Blood Test May Predict Imdelltra Benefit in Small Cell Lung Cancer

In an interview with CURE, Dr. Justin Gainor, director of the Center for Thoracic Cancers Program at Massachusetts General Hospital, discussed a study showing that a blood marker called DLL3 on circulating tumor cells may predict whether patients with small cell lung cancer benefit from Imdelltra (tarlatamab), a newly approved immunotherapy.

The Mass General Brigham Cancer Institute team analyzed 20 patients and found those with high DLL3 expression all responded to treatment, while nearly all with low expression did not. The test correctly predicted 85% of responders and 100% of nonresponders.

CURE: For patients with small cell lung cancer who may be considered for Imdelltra, what does this blood test potentially change about how treatment decisions are made?

Gainor: The first thing I would say is that this is really meant to be a pilot study. I think the results are impressive. I also think we are doing this with the understanding that the treatment landscape for small cell lung cancer is evolving. What we saw here was that a circulating tumor cell, or CTC, assay, where we are quantitating DLL3 expression, was predictive of benefit to Imdelltra, which is a T-cell engager that was recently U.S. Food and Drug Administration (FDA) approved. The current indication for Imdelltra is as a second-line therapy, after patients have received prior chemotherapy.

Where I really see things moving is that we know there are multiple clinical trials testing Imdelltra earlier in the treatment of small cell lung cancer. We saw at ESMO this past year some first-line data. We know there are trials exploring this in limited-stage small cell lung cancer, and there are efforts to look at this as what’s called consolidation therapy, between first- and second-line therapy. Where this is going to be most actionable is how we think about first line, how we think about consolidation and limited stage.

These data are really encouraging. They need to be validated in larger cohorts and across multiple lines of therapy to really understand how we use this therapy. The answer today is that while these results are impressive, I am still using Zepzelca (lurbinectedin) as my standard second-line therapy. But we know the landscape is going to change very quickly, and I think that’s where this is going to have the most power.

You talked about circulating tumor cells. Can you explain in simple terms what those are and why testing them through a blood test may be meaningful for patients?

Over the last two decades, we’ve seen two different types of so-called liquid biopsies. That is, you do a blood test and you’re looking for biomarkers in blood. The two major liquid biopsies developed over the last two decades have been circulating tumor DNA, or ctDNA, and circulating tumor cells, where you’re looking at whole tumor cells identified in the blood.

So far, in terms of what has been used in clinical practice, it’s really been circulating tumor DNA that is now routinely used to guide the use of targeted therapies. You’re looking for genomic alterations in rare fragments of DNA released into the bloodstream. These tests have gotten very good. They’re commercially available, have rapid turnaround times, and I use them all the time for management of non-small cell lung cancer, where we have about 10 genomic alterations for which we have approved targeted therapies.

The challenge with small cell lung cancer is that it doesn’t have the classical genomic alterations for which we can use targeted therapies. Our most exciting therapies in small cell aren’t targeting genomic alterations. They’re targeting epitopes on the surface of cancer cells. These aren’t genomic targets; they’re on the surface of the tumor cell. If you try to use a liquid biopsy that just looks at DNA, you’re not going to be able to find that target. This is where we think looking at CTCs may have unique clinical utility, because we can find surface expression of the target of our antibody on the CTCs.

Many patients hear that a treatment is approved but still worry it may not work for them. How could this test help set more realistic expectations before starting Imdelltra?

It’s a great point. I’m a researcher and also a practicing oncologist. When I talk about drugs like Imdelltra, before this study I had to rely on data from pivotal studies showing that 30% to 40% of patients experienced a response. Those numbers are based on an all-comers data set.

From a prognostic standpoint, it’s helpful for expectation setting if we had a biomarker showing that someone was much more likely to benefit. That’s really powerful. Likewise, patients with small cell lung cancer tend to have a lot of comorbidities and a heavy symptom burden, which can affect functional status. Many patients are genuinely torn about whether they want to continue anticancer therapy with potential side effects. This test could help guide those decisions by giving us better insight into how likely the therapy is to work.

What did it mean clinically that the test correctly identified patients who did not benefit from Imdelltra, and why is that important from a patient perspective?

What we saw in this study was that we were able to stratify patients into two categories: DLL3 high or DLL3 low based on their CTCs. Among the 11 patients who were DLL3 high, all 11 experienced clinical benefit, meaning a partial response or stable disease, which is really meaningful. Among the nine patients who were DLL3 low, only one had an objective response.

That was an interesting case because it didn’t line up with the rest of the patients. When we took a deeper dive, we found it was a false negative. The patient had an abnormal splice variant of the gene such that the antibody could not target it. Part of our next steps are to refine the assay, refine the antibody, refine the scoring and validate it in larger cohorts.

How might a noninvasive blood test like this reduce the burden of care or uncertainty for patients who have already been through chemotherapy?

This has enormous potential. Right now, it’s really challenging to pursue additional biopsies in patients with small cell lung cancer. These patients often have other medical problems, and the location of the tumor can make biopsy difficult. When the cancer grows, patients can become symptomatic very quickly, and waiting weeks for a biopsy and results can be difficult. If it’s not going to change management, that has been a major reason we haven’t pursued biopsies.

This is a noninvasive test. It’s a standard phlebotomy where patients have 20 milliliters of blood drawn in two tubes. This could greatly facilitate testing and ease of testing for patients.

Looking ahead, how do you see this approach to testing circulating tumor cells applying to other DLL3-targeted therapies or other aggressive cancers?

I’ll answer that in two ways. First, we spent time understanding not just predictive aspects, but mechanisms of resistance. We tracked patients longitudinally and looked at CTCs at the time of progression. In about 60% of patients, they retained DLL3 expression, which has major therapeutic implications. Beyond T-cell engagers, there are antibody-drug conjugates and radioligands being developed against DLL3. If someone develops resistance to a T-cell engager, you could potentially switch to another DLL3-targeted approach.

In about 40% of patients, DLL3 expression was lost, which may direct you away from DLL3-targeted therapy. We also looked at other targets and saw they were maintained. This suggests this could be an iterative biomarker used longitudinally.

More broadly, I view this as a platform. While DLL3 is my target of interest, many other T-cell engagers are being developed across different tumor types. This approach could be deployed for other cell surface epitopes. The technology and approach are the same, and that’s another major area we hope to explore.

Transcript has been edited for clarity and conciseness.

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