And for many years, the standard treatment has, of course, been either to recommend radical cystectomy if it's T1B or large volume disease, or at least intravesical immunotherapy with BCG for most patients. This is a randomized non-inferiority phase three study that was performed that actually looked at active surveillance in patients versus intravesical BCG for high grade T1 bladder cancer with a negative second translate for resection, and really very provocative and exciting results. So, Professor Kitamura, really excited to hear what you have to say.
Hiroshi Kitamura: Thank you very much. Thank you for your kind introduction. I'm going to talk about the result of our phase three trial called JCOG1019. So this study design of JCOG1019. We focused on the patients with T1 bladder cancer. T1 bladder cancer diagnosed at the first TURBT, and the participants moved to second TUR. If the specimens of second TUR showed no residual disease, we randomized participants to intravesical BCG or watchful rating active surveillance.
The primary endpoint of this study was relapsed free survival for T1 or deeper intravesical and/or extravesical recurrence or tests. We call the recurrence free survival RFS in the European Urology paper. And select secondary endopoints were overall survival, metastasis-free survival, annual proportion of intravesical RFS and adverse events. So this is a result of primary endpoint intravesical RFS. As you can see, active surveillance was known inferior to intravesical BCG with respect to IRFS.
So margin of the inferiority was 0.60 of hazard ratio. So as you can see, the hazard ratio was 0.69, so this was statistically significant. This is one of the key secondary endpoints overall survival. The active surveillance group does not seem to be inferior to intravesical BCG. The ratio was 0.64 and five-year overall survival of active surveillance was 92% and intravesical BCG group was 91.7%.
So this is a summary of BCG treatment-related adverse events and the frequency of adverse events, including fever, fatigue, haematuria, urinary frequency, urinary tract pain was similar to that previously reported. And in the intravesical BCG group, there were some grade three adverse events, including anemia, urinary tract pain, renal infection, cytokine related syndrome, basically dermatitis, arthritis, and so on. And no deaths occurred during the treatment and protocol treatment within 30 days of the last treatment.
So in conclusion, active surveillance demonstrated statistically significant non-inferiority to intravesical BCG in relapse-free survival for T1 or deeper intravesical and/or extravesical recurrence of death in patients with bladder cancer with high-grade pT1 at the initial TURBT and pT0 at the second TUR. Overall survival was similar in both groups. The safety profile of active surveillance was better than that of intravesical BCG.
So we concluded that the active surveillance for patients with negative residual tumor at second TUR is one of the option in daily practice. So this is take-home message. The results support active surveillance as a potential new standard of care for patients with high-grade T1 bladder cancer without residual tumors at the second TUR. Thank you very much.
Ashish Kamat: Great. Thank you so much for that presentation. Like I said, very provocative results. I do have a question about the trial design. So the patients were only given induction BCG. Was there a reason for lack of maintenance? Because of course, including in Japan, studies have shown clearly that in order to drive the best and the full benefit from BCG, you need at least one year, if not three years of maintenance therapy. So what was the thought process behind not using maintenance?
Hiroshi Kitamura: Yes, that's a great question. When we had a plan of this trial, the standard of treatment of intravesical BCG was eight courses of induction alone in Japan. And I think that the SWOG study by Dr. Lamm was presented BCG maintenance provided better recurrence-free survival, but the international guidelines did not recommend BCG maintenance at that time. So we know that nowadays BCG maintenance is a global standard, so this is a limitation of this study.
Ashish Kamat: Okay. Okay. So just to clarify, at the time that the study was designed, it was designed just based on induction, but of course, things have evolved over time. So in your practice, do you use maintenance BCG today for patients or do you just do induction alone?
Professor Hiroshi Kitamura:
Yes. And nowadays in Japan, the BCG induction of six courses of BCG induction and maintenance more than at least one year, between one and three years. So I think that this standard treatment in Japan is same as global standard.
Ashish Kamat: Okay. And of course, I've been to Japan many times, so that's what I have gathered talking and touring the country. So I just wanted to clarify that in your university, that is the practice as well. The other thing that's interesting is your endpoint, because you use T1 or greater and included those as events. Do you have data on recurrence of any kind, TA high grade, CIS? Do you have any of that data you could share with us?
Hiroshi Kitamura: Yeah, that's a great question because one of the secondary end point was intravesical recurrence-free survival, including TA and TIS recurrence. And the bottom line is that the intravesical BCG globe was a little bit superior to the active surveillance globe in terms of all intravesical recurrence.
But we focused on the life-threatening disease and radical cystectomy for patients with T1 bladder cancer, because T1 blood cancer may progress to muscle-invasive or metastatic disease. So the primary endpoint was intravesical BCG-T1 or deeper and/or extra physical recurrence. So we have to pay attention to the design, the result of the study, because in terms of all intravesical records, including including TA or TIS, the active surveillance was not superior to intravesical BCG group.
Ashish Kamat: Okay. No, and that's another important point. So today we are in a world where we're trying to enhance the results from BCG with, for example, the CREST trial, the POTOMAC study using BCG plus systemic IO therapy. And in those studies, any recurrence, of course, was considered an event. Here, you're going the other direction and looking to see if you could deescalate therapy.
So on the one hand, we're trying to see if we can escalate BCG. On the other hand, we're trying to see in this trial, at least, if we can deescalate BCG. Using the data from your own study and what is currently standard of care and what's known, how do you counsel patients in your clinical practice on what they should do if they have T1 disease? What's your current recommendation?
Hiroshi Kitamura: Yes. As you know, the T1 blood cancer is heterogeneous. I mean that some patients may have progress disease to muscle invasive or metastatic status. On the contrary, some patients have no such as severe recurrence during follow-up, and we focused on the pT1 blood cancer without residual disease at the second TUR. And in our study, two consecutive negative cytology was mandatory.
So we considered that the patients underwent a complete eradication of intravesical tumor at first TURBT. So I know that some patients need intensive treatment BCG with immune checkpoint inhibitor and so on. On the contrary, some patients do not need such intensive treatment. So in this trial, JCOG1019, we have to pay attention to the limited, highly selected patients who do not have any bad factors for future recurrence.
Ashish Kamat: Yeah, no, and I think that's a critical point that you make in that the study should highlight is it really is very important the quality of the TURBT. If the initial TURBT was very high quality and you're able to resect the tumor completely and eradicate all the cancer and prove that on a second TURBT and negative cytology, then that very selected population, there might be some role of maybe reserving or deescalating therapy based on various factors. And I think that's important to discuss with the patient.
So again, I think why I'm really pleased to see these results presented, even though it's not very contemporary based on what we do today, because this challenges us as a field to reconsider this whole paradigm of the TURBT just being one part, it this emphasizes that the resection is a critical part of the first step in the journey of a bladder cancer patient. So, Professor Kitamura, thank you so much for taking the time. It was a pleasure.
Hiroshi Kitamura: Thank you very much.