Perioperative novel systemic immunotherapy-based approaches in urinary cancers

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Published: 9 Jun 2020
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Dr Shilpa Gupta - Cleveland Clinic, Cleveland, USA

Dr Shilpa Gupta talks to ecancer in an online interview at the virtual ASCO meeting 2020 about the role of perioperative systemic immunotherapy in patients with urothelial cancer based on four abstracts.

The four trials are:

GU14-188 - Neoadjuvant gemcitabine and pembrolizumab prior to cystectomy in patients with cT2-4aN0M0 urothelial carcinoma.

NABUCCO - Neoadjuvant use of checkpoint inhibitor monotherapy (pembrolizumab or atezolizumab).

Neoadjuvant/adjuvant durvalumab with/without tremelimumab in renal cell carcinoma (RCC).

SWOG S1605 - Checkpoint inhibition using atezolizumab in Bacillus Calmette-Guérin (BCG) refractory nonmuscle-invasive bladder cancer.

The abstracts that I discussed for neoadjuvant therapies in muscle-invasive bladder cancer were two. One was the use of gemcitabine and pembrolizumab in patients with muscle-invasive bladder cancer who were not eligible to receive cisplatin and this was the Hoosier Cancer Network trial. In this there were 37 patients that were enrolled, they received gemcitabine and pembrolizumab. The primary endpoint was pathologic downstaging to non-invasive disease, that is EP1 and 0 or lower. This study had about 43% of patients who had clinical T2 and 56% of patients had clinical T3 and T4 disease so a lot of patients had more advanced disease. All patients got all the intended doses of both the drugs and toxicities were manageable, the grade 3, grade 4 events. There were no treatment related deaths. There was no delay to cystectomy, most patients got cystectomy within six weeks. The primary endpoint was seen, the pathologic downstaging rates were 51% and that was pretty remarkable for the patients who are cisplatin ineligible. Patients who had complete responses was around 45%. So overall this was feasible and a safe regimen with manageable toxicities, it did not cause any delays to cystectomy and shows that immunotherapy can be effective in this setting.

The NABUCCO trial

The second study that I discussed was the NABUCCO trial out of Amsterdam. This was a more advanced disease, that is stage 3 cisplatin ineligible bladder cancer patients, including N1 to N3 disease. 24 patients were enrolled, they were treated with ipilimumab followed by a single dose of ipilimumab and nivolumab combination followed by one dose of nivolumab. The primary endpoint, really, was feasibility – just whether they could get surgery within twelve weeks. There were several secondary endpoints of responses and biomarker analyses.

The authors had previously reported at ESMO 2019 that complete responses occurred in 46% of patients and the responses correlated with PD-L1 expression. Now at ASCO they reported more long-term data that had a median follow-up of about 15 months. 92% of patients were relapse free. They also reported several interesting biomarker analyses, that tumour mutational burden correlated with responses and TGF-β was a biomarker of resistance. These were the interesting findings from this study.

The renal cell carcinoma study

The renal cell carcinoma study was a phase Ib study of neoadjuvant and adjuvant durvalumab plus/minus CTLA-4 inhibitor tremelimumab in locally advanced renal cell carcinoma patients. There were four cohorts treated with different dosing regimens – some patients got single agent durvalumab, some patients got durvalumab and tremelimumab prior to surgery followed by durvalumab post-op, and some got durvalumab and tremelimumab prior to surgery followed by durvalumab and tremelimumab post-op. The primary objective was safety and feasibility.

This study, unfortunately, did show that there was a lot of grade 3 and grade 4 treatment related adverse events across the board which were all immune related since these were a dual immunotherapy combination. About 56% of patients discontinued treatment due to the side effects and there were no surgical complications as reported so far, or delay to surgery. Most patients got surgery within seven weeks at a median. But the study was discontinued due to the safety concerns.

So, as of now, we traditionally don’t use neoadjuvant therapies in kidney cancer while there are some phase III trials going on, like the PROSPER-RCC and some in planning. This early phase I study does show that we have to be cautious about the potential safety of immunotherapy pre- and post-op and we’ll learn more from the phase III studies.

The SWOG S1605 study

The SWOG 1605 study was a phase II trial of atezolizumab in BCG unresponsive non-muscle invasive bladder cancer patients. The cohort that was presented was the CIS cohort. The primary endpoint was complete response at six months, mandated by a biopsy. Now, notably, in the other trials in the field in a similar population, like the pembrolizumab trial and the [?? 5:21] trial, the six month biopsy was not mandated by the FDA, this was a result of evolving the guidelines. There the primary endpoint was three month complete response rate.

In this study the FDA mandated a futility analysis and it required 25 eligible CIS patients to have reached the primary endpoint. So the primary endpoint in this of complete response in CIS patients at six months, it was seen in 20 out of 74 patients and the response rate was 27%. The unplanned secondary endpoint to compare to the other trials, to put things into perspective, that is the CR rate at three months was 42%. From the KEYNOTE-057 study, which established pembrolizumab as an FDA approved standard in this similar population, the three month response rates were similar, around 40%.

So the main question with these trials in the non-muscle invasive space for patients who are BCG unresponsive are that what are the long-term durability results? Because radical cystectomy can be curative in these patients and we want to make sure the long-term durable responses are seen. We saw that in the KEYNOTE-057 where more data is available and at six months only 75% of patients who had achieved a complete response at three months were maintaining the complete responses and it fell lower as the follow-up went on. So long-term data will be crucial to establish if these therapies are effective and can replace radical cystectomy. But, as of today, pembrolizumab is a standard of care for such patients and this atezolizumab S-1605 did not meet its primary endpoint.