ASCO 2021: Conundrums in First-Line Urothelial Carcinoma: Are More Drugs Beyond Platinum Chemotherapy Always Better?

( Dr. Shilpa Gupta discussed the prior three abstracts in the context of a conundrum in first-line treatment of advanced urothelial carcinoma – are more drugs beyond platinum chemotherapy always better? She began her discussion with a timeline of approvals over the past several decades, focusing on the initial approvals of immunotherapy in 2016.


Cisplatin-based chemotherapies yield an overall survival of approximately 14 months in the first-line setting, with carboplatin associated with overall survival of 13 months. There remains a clear need to improve survival from 1st-line treatment as only a minority of patients with advanced urothelial cancer receive 2nd line therapy. However, phase 3 clinical trials of adding chemotherapy to cisplatin and gemcitabine have not improved survival, as evidenced by EORTC30987 (addition of paclitaxel) and CALGB90601 (bevacizumab). Furthermore, first-line immunotherapy-chemotherapy combinations have not demonstrated overall survival to date, as evidenced by the IMvigor130 and KEYNOTE-361 trials.

Dr. Gupta then discussed the abstract from Dr. Monty Pal and colleagues, testing the scientific hypothesis that inhibiting chemotherapy-induced DNA damage repair via inhibition of the ATR protein could augment patient outcomes. Early phase data testing the ATR inhibitor berzosertib in combination with gemcitabine in ovarian cancer showed improved PFS and durable tumor regressions were seen in combination with topotecan in small cell lung cancer. Preclinical data of berzosertib in combination with cisplatin and gemcitabine was suggestive of increased anti-tumor effects. Therefore, a randomized trial with cis/gem +/- berzosertib was carried out. Of note, because of the addition of berzosertib, the dose of cisplatin and gemcitabine had to be reduced by 15% and 12.5%, respectively, to ameliorate myelosuppression. This trial showed that the addition of berzosertib to standard of care chemotherapy did not improve progression-free survival (8 months in both arms), resulted in higher rates of myelosuppression, had lower response rates, and worse overall survival (14.4 versus 19.8 months). A possible explanation for the worse overall survival may be that patients in this arm received lower doses of cytotoxic chemotherapy.

The results of this study parallel other recent studies adding agents that interfere with DNA damage repair (PARP inhibitors) have not shown improved efficacy. For example, the PARP inhibitor rucaparib did not show any confirmed responses in urothelial carcinoma regardless of homologous recombination deficiency. In the BISCAY trial, the addition of olaparib to durvalumab in patients with evidence of homologous recombination deficiency did not meet study endpoints. Therefore, Dr. Gupta concluded that cisplatin doses should not be compromised in metastatic urothelial cancers and though alterations in the DNA damage repair pathway appear to be prognostic and predictive, there is no role for further targeting this pathway with PARP or ATR inhibitors in this disease.

Dr. Gupta then summarized the five-year follow-up from the phase 2 KEYNOTE-052 of first-line pembrolizumab in cisplatin-ineligible advanced urothelial cancer. She first showed a timeline of management and approvals for patients with cisplatin-ineligible disease.


KEYNOTE-052 was a non-randomized phase 2 study where patients with cisplatin-ineligible disease were treated with pembrolizumab monotherapy as first-line therapy. The primary endpoint was overall response rate. This long-term follow-up confirmed the clinical activity of pembrolizumab monotherapy. To further understand the utility of this treatment modality, Dr. Gupta compared this trial with the KEYNOTE-361 trial, which randomized patients to either pembrolizumab monotherapy or gemcitabine + platinum or pembrolizumab + gemcitabine + platinum. She noted that the reponse rate of pembrolizumab monotherapy was lower than that of carboplatin and gemcitabine, and while there were early deaths in the pembrolizumab arm, the overall survival trend did not catch up over time enough to prove a benefit for pembrolizumab over carboplatin/gemcitabine.



Dr. Gupta did note that the duration of response is better for pembrolizumab especially in patients with high PD-L1 expression. This trend is also confirmed in exploratory analyses of IMvigor130, which suggested higher survival rates in PD-L1 expressing tumors. Based on the JAVELIN-100 data, the field has moved towards maintenance avelumab after platinum-containing therapy. Therefore, she concluded that the use of pembrolizumab in cisplatin-ineligible patients should only be limited to a select patient population not eligible for carboplatin therapy as well.

Finally, Dr. Gupta discussed the phase 1 first-in-human study of the ICOS-agonist feladilimab either as monotherapy in patients previously treated with pembrolizumab or as combination therapy with pembrolizumab in pre-treated urothelial carcinoma patients. The data from this study showed manageable safety and an early encouraging efficacy single, but much more data and experience is required to further understand the utility of this agent.

Dr. Gupta then discussed the current state of first-line treatment in urothelial carcinoma. The preferred option for patients if medically eligible is cisplatin-based chemotherapy with either maintenance avelumab if at least stable disease or immunotherapy if progressive disease. If cisplatin-ineligible patients can receive carboplatin, then a similar paradigm applies. Third-line therapies include multiple options such as erdafitinib, enfortumab vedotin, and sacituzumab govitecan. The percentage of patients that are truly platinum ineligible is increasingly small, but these are the patients that should receive upfront immunotherapy as monotherapy.


Ongoing trials such as ChekMate 901, NILE, and EV-302 will help further define the first-line treatment landscape. But for now, platinum-based chemotherapy remains king in the first-line treatment for advanced urothelial carcinoma. Hopefully, further pragmatic, biomarker-based trials will help further define ways to optimize first-line therapy in this disease.

Presented by: Shilpa Gupta, MD, Director of Genitourinary Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021