Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

Author(s): Peter H. O’Donnell, MD¹; Matthew I. Milowsky, MD²; Daniel P. Petrylak, MD³; Christopher J. Hoimes, DO⁴; Thomas W. Flaig, MD⁵; Nataliya Mar, MD⁶; Helen H. Moon, MD⁷; Terence W. Friedlander, MD⁸; Rana R. McKay, MD⁹; Mehmet A. Bilen, MD¹⁰; Sandy Srinivas, MD¹¹; Earle F. Burgess, MD¹²; Chethan Ramamurthy, MD¹³; Saby George, MD¹⁴; Daniel M. Geynisman, MD¹⁵; Sergio Bracarda, MD¹⁶; Delphine Borchiellini, MD¹⁷; Lionnel Geoffrois, MD¹⁸; Jose Pablo Maroto Rey, MD¹⁹; Christiano Ferrario, MD²⁰; Anne-Sophie Carret, MD²¹; Yao Yu, PhD²¹; Maria Guseva, MD, PharmD²²; Blanca Homet Moreno, MD, PhD²³; and Jonathan E. Rosenberg, MD²⁴

Source: DOI: 10.1200/JCO.22.02887 Journal of Clinical Oncology 41, no. 25 (September 01, 2023) 4107-4117.

Dr. Anjan Patel's Thoughts

A very compelling option to keep an eye out for as larger studies are sure to come in the future. EV + pembrolizumab had an ORR of ~65% with durable responses. The combo arm had unsurprisingly higher grade 3-4 AE’s. For platinum-ineligible patients, it would be worth considering this regimen even today.

PURPOSE

Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.

PATIENTS AND METHODS

In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.

RESULTS

The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).

CONCLUSION

EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

Author Affiliations

¹University of Chicago, Chicago, IL; ²University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; ³Yale Cancer Center, New Haven, CT; ⁴Duke Cancer Institute, Duke University, Durham, NC; ⁵University of Colorado Comprehensive Cancer Center, Aurora, CO; ⁶University of California at Irvine, Irvine, CA; ⁷Kaiser Permanente Southern California, Riverside, CA; ⁸University of California at San Francisco, San Francisco, CA; ⁹University of California at San Diego, San Diego, CA; ¹⁰Emory University Winship Cancer Institute, Atlanta, GA; ¹¹Stanford Cancer Center, Stanford, CA; ¹²Levine Cancer Center, Charlotte, NC; ¹³University of Texas Health Sciences Center at San Antonio, San Antonio, TX; ¹⁴Roswell Park Cancer Center, Buffalo, NY; ¹⁵Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA; ¹⁶Azienda Ospedaliera Santa Maria di Terni, Terni, Italy; ¹⁷Centre Antoine Lacassagne, Université Côte d’Azur, Nice, France; ¹⁸Institut de Cancerologie de Lorraine, Vandoeuvre Les Nancy, France; ¹⁹Hospital de la Santa Creu i Sant Paul, Barcelona, Spain; ²⁰Jewish General Hospital, Montreal, Quebec, Canada; ²¹Seagen Inc, Bothell, WA; ²²Astellas Pharma, Northbrook, IL; ²³Merck & Co Inc, Rahway, NJ; ²⁴Memorial Sloan Kettering Cancer Center, New York, NY

TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy

Small testing size, but still with high overall response rate (32%) with progression-free survival of 5.6 months. Now, this is not randomized and is after failure of check point inhibitors. Of note this medication will not be marketed for second line therapy since it did not show overall survival advantage.

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3

Both medications are approved as a single agent in second-filine therapy, and now the combination seems to be promising with manageable toxicity. Overall Response Rate (ORR): 41% I think we need phase 3 data to show superiority over single agent therapy. And now with pembrolizumab used in first-line therapy, this regimen may disappear.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

This antibody doublet is essentially the new SOC in met-urothelial cancer. The anti-PD1 and ADC combination is compelling in many ways and the survival outcomes compared to chemo were very significant. This combination is on NCCN, as well.

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study

This is a negative study looking at atezolizumab + chemo vs. chemo alone in metastatic urothelial carcinoma. In the same issue, there is a negative study on atezolizumab vs. chemo alone, as well. It does seem that atezolizumab has limited disease activity versus some comparable agents.

Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma

Erdafatinib was compared to chemo in the >=2nd line in patients who had FGFR2/3 mutations, fusions or alterations with metastatic bladder cancer. Survival endpoints were superior in the targeted group with a overall survival of 12 vs. eight months. In my experience, the challenge with this group of targeted agents is tolerability.