Implications of Clinical Response Following Neoadjuvant Chemotherapy - Seth Lerner

April 19, 2019

Seth Lerner discusses the evidence supporting the integrated treatment approaches to advanced bladder cancer that begins with neoadjuvant chemotherapy (cisplatin-based therapy) followed by cystectomy demonstrates clinical response for patients with Ashish Kamat. Advances in chemotherapy for metastatic disease have prompted trials of systemic therapy in patients with early stage, high-risk disease administered before or after local therapy consisting of cystectomy or radiotherapy. There may be a highly selective subset of patients who are potentially curable with chemotherapy alone and do not need a cystectomy. He and Ashish Kamat explore the retrospective cohort data from Cora Sternberg and James McKiernan that contributed to this hypothesis, followed by the impact of data from The Cancer Genome Atlas (TCGA) on this area of bladder cancer research. Seth Lerner discussed what we are learning about checkpoint inhibitors in this same patient population. The treatment of improved patient outcomes in bladder cancer supports a multidisciplinary approach to care including roles for the urologists, the medical oncologists and the radiation oncologists.

Seth Paul Lerner, MD, FACS, is Professor of Urology and holds the Beth and Dave Swalm Chair in Urologic Oncology, in the Scott Department of Urology, Baylor College of Medicine. He is Director of Urologic Oncology and the Multidisciplinary Bladder Cancer Program and Faculty Group Practice Medical Director for the Urology Clinic. He earned his medical degree from Baylor College of Medicine, completed a surgical internship at Virginia Mason Hospital in Seattle, and returned to Baylor for his residency training. He completed a two-year fellowship at the University of Southern California in urologic oncology and reconstructive surgery under Peter Jones and Don Skinner before returning to join the full-time Baylor faculty in 1992. His clinical practice, education, and research activities are devoted to urologic oncology and particularly lower and upper tract urothelial cancer. Dr. Lerner is author of over190 peer-reviewed articles, and co-editor of a comprehensive Textbook of Bladder Cancer. He is the founding co-editor-in-chief of the Bladder Cancer journal. He established and directs the multi-disciplinary Bladder Cancer Research Program at Baylor and his research interests include use of selective estrogen receptor modulators for treatment of bladder cancer, gene therapy, integrated genomic analysis of bladder and upper urinary tract cancers, and outcomes of radical cystectomy and pelvic lymphadenectomy. He has 26 years experience as a clinical investigator for both NCI and industry funded clinical trials. He is the PI of the ongoing SWOG NCI Phase III trial comparing extended vs. standard pelvic lymphadenectomy at time of radical cystectomy. He is active in the leadership of several national bladder cancer research enterprises including chair of the Local Bladder Cancer committee of SWOG, founding and former co-chair of the NCI Bladder Cancer Task Force and current co-chair of the NCI CTEP Genitourinary Steering Committee, and he has co-chaired the Analysis Working Group of The Cancer Genome Atlas Project for muscle invasive bladder cancer for the past 7 years. He is very active in the Bladder Cancer Advocacy Network (BCAN) as a member of the Board of Directors, past chair of the Bladder Cancer Think Tank and co-chair of the management committee of the Bladder Cancer Research Network. Dr. Lerner is an active member of the prestigious American Association of Genitourinary Surgeons and is listed routinely among “America’s Top Doctors” and “Best Doctors in America.

Ashish Kamat, MD, MBBS Professor of Urology and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas.

Read the Full Video Transcript

Ashish Kamat: Welcome. I have with me today a very distinguished guest, Dr. Seth Lerner, who's not only a good friend but also a true leader in the field of bladder cancer.

He's a Professor of Urology at The Baylor College of Medicine in Houston, Texas. He is Director of the Multidisciplinary Bladder Cancer Center over there. He's led the TCGA efforts that have led to the understanding of bladder cancer genomics. He leads SWOG efforts. I better stop here because we only have a few minutes for this interview. Welcome, Seth.

Seth Lerner: Thanks, thanks.

Ashish Kamat: Tell us, Seth, at this EAU we had a really phenomenal session that you participated in.

One of the things that you talked about was the implications of having a clinical response after chemo and what that means for patients. Could you tell us a little bit more about that?

Seth Lerner: Yeah. I think what's driving this ... We've gotten to the point of where we have very good evidence that patients do better in the long run with integrated treatment approaches. Cisplatin-based chemotherapy followed by cystectomy, and though that's been an incremental gain in terms of improving outcomes for patients, it comes at a cost, right?

Cystectomy, as we both know all too well, is a morbid procedure. There's clearly a patient population out there that is potentially curable with chemotherapy alone. That was kind of the topic of our discussion, and potentially doesn't need a cystectomy, or maybe can come in with radiation therapy.

We learned a couple of things. There have been two fairly significant kind of retrospective cohort studies. One from Cora Sternberg and one from James McKiernan at Columbia.  They both showed that in highly-selected patients, so these would probably be smaller volume, clinical T2s, no high-risk features, that if they have a ... what we call a clinical T0 response, we define that by a normal cystoscopy, a normal cytology, and a re-resection of the tumor site not showing any cancer, that in those highly-selected patients they can be observed without further therapy and potentially can enjoy long-term survival without having to go through a cystectomy.

What's happened since that time is, in part some of the work that we've done and learned through the Cancer Genome Atlas Project in muscle invasive bladder cancer, is that there's a number of different genes that are called DNA damage repair genes. When they're altered and ... those patients may have a significant response to chemotherapy such that the chemotherapy may be curative, so that's the hypothesis, right?

There's now three trials that are going on really asking the question that you get neoadjuvant chemotherapy, and this is cisplatin-based chemotherapy as standard of care, and you have one or more of these gene alterations, and you have a clinical T0 response too, can you safely oversee those patients?

Ashish Kamat: What's your sense as far as moving forward, having a similar clinical response in patients getting immunotherapy? Andrea Necchi presented some fairly impressive data, which you're aware of. What's your sense there?

Seth Lerner: Yeah. They have been two trials, Andrea's was one of them, looking at one of the checkpoint inhibitors in the same patient population. I believe the overall clinical T0 response was about 42%. It appeared to be better in patients that were PDL-1 high versus PDL-1 low. That's also very exciting.

This is not nontoxic therapy, but appears to have a fairly good toxicity profile. That's another potential avenue. What he also showed, which was quite interesting, that in addition to PDL-1 high that DNA damage repair alterations also, when you combine with that, seemed to identify a smaller subset that was highly likely to have a cT0 response. Got to test it in clinical trials and see if it plays out.

Ashish Kamat: Right, right. No. Certainly some impressive data about tumor mutational burden as well.

I think Roland Seiler looked at the subset and saw that maybe younger patients might not have the same alterations. Is there a sense you have from all your work with the TCGA that age factors into these mutations and responsive characteristics?

Seth Lerner: I can't tell you from the TCGA. We've looked at every potential clinical co-variate, and age really was not any ... It didn't really fall out in our analysis.

One thing I will put a little bit of a plugin for is that we've just published a paper in European Urology looking at the TCGA subtypes in metastatic disease, so patients with advanced disease that got a checkpoint inhibitor and the neuronal subtype, was associated with an extraordinary response. I think it was about an 89% survival probability.

There may be something there about molecular subtypes that are associated with response to immunotherapy.

Ashish Kamat: Now, you've always been a champion of the role of gender in response and carcinogenesis in bladder cancer. Any clues as far as gender's concerned with response to chemo, response to immuno-oncology agents?

Seth Lerner: Yeah. Well, back to the TCGA work that we've done and work that others have done, I identified David McConkey at MD Anderson. You mentioned Roland Seiler. There's a basal squamous subtype, which makes up about probably 25% of patients with muscle invasive bladder cancer.

The squamous histology and enriched with female gender. Those patients appear to be perhaps a bit more sensitive to cisplatin-based chemotherapy and immunotherapy, so it could be that women who have, say, MIBC with this particular expression subtype may be more responsive. These are all testable hypotheses that we've got to really look at in our clinical trials.

Ashish Kamat: Great. If we circle back to the question of the cT0 and how it correlates with outcomes, what is your sense of the role of resection, or the urologist, in that cT0 that we see in these trials?

Seth Lerner: Yeah. Well, we're the key because we're making the diagnosis. Then, it's really ... This idea of the urologist makes the diagnosis, patient goes off to a medical oncologist and gets treated, and then comes back is we really have to be working together in a multidisciplinary format.

I think that's now in our guidelines that patients with muscle invasive bladder cancer should be seeing at least the urologist and the medical oncologist. Quite frankly, I think we have to for equipoise talk about chemoradiation therapy.

The interesting thing is that we're not used to dealing with ... Sorry. We're not used to the bladder in place, right? It's always been chemotherapy and surgery. These patients need to be surveilled just like every other non-muscle invasive bladder cancer. In Jim McInerney’s trial, a bunch of those patients had non-muscle invasive either persistent disease or recurrent disease. We know how to treat that.

All of those things are factors that we've never really had to address before, at least outside the context of chemoradiation therapy.

Ashish Kamat: Right, right. Since I have you here, which is a rarity, and you did mention chemoradiation, you know that Nick James has a trial going on where he is attempting to bypass the urologist completely.

A patient has a tumor, do an MRI, go straight to cystectomy or radiation therapy. Tell me your thoughts about that in the context of what you just said about the surgeon being an integral part of the procedure.

Seth Lerner: Yeah. I've talked to Nick, and Jim Catto is involved in this as well. I think conceptually there's a lot of questions that, and assumptions that are being made in there.

For instance, with a biopsy, right? I think the idea is biopsy, establish at least histology, but they also bring in MRI to try to give them a little bit more precision around clinical stage. Then, hit the go button.

You and I both know that delays from time of diagnosis to even chemotherapy or delays to surgery can be significant. There's lots of barriers as to why this occurs, so I think that they're trying to overcome a lot of that, but I think there's some assumptions in there that need to be proven.

We don't really know that a biopsy in the office ... What's the correlation both histologically and grade with the TURBT? We certainly don't know the answer to that from a molecular standpoint. All testable hypotheses.

If I may just put a plug in for a trial, maybe this is where you were going, that's about to be activated in the U.S. cooperative groups, where we're looking at chemotherapy plus radiation. Then, testing the hypothesis as a checkpoint inhibitor improve outcomes. These are important trials.

Ashish Kamat: Right, right. You almost read my mind with that plug that you made there. We could chat forever, but in the interest of time we do have to close. In closing, however, for the listening audience, just sort of a summary statement on how you would counsel a patient that comes to you and says, "Hey, Doc. There's no tumor present. I had chemotherapy. What should I do next?"

Seth Lerner: Yeah. We probably both get this question, and not infrequently. The caveat and sort of the warning is there was a trial done in SWOG, which was really maybe ahead of its time, this started in 2002, that was really asking this question about chemotherapy and bladder preservation.

The patients that went on ... That had a clinical T0 response that went onto get cystectomy, 60% of those had residual invasive cancers. I think it's a testable hypothesis.

As you know, we're both clinical trialists. I think that that really ought to be looked at in the context of a clinical trial. Outside of a clinical trial I'd have to say that cystectomy or radiation really is the standard of care. Observation is still experimental.

Ashish Kamat: Yeah. Those are great points. Thank you very much for taking the time for this little conversation we had. This was phenomenal as always and hope you have you here again.

Seth Lerner: Thank you.

Ashish Kamat: Thank you very much.
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