Outcomes with Immune Checkpoint Inhibitors in Patients with MTAP Alterations in Advanced Urothelial Carcinoma - Rafee Talukder

July 3, 2023

Rafee Talukder discusses his presentation on his research into the effects of MTAP loss on survival rates among advanced urothelial cancer patients undergoing immunotherapy. With the help of an extensive international database, his team found that patients with this MTAP loss exhibited worse observed response rates and a trend toward poorer progression-free survival. In addition, the conversation pivots towards the broader theme of precision oncology and the need for interpreting genomic reports more effectively to enhance patient care. Dr. Talukder also discusses a significant paper he published, highlighting the necessity for more personalized treatment strategies for patients showing early progression to platinum chemotherapy.


Rafee Talukder, MD, Hematology/Oncology Fellow at Fred Hutch Cancer Center, University of Washington, Seattle, WA

Petros Grivas, MD, PhD, Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm a medical oncologist in Seattle. I'm a professor in the Division of Oncology and Clinical Research Division in Fred Hutchinson Cancer Center. I'm very excited to host Dr. Rafee Talukder, one of our graduating fellows, superstar fellow, I would say, Who's going to join faculty at Baylor as an assistant professor in oncology. Rafee, welcome.

Rafee Talukder: Thank you. I'm happy to be here.

Petros Grivas: Great to have you here. Rafee, you're presenting a poster tomorrow. You're looking at the potential impact or association between genomic alterations in the MTAP, specifically MTAP loss, and response or survival to immunotherapy for advanced urothelial cancer. Can you tell us a little bit more about this work?

Rafee Talukder: Yeah, actually, we have this really international database of real-world data, over 26 institutions from all over the US, Europe. Essentially, we have over 1500 patients with real-world data, both clinical pathological as well as molecular data as well. One thing we wanted to look with this paper was if patients that have an MTAP loss alteration, how do they do with immune checkpoint inhibitors in patients that have advanced bladder cancer.

There has been some data in the past showing that MTAP loss, the MTAP protein is a protein that's vital in the DNA repair pathway, and when you have a loss of that protein, there is data that shows that it's associated with worse outcomes in patients with advanced urothelial carcinoma. And there is data showing that patients that have this MTAP loss, it's associated with an immunosuppressive microenvironment, aka a cold tumor. So there is some thought that maybe these patients might be less responsive to immune checkpoint inhibitors. So, what we wanted to look here was, well, we have this huge database and we have a significant amount of patients with this MTAP loss, we wanted to see, well, these patients that got immune checkpoint inhibitors, either in the first-line setting or second-line and beyond setting, those that had the MTAP loss, did they have worse outcomes compared to those that did not have the alteration?

Petros Grivas: Very interesting. This rationale, as you mentioned, regarding the biology of disease, it sounds like that the MTAP loss may potentially be shed with cold tumors. The findings of the poster and the next steps?

Rafee Talukder: The findings were actually pretty interesting. We had over 174 patients that got immune checkpoint inhibitors, either in the first-line setting or second-line and beyond setting in the metastatic setting. And what we found was that patients that had this MTAP loss alteration, it was associated with worse observed response rate compared to those that did not have this MTAP loss, and there was a trend towards significance with worse progression-free survival. Those that had the MTAP loss, median progression-free survival was about 3 months, whereas those without the alteration was about 6 months.

Petros Grivas: Interesting. Interesting. So it sounds like we need to do more studies to evaluate the mechanism, also the situation with outcomes. So this database is very interesting and I'm sure you will write the paper soon and look at those potential differences, and, of course, a higher sample size can give us more power. Can you tell us more about this database and what other questions can be answered using this real-world crowdsourcing, I call it?

Rafee Talukder: Yeah, I think this database provided us a really good opportunity to look at clinical pathologic and also molecular biomarkers to see if we can help predict response to response to immune checkpoint inhibitors. We've actually done a multitude of studies with this. One thing we looked at was in patients with FGFR2 or 3 alterations, how did they fare with immune type one inhibitors? We actually presented that at the GU ASCO back in February, and we showed that patients that do have this FGFR2/3 alteration, they do have worse outcomes to immune checkpoint inhibitors. Again, this is all retrospective and need external validation, but it kind of helps put data out into the field, and hopefully in the future, might help inform sequence of therapies.

Petros Grivas: Absolutely. And to your point, these are not practice changing right data. Neither the FGFR alterations or the MTAP loss are not influencing practice, but I think the more data we generate, I think we may get to the point in the future and we may come up with some, hopefully, validated in the future signatures or biomarkers to help select patients for the right therapy and potentially help the sequence of different therapies.

Rafee Talukder: Exactly. I think this is getting one step closer to that personalized precision medicine. We need both prospective data, of course, but we also need retrospective data to help guide these prospective data and trials.

Petros Grivas: Absolutely agree. And I think about the interpretation of the next generation sequencing, the genomic reports. I think there is an unmet need, I would say, in the broader oncology practices, community practices, academic practices to interpret those genomic findings and know what is the functional impacts of particular alterations, pathogenic or not.

Rafee Talukder: Exactly.

Petros Grivas: I think that's another area of oncology to try to practically implement precision oncology by interpreting, first of all, the genomic reports.

Rafee Talukder: Exactly. Exactly. I think we're heading more towards precision medicine, and the more we know about these alterations and genomic mutations, hopefully they'll help paint a better picture of which therapy might benefit which patient better. Hopefully this is just the first step, but I think this will help guide future studies and trials and hopefully we'll have a better understanding in the future.

Petros Grivas: That's fantastic. I think real-world studies, real-world data like the one you're presenting here at ASCO, can help complement data from clinical trials and create this level of evidence and emerging, mounting evidence in order to be able to sequence the right therapies for the right patient and get towards a more personalized approach in the future.

Rafee Talukder: Exactly right. This is complimenting everything has out there. I think we need all different types of data out there, retrospective, prospective, and I think this is complimentary, and hopefully this will lead to some more exciting studies and trials.

Petros Grivas: Absolutely. Because you can identify putative biomarkers and then design a clinical trial to answer the question. Rafee, before we go, you also published a very important paper recently looking at the time of resistance to progression to platinum-based chemotherapy. And those patients with short time, early progression to platinum chemotherapy did not do that well on second-line checkpoint inhibitor. So you may prioritize maybe an antibody-drug conjugate or erdafitinib. Any comments on that paper?

Rafee Talukder: Yeah. This was another really interesting study we were able to ascertain from this really big database that we have. I think what we showed was patients who progressed on platinum-based chemotherapy less than 6 months, they did worse with second-line immune checkpoint inhibitors. This could just be a surrogate for bad disease, and I think this might help identify patients that probably need upfront treatment intensification. And so, I think these are the patients you might want to consider trial or combination treatments upfront. Again, this was also a retrospective study, but I think this can help guide clinicians to help determine which patients are at higher risk for progression and higher risk of having poor prognosis.

Petros Grivas: Absolutely. And I think this an unmet need, again, to have the actual implementation of precision oncology. I think we need more and more clinical data, to your point, like the time to progression platinum chemotherapy, genomics data. Maybe the integration of those elements down the road maybe can lead to some models, prognostic models, maybe predictive models. We need more work, but I think we're getting in that direction.

Rafee Talukder: Exactly. Once step at a time.

Petros Grivas: Absolutely. Congratulations on the great work.

Rafee Talukder: Thank you.

Petros Grivas: Looking forward to your poster.

Rafee Talukder: Of course.

Petros Grivas: Also, congratulations because you're joining Baylor as an assistant professor in a couple of months. So, congratulations.

Rafee Talukder: Yes, sir. Thank you so much.

Petros Grivas: Looking forward to seeing great things from your work.

Rafee Talukder: Absolutely.