I’m thrilled to sit down with Ivan Kairatov, a biopharma expert with extensive experience in research and development, particularly in the realm of innovative cancer treatments. With a deep understanding of technology and its application in the industry, Ivan is here to share insights on a groundbreaking approach for extensive-stage small cell lung cancer (ES-SCLC). Today, we’ll explore the potential of tarlatamab, a novel immunotherapy, when combined with anti-PD-L1 therapy, diving into its mechanism, the results of recent clinical trials, and what this could mean for patients facing this aggressive disease. We’ll also discuss the challenges and future possibilities in this evolving field of oncology.
How did you first become involved in the research surrounding tarlatamab, and what drew you to its potential for treating extensive-stage small cell lung cancer?
My journey with tarlatamab began a few years ago when I was working on novel immunotherapies that could address some of the toughest challenges in oncology. ES-SCLC is particularly aggressive, with limited options for long-term survival, so when I came across early data on tarlatamab as a bispecific T-cell engager, I was intrigued. Its ability to direct the body’s own T cells to attack cancer cells expressing a specific marker called DLL3 seemed like a game-changer. I knew I wanted to contribute to advancing this therapy, especially for a disease where patients desperately need better outcomes.
Can you explain what tarlatamab is and how its unique design helps in targeting cancer cells in ES-SCLC?
Absolutely. Tarlatamab is a type of immunotherapy known as a bispecific T-cell engager, or BiTE. It’s engineered to act like a bridge, with one arm binding to T cells—key players in our immune system—and the other arm binding to a protein called delta-like ligand 3, or DLL3, which is often found on the surface of small cell lung cancer cells. By connecting these two, tarlatamab essentially guides the T cells right to the cancer cells, triggering a targeted attack to destroy them. What makes it stand out is this precision; it’s not just a broad immune boost but a highly specific weapon against ES-SCLC.
What was the primary focus of the DeLLphi-303 trial, and why was first-line maintenance chosen as the stage to test this combination therapy?
The DeLLphi-303 trial was a phase 1b study aimed at evaluating the safety and effectiveness of tarlatamab combined with anti-PD-L1 therapies, like atezolizumab or durvalumab, as a first-line maintenance treatment for ES-SCLC. First-line maintenance refers to the treatment given after initial chemotherapy to keep the cancer under control and prevent progression. We focused on this stage because ES-SCLC often comes back quickly after initial treatment, and there’s a huge unmet need for therapies that can extend survival early in the disease course. By intervening at this point, we hoped to sustain the benefits of initial therapy and give patients more time.
Can you walk us through how the trial was structured, particularly in terms of the patients involved and the treatment schedule?
Of course. The trial enrolled 88 patients with ES-SCLC who had already completed 4 to 6 cycles of standard platinum-etoposide chemotherapy, often with an anti-PD-L1 drug if available, and hadn’t shown disease progression. Within 8 weeks of their last chemo cycle, they started maintenance treatment with tarlatamab, given intravenously at 10 milligrams every two weeks, alongside either atezolizumab or durvalumab, which were dosed every four weeks at 1680 milligrams and 1500 milligrams, respectively. This continued until the disease progressed, allowing us to assess both safety and how long the therapy could control the cancer.
The trial reported a median overall survival of 25.3 months, which has been described as unprecedented. What makes this result so significant compared to existing treatments?
This result is truly remarkable because ES-SCLC historically has a very poor prognosis, with median overall survival often ranging from 10 to 13 months with standard treatments. To see 25.3 months—over two years—means we’re more than doubling the time patients can live with this disease. It’s a signal that combining tarlatamab with anti-PD-L1 therapy could redefine what’s possible for these patients, offering not just more time but potentially better quality of life during that period. It’s a step toward turning a devastating diagnosis into something more manageable.
Another key finding was a progression-free survival of 5.6 months. Can you help us understand what this tells us about the treatment’s impact?
Progression-free survival, or PFS, measures the time from the start of treatment until the cancer starts growing again or the patient passes away. A median PFS of 5.6 months in this trial indicates that half of the patients had their disease controlled for at least that long during maintenance. While it may not sound like a huge number on its own, it’s meaningful in the context of ES-SCLC, where progression often happens much sooner. It shows the combination is buying critical time, and when paired with the overall survival data, it suggests the therapy is laying a foundation for longer-term benefits.
Let’s discuss the safety aspect. What were some of the most common side effects observed with this combination therapy in the trial?
Safety is always a top concern with new therapies, especially immunotherapies that rev up the immune system. In the DeLLphi-303 trial, the most frequent side effect linked to tarlatamab was cytokine release syndrome, which occurred in 56% of patients, though mostly at a mild, grade 1 level. Another issue was immune effector cell-associated neurotoxicity syndrome, seen in 6% of patients. The good news is that treatment-related side effects tended to decrease over time, suggesting that patients could tolerate the therapy well in the long run with proper management.
Can you dive deeper into cytokine release syndrome? What is it, and how was it handled during the trial?
Cytokine release syndrome, or CRS, is a reaction that happens when the immune system gets activated rapidly, releasing a flood of signaling molecules called cytokines. This can cause symptoms like fever, fatigue, or low blood pressure, ranging from mild to severe. In the trial, since most cases were grade 1, they were manageable with supportive care—think hydration, fever-reducing meds, and close monitoring. For more intense cases, treatments like steroids or specific drugs to calm the immune response were on hand. The key was catching it early and tailoring the response to each patient’s needs, which helped keep it under control.
Looking at the bigger picture, how do you see this combination of tarlatamab and anti-PD-L1 therapy shaping the future of ES-SCLC treatment?
I’m really optimistic about where this could lead. The data from DeLLphi-303, especially the survival numbers, suggest we’re on the cusp of a new standard for ES-SCLC. Combining tarlatamab’s targeted T-cell engagement with the immune checkpoint inhibition of anti-PD-L1 drugs seems to create a powerful synergy. It’s not just about one drug working well—it’s about how they amplify each other. With the ongoing phase 3 DeLLphi-305 trial, we’re hoping to confirm these results on a larger scale. If successful, this could become a go-to option for first-line maintenance, potentially changing the trajectory for countless patients.
What is your forecast for the future of immunotherapy in lung cancer, especially for challenging cases like ES-SCLC?
I believe we’re entering a golden era for immunotherapy in lung cancer, particularly for tough cases like ES-SCLC. The success of approaches like tarlatamab shows we’re getting better at harnessing the immune system with precision. In the next five to ten years, I expect we’ll see even more tailored combinations—think pairing BiTEs with other novel agents or personalized vaccines based on a patient’s tumor profile. The goal is to move beyond one-size-fits-all treatments to truly individualized care. There’s also a lot of promise in overcoming resistance mechanisms, which is a big hurdle in SCLC. If we keep pushing the boundaries of science and collaboration, I think we’ll turn this disease from a dire prognosis into a chronic, manageable condition.
