He first began with a short overview of the current landscape for first-line therapy for advanced urothelial carcinoma. Patients are generally stratified by their eligibility for first-line chemotherapy with a platinum-based regimen. Should patients have good performance status, good renal function, and no other precluding significant baseline comorbidities such as neuropathy or hearing loss, they are generally deemed eligible for cisplatin-based chemotherapy as upfront management. Some patients may have lower performance status but are felt to be eligible for carboplatin containing therapy. These patients can either receive carboplatin containing chemotherapy regimen or if positive for PD-L1 expression by the relevant companion diagnostic, can receive upfront immunotherapy with pembrolizumab or atezolizumab as monotherapy. Patients thought to be platinum ineligible may receive first-line single-agent immunotherapy with pembrolizumab or atezolizumab, or best supportive care.
Despite upfront responses to first-line chemotherapy, durable remissions are not common and so improved first-line treatment options are critically needed. Furthermore, as the approvals of PD-1 axis immunotherapy as front-line therapy in cisplatin-ineligible patients was based on single-arm phase 2 trials, randomized clinical trial data to further delineate the optimal usage of these agents is required.
To address these questions, several randomized trials in the first-line setting exploring either immunotherapy alone, in combination with chemotherapy, or immunotherapy as switch maintenance after chemotherapy response have been designed and are in various stages. The IMvigor130 trial, reported at ESMO 2019, randomized platinum-eligible patients with advanced urothelial carcinoma to anti-PD-L1 monotherapy with atezolizumab, atezolizumab plus platinum/gemcitabine chemotherapy, or placebo + platinum/gemcitabine therapy. This trial showed a PFS benefit for the addition of atezolizumab to platinum/gemcitabine in the intention to treat arm, but overall survival data from this comparison are not mature. Atezolizumab monotherapy as first line-therapy did not offer a survival benefit relative to standard chemotherapy at that data-cutoff.
Two trials were reported in this session with similar goals to IMVigor130 – to compare immunotherapy monotherapy with either immunotherapy-chemotherapy or dual immunotherapy combinations. These were the KEYNOTE-361 trial of pembrolizumab (anti-PD-1) monotherapy versus combination pembrolizumab and platinum/gemcitabine versus platinum/gemcitabine, and the DANUBE study of the anti-PD-L1 antibody durvalumab as monotherapy versus combination durvalumab with the anti-CTLA4 antibody tremelimumab versus platinum/gemcitabine chemotherapy. The relevant design, stratification, and endpoint information is summarized below.
Dr. Cathomas highlighted the results of these two trials within the context of the results available from IMVigor130 and JAVELIN-100 Bladder. With regards to the combinations (Either IO-chemo or IO-IO), neither KEYNOTE-361 nor DANUBE demonstrated an overall survival benefit for combination relative to platinum-based chemotherapy in the intention-to-treat population.
No significant advantage was observed for immunotherapy monotherapy relative to chemotherapy.
Perhaps most intriguingly, in secondary endpoint analysis of combined IO with durvalumab and tremelimumab in the PD-L1 positive subpopulation, the response rate was similar to that of platinum chemotherapy, with a hazard ratio for survival of 0.74 (0.59 – 0.93). This was not chosen as a primary endpoint for the trial, but is an important hypothesis to consider follow-up on.
Both the KEYNOTE-361 and DANUBE studies were negative for their primary endpoints, highlighting the challenges of trial design and therapy optimization in the first-line setting for advanced urothelial carcinoma in platinum-eligible patients. One important point mentioned is that pre-clinical evidence for synergy with
Dr. Cathomas made the following summary statements:
- Across all platinum-eligible patients, combination treatment (Either IO-chemo or IO-IO) does not appear to offer a survival benefit. However, further investigation is warranted to understand if combining PD-1 axis and CTLA-4 axis therapy in the PD-L1 positive patient population improves survival.
- Immunotherapy as monotherapy does not appear to prolong overall survival in platinum-eligible patients, regardless of PD-L1 expression
- There is still no randomized trial data for immunotherapy monotherapy as first-line treatment in platinum-ineligible patients.
He closed by offering the following slide regarding first line management of advanced urothelial carcinoma:
There are several potentially exciting lines of investigation ongoing. These include final survival analysis of the IMvigor 130 trial, data from the NILE and Checkmate 901 studies, and further studies looking at biomarker subgroups as well as combination therapy with novel agents such as antibody-drug conjugates (enfortumab, sacituzumab) and FGFR inhibitors. These and other studies
Presented by: Richard Cathomas, PD Dr. med. Kantonsspital Graubünden, Chur, Switzerland
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020
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