Perioperative Multimodality Treatment for Resectable MIUC
– High event-free and overall survival rates with neoadjuvant chemo-immunotherapy, adjuvant immunotherapy after resection
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In the management of resectable muscle-invasive urothelial cancer (MIUC), the addition of adjuvant nivolumab following standard neoadjuvant cisplatin-based chemotherapy and radical surgery has been shown to significantly prolong disease-free survival (DFS). Still, in spite of this, approximately eventually relapse and die.
Recently, the integration of immunotherapy in the perioperative setting with immune checkpoint inhibitors (ICIs), small molecules, and antibody-drug conjugates has shown promise for improving outcomes.
Now, results from a phase II single-arm trial, published in the , showed that the addition of the PD-L1 inhibitor durvalumab to neoadjuvant gemcitabine/cisplatin chemotherapy, followed by radical surgery and adjuvant durvalumab was associated with 2- and 3-year event-free survival (EFS) rates of 76% and 73%, respectively. With a median follow-up of 40 months, 2- and 3-year overall survival (OS) rates were 85% and 81%.
Richard Cathomas, MD, of Cantonal Hospital Graubunden in Chur, Switzerland, and colleagues reported that complete pathologic responses (pCRs) occurred in 17 of 52 resected patients (33%), while 31 (60%) had pathologic response
"The results of our trial SAKK 06/17 demonstrate that perioperative multimodality treatment with neoadjuvant gemcitabine/cisplatin plus durvalumab followed by surgery and adjuvant durvalumab is feasible and achieves promising EFS and OS rates," the team wrote. "The outcome of several ongoing phase III trials will inform us if this kind of treatment can become standard of care for patients with localized MIUC."
None of the authors were available for interviews, and the following highlights from the text of the study were edited for length and clarity.
What factors led you to make event-free survival the primary endpoint?
The achievement of non–muscle-invasive disease (<ypT2) or pCR with neoadjuvant treatment is an important milestone and has been correlated with improved outcomes. It is clear, however, that only time-to-event end points such as EFS or OS are true measurements for the benefit of such treatments. This is especially true in the case of combined use of neoadjuvant and adjuvant systemic treatment.
Were there any new safety signals?
All 57 patients included in the analysis experienced at least one treatment-related adverse event. However, the majority were able to receive the full course of neoadjuvant chemo-immunotherapy without excessive toxicity.
What outcomes were reported for patients who didn't have an adequate response to neoadjuvant treatment?
Patients with ypT3/4 and ypN1 continued to have a poor outcome, with EFS at 2 years of approximately 50% and 30%, respectively. It is interesting to note that patients with pathologic ypT2 disease after neoadjuvant treatment did very well with adjuvant durvalumab since none of them relapsed.
What other trials have investigated immunotherapy-based neoadjuvant treatment for patients with MIUC?
Three trials looked at single-agent PD-1/PD-L1 ICI atezolizumab and pembrolizumab -- two at combined PD-1 plus CTLA-4 ICI (durvalumab/tremelimumab, nivolumab/ipilimumab), and four tested the combination of gemcitabine/cisplatin (GC) chemotherapy with an ICI (atezolizumab, pembrolizumab, and nivolumab). All had a single-arm phase II design, a relatively low number of patients, and the primary end point was always pCR.
How do results from these trials compare with yours?
Trial comparison is obviously difficult in view of the different patient populations included, but overall pCR and pathologic response <ypT2 appear similar in all studies, including ours, with rates of 30%-40% and 55%-65%, respectively. Interestingly, results from the perioperative comparing cisplatin-based and immunotherapy-free regimens demonstrated a benefit for the use of dose-dense methotrexate/vinblastine/doxorubicin/cisplatin compared with GC with a pCR rate of 42% and an EFS at 2 years of approximately 77%.
The difference between our trial and these other trials is that our patients were offered adjuvant immunotherapy with durvalumab, which affects the interpretation of EFS.
What previous results have been reported for the use of adjuvant ICI treatment?
There have been two recent phase III trials. In the first, adjuvant atezolizumab did not improve DFS, although a subgroup analysis demonstrated benefit for patients with persistent circulating cell-free tumor DNA after resection. The second trial reported a significant DFS benefit with adjuvant nivolumab, and subgroup analysis showed that patients with previous neoadjuvant cisplatin-based chemotherapy derived the highest benefit.
Did you find any potential biomarkers of treatment response?
We could not find a significant correlation to PD-L1, MTAP [methylthioadenosine phosphorylase], or SLFN [Schlafen] status. Further translational research is ongoing and will be published in a separate manuscript.
What were the limitations?
Our trial is a single-arm phase II trial with a rather small number of patients limiting interpretation and clinical impact. The field is, however, moving fast since several phase III trials for cisplatin-eligible patients in the perioperative setting are underway.
Can you describe some of these trials?
The phase III tested the same regimen as we did in SAKK 06/17, and the and the trials are looking at the combination of cisplatin/gemcitabine chemotherapy with perioperative pembrolizumab, while the trial is looking at cisplatin/gemcitabine chemotherapy plus nivolumab.
In cisplatin-ineligible muscle-invasive bladder cancer, the trial is looking at the use of the antibody-drug conjugate enfortumab vedotin in combination with pembrolizumab, and the phase III trial is looking at the introduction of enfortumab vedotin into the neoadjuvant treatment setting.
Read the study here and expert commentary about it here.
The study was funded by AstraZeneca.
Cathomas reported relationships with Janssen-Cilag, Astellas Pharma, Merck KGaA, Bristol Myers Squibb, Pfizer, Roche, MSD Oncology, Bayer, Ipsen, Accord Healthcare, Sandoz, and Novartis; several co-authors also disclosed relationships with industry.
Primary Source
Journal of Clinical Oncology
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