steps in clinical development?

Having been evaluated in clinical studies across a wide variety of tumor types and in over 700 patients, we are pleased to see that the novel design of evorpacept is working as intended. We reported results from the Phase 2 ASPEN-06 trial, our most advanced clinical trial to-date, in July 2024 and provided a more robust data readout recently at the ASCO GI Conference in January 2025. At a high level, the ASPEN-06 trial demonstrated that evorpacept generates strong response and durable clinical benefit in patients with HER2-positive gastric cancer.

Among the most valuable findings of the trial—and a key trial endpoint—is that in patients with confirmed HER2-positive expression, the addition of evorpacept to the internal control resulted in an overall response rate of nearly 50%, compared to only approximately 25% in the control arm. Further, the evorpacept arm resulted in a median duration of response of 15.7 months versus 9.1 months and media progression-free survival of 7.5 months compared to 6.7 months.

The results from this trial tell a clear story that when a cancer cell is expressing HER2, evorpacept can combine with a regimen containing an anti-HER2 antibody, such as trastuzumab, to improve upon the activity you would expect from that regimen alone.

Looking ahead, in addition to reviewing the ASPEN-06 clinical data with the FDA to determine program next steps, we remain confident in and committed to delivering on the potential for evorpacept to offer a potential first- and best-in-class therapy for a wide variety of tumor types—ranging from breast, gastric and urothelial cancers to HNSCC and multiple myeloma.

ALX Oncology operates at the intersection of cutting-edge science and real-world clinical application. What do you see as the biggest challenge in translating scientific breakthroughs into widely accessible treatments, and how is ALX working to overcome it?

If you look through the history of oncology and certainly immuno-oncology, the past is littered with mechanisms that didn’t pan out in the way everyone anticipated they may work. Our challenge at ALX is similar in that the CD47 space has consistently been viewed as a tough area for drug development. There is no question the CD47 axis is one of the most important areas of immune evasion uniquely adopted by cancer cells.

Our highly differentiated design of evorpacept has always been intentional and is something that we feel has set us apart from our competitors in the space. To date, we have found that much of the early scientific findings from other prospects in the CD47 landscape have, frankly, been predictive for reasons we as a company had foreseen. At ALX we’ve been very focused on running and conducting the clinical studies necessary to answer the question of where our therapeutic has the greatest potential, and we are viewing the data with an honest, open mind—using what the data shows to us as a guiding line of sight for where we go next.

As someone who has navigated both venture capital and leadership in biotech, what advice would you offer to emerging life science entrepreneurs?

One piece of advice I’d give entrepreneurs coming into the field of life science and biotech is do not feel like you need to have every step in your career or every strategic move nailed down. I would encourage them to get comfortable with not knowing exactly what’s next and accept that luck plays a key role in your success.

One thing you learn in venture capital is that about one out of every ten companies are those driving returns for the entire fund. In other words: Failure in biotech is the norm. It can be easy to get lost in the headlines that feature widely successful IPOs and exits and assume that to be the norm, while the reality is that wild successes are not as common as one would believe and are the exception. I always think it’s important, especially for entrepreneurs starting out in the field and are already focused on an exit strategy to remember the adage that “companies are bought not sold” and that you’ll often find the most success when you focus on building something to last with a long-term vision and plan.

What’s one key lesson or insight you wish you had known earlier, and how has it influenced your leadership approach?

One key lesson I wish someone would have told me earlier in my career is that, when faced with big challenges, no one has the right answer. This has influenced my leadership approach and shown me that if you have conviction, know you have the right people around you on your team and you have the faith and belief that you can do what it takes to get it right, you can in fact work through anything. I spent a lot of time earlier on in my career looking for the one perfect expert or the “one answer” and the reality is it simply doesn’t exist!