Dr. Ali, thank you so much for joining us.
Muhammad Ali: Thank you for the kind introduction and it's a pleasure to be here and thanks to the UroToday for the opportunity to discuss this trial, which is a phase two trial, but it will give us some good insight for future.
So today I would be talking about neoadjuvant pembrolizumab and stereotactic radiotherapy prior to nephrectomy for renal cell carcinoma. It is a phase two randomized clinical trial. And the trial is the investigator-initiated and it was funded by MST and it was a multi-institutional trial done at two centers in Australia, one Peter Mac and one was in Brisbane, Queensland. So in this presentation we will just briefly go through background and then some detail about the study before giving my conclusion what my thoughts are from the small randomized trial.
So if we look for the renal cell carcinoma, surgery remains the standard of care. Radical nephrectomy is most commonly used for high-risk large tumors, but partial nephrectomy can also be considered. However, quite significant number of patients up to 15% and 50% experience local as well as distant spread. So far over last three decades, multiple more than 10 phase three randomized trial have looked at tyrosine kinase inhibitors or immune checkpoint inhibitors more recently in the adjuvant setting. And out of those only two trials per their primary endpoint.
S-TRAC, which was the adjuvant sunitinib for one year, it translated into one year median disease-free survival benefit, but was never positive for overall survival. Though this drug gained the FDA approval, but it was not very commonly used because of significant impact on quality of life and without any overall survival benefit. And now most recently we have over last four years, four ICI trials have been reported and one the last one, RAMPART, which is still awaiting it is a UK-based trial. So hopefully we will be expecting the result of this combination in coming one or one and a half year. But only trial out of those four reported so far, KEYNOTE-564 which showed improvement.
If we look at the KEYNOTE-564 trial. So the trial randomized high-risk renal cell carcinoma patients following nephrectomy into adjuvant pembrolizumab or placebo for a year. The primary endpoint was disease-free survival, which the trial met with the absolute benefit of around 9% at five-year. And the hazard ratio was quite strong as well around at 0.62, means 38% relative risk reduction. But the most important, this is the first trial in the adjuvant setting which met their overall survival benefit as well. And the absolute benefit of 5% at four year, 91 versus 86%. In this trial almost one-third of the patients experienced grade three plus toxicity, around 19 to 20% of the patients were not able to complete the treatment and have to discontinue because of the side effects.
However, still quite significant number of patients they experienced local as well as distant recurrence. So we can see almost one-third of the patients within the first four year had a recurrence despite receiving one year of pembrolizumab. So definitely we need more intensification or some newer way of trying to minimize the incidence of recurrence.
In the neoadjuvant stereotactic radiation. We don't have a lot of data. There was only one study when we planned this trial. There was only one pilot study from Roswell Park, Dr. Anurag Singh. So 16 patients in this study all were having a stage four metastatic of clear cell carcinoma and the patients were planned for cytoreductive nephrectomy. So they have given 15 gray single fraction four weeks prior to surgery. So this treatment was well tolerated, no significant complications. And what they have found on the molecular analysis, they found that there was increased expression of tumor-specific antigens. It includes but not limited to CA9 and MUC-1. There were other like [inaudible 00:05:10] and other tumor-specific antigens significantly increase as well.
And another thing they found is that there was increased density of proliferating CD8 positive T-cells in the SBRT group and they compared it with the control group which had the surgery before. So they concluded that the single fraction SABR is well tolerated, result in more tumor-specific antigens and increased the proliferating CD8 positive cells as well. So this was the rationale for starting this trial. We start thinking about it early 2019. Keep in mind, until then we don't have any data from ICI trials when we started this 2019.
So the NAPSTER, it's a phase two non-comparative one-on-one randomized trial. The patients meeting the inclusion criteria, clear cell carcinoma, T1b to T3a, N1 are low volume, M1 were planned for nephrectomy and also planned for metastatic directed treatment were randomized one to one to 42 gray three fraction stereotactic ablative radiotherapy or the same radiation with three cycles of pembrolizumab and the first cycle was given a week before stereotactic radiation. So the radiation was basically sandwiched between cycle one and cycle two.
And then following the treatment all the patients had nephrectomy and we planned nephrectomy 9 to 12 weeks. And that was a safe period because most of the surgeons, or particularly some patient as well, they become anxious about leaving the large tumor behind and risk of progression which can avoid the surgery. The primary endpoint was to assess changes in tumor responsive T-cells and also major pathological response. It was defined as less than 10% residual tumor and post nephrectomy specimen. So this major pathological response, it was basically based on studies from breast, melanoma and lung. There was no well-defined criteria to assess response post-neural treatment in renal cell carcinoma and still we don't have it.
So we look at the trials. We first patient recruited in June 2022, so from '22 to October '24, over around two and a half years, 23 patients were screened. Out of those, three were non-clear cell histology on biopsy and were excluded. And 20 patients randomized nine into Neo-SABR and 11 into combination group. And all the patients after completing were scheduled for nephrectomy, but two patients declined surgery and withdraw. One was high risk for anesthesia and the other patient declined surgery. So eventually 18 patients went on to have the nephrectomy.
From safety perspective point of view, Neo-SABR or combination was well tolerated. There was no grade four or five toxicity. All the patients completed all the scheduled treatment courses. In the SABR only arm. There was two grade three even, sorry, one was duodenitis and one patients who had before SABR was having hematuria and continued to have hematuria following treatment and had surgery at six to seven weeks after SABR because of persistent hematuria. So it was basically not related to SABR, it was just ongoing hematuria. And for Neo-SABR and IO group, we had only one grade three fatigue.
If we look at the surgical complications, so 18 patients who had surgery, the operating surgeons didn't report any technical challenges and all the patients had laparoscopic or robotic surgery, no additional timing. And the surgery was performed at four different hospitals. So we can see that there were different surgical teams involved and all were confident and no issues with it. If we look at the surgical complications overall, no grade four, five. Only we had one grade three hematoma in the SABR and IO group and that patient's required drainage of hematoma two weeks following.
So far we are still doing the molecular analysis. So we have limited 14 patients so far, we had a nephrectomy specimen, T-cell CDA positive T-cell changes and what we have found that exhausted T-cells, so these are, the bar height represents the mean and the standard deviation is basically the length of these line solid. So what we have noticed that there were increased exhausted T-cell in the Neo-SABR and IO group. And it is mainly because pembrolizumab binding to PD-1 and it results in reinvigoration and proliferation of exhausted T-cell. While exhausted T-cell remain low in the Neo-SABR only. Further what we've found that in both groups effective T-cells were higher, like mean of around 40%. So we need to understand that this trial was not comparative. So we are not comparing the both groups. So statistically both are similar, but we will be planning to compare it with their pre-treatment biopsy samples. That one will give us the idea of whether there were any change in effect T-cell or not.
And what we found, interestingly, the terminal effective T-cell remained high in the SABR group while it significantly reduced in the combination group with mean of around 10 to 13%. And if we look at more further molecular analysis, what we found there was increased expression of CD8 on the exhausted and affected T-cell, which are more like a tumor specific phenotype. But again, we are still awaiting the baseline biopsy comparison to see where we are going.
This is the first patient who declined this surgery. So the patient, this was one of our first patient, quite large tumor, a bit anxious, but as getting the first patient you are always desperate. So we went, had 42 grade three fractions and three cycles of pembro. The patient tolerated well but because of cardiac issues, she was given high risk for anesthesia complications. So patient declined surgery. And three years post-treatment still there is no systemic relapse and the primary is decreasing T-cell. And if we look at the center, we can see quite significant necrotic component within the tumor. And this patient didn't have any grade three event at all.
So in conclusion, we concluded that NAPSTER is the first randomized trial in the neoadjuvant setting, which have reported the safety of SABR plus minus pembro prior to nephrectomy. Neoadjuvant SABR and short course of pembro is safe. It trends towards increased tumor specific T-cell phenotypes. It can be less toxic and possibly cost-effective than other drug combinations. However, still as I mentioned, we are awaiting the comprehensive analysis including the peripheral blood as well to see whether we can go ahead and do some other large trial in this phase. Thank you very much.
Leslie Ballas: Perfect. Thank you. Thank you, Dr. Ali. That's really exciting data that you present. One thing that I was curious about is did all patients get adjuvant pembro following their nephrectomy?
Muhammad Ali: No. So none of the patients had any adjuvant pembro. So far in Australia the adjuvant pembro is not approved. I know it's approved in FDA in USA and Europe. But in Australia still adjuvant pembro is not approved. And so it's still ongoing discussion and most of the medical oncologists over here, they offered the patients a, but it's quite expensive. So far it's not being used in Australia and all these patients didn't have it. And another thing, like I mentioned in the beginning, those trials started and designed before even having the disease-free survival outcome from the KEYNOTE-564. So it was not part of the trial at that time.
Leslie Ballas: If you think about broadening the applicability outside of Australia, would you envision that patients, if they were to get neoadjuvant immunotherapy and stereotactic radiation, that they would then continue pembro after nephrectomy?
Muhammad Ali: I think there are few important things which still we are awaiting the number one, we need to see what kind of peripheral immune changes we are experiencing with this combination. Like if SABR and short course of pembrolizumab, if it can enhance the peripheral immune system, then definitely it's worth trying this combination and then following with the adjunct treatment. But it should be based on immune changes. The patients who had quite significant immune response, maybe we can spare them. But the patients who had immune response, but it's not quite significant, maybe we can think about adding adjunct pembrolizumab. But it's an interesting thing which may be in future we would be looking at, but first we need to wait whether it translate into significant peripheral response or no. That's where we are minimizing the risk of spread.
And another thing about this approach is if we look at the perioperative ICI, there is only one trial which have tried phase three trial, PROSPER. So PROSPER, they give one cycle of neoadjuvant nivolumab and they'd just given one cycle and within four week they need to have a surgery. And the reason for designing that trial in that way was that because of the anxiety and most of the patients and the surgeons because of their anxiety and fear of progression, so they don't want to extend the neoadjuvant immune checkpoint inhibitors.
So combining SABR, which has shown more than 90% local control rate in RCC, so maybe we can extend it a bit longer, like 9 to 12 weeks of neoadjuvant treatment without fear of progression and patients can have the surgery in three to four months. So that we can prime the immune cells better rather than just like a three to four weeks, which I personally think maybe will not give us a good immune changes.
Leslie Ballas: I noticed that you had reasonable Clavien-Dindo scores for toxicity or sort of surgical complications. You didn't comment, did anyone have a delay in getting to surgery on either arm or did everyone get to surgery within the 9 to 12 weeks?
Muhammad Ali: So all the patients had surgery within 12 weeks. Only one patient, which I said had hematuria, so he had surgery at six weeks because of persistent hematuria. So it was earlier surgery, but there was no delay in surgery.
Leslie Ballas: Well, I think that there is so many exciting things going on with the integration of stereotactic body radiotherapy with renal cell carcinoma, much of which from Peter Mac. And so we look forward to seeing what the next step in the progression of use of radiation is with renal cell carcinoma. Thank you so much for joining us today.
Muhammad Ali: Thank you very much. It was a pleasure having a chat and presenting our results.