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Rat sarcoma virus (RAS) proteins are a family of prototypical oncogenes frequently mutated in human cancers. Mutations in the RAS gene account for 19% of all pathogenic alterations and are the subject of extensive research in molecular and clinical oncology.1 The RAS family consists of three major isoforms, namely the Harvey rat sarcoma virus (HRAS), the neuroblastoma RAS […]

Highlights in genitourinary cancers (non-prostate) – SunRISe-1, THOR-2, EV-302 CheckMate 901: Petros Grivas, ESMO 2023

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Published Online: Nov 9th 2023

ESMO 2023 brought forth some practice-changing data in the field of non-prostate genitourinary cancer. To understand these, as well as the other key trials and highlights from the meeting, we engaged in a conversation with the Clinical Director of the Genitourinary Cancer Program at the University of Washington and Fred Hutchinson Cancer Center, Prof. Petros Grivas.

In this interview, Prof. Grivas delves into the findings from the SunRISe-1 (NCT04640623), THOR-2 (NCT04172675), EV-302 (NCT04223856), CheckMate 901 (NCT03036098) and other trials, offering his valuable insights into the impact the results could have on clinical practice, and particularly in the treatment of bladder and urothelial cancer.

Associated abstracts:

Necchi A, et al. Results from SunRISe-1 in patients (Pts) with bacillus Calmette–Guérin (BCG)-unresponsive high-risk non–muscle-invasive bladder cancer (HR NMIBC) receiving TAR-200 monotherapy. ESMO Congress 2023, LBA105 

Catto J, et al. THOR-2 Cohort 1: Results of Erdafitinib (Erda) vs Intravesical Chemotherapy (Chemo) in Patients (Pts) With High-Risk Non–Muscle-Invasive Bladder Cancer (HR NMIBC) With Select Fibroblast Growth Factor Receptor Alterations (FGFRalt) Who Received Prior Bacillus Calmette-Guérin (BCG) Treatment. ESMO Congress 2023, LBA105 

Van der Heijden, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial. ESMO Congress 2023, LBA7

Powles TB, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase 3 study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemo. ESMO Congress 2023, LBA1

Siefker-Radtke AO, et al. Phase III THOR study: Results of erdafitinib (erda) vs pembrolizumab (pembro) in pretreated patients (pts) with advanced or metastatic urothelial cancer (muc) with select fibroblast growth factor receptor alterations (FGFRalt). ESMO Congress 2023, 2359.

Vilaseca A, et al. TAR-210 Erdafitinib Intravesical Delivery System in Patients with Non–Muscle-Invasive Bladder Cancer with Select FGFR Alterations: First Safety and Efficacy Results. ESMO Congress 2023

Disclosures: Petros Grivas has received institutional research funding from Acrivon Therapeutics, ALX Oncology, Bavarian Nordic, BMS, Debiopharm, Merck KGaA, Gilead, Pfizer, MSD, QED Therapeutics, GSK; G1 Therapeutics and Mirati Therapeutics; acted as consultant for 4D Pharma PLC, Aadi Bioscience, AstraZeneca; Asieris Pharmaceuticals, Astellas Pharma, BMS, Boston Gene, CG Oncology, Dyania Health, Lucence Health, Fresenius Kabi, G1 Therapeutics, Gilead, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Merck KGaA, MSD, Pfizer, PureTech, Roche, Seattle Genetics, Strata Oncology, Silverback Therapeutics and UroGen.

Support: Interview and filming supported by Touch Medical Media Ltd. Interview conducted by Gina Furnival.

Filmed in coverage of the ESMO 2023

Click here for more content on genitourinary cancer & for further ESMO 2023 highlights visit here.

Transcript

I am Dr. Petros Grivas, I’m a medical oncologist in Seattle, Washington, the United States. I’m a Professor and the Clinical Director of the Genitourinary Cancer Program at the University of Washington and Fred Hutchinson Cancer Center.

We saw a fantastic, very impressive, and I would say informative datasets, overall across GU cancers. I will start by saying that, the most impressive data was in urothelial cancer. I would say starting from the early disease state, early bladder cancer, non-muscle invasive bladder cancer, we know that patients require and want more options when they have BCG-unresponsive non-muscle invasive disease. Many of those patients may ultimately get a radical cystectomy, with lymph node dissection, but many patients are not fit enough to undergo this procedure. Also, they are asking for other options for bladder preservation.

So, we saw some interesting datasets in this disease state. We saw data from Dr. Necchi with, the ‘pretzel’, as we call it, intravesical delivery of this, TAR-200, administering gemcitabine intravesically, with a centrally reviewed, 77% clinical complete response rate, in BCG-unresponsive NMIBC this is very promising. This was a small sample size, but we are awaiting more data in this context and from this trial called, SunRISe-1.

Now we also saw data, in BCG-experienced patients who had reoccurrence after BCG with NMIBC from Dr. Catto, with oral erdafitinib at 6 milligrams, a little bit of a lower dose, compared to the 8 milligrams we use for metastatic disease. This was compared to single agent chemotherapy, a randomized, phase 2 study. This trial closed early because of slow accrual. However, there was a very significant, dramatic, difference favouring erdafitinib orally, in terms of recurrence-free survival for papillary-only tumours Ta/T1. However, because of the toxicity noted with oral edafitinib, I think the enthusiasm was tempered in that regard.  I think, activities there, so the target is valid for FGFR inhibition, however, the attention has been shifted to intravesical delivery of erdafitinib and now that the ‘pretzel’, called TAR-210, now has intravesical delivery of erdafitinib. It will show early data with Dr. Vilaseca in that regard, not practice changing yet, but I think we can see more data with intravesical delivery of erdafitinib but maybe other agents in the future. The most impressive and traumatic data was, in a good way, was in metastatic urothelial carcinoma, in the front-line setting, we had two practice-changing phase 3 trials.

We saw data from CheckMate 901, gemcitabine-cis + nivolumab (NIVO) versus gemcitabine-cis. This was a positive trial for overall survival and progress free survival benefit with a gemcitabine-cis + NIVO, concurrent nivolumab with chemotherapy and then nivolumab maintence for up to 2 years, or progression or toxicity. The trial had a hazard ratio of 0.78 in terms of a overall survival benefit, and also as I mentioned, there was a PFS benefit by a blinded independent review committee. And, there was a subset of patients, about 22 percent had clinical complete response, and the median duration of response in these complete responders was approximately 3 years. So, there are some patients who benefit a lot.

This was a positive trial, practice-changing but even more impressive, I think, was the data from EV-302. Both of those trials, CheckMate 901 and EV-302, were part of the Presidential Symposium on Sunday, October 22, and we experienced a thrilling moment of standing ovation when we saw the data from the EV-302 trial, this was a combination of pembrolizumab, anti PD1, plus enfortumab vedotin, the nectin 4-directed antibody-drug conjugate, compared to chemotherapy, phase 3 trial. It could be a 0, 1 or 2 front-line setting. This trial showed a significant PFS and OS benefit, the hazard ratio for PFS was 0.45, favouring pembrolizumab plus enfortumab compared to chemo and the hazard ratio for OS was 0.47, again favouring enfortumab + pembrolizumab. About a third of patients, about 30 percent or so, received the maintenance avelumab in the control arm.

Ideally, we’d like to see that even higher, but in the real world, maybe the uptake of avelumab maintenance, if you take into account a more stable disease and real world scenarios, might be closer to 56 percent. So this was a little bit lower, but still, I would say a meaningful proportion of patients got avelumab and the degree of benefit with pembro EV I think, is high enough that makes it standard-of-care. So in the frontline setting right now in patients who have access, in countries where the combination is reimbursed, I think pembrolizumab + enfortumab is a new standard-of-care in the frontline setting.

To complete the review, I would mention the THOR trial, phase 3 trial, that had two cohorts, and this was cohort 2 that was presented in this meeting by Dr. Siefker-Radtke from the MD Anderson Cancer Centre. This was erdafitinib versus pembrolizumab, in a selective population of patients, with tumors having FGFR2 or FGFR3, activating mutation or fusion, so a selective population, platinum-refractory disease, immunotherapy naïve pembro versus erda. There was no significant difference in overall survival. The PFS, numerically slightly favoured erda but there was no significant difference in PFS either. And the overall response rate was almost double with erdafitinib with 40 percent versus 21 percent.

So, my take is that in platinum-refractory disease, patients who progress, upfront on platinum chemotherapy, you can potentially give pembro EV second line, at least in the US, the approval of pembro EV was in eligible patients regardless of line of therapy. And now, of course, the label will be adjusted based on the EV-302 data. But, you can argue that now if you were were to choose between erda and pembro, I think multiple factors may play a role. But if you want the response right away, symptomatic visceral metastasis, erdafitinib has double response rate compared to pembo, but pembrolizumab, if you have a response, that is often a durable one. That’s why, the standard-of-care was with Pembro, and there was no significant OS benefit within erda and pembro.

Overall, very exciting datasets. There are many more that were presented. Congratulations to all the presenters an discussants. It was one of the most fantastic impressive, and I would say transformative oncology meetings in terms of GU cancers.

 

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