In an interview with Targeted Oncology™, Guru Sonpavde, MD, discussed the safety and efficacy of fixed-dose durvalumab for UTC along with an overview of the ongoing CheckMate 274 trial, which evaluates nivolumab compared to placebo in this patient population.
The promise of monoclonal antibodies in the genitourinary cancer space was first identified in 2002,1 and since then, improvement in survival has encouraged the development of these therapies across genitourinary tumors. Moreover, the introduction of immunotherapies offer even more promise for these patients.
For patients with urinary tract carcinoma (UTC who fail the first line of therapy, the prognosis is poor. The need for second-line options are needed by this population led to the study of the monoclonal antibody, durvalumab (Imfinzi) used alone and as part of a combination.2
The ongoing STRONG study (NCT03084471)2 is evaluating the safety and efficacy of fixed-dose durvalumab monotherapy versus the combination of durvalumab and tremelimumab. It has an actual enrollment of 867 participants and an estimated completion date of March 2022. The primary end point of the study is the number of participants with adverse events (AEs) of special interest. Secondary end points include overall survival and the number of patients with AEs.
During the study, patients were assigned to receive either the combination or durvalumab monotherapy.
In an interview with Targeted Oncology™, Guru Sonpavde, MD, a medical oncologist at the Dana-Farber Cancer Institute, discussed the safety and efficacy of fixed-dose durvalumab for UTC along with an overview of the ongoing CheckMate 274 trial (NCT02632409), which evaluates nivolumab (Opdivo) compared to placebo in this patient population.
Targeted Oncology™: Why was this drug used in this patient population?
SONPAVDE: The STRONG study was a phase 3B study, examining fixed dose durvalumab. So, durvalumab was administered at 1500 milligrams intravenously every 4 weeks in patients with metastatic urothelial carcinoma, who have progressed on or after platinum-based chemotherapy. So, that is a little bit different than the experience so for, for which durvalumab was approved for, which was metastatic urothelial cancer, which was basically using the 10 milligram per kilogram dose once every 2 weeks. And the other difference in the STRONG study was that the study allowed both urothelial and non-urothelial carcinoma. Also, in terms of prior therapy, in addition to platinum-based chemotherapy, it allowed other types of chemotherapy. So, this is why the STONG study was done, essentially to look at the safety and toxicity profile of this fixed dosing primarily, but also to look at these other groups of patients that were not studied in the initial studies.
What results have you seen thus far?
What was previously presented was a phase 2 trial, it was a large non-randomized phase2 trial, also called the 1108 trial (NCT01693562), in which durvalumab at the dose of 10 milligram per kilo, every 2 weeks intravenously, was looked at in patients with metastatic urothelial or predominantly urothelial carcinoma. Based on that study, which showed a response rate in the 15% range with safety, is what led to the approval of durvalumab in this population, and this has been about 3 years ago no.
The STRONG study essentially was a large phase 3B study, which enrolled 867 patients. It was a global study and looked at the fixed dose of 1500 milligrams intravenously every 4 weeks. So, the bottom line is that the study established the safety of this dosage. And in fact, this dosage, the fixed dose of every 4 weeks, 1500 milligrams is now even FDA approved for this setting. So, the safety was established, immune mediated adverse events of any grade were seen in approximately the same range of patients that was seen with historical data. So, about 15% range of immune adverse events, serious immune adverse events. Also, when you looked at efficacy outcomes, the outcomes look similar, the median survival of s7 months, and a 2-year survival of 20.2%. And also, when they look at tumor regressions, in this strong study, 17.5% of patients had tumor responses, including complete responses in 5.1% and partial responses in 12.5%. So based on these data, and also looking at comparing with historical data, the efficacy and safety look consistent and similar to historical data. And as I said, this dosage of 1500 milligrams every 4 weeks is also now FDA approved for treatment of metastatic urothelial carcinoma patients progressing past platinum-based chemotherapy.
Were there any unique safety signals that you observed in this study at all?
We did not. This was reassuring that the safety signal and toxicity profile with the fixed dose formulation was similar to what is known in previous studies with serious immune adverse events occurring in approximately 10% to 15% of patients. There were also some other interesting signals in this study, because the study did include patients that had non-urothelial carcinoma without any urothelial component, and also had a minority but a reasonably good number of patients in the minority that were preferred status 2 patients. When they look at all these subgroups of patients, benefit was seen in these other subgroups. There also appears to be more benefit in patients with performance status 0 or 1 or PD-L1 high expressing tumors, and also in patients with lymph node only metastasis. We know these are major prognostic factors. And so, all of these data were consistent with what's been seen in the past.
Can you give a key takeaway from this research?
I think the key takeaway from the STRONG study is that fixed dose durvalumab 1500 milligrams intravenously every 4 weeks is convenient and has a similar safety profile in patients with progressive metastatic urothelial carcinoma following prior chemotherapy, similar to previous every 2-week dosing. And so, this safety and efficacy was accomplished using a more convenient regimen, and therefore this is a regimen that could be used in patients in this setting.
In the STRONG study, there are translational studies being conducted, analyzing baseline tumor tissue and blood samples. So, this is forthcoming. We also have interesting sub analyses of the STRONG study, because it's a large data set of patients that received durvalumab for progressive disease post platinum. This is a good data set to explore and discover new associations and translational biomarkers. So those data will be something to keep an eye on for the future.
Moving on to CheckMate 274, can you provide an update on this study?
CheckMate 274 is, I think, a very important study. The backdrop to the study is that IMvigor010 (NCT02108652) was presented, which examine adjuvant atezolizumab [Tecentriq] in patients with high-risk muscle invasive urothelial carcinoma. So, these are high risk patients because these patients have extra vesicle disease extending outside the bladder or upper urinary tract without prior neoadjuvant chemotherapy. And it also had a group of patients that had prior neoadjuvant chemotherapy with cisplatin-based chemotherapy, but had muscle invasive disease at least, at radical cystectomy or nephroureterectomy.
So, in these patients, we don't have great evidence for adjuvant therapy. So, these adjuvant immune checkpoint inhibitors PD-1 or PD-L1 inhibitors have been examined, the IMvigor010 trial was negative for disease free survival. But surprisingly, the CheckMate 274 trials that examine nivolumab, a different drug, a PD-1 inhibitor, was reported to be positive for improvement in disease-free survival in all comers, as well as in PD-L1 high patients.
Another data set I wanted to mention In the IMvigor010 trial, although the overall trial was negative, there was a sub analysis done later, which showed that patients who had post-operative circulating tumor DNA positive for minimal residual disease, this was using a platform that used the tumor informed ctDNA profiling, In fact, in this population who were ctDNA positive, there was a benefit for adjuvant atezolizumab. So, these are exciting time for developing and selecting patients rationally for adjuvant therapy. One other comment I will make about CheckMate 274 is assuming that a disease-free survival benefit is robust, I would expect a disease-free survival benefit with an immune checkpoint inhibitor to be more likely to translate into survival benefit, as opposed to chemotherapy, given the duration of benefit with an immune checkpoint inhibitor tends to be long, much longer than with chemotherapy. The second point I would make is that if adjuvant nivolumab is out there for us in the clinic. This will force us to go back to the drawing board to design and redesign our first line trials, because now we have to wonder what to do with patients who progress or recur while on the adjuvant nivolumab therapy or immediately after the nivolumab therapy. So, I think this will force us to really go back and rethink our first-line trials if nivolumab is going to be there in the clinic.