Dr Robert Iannone on Efficacy, Safety of Lurbinectedin, Irinotecan Combination Therapy in Advanced Endometrial Carcinoma

Approximately 19% of patients with advanced endometrial carcinoma undergoing lurbinectedin in combination with irinotecan achieved an objective response rate, whereas more than half were able to continue on the therapy with some degree of benefit, said Robert Iannone, MD, MSCE.

Transcript

Can you discuss the historic lack of research and therapy development generally in endometrial cancer, and the patterns of off-label use in this condition?

I would say that I don't necessarily agree that there's been a lack of research in the area. I think what has been true is that for the many different approaches tried in new therapies, old therapies, new combinations, there hasn't been as much progress toward a cure or improvements in outcomes in endometrial cancer, as there has been in other areas.

I would say it's not necessarily for a lack of trying. It's been a difficult tumor type to treat, with the exception of some rare subtypes, where there has been more progress. And as a result, there continues to be a really serious unmet medical need, and a continued need for novel research, such as the kind that Jazz is doing with lurbinectedin.

In terms of off-label use, it is hard for me to comment on that. I'm not practicing as an oncologist anymore, but I would say in the context of a life-threatening illness where there are a few treatment options, especially after frontline treatment, physicians often try things that are less proven.

Can you discuss the mechanisms that would make a combination of lurbinectedin (Zepzelca) and irinotecan effective in endometrial cancer?

For Zepzelca, what we understand about the mechanism is that Zepzelca binds to the so-called guanine rich elements of a promoter region in a gene. And because cancer cells divide more rapidly than non-cancerous cells, they rely on those promoter regions for initiating transcription of new DNA to support that rapid replication of cancer cells. And so by binding in those guanine rich promoter regions, it actually interrupts that replication process.

As a result, it results in breakage of the DNA, and ultimately cell death for those cancer cells, and it does it again disproportionately in cancer cells versus normal cells, because of the major difference in replication rate.

There's a hypothesis that combining it with irinotecan, which is a so-called topoisomerase 1 inhibitor, that the mechanisms would work hand in hand, so to speak. And that's because topoisomerase’s normal function is to enable DNA replication, and by inhibiting topoisomerase, it interferes with DNA replication and itself results then in both single and double stranded DNA breaks.

The combination of these 2 drugs acting on DNA that way, could be at least additive or potentially synergistic. There has been some preclinical work to suggest that this combination would be effective, and that's what's led ultimately to the clinical work that's ongoing.

Can you discuss the updated results that will be presented during ASCO?

The first part of the results that I think is really critical is how well was the combination tolerated. And we know that combinations are really the hallmark of cancer therapy really, coming at the cancer cells in multiple different directions to ensure that cancer cells don't subvert the therapy, and so combinations is a hallmark.

What is often a challenge is combining drugs in a way that is still well tolerated enough for patients to take. And so that really is the primary objective of the study–to attempt to combine the drugs, establish that they can be well tolerated, and in particular, establish at what doses can they be well tolerated.

So, I think the first important major outcome of the study is that the 2 drugs can be combined effectively. And that information has been provided around how to use those 2 drugs together in terms of the dose and schedule. So, that's the first important outcome, and then the next stage of that study is to look to see, okay, is it efficacious in that combination? The drugs at the doses and schedule that it's being used.

So, we now also have preliminary efficacy data, and again, this is an early-phase trial. So, it's not a randomized, controlled trial, it's a single-arm study to get preliminary efficacy, but those results are promising. In the abstract, there's a report in the first 21 patients, and by all accounts, it's looking very promising.

About 19% of patients had what we consider an objective response rate, meaning the tumor shrank to meet the criteria, the so-called RECIST criteria for an objective response. In addition to that, there was a decent proportion of patients who, while they didn't quite meet that criteria for an objective response, were able to continue on the therapy with some degree of benefit, meaning that their disease was at least stable for more than 4 months, and that reached about 50%, 52.4% to be exact.

Then estimates around progression-free survival, which could help planning and future studies, was also promising. Looking at the landmark of 6 months progression-free survival, that was 40.4%. So, the conclusion ultimately is the combination appears to be well tolerated, it looks to have promising efficacy, and I think that encourages us to want to study this further in future clinical trials.

What are the next steps and the general timeline for development of this combination?

The very next step is to complete this trial. There's a planned enrollment of 50 patients, and this report is really an interim report. And those additional patients will give us more information around the preliminary efficacy. And then it's a matter of, okay, where can this combination be helpful or useful, and that planning is still underway. But there are other places where we think, even beyond endometrial cancer where this combination could be useful.

For example, Zepzelca is approved in small cell lung cancer. Irinotecan is not approved in small cell lung cancer, but it is one of those agents that is known to have some level of activity in small cell lung cancer. And so, one idea is to use this combination beyond endometrial cancer, for example, in small cell lung cancer, and that's one thing we’re considering.

Reference

Gonzalez AF, Paz-Ares LG, Cote GM, et al. Lurbinectedin (LUR) in combination with irinotecan (IRI) in patients (pts) with advanced endometrial carcinoma. J Clin Oncol 39, 2021 (suppl 15; abstr 5586) doi:10.1200/JCO.2021.39.15_suppl.5586