Dr Bilusic on the Investigation of Enfortumab Vedotin in Rare GU Cancers

Marijo Bilusic, MD, PhD, GU site disease group lead, GU SDD medical oncology lead, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, discusses the rationale for investigating enfortumab vedotin-ejfv (Padcev) with or without pembrolizumab (Keytruda) in patients with rare genitourinary (GU) tumors in the phase 2 E-VIRTUE study (NCT06041503).

Notably, information on the multicenter study was presented at the 

. E-VIRTUE is an open-label, nonrandomized study that is evaluating patients with locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure squamous cell carcinoma (SCC), or refractory germ cell tumors with measurable disease per RECIST v1.1 criteria. The primary objective of the study is to assess objective response rate across all cohorts. Secondary objectives include safety, progression-free survival, and overall survival.

Bilusic begins by stating that there is a strong rationale for conducting this research in the population of patients with rare GU cancer histologies that is being enrolled, as this population currently has no standard of care. This investigation builds on preclinical work showing that NECTIN-4 is overexpressed in most patients with bladder adenocarcinoma, bladder SCC, and testicular cancer, he emphasizes. Therefore, there is a hypothesis that NECTIN-4 could be a potential target for antibody-drug conjugates, Bilusic explains.

The trial is enrolling patients with these rare histologies, including those who may have previously received checkpoint inhibitors, Bilusic continues. Patients will be divided into 2 cohorts. One cohort will consist of checkpoint inhibitor–naïve patients who will receive the combination of enfortumab vedotin and pembrolizumab 

. The second cohort will include patients who have progressed on checkpoint inhibitors and will receive enfortumab vedotin monotherapy, also on a standard schedule, he reports. Patients will continue enfortumab vedotin treatment for up to 5 years andpembrolizumab treatment for up to 2 years. Patients in the combination arm who achieve complete responses can stop pembrolizumab but may resume it if they experience disease progression in the future, Bilusic concludes.

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Marijo Bilusic, MD, PhD, discusses the investigation of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors.


Dr Bilusic on the Non-ccRCC Treatment Armamentarium

Marijo Bilusic, MD, PhD, GU site disease group lead, GU SDD medical oncology lead, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, discusses combination regimens under investigation for patients with non–clear cell renal cell carcinoma (ccRCC).

The continued enrollment of patients with non-ccRCC onto clinical trials is important for the expansion of the treatment armamentarium in this disease setting, Bilusic says. During an 

 State of the Science Summit™ on prostate cancer and RCC, which Bilusic chaired, Jaime R. Merchán, MD, of Sylvester Comprehensive Cancer Center, presented a case discussion about the use of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in patients with non-ccRCC. Merchán noted that a subset of patients with non–clear cell disease benefit from this regimen. The single-arm, phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated lenvatinib plus pembrolizumab in patients with advanced non-ccRCC and demonstrated that the overall response rate (ORR) was 49% (95% CI, 41%-57%) at a median follow-up of 14.9 months (interquartile range, 11.1-17.4). This included a 6% confirmed complete response rate and a 44% confirmed partial response (PR) rate.

Although these data are encouraging, further research in this area is always necessary, Bilusic emphasizes. Treatment regimens including cabozantinib (Cabometyx), lenvatinib, and pembrolizumab are all under investigation for patients with non-ccRCC. For instance, a phase 2 trial (NCT03635892) evaluated cabozantinib in combination with nivolumab in patients with metastatic non-ccRCC. In the population of patients with papillary, translocation, or unclassified disease histologies, at a median follow-up of 34 months (range, 20-51), the combination elicited a 48% ORR (95% CI, 31.5%-63.9%), and the median progression-free survival (PFS) was 13 months (95% CI, 7-16).

Furthermore, the phase 1b COSMIC-021 trial (NCT03170960) evaluated cabozantinib plus atezolizumab (Tecentriq) in patients with advanced non-ccRCC. At a median follow-up of 37.2 months (range, 32.1-58.5), the combination elicited a 31% ORR, all of which were PRs. The median PFS was 9.3 months (95% CI, 5.5-12.3). However, there have been no recent practice-changing additions to the non-ccRCC treatment arsenal, Bilusic concludes.

Marijo Bilusic, MD, PhD, discusses combination regimens under investigation for patients with non–clear cell renal cell carcinoma.

Dr Bilusic on the Use of PARP Inhibitors in Prostate Cancer

Marijo Bilusic, MD, PhD, genitourinary (GU) site disease group lead, GU SDD medical oncology lead, the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, discusses key considerations and unanswered questions regarding the use of PARP inhibitors in patients with prostate cancer.

In 2023, the FDA approved 3 combinations of PARP inhibitors plus anti-androgen therapy for patients with prostate cancer, Bilusic says. Olaparib (Lynparza) in combination with abiraterone (Zytiga) and prednisone or prednisolone 

-positive metastatic castration-resistant prostate cancer (mCRPC). This regulatory decision was supported by findings from the phase 3 PROpel trial (NCT03732820). Talazoparib (Talzenna) plus enzalutamide (Xtandi) 

for patients with homologous recombination repair gene–mutated mCRPC based on findings from the phase 3 TALAPRO-2 trial (NCT03395197). Niraparib (Zejula) plus abiraterone acetate and prednisone 

 for the treatment of patients with mCRPC with deleterious or suspected deleterious 

 mutations, a regulatory decision that was based on findings from the phase 3 MAGNITUDE trial (NCT03748641). Each of these trials demonstrated that PARP inhibitors plus anti-androgen therapy prolong radiographic progression-free survival (rPFS).

The overall survival data from these trials are not yet mature, and questions remain about the optimal role and sequencing of PARP inhibitors in prostate cancer, Bilusic explains. For instance, it is unclear whether PARP inhibitors should be used in upfront combinations to generate favorable rPFS outcomes or as monotherapy followed by anti-androgen therapy, which may improve quality of life and reduce the risk of adverse effects (AEs), Bilusic emphasizes. As data from PROpel, TALAPRO-2, and MAGNITUDE mature, they may come to address these questions, Bilusic notes. After personalized patient discussions, patients may currently receive PARP inhibitors as monotherapy or as part of combination regimens, according to Bilusic.

With a variety of FDA-approved PARP inhibitors in the armamentarium, questions arise regarding the differences between these agents, Bilusic says. These agents have yet to be directly compared in prospective clinical trials, and cross-trial comparisons should be interpreted with caution, Bilusic notes. Although meta-analyses demonstrate that olaparib, talazoparib, and niraparib are generally associated with similar efficacy outcomes and slight differences in AE profiles, current data do not show that 1 agent is more toxic than the others, Bilusic explains. Patients who received talazoparib in TALAPRO-2 required more dose reductions than patients who received niraparib in MAGNITUDE, but overall, these agents are comparable, Bilusic concludes.

Marijo Bilusic, MD, PhD, discusses key considerations and unanswered questions regarding the use of PARP inhibitors in patients with prostate cancer.

Marijo Bilusic, MD, PhD, medical oncologist, Genitourinary Medical Oncology, University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses key trials in the treatment armamentarium for patients with urothelial carcinoma, as presented at the 2023 Sylvester Annual Oncology Updates Meeting.

Bilusic presented on the topic of the phase 1/2 EV-103/KEYNOTE-869 study (NCT03288545),which evaluated enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in cisplatin-ineligable patients with locally advanced or metastatic urothelial carcinoma. Based on the findings from this study, in April 2023, 

this treatment for use in the frontline setting in this patient population

. Notably, this approval marks a significant shift in how oncologists approach the treatment of patients with metastatic urothelial cancer, particularly in the frontline setting, Bilusic emphasizes. 

Another topic addressed at the meeting was the SWOG S1011 study (NCT01224665), which delved into surgical considerations, evaluating standard or extended pelvic lymphadenectomyin the treatment of patients undergoing surgery for invasive bladder cancer. This topic is significant for patients, who often inquire about the necessity of lymph node removal, Bilusic emphasizes. One crucial takeaway from this trial, findings from which were presented in 2023, is that extensive lymphadenectomies are not imperative, he states. Adhering to the standard node removal procedure yields survival outcomes equivalent to those achieved with extensive pelvic lymphadenectomies and is less morbid, Bilusic explains. This study offers valuable insights into optimizing surgical procedures for patients who have undergone chemotherapy, he notes.

Bilusic continues that the final aspect of the discussion centered on the treatment sequence for managing urothelial carcinoma. Although enfortumab vedotin plus pembrolizumab is not yet FDA approved for cisplatin-eligible patients, data to support the use of this combination in this population may be presented at upcoming medical meetings, he explains. Bilusic anticipates that this potential approval will reconfigure treatment approaches in urothelial cancer and may position the combination as the most frequently prescribed frontline therapy for patients with urothelial cancer, he concludes.

Marijo Bilusic, MD, PhD, discusses key trials in the treatment armamentarium for patients with urothelial carcinoma, as presented at the 2023 Sylvester Annual Oncology Updates Meeting. 


Dr Bilusic on Key Trials That Inform the Treatment of Patients With Urothelial Carcinoma

Marijo Bilusic, MD, PhD, medical oncologist, Genitourinary Medical Oncology, University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses updates seen in the treatment armamentarium for patients with urothelial carcinoma, as presented at the 2023 Sylvester Annual Oncology Updates Meeting.

Numerous topics were covered during the event, which primarily focused on the phase 3 VESPER trial (NCT01812369), Bilusic begins. This trial involved a comparison between 2 chemotherapy regimens, 6 cycles of high-dose MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) vs 4 cycles of gemcitabine/cisplatin, in patients with locally advanced bladder cancer, he says. The initial findings from this trial, which were published in 2020, yielded a positive outcome with high-dose MVAC. However, the significant development with this trial in 2023 was the report of the 5-year overall survival (OS) data, which revealed an improvement in OS rates with MVAC vs gemcitabine plus cisplatin, Bilusic explains. These findings demonstrated the importance of delivering more cisplatin-based chemotherapy, as opposed to less, in patients with locally advanced bladder cancer, he notes. 

Both regimens used in VEPSER are cisplatin-based, Bilusic expands. It is important to recognize that the VESPER data likely indicate the benefit of higher cisplatin doses, rather than a benefit of MVAC over gemcitabine plus cisplatin, he adds. Notably, approximately 80% of patients in the MVAC arm could not complete all 6 cycles of treatment because of treatment-related toxicity, a vital point to consider when discussing chemotherapy options with patients, he emphasizes. Prior to this trial, the treatment recommendation for patients with locally advanced urothelial carcinoma was 3 to 4 cycles of chemotherapy. However, the VESPER data indicate that a more extended treatment duration is advisable, Bilusic explains. This shift in recommendation is a central message that was conveyed during the Sylvester Annual Oncology Updates Meeting.

A notable number of patients who received 6 cycles of chemotherapy died within the 5-year survival timeframe, a result that fell short of desired outcomes, Bilusic continues. The findings from VESPER and other trials emphasize the need for a critical reevaluation of bladder cancer treatment strategies, specifically concerning the delivery of cisplatin-based chemotherapy, Bilusic adds. The lessons learned from bladder cancer research will guide discussions with patients and inform decision-making processes as clinicians continue to aim for improved survival rates and better patient outcomes, Bilusic concludes.

Marijo Bilusic, MD, PhD, discusses updates seen in the treatment armamentarium for patients with urothelial carcinoma, as presented at the 2023 Sylvester Annual Oncology Updates Meeting.


Marijo Bilusic, MD, PhD

Articles

Dr Bilusic on the Investigation of Enfortumab Vedotin in Rare GU Cancers

Dr Bilusic on the Non-ccRCC Treatment Armamentarium

Dr Bilusic on the Use of PARP Inhibitors in Prostate Cancer

Dr Bilusic on Key Trials That Inform the Treatment of Patients With Urothelial Carcinoma

Dr Bilusic on Updates to the Urothelial Carcinoma Treatment Armamentarium