Meeting Updates Refine Approaches Toward Urothelial Carcinoma

Publication
Article
Targeted Therapies in OncologyNovember 1 2020
Volume 9
Issue 15
Pages: 16

Treatment strategies that build on standard therapies plus the use of novel agents in metastatic urothelial carcinoma were spotlighted at the European Society for Medical Oncology Virtual Congress 2020, with some having the potential to affect treatment regimens of patients who are receiving therapy in the frontline setting.

Jürgen Gschwend, MD

Multiple clinical trials in the treatment of metastatic urothelial cancer across lines of therapy were presented at the European Society for Medical Oncology Virtual Congress 2020, with investigational and established agents explored in areas of unmet medical need.

Newly presented and follow-up data from phase 3 trials further served to clarify the role of immunotherapy in the treatment of patients with frontline metastatic disease and introduced interesting research questions for further exploration (TABLE).1 For example, subgroup analyses from the pivotal JAVELIN Bladder 100 trial (NCT02603432) demonstrated that avelumab (Bavencio) as maintenance therapy in patients without disease progression following frontline chemotherapy is effective across subgroups stratified by best therapy response, creatinine clearance, as well as ECOG and PD-L1 expression status.2

Other promising data at the meeting involved earlier-phase trials exploring investigational agents in the treatment of tumors in the second-line and later settings.

Richard Cathomas, MD

Following presentations of abstracts related to the treatment of metastatic urothelial cancer across settings, invited discussants Jürgen Gschwend, MD, and Richard Cathomas, MD, stepped in to assess and posit the newly available data in relation to the current treatment landscape and address hypothesis-generating questions about the treatment landscape of metastatic urothelial carcinoma.1,3

Placing Immunotherapy in the Frontline Setting

Checkpoint inhibitors are already approved for use in urothelial carcinoma in patients who have previously received or are ineligible for platinum therapy, but interest regarding the potential role of these agents in the frontline setting has been the motivation behind large, randomized phase 3 trials.

Avelumab

Following on a supplementary approval of avelumab in the maintenance treatment of patients with urothelial cancer receiving frontline platinum therapy,4 additional examinations into the JAVELIN Bladder 100 were presented during the conference. Updated survival data showed a 7.1-month median OS improvement with avelumab maintenance plus best supportive care (BSC) versus BSC alone (HR, 0.69; 95% CI, 0.56-0.86; 2-side P < .001). In subgroup analysis, the median PFS also favored the avelumab arm at 3.7 months versus 2.0 months in the BSC-alone arm per blinded independent central review (HR, 0.62; 95% CI, 0.52-0.75; P <.001).2

Survival was not significantly correlated with avelumab therapy in patients, regardless of ECOG performance score. Patients stratified to groups of performance score 0 (HR, 0.64; 95% CI, 0.48-0.85) and 1 or greater (HR, 0.74; 95% CI, 0.54-1.03) saw similar benefit with immunotherapy maintenance. The hazard ratio for survival improvement was 0.69 favoring avelumab for patients with creatinine clearance of 60 mL/min or greater (95% CI, 0.50-0.92) as well as for those with less than 60 mL/min (95% CI, 0.50-0.94).

The median OS was not reach for either the avelumab or best supportive care arm in patients with a best response to therapy of complete response, with available data favoring the experimental arm (HR, 0.81; 95% CI, 0.47-1.38). In those with partial responses, median OS was 19.2 months with avelumab versus 12.1 months with best supportive case (HR, 0.62; 95% CI, 0.46-0.83).

Another analysis attempted to determine biomarkers of response and survival with avelumab and demonstrated that established biomarkers of immunotherapy response, such as PD-L1, were not capable of optimally predicting OS benefit with maintenance avelumab.5

“The presentation here was about exploratory end points—the assessment of tumor biomarkers that may be potentially related to antitumor immune activity or OS benefit with avelumab,” said Gschwend, who is professor of urology and vice dean at the Technical University of Munich School of Medicine in Germany. “In this study, PD-L1 was [found to be] more predictive than prognostic…there was no clear prediction by either TMB [tumor mutational burden] or PD-L1 status.”

Gschwend said multiple other biomarkers, including gene expression signatures, were identified as potentially predictive. Immune-related genes crossing the prespecified significance threshold of 0.001 included CD8, CXCL9, IFNG, LAG3, and TIGIT, but he said these are more hypothesis generating than clinically relevant.

These results together led the investigators to conclude that avelumab may be used in patients as maintenance therapy, regardless of the PD-L1 expression and that combinations of biomarkers may help further characterize those who may receive the most benefit with avelumab.

“[Questions remain regarding] whether the tissue comes from the primary or metastatic [site] and the time of tissue sampling,” added Gschwend. “This is critical during the course of the disease [because] there is proven tumor heterogeneity within the same tumor.”

Checkpoint Inhibitor Combinations

In addition to these data, the anticipated phase 3 DANUBE trial (NCT02516241) comparing durvalumab (Imfinzi) monotherapy or durvalumab plus the CTLA-4 inhibitor tremelimumab versus chemotherapy in patients with metastatic urothelial cancer in the frontline setting were presented. Although the study failed to meet its coprimary end points of overall survival (OS) with the experimental regimens versus standard of care, secondary analyses suggested that the combination had improved antitumor activity, particularly in the group of patients with high PD-L1 expression.6

“Long-awaited [trial data were presented that] help answer some important clinical questions of best uses of immunotherapy in the first-line setting,2” said Cathomas, who is deputy head physician at the Cantonal Hospital of Graubünden in Loestrasse, Switzerland. “The most interesting subgroup analysis… in my view is the PD-L1–positive group of the DANUBE trial treated with the tremelimumab/durvalumab combination, reaching a significant and interesting overall survival benefit of almost 6 months.

Cathomas detailed findings from DANUBE as well as those of the phase 3 KEYNOTE-361
trial (NCT02853305) of pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with treatment-naïve disease.1,6,7 “The overall survival results for the [intention-to-treat] populations for either combination did not reach statistically significant differences in either of the trials,” Cathomas said. “Looking at the results of single-agent therapy in patients with high PD-L1 expression, no overall survival advantage over chemotherapy can be found.”

Also notable were lower rates of response with single-agent immunotherapy versus chemotherapy in these trials; yet when responses were achieved, duration of responses appeared to be longer in patients receiving immunotherapy versus chemotherapy.

Looking to the results of DANUBE for signals that may motivate further exploration into the use of immunotherapy in these populations, Cathomas noted that the secondary end point of median OS in the PD-L1–high positive subgroup reached statistical significance with the durvalumab/tremelimumab combination versus chemotherapy, at 17.9 months versus 12.1 months, respectively (HR, 0.74; 95% CI, 0.59-0.93).1,6

Although these data are only hypothesis generating at this point, Thomas Powles, MD, MBBS, MRCP, lead study author and presenter of DANUBE, thought the results could warrant further investigation. “We pursued a biomarker strategy that included 60% of the population, and it’s possible that further enrichment may have improved these data,” said Powles, who is also director of the Barts Cancer Centre in London, United Kingdom.

Another immune checkpoint inhibitor combination being explored in this setting, nivolumab plus ipilimumab showed continued antitumor activity and survival benefits in an extended follow-up of the CheckMate 032 trial (NCT01928394) with benefits observed regardless of PD-L1 status. Patients included in the metastatic urothelial cancer cohort of the trial had previously treated disease and received either single-agent nivolumab at 3 mg/kg (NIVO3), NIVO3 plus ipilimumab at 1 mg/kg, or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (NIVO1/IPI3). Median OS results were 9.9, 7.4, and 15.3 months, respectively. Based on these results and an expected safety profile, the investigators concluded that the NIVO1/IPI3 dosing schedule shows promise and that these data further support the development of NIVO1/IPI3 versus chemotherapy in the phase 3 CheckMate 901 trial (NCT03036098) in treatment-naïve patients.8

Potential for New Agents in Second and Later Lines

Most cases of metastatic urothelial carcinoma are not curable, making the introduction of effective regimens for therapy in the second-line setting and beyond a salient need for improved outcomes in this disease…. There [has been] an evolution of systemic treatment options in metastatic [urothelial carcinoma] in the last 20 years…most recently, we have seen second-line options with erdafitinib [Balversa] and enfortumab vedotin [Padcev], and at this meeting, we have seen data for sacituzumab govitecan [Trodelvy] in the second- and third-line settings.”

Sacituzumab Govitecan

Gschwend discussed findings from the phase 2 TROPHY U-01 trial (NCT03547973), which included 113 patients with metastatic urothelialcarcinoma who were treated with sacituzumab govitecan following progression on prior platinum- based chemotherapy and immunotherapy.9

Sacituzumab govitecan is a TROP-2–directed antibody-drug conjugate (ADC) coupled to SN-38, the active metabolite of irinotecan, and has a high drug-to-antibody ratio. It is distinct from other ADCs thanks to its bystander effect due to hydrolysable linker hydrolysis.

In cohort 1 of the trial, promising response rates were observed with the use of single-agent sacituzumab govitecan. The antibody-drug conjugate induced an objective response rate (ORR) of 27% (95% CI, 19.0%-37.0%), comprising 6 complete responses (CRs) and 25 partial responses (PRs). The median duration of response was 5.9 months with a median response onset time of 1.6 months.

“When we look at the results, they are promising,” said Gschwend, who compared the sacituzumab govitecan data with previously reported trial results from the pivotal EV-201 trial (NCT03219333) of enfortumab vedotin. He used the Nectin-4–directed antibody as a comparator in this case because the drug recently received FDA approval for the treatment of patients who previously received both platinum chemotherapy and immunotherapy for urothelial cancer based on phase 2 trial data, thus closely mirroring the patient population in the TROPHY-U 01 trial.3,10

The median progression-free survival (PFS) was 5.4 months with sacituzumab govitecan in TROPHY U-01 compared with 5.8 months with enfortumab vedotin in EV-201. These results demonstrated that the agent is still effective, even after use of an immune checkpoint inhibitor in earlier lines of therapy.

BGB-A333

In the phase 1/2 BGB-900-101 study (NCT03379259), the addition of the investigational PD-L1 inhibitor BGB-A333 to the PD-1 inhibitor tislelizumab led to marked antitumor activity and durable responses in patients with locally advanced or metastatic urothelial carcinoma following progression on 1 platinum-containing regimen.11 Patients in the phase 2b, dose-expansion portion (n = 12) who were evaluated for responses had an ORR of 42% (95% CI, 15.2%-72.3%) with the combination. Patients in the PD-L1–high group (n = 6), defined as having 25% or more of tumor or immune cells positive for PD-L1 staining by the Ventana SP263 assay, had an ORR of 67% (95% CI, 22.3%-95.7%), which comprised 2 CRs and 2 PRs. Patients in the PD-L1–low group (n = 6) had an ORR of 17% (95% CI, 0.42%-64.1%), which comprised 1 CR.

The median PFS was 6.1 months in the overall population. In the PD-L1–high subgroup, the median PFS was 10.0 months versus 4.1 months in patients with low PD-L1 expression. In the entire trial cohort (n = 39), 20 patients had adverse events (AEs) of any grade, and 7 patients experienced AEs of grade 3 or higher; no patients experienced fatal treatment-related AEs.

“Simultaneous PD-L1 and PD-1 blockade has been hypothesized to provide synergistic antitumor effects, as inhibitors may have distinct mechanisms of action,” said lead study author Juan Martin-Liberal, MD, PhD, a consulting medical oncologist in the Melanoma, Sarcoma, and Genitourinary Tumors Unit at Institut Català d’Oncologia Hospitalet in Barcelona, Spain. “[Although] these differences should be taken cautiously given the sample size, these data have provided insights into combining tislelizumab, a clinical-stage anti– PD-1 antibody, with anti–PD-L1 antibodies.”

Evaluating Results for Future Paradigm

The results presented at the conference have brought investigators closer to answering important clinical questions about the placement of immunotherapy in the urothelial carcinoma treatment paradigm. The practice-changing potential of these data offer exciting possibilities that may provide options for patients for whom limited systemic options currently exist.

“Numerous trials using different combinations of the aforementioned treatments are already ongoing and will likely alter the treatment landscape of urothelial cancer in the near. future,” Cathomas said.

It is clear from trial results that positioning of immunotherapy-based combinations in treatment sequencing needs further clarification, but many more results and improvements are expected in the future.

“We will soon have final results of combination trials, including IMvigor130 [NCT02807636], CheckMate 901, and the NILE trial [NCT03682068; TABLE2],” Cathomas said. “Another step forward might be the identification of subgroups to predict responders from nonresponders.”

Cathomas added that he is especially interested to see phase 3 results of nivolumab/ipilimumab in tumors with high PD-L1 expression.

“The next major step appears to be the integration of novel drugs in the frontline setting,” Cathomas said, referring to positive phase 2 trial results of agents showing efficacy in metastatic disease. He went on to list multiple agents, such as the ADC enfortumab vedotin, sacituzumab govitecan, and targeted treatments for patients with FGFR2 alterations, such as erdafitinib.

References:

1. Cathomas R. Invited discussant LBA23 and 6790. Presented at: European Society for Medical Oncology Virtual Congress 2020; September 19-21, 2020. Accessed October 14, 2020. https://bit.ly/3jzQDor

2. Grivas P, Park SH, Voog E, et al. Avelumab 1L maintenance + best supportive care (BSC) vs BSC alone with 1L chemotherapy for advanced urothelial carcinoma: subgroup analyses from JAVELIN Bladder 100. Ann Oncol. 2020;31(suppl 4):S550. doi:10.1016/annonc/annonc274

3. Gschwend J. Invited discussant LBA24, 698O and 699O. Presented at: European Society for Medical Oncology Virtual Congress 2020; September 19-21, 2020. Accessed October 14, 2020. https://bit.ly/30Bbccs

4. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. June 30, 2020. Accessed October 1, 2020. https://bit.ly/3iplzWW

5. Powles T, Loriot Y, Bellmunt J, et al. Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): association between clinical outcomes and exploratory biomarkers. Ann Oncol. 2020;31(suppl 4):S550. doi:10.1016/annonc/annonc274

6. Powles TB, van der Heijden MS, Castellano Gauna D, et al. A phase III,randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Ann Oncol. 2020;31(suppl 4):S550. doi:10.1016/annonc/annonc274

7. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

8. Sharma P, Siefker-Radtke AO, de Braud F, et al. Nivolumab (N) alone or in combination with ipilimumab (I) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (mUC): extended follow-up from CheckMate 032. Ann Oncol. 2020;31(suppl 4):S550. doi:10.1016/annonc/annonc274

9. Loriot Y, Balar AV, Petrylak DP, et al. TROPHY-U-01 cohort 1 final results: a phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

10. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. December 18, 2019. Accessed October 2, 2020. https://bit.ly/2GrSc9k

11. Martin-Liberal H, Fong PC, Moreno V, et al. BGB-A333, an anti-PD-L1 monoclonal antibody, in combination with tislelizumab in patients with urothelial carcinoma. Ann Oncol. 2020;31(suppl 4):S462-S504 doi:10.1016/annonc/annonc271

Related Videos
Thomas Powles, MBBS, MRCP, MD, with Rohit Gosain, MD, and Rahul Gosain, MD, presenting slides
Thomas Powles, MBBS, MRCP, MD, with Rohit Gosain, MD, and Rahul Gosain, MD, presenting slides
Thomas Powles, MBBS, MRCP, MD, with Rohit Gosain, MD, and Rahul Gosain, MD, presenting slides
Thomas Powles, MBBS, MRCP, MD, with Rohit Gosain, MD, and Rahul Gosain, MD, presenting slides
Related Content