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DLL3-Targeted and Chemo-Sensitive Therapy

Panelists: Naiyer A. Rizvi, MD, NewYork-Presbyterian Hospital; Taofeek K. Owonikoko, MD, PhD, Winship Cancer Institute of Emory University ; Ticiana Leal, MD, University of Wisconsin-Madison; Jamie E. Chaft, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Nov 11, 2019



Transcript: 

Naiyer A. Rizvi, MD: We are waiting for a lot of the additional immunotherapy data, such as the DURVA [durvalumab]–TREME [tremelimumab] arm of the CASPIAN trial, to read out. But I think we have options first-line. We discussed second-line options. And we really want to just kind of look at the literature and see what’s next. I’ll pick on Jamie because she was involved in this trial—not directly, but she treated some of the patients on the DLL3-targeting therapy with Rova-T [rovalpituzumab tesirine]. Do you want to talk about your experience with this and why it’s so difficult to develop drugs in small cell lung cancer?

Jamie E. Chaft, MD: DLL3 was a hugely exciting target and still is. There are multiple new drugs in development targeting DLL3 as a part of the notch signaling pathway. Developmentally it makes sense to target. And I think we saw an expression-based response. So immunohistochemistry for DLL3, enriched to response to the agent, Rova-T [rovalpituzumab tesirine]. We were just limited by toxicity.

The drug, while effective, was exceptionally hard on patients, including severe life-threatening toxicities, notably edema and infusions. To my understanding the development of the initial DLL3...is done. But I think we’re still enthusiastic about DLL3 as a target. It’s expressed particularly in certain subsets of small cell and up to two-thirds. And this should be a promising target for the future within other immune-directed approaches by specific antibodies, CAR-T cells [cancer antigen receptor T cells], things like that.

Naiyer A. Rizvi, MD: Taofeek, I know you’ve been involved in the lurbinectedin experience. When I look at the data it’s pretty impressive, and you’ve been very involved in these trials. I’d love to hear more about this agent and where you see its future.

Taofeek K. Owonikoko, MD, PhD: In the interest of full disclosure, I’ve actually not been directly involved with the trial, but I’ve been following the data, and some of the investigators there, like the rest of us, we’re good friends. So I think the lurbinectedin is a very interesting compound. At least based on what we now know from published data presented at meetings, this is an agent that seems to be particularly effective in patients with chemo-sensitive disease. And the mechanism of action also is rational for small cell lung disease, which we now know to be a transcriptionally addicted tumor. This is an agent that works by inhibiting RNA polymerase to function, and therefore preventing transcription to occur.

The earliest evidence that this could be an agent that we’d use in our patient population came from the doublet trial looking at the combination of lurbinectedin with doxorubicin. And that was from the attempt originally to develop this in sarcoma patients where doxorubicin was the backbone. They just layered this on. And they saw some signal then that led to the launching of the ATLANTIS trial, which is the randomized phase III trial of that combination versus standard of care.

In retrospect, the observation was then made that perhaps for this group of patients, maybe you don’t need a doublet. They went back to now do the single-agent trial, which is now what is looking really promising and was not that different from what they saw with the original single-arm phase II trial with the doublet chemotherapy. We did the overall response rate about 35%. But when you look at patient with chemotherapy-sensitive disease, that’s actually close to 50%. For those with chemotherapy-resistant disease it’s low double digits, maybe around 20%. But regardless of whether you’re chemotherapy sensitive or refractory, or chemotherapy resistant, there is something to be said for this agent in relapsed small cell.

The disappointment I see with this is that despite the higher response rates, you know, PFS [progression-free survival] was still around 5 months. Overall survival around 9 months. I think for the [chemo-therapy] sensitive, perhaps up to about 12 months, which is still better than what we have now. Whether this will become standard of care that we can use for our patient outside the ongoing clinical trials remains to be seen. We will know maybe a little later this year or early next year whether there will be regulatory approval for it. That is where we stand with this agent.

Transcript Edited for Clarity

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Transcript: 

Naiyer A. Rizvi, MD: We are waiting for a lot of the additional immunotherapy data, such as the DURVA [durvalumab]–TREME [tremelimumab] arm of the CASPIAN trial, to read out. But I think we have options first-line. We discussed second-line options. And we really want to just kind of look at the literature and see what’s next. I’ll pick on Jamie because she was involved in this trial—not directly, but she treated some of the patients on the DLL3-targeting therapy with Rova-T [rovalpituzumab tesirine]. Do you want to talk about your experience with this and why it’s so difficult to develop drugs in small cell lung cancer?

Jamie E. Chaft, MD: DLL3 was a hugely exciting target and still is. There are multiple new drugs in development targeting DLL3 as a part of the notch signaling pathway. Developmentally it makes sense to target. And I think we saw an expression-based response. So immunohistochemistry for DLL3, enriched to response to the agent, Rova-T [rovalpituzumab tesirine]. We were just limited by toxicity.

The drug, while effective, was exceptionally hard on patients, including severe life-threatening toxicities, notably edema and infusions. To my understanding the development of the initial DLL3...is done. But I think we’re still enthusiastic about DLL3 as a target. It’s expressed particularly in certain subsets of small cell and up to two-thirds. And this should be a promising target for the future within other immune-directed approaches by specific antibodies, CAR-T cells [cancer antigen receptor T cells], things like that.

Naiyer A. Rizvi, MD: Taofeek, I know you’ve been involved in the lurbinectedin experience. When I look at the data it’s pretty impressive, and you’ve been very involved in these trials. I’d love to hear more about this agent and where you see its future.

Taofeek K. Owonikoko, MD, PhD: In the interest of full disclosure, I’ve actually not been directly involved with the trial, but I’ve been following the data, and some of the investigators there, like the rest of us, we’re good friends. So I think the lurbinectedin is a very interesting compound. At least based on what we now know from published data presented at meetings, this is an agent that seems to be particularly effective in patients with chemo-sensitive disease. And the mechanism of action also is rational for small cell lung disease, which we now know to be a transcriptionally addicted tumor. This is an agent that works by inhibiting RNA polymerase to function, and therefore preventing transcription to occur.

The earliest evidence that this could be an agent that we’d use in our patient population came from the doublet trial looking at the combination of lurbinectedin with doxorubicin. And that was from the attempt originally to develop this in sarcoma patients where doxorubicin was the backbone. They just layered this on. And they saw some signal then that led to the launching of the ATLANTIS trial, which is the randomized phase III trial of that combination versus standard of care.

In retrospect, the observation was then made that perhaps for this group of patients, maybe you don’t need a doublet. They went back to now do the single-agent trial, which is now what is looking really promising and was not that different from what they saw with the original single-arm phase II trial with the doublet chemotherapy. We did the overall response rate about 35%. But when you look at patient with chemotherapy-sensitive disease, that’s actually close to 50%. For those with chemotherapy-resistant disease it’s low double digits, maybe around 20%. But regardless of whether you’re chemotherapy sensitive or refractory, or chemotherapy resistant, there is something to be said for this agent in relapsed small cell.

The disappointment I see with this is that despite the higher response rates, you know, PFS [progression-free survival] was still around 5 months. Overall survival around 9 months. I think for the [chemo-therapy] sensitive, perhaps up to about 12 months, which is still better than what we have now. Whether this will become standard of care that we can use for our patient outside the ongoing clinical trials remains to be seen. We will know maybe a little later this year or early next year whether there will be regulatory approval for it. That is where we stand with this agent.

Transcript Edited for Clarity
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