Approximately 25% of patients with bladder cancer have muscle disease and will present with or develop subsequent metastatic disease.1 Systemic chemotherapy is the standard initial treatment for patients with inoperable metastatic urothelial cancer (mUC).1 Recent years have seen the introduction of immunotherapies and novel agents in mUC.2 Combinations with immunotherapies are currently being investigated to improve the patient outcomes in this population.3 At the Uro-Oncology Asia 2020 organized by The Hong Kong Society of Uro-Oncology, Dr. Enrique Grande, Head of the Medical Oncology Service at MD Anderson Cancer Center in Madrid, presented the latest data about the immunotherapy combination strategies for mUC.
The current treatment landscape for mUC
Stage 4 mUC is associated with only a 5% survival rate at 5 years.4 The choice of therapy for advanced or mUC is heavily impacted by the performance status, and systemic chemotherapy is generally reserved for advanced disease.4 Patients with negative prognostic factors, such as poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), receive minimal survival benefit from chemotherapy, and may be classed as cisplatin-ineligible.5 In recent years, checkpoint inhibitor agents blocking PD-L1/PD-1, such as atezolizumab, nivolumab, durvalumab, and avelumab have received US Food and Drug Administration approval for the treatment of locally advanced or mUC with disease progression during or after platinum-based chemotherapy.2 These inhibitors now form part of the armamentarium for the first-line mUC therapy.6,7
The need for combination therapies
Although chemotherapy is the standard first-line treatment for mUC, response duration is generally short, and the majority of patients would ultimately experience disease progression.8 In contrast, rapid and sustained treatment response is observed with immunotherapy when administered as monotherapy, but only in 20-23% of patients.3,8 A majority of patients receiving immunotherapy will also ultimately experience disease progression.3 “Immunotherapy is changing the field, but not impacting the majority of patients” commented Dr. Grande. Novel targeted agents, such as enfortumab vedotin, have shown a response rate of 44%, but only a short median duration of response (DoR) of 7.6 months.9 It is therefore necessary to explore additional strategies to improve the outcome of patients with mUC.3 Dr. Grande also outlined the key strategies for immunotherapy combinations, which included immunotherapy plus chemotherapy, immunotherapy doublets, and immunotherapy plus novel targeted agents.
Combining immunotherapy and chemotherapy in mUC
IMvigor130 is a phase 3 study of atezolizumab with or without platinum-based chemotherapy in previously untreated mUC.10 Both cisplatin-eligible and -ineligible patients were included, and patients had to have had an ECOG PS 0-2.10 1,213 patients were randomized in a 1:1:1 ratio to receive either atezolizumab plus platinum/gemcitabine (Arm A), atezolizumab alone (Arm B), or placebo plus platinum/gemcitabine (Arm C).10 The co-primary endpoints for this trial were investigator-assessed PFS and OS (Arm A vs. C), and OS (Arm B vs. C).10 Key secondary endpoints included investigator-assessed overall response rate (ORR), DoR, PFS, and OS.10 Baseline characteristics were well balanced between treatment arms, although Dr. Grande noted that 45% of patients were cisplatin-ineligible according to the guideline criteria in the atezolizumab plus chemotherapy arm. 52% of patients eligible for cisplatin therapy only received carboplatin.
Interim results were presented at the European Society of Medical Oncology (ESMO) Annual Congress 2019. At the interim analysis, the study met the co-primary endpoint of investigator assessed PFS, with a median follow-up of 11.8 months.10 The combination of atezolizumab plus platinum-based chemotherapy prolonged median PFS to 8.2 months, compared to 6.3 months with the placebo arm (Figure 1).10 Exploratory subgroup analysis suggested that patients who received cisplatin, and those with the highest levels of PD-L1 and best PS most benefited from the combination of atezolizumab plus chemotherapy.
While OS did not cross the prespecified interim efficacy boundary, subgroup analysis showed that patients with ECOG PS 0/1 and Bajorin risk factor score 0/1 have better responses in terms of OS.10 13% of patients receiving combination atezolizumab plus chemotherapy had a complete response, as compared to 7% with the placebo arm, and 6% in the atezolizumab monotherapy arm.10
Atezolizumab plus platinum-based chemotherapy was well tolerated, and the safety profile was consistent with each individual agent.10 34% of patients in both the atezolizumab plus chemotherapy and placebo plus chemotherapy arm discontinued treatment due to an adverse event (AE).10
Two other phase 2 trials investigating the combination of immunotherapy and chemotherapy are underway, KEYNOTE 361 and NILE, which combine pembrolizumab with chemotherapy, and durvalumab plus tremlimumab with chemotherapy, respectively.11,12
The prospect of immunotherapy doublets
Immunotherapy doublets are being explored in a number of trials, one of which is the CheckMate 032 trial, where nivolumab is being investigated as monotherapy, and in combination with ipilimumab in previously treated mUC.13 The primary endpoint was investigator-assessed ORR, and secondary endpoints included PFS, OS, safety, and tolerability.13 Patients received either nivolumab monotherapy (nivolumab 3mg/kg [NIVO3]), or one of two nivolumab plus ipilimumab combination regimens (nivolumab 3mg/kg + ipilimumab 1mg/kg [NIVO3+IPI1] or nivolumab 1mg/kg + ipilimumab 3mg/kg [NIVO1+IPI3]).13
ORR was highest (38.0%) in patients receiving NIVO1+IPI3.13 Median PFS was similarly the longest in the NIVO1+IPI3 arm, and was prolonged to 4.9 months.13 Median duration of response was more than 22 months in all arms.13 The safety profiles of all three treatment arms were consistent with the previously reported safety profiles of nivolumab monotherapy and nivolumab plus ipilimumab combination therapy.13 The results of this trial demonstrated a continued clinical benefit with nivolumab 3mg/kg monotherapy, and highlighted the promising efficacy of the nivolumab 1mg/kg plus ipilimumab 3mg/kg combination in patients with platinum-pre-treated locally advanced or mUC.13
CheckMate 901 is another trial investigating nivolumab plus ipilimumab. Patients will receive nivolumab 1mg/kg plus ipilimumab 3mg/kg every 3 weeks up to 4 doses, followed by nivolumab 480mg every 4 weeks until disease progression, or receive chemotherapy for up to 6 cycles. Patients must have not received prior systemic chemotherapy for unresectable/mUC.14 The study has closed for recruitment.
Immunotherapy and novel targeted agent combinations
Enfortumab vedotin, an antibody-drug conjugate that delivers a microtubule-disrupting agent to tumors expressing Nectin-4, was evaluated in the EV-103 trial in combination with pembrolizumab.15 Dr. Grande commented that this is likely the most promising of the immunotherapy plus novel targeted agent combinations. Patients were cisplatin-ineligible, and the ORR in this phase 1 trial was 71%.15 Enfortumab vedotin in combination with pembrolizumab is now being evaluated in a phase 3 trial, EV-302, that will investigate the combination with or without chemotherapy versus chemotherapy alone.
Other combinations of immunotherapy and novel targeted agents will be investigated in the MORPHEUS-mUC trial, which is an umbrella study of atezolizumab in combination with different agents in platinum-refractory mUC. Atezolizumab monotherapy will be the controlled arm, and it will be evaluated in combination with several agents, including niraparib, enfortumab vedotin and tocilizumab.
The need for biomarkers in the future mUC treatment
Although with several treatment options available, the one that could provide broad, rapid and sustained treatment responses is still lacking, Dr. Grande emphasized that it is imperative to find biomarkers. PD-L1 expression in tumors has been associated with the urothelial carcinoma severity and treatment outcome, and has been adopted in the clinical trials investigating the checkpoint inhibitors in urothelial carcinoma.5 However, there are still several factors impacting the use of PD-L1 as a biomarker, including the heterogeneity of PD-L1 expression level within tumors and variability in the tissue collection requirements across trials.5 Nevertheless, active research is ongoing to develop new predictive biomarkers to allow clinicians to select the best agent for their patients according to the molecular profile of their diseases.3
During an interview with Omnihealth Practice, Dr. Grande further elaborated on his thoughts in this exciting time for mUC, saying “the field of first-line mUC is going to change in the next couple of years for sure”. The combination of enfortumab plus pembrolizumab seems to be very active and very well tolerated, so the combination of immunotherapy plus novel targeted agents is very promising. Regarding the most promising biomarkers for this field, he remarked that PD-L1 would probably not be the way forward. “I believe that probably, composite biomarkers are the best to have. When I say composite biomarkers, I mean this is not a matter of the expression of one single protein, this is a matter of the combination of several proteins of several genes. This is what we will have in the future.”
1. Bukhari N et al. Update on the Treatment of Metastatic Urothelial Carcinoma. Sci World J. 2018;2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011065/. Accessed January 16, 2020.
2. Siefker-Radtke AO et al. Immunotherapy with Checkpoint Blockade in the Treatment of Urothelial Carcinoma. J Urol. 2018;199(5):1129-1142.
3. Rodriguez-Vida A et al. Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes. Clin Cancer Res. 2018;24(24):6115-6124.
4. Hanna KS. A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma. Pharmacother J Hum Pharmacol Drug Ther. 2017;37(11):1391-1405.
5. Powles T et al. Anti-programmed cell death-1/ligand-1 (PD-1/PD-L1) antibodies for the treatment of urothelial carcinoma: state-of-the-art and future development. Clin Genitourin Cancer. 2018;16(2):117-129.
6. Balar AV et al. Long-term outcomes in elderly patients (pts) from IMvigor210: Atezolizumab (atezo) in metastatic urothelial cancer (mUC). J Clin Oncol. 2019;37(7_suppl):394-394.
7. O’Donnell PH et al. KEYNOTE-052: Phase 2 study evaluating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC)— Updated response and survival results. J Clin Oncol. 2019;37(15_suppl):4546-4546.
8. Niglio SA et al. Programmed Death-1 or Programmed Death Ligand-1 Blockade in Patients with Platinum-resistant Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2019;76(6):782-789.
9. Rosenberg JE et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019;37(29):2592-2600.
10. Grande E. LBA14_PR: IMvigor130: efficacy and safety from a Phase 3 study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). Presidential Symposium III presented at the: ESMO 2019 Congress; September 30, 2019; Barcelona, Spain.
11. Powles T et al. Phase 3 KEYNOTE-361 trial: Pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. J Clin Oncol. 2017;35(15_suppl):TPS4590-TPS4590.
12. Galsky MD et al. A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC). J Clin Oncol. 2019;37(7_suppl):TPS499-TPS499.
13. Sharma P et al. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol. 2019;37(19):1608-1616.
14. Galsky MD et al. A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901). J Clin Oncol. 2018;36(6_suppl):TPS539-TPS539.
15. Hoimes CJ. EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Presented at the: ESMO 2019 Congress; September 28, 2019; Barcelona, Spain.