Up until recently, aside from cisplatin-based chemotherapy, there were no alternative therapeutic options for metastatic urothelial carcinoma (mUC). However, with the introduction of immunotherapy, additional options now exist in our armamentarium for the treatment of mUC in different settings (Figure 1).
Figure 1 – First-line therapy options for metastatic urothelial carcinoma:
There are some important expectations and questions from the proposed treatment alternatives in the setting of first-line mUC therapy. These include: whether combination treatment options of immunotherapy and chemotherapy or immunotherapy + immunotherapy can improve the overall survival (OS) of mUC patients and whether immunotherapy monotherapy can improve OS. Other important questions include the understanding of the role of PD-L1 as a useful biomarker for treatment decisions. Lastly, we urgently need to find some promising options for patients who are platinum-ineligible.
Dr. Cathomas presented a nice summary slide of the two discussed abstracts showing their stratification, primary endpoints, and minimum follow-up time (Figure 2). KEYNOTE 361 compared pembrolizumab with and without chemotherapy to chemotherapy, while DANUBE compared durvalumab with and without chemotherapy to chemotherapy. Both these studies failed to show a positive, beneficial effect of adding immunotherapy to chemotherapy that was statistically significant.
Figure 2 – Summary of the design and methodology of abstracts LBA23 and 697:
Next, Dr. Cathomas compared the KEYNOTE 361 study to the IMvigor130 study and the DANUBE study to JAVELIN 100 switch maintenance study in the ITT population (Figure 3). The results of the KEYNOTE 361 and IMvigor130 study were quite similar; however, the JAVELIN 100 study demonstrated a statistically significant difference in overall survival (OS) in favor of immunotherapy when compared to the best standard of care, although the DANUBE study did not show that.
When comparing the KEYNOTE 361 trial to the IMvigor130 trial for the PD-L1 positive population (Figure 4), the objective response rate (ORR) was not reported for this population in the KEYNOTE 361 study, while it was quite similar in both treatment arms in the IMvigor130 study (34% vs. 37%).
Figure 3 – Comparison of studies in the intention to treat population:
Figure 4 – Overall survival comparison of studies in the PD-L1 high population:
Dr. Cathomas continued and delved deeper, elaborating on the significance of these two negative trials. According to him, in retrospect, the study design of the discussed abstracts was quite ambitious. Furthermore, there is no established synergistic activity for immunotherapy and chemotherapy in mUC space to date. Dr. Cathomas also stated that there are major differences in cisplatin and carboplatin that may be related to drug sensitivity and not to patient characteristics. Lastly, Dr. Cathomas mentioned the PD-L1 is a difficult biomarker with known sampling and methodological issues.
Some potential ideas arise from both these abstracts. First, combination treatment with either immunotherapy + chemotherapy or immunotherapy + immunotherapy is not proven for the entire population of platinum-ineligible patients. The combination of immunotherapy + immunotherapy might prove beneficial for patients with high PD-L1 disease. It is also most likely that immunotherapy as monotherapy cannot improve OS in the entire platinum-ineligible population, and it has not improved OS in the high PD-L1 patient population. PD-L1 was not shown to be a useful biomarker for treatment decisions in the entire population of cisplatin-ineligible patients. Lastly, in the cisplatin-ineligible patients, it is unclear if there is any benefit from immunotherapy monotherapy, as there are to date no randomized trials.
The currently recommended treatment paradigm of mUC patients, according to Dr. Cathomas, is shown in figure 5:
Figure 5- Current treatment paradigm in metastatic urothelial carcinoma patients:
Dr. Cathomas concluded his talk stating that we eagerly await the results of the IMvigor 130 trial final OS analysis, the Checkmate 901 with the separate Cisplatin eligibility design, assessing the combination of immunotherapy + immunotherapy and immunotherapy + chemotherapy, and the NILE study assessing the combination of chemotherapy and Durvalumab.
There are also novel treatments that are currently being explored, including enfortumab vedotin (anti-Nectin 4), sacituzumab govitecan (anti-Trop-2), and erdafitinib and pemigatinib (FGFR3 alterations). Lastly, there are several ongoing combination trials that have included these novel medications as well. The data that will be provided by these trials are eagerly awaited.
Presented by: Richard Cathomas, Oncology Kantonsspital Graubunden, Switzerland
Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA@GoldbergHanan at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
Related Content:
ESMO Virtual Congress 2020: Pembrolizumab Combined With Chemotherapy vs. C Alone As First-Line Therapy for Advanced Urothelial Carcinoma: KEYNOTE-361
ESMO Virtual Congress 2020: A Phase 3, Randomized, Open-Label Study (DANUBE) First Line Durvalumab with or without Tremelimumab vs Standard of Care Chemotherapy in Patients with Unresectable, Locally Advanced or Metastatic Urothelial Carcinoma