The Rationale For the SWOG-1931/PROBE Trial in Advanced RCC

Dr Vaishampayan on the Rationale For the SWOG-1931/PROBE Trial in Advanced RCC

Ulka Nitin Vaishampayan, MBBS, director, the Phase I Program at Rogel Cancer Center, professor, internal medicine, University of Michigan, discusses the rationale for conducting the phase 3 SWOG 1931 trial (NCT04510597) in patients with advanced renal cell carcinoma (RCC).

Vaishampayan begins by stating that she presented the rationale and design of the SWOG 1931 trial, also known as the PROBE study, at the 2023 International Kidney Cancer Symposium (IKCS). This trial will examine the role of cytoreductive nephrectomy vs continuation of systemic therapy alone in patients with advanced RCC, she states. With the recent advancements in systemic therapy for patients with RCC, the necessity of cytoreductive nephrectomy remains inconclusive. Findings from previous studies, such as the phase 3 CARMENA study (NCT00930033), indicated that in the context of VEGF/TKI therapy, radical nephrectomy did not significantly impact overall patient outcomes, Vaishampayan explains.

A dilemma arises in the era of immune checkpoint–based therapy regarding whether cytoreductive nephrectomy still holds relevance, she says. It is known that patients with synchronous metastatic disease fare worse than those who undergo nephrectomy and later develop metastases, Vaishampayan notes. However, the patient population simultaneously presenting with primary tumors and metastases has not been extensively studied, as clinical trials predominantly include post-nephrectomy patients, she notes.

Data from the phase 3 CheckMate 214 trial (NCT02231749) with ipilimumab (Yervoy) and nivolumab (Opdivo) showed reduced median overall survival in patients with advanced RCC who did not undergo nephrectomy compared with the overall study population, Vaishampayan expands. This finding underscores the need for focused research and tailored strategies to improve outcomes in this specific patient subgroup.

Because neoadjuvant immune-based regimens followed by primary tumor removal have shown promise in preclinical RCC settings, investigators continue to initiate phase 3 trials to assess the benefit of these approaches. It is importance to note that the current standard of care for patients with advanced RCC is continuation of systemic therapy without cytoreductive nephrectomy, Vaishampayan concludes.

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Ulka Nitin Vaishampayan, MBBS, discusses the rationale for conducting the phase 3 SWOG 1931 trial in patients with advanced renal cell carcinoma.


Ulka Nitin Vaishampayan, MBBS, director, the Phase I Program, Rogel Cancer Center, professor, internal medicine, University of Michigan, discusses the need for improved identification of patients with homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (mCRPC) who may benefit from treatment with talazoparib (Talzenna) and enzalutamide (Xtandi).

the FDA approved talazoparib plus enzalutamide for patients with HRR gene–mutated mCRPC

 based on findings from the phase 3 TALAPRO-2 trial (NCT03395197). Notably, the double-blind, placebo-controlled, multicohort trial included patients previously treated with docetaxel in the metastatic hormone-sensitive setting, although they made up a small proportion of the study population, Vaishampayan says. Patients were also required to have progressed on prior androgen deprivation therapy (ADT), she adds.

Results showed that radiographic progression-free survival (rPFS) significantly improved with talazoparib and enzalutamide vs enzalutamide alone in this population, Vaishampayan reports. Median rPFS was not yet reached in the experimental arm, and was 13.8 months in the control arm.

Ideal candidates for this regimen may include patients without prior exposure to an androgen receptor (AR) inhibitor, Vaishampayan continues. However, the use of AR inhibitors in intensified therapeutic regimens has become a standard approach for patients with metastatic hormone-sensitive prostate cancer, Vaishampayan states. Moreover, there is a lack of evidence supporting the regimen's use in patients with mCRPC who already received abiraterone acetate (Zytiga), enzalutamide, or apalutamide (Erleada), or a triplet regimen consisting of ADT plus darolutamide and docetaxel, she notes. Accordingly, it can be difficult to justify administering talazoparib plus enzalutamide to this AR inhibitor–naive population, Vaishampayan says.

These data also suggest that talazoparib plus enzalutamide may provide benefit to patients who experienced disease progression with prostate-specific antigen relapse after treatment with ADT, and now have mCRPC, Vaishampayan adds. Patients in this population who harbor 

 mutations, should be considered for this regimen, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the need for improved identification of patients with homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer who may benefit from treatment with talazoparib and enzalutamide.

Dr Vaishampayan on the Use of Talazoparib and Enzalutamide in Patients With HRR Gene–Mutated mCRPC

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, University of Michigan, discusses findings from the phase 3 CONTACT-03 trial (NCT04338269) in patients with renal cell carcinoma (RCC).

Data from the primary analysis of CONTACT-03, which were presented at the 2023 ASCO Annual Meeting, showed that the addition of atezolizumab (Tecentriq), a PD-L1 inhibitor, to cabozantinib (Cabometyx), a TKI, did not improve clinical outcomes compared with cabozantinib alone in patients with metastatic RCC who had progressed during or after prior therapy with immune checkpoint inhibitors, Vaishampayan says. The median progression-free survival (PFS) was 10.6 months (95% CI, 9.8-12.3) with the combination vs 10.8 months (95% CI, 10.0-12.5) with cabozantinib alone. The 12-month PFS rates were 44% (95% CI, 38%-50%) and 48% (95% CI, 42%-54%) in the combination and cabozantinib monotherapy arms, respectively. The stratified hazard ratio for PFS was 1.03 (95% CI, 0.83-1.28; 

In CONTACT-03, 63.1% and 61.4% of patients in the combination and monotherapy arms had received 1 prior VEGF TKI, respectively, and 1.5% and 1.9% of these patients had received 2 prior VEGF TKIs, respectively. In patients who had received no prior VEGF TKI treatment, the median PFS was 9.7 months and 10.4 months in the combination and monotherapy arms, respectively (HR, 1.02; 95% CI, 0.71-1.46). In patients who had received 1 prior VEGF TKI, the median PFS was 10.6 months in the combination arm vs 11.7 months in the monotherapy arm (HR, 1.06; 95% CI, 0.80-1.39). In patients who had received 2 prior VEGF TKIs, the median PFS was 6.7 months and 11.3 months in the combination and monotherapy arms, respectively (HR, 1.64; 95% CI, 0.36-7.47).

Despite the lack of clinical benefit with atezolizumab plus cabozantinib in this trial, CONTACT-03 is the first large, randomized clinical trial to show the efficacy of a TKI in patients who have received prior immune checkpoint inhibitors, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses findings from the phase 3 CONTACT-03 trial in patients with renal cell carcinoma. 

Dr Vaishampayan on Cabozantinib Plus Atezolizumab in RCC

Ulka Nitin Vaishampayan, MBBS, director, the Phase I Program at Rogel Cancer Center, professor of internal medicine, University of Michigan, discusses updated data for frontline TKI combination therapies in the treatment of patients with metastatic renal cell carcinoma (RCC).

® State of the Science Summit™, Vaishampayan discussed frontline therapy in metastatic RCC and detailed updates presented at the 2023 ASCO Annual Meeting. These updated results included the 5-year analysis of axitinib (Inlyta) plus pembrolizumab (Keytruda) in the phase 3 KEYNOTE-426 (NCT02853331) trial, and the prespecified overall survival (OS) analysis at 4 years of follow-up for lenvatinib (Lenvima) plus pembrolizumab in the phase 3 CLEAR trial (NCT02811861).

Sunitinib (Sutent) monotherapy served as the control arm in both of these studies, and the survival improvement vs sunitinib remained consistent for both combinations, Vaishampayan expands. In KEYNOTE-426, pembrolizumab plus axitinib elicited a median OS of 47.2 months (95% CI, 43.6-54.8) compared with 40.8 months (95% CI, 34.3-47.5) for sunitinib (HR, 0.84; 95% CI, 0.71-0.99). In CLEAR, the median OS was 53.7 months (95% CI, 48.7–not evaluable [NE]) for pembrolizumab plus lenvatinib vs 54.3 months (95% CI, 40.9-NE) for sunitinib (HR, 0.79; 95% CI, 0.63-0.99; 

Moreover, the progression-free survival (PFS) continued to be superior with the combination therapies vs sunitinb, she says. For KEYNOTE-426, the median PFS was 15.7 months (95% CI, 13.6-20.2) for pembrolizumab plus axitinib vs 11.1 months (95% CI, 8.9-12.5) for sunitinib (HR, 0.69; 95% CI, 0.59-0.81). In CLEAR, the median PFS was 23.9 months (95% CI, 20.8-27.7) for pembrolizumab plus lenvatinib compared with 9.2 months (95% CI, 6.0-11.0) for sunitinib (HR, -.47; 95% CI, 0.38-0.57; 

The other intriguing aspect to emerge from KEYNOTE-426 study was that 62.2% of patients in the experimental arm who discontinued treatment went on to receive subsequent therapy. A previous analysis of patients in the International Metastatic RCC Database Consortium showed that approximately only half of patients were able to proceed to second-line therapy, Vaishampayan continues. Being able to put more patients in position to receive subsequent therapy would serve as a step toward improving outcomes for this patient population, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses updated data for frontline TKI combination therapies in the treatment of patients with metastatic renal cell carcinoma.


Dr Vaishampayan on the Impact of TKI Combination Therapies in the Treatment of RCC

Ulka Nitin Vaishampayan, MBBS, director, Phase I Program, Rogel Cancer Center, Michigan Medicine, professor of internal medicine, University of Michigan, discusses the intent of the phase 3 PROBE trial (NCT04510597) in advanced renal cell carcinoma (RCC).

The PROBE trial builds off the phase 3 CARMENA trial (NCT00930033), which reported interim results in 2018, Vaishampayan says. The CARMENA trial investigated whether the addition of cytoreductive nephrectomy to targeted therapy affected overall outcomes in patients with metastatic RCC. CARMENA determined that treatment with sunitinib (Sutent) alone was noninferior to cytoreductive nephrectomy followed by sunitinib in terms of overall survival.

Because advanced RCC treatment standards have shifted since the CARMENA trial, the PROBE trial seeks to determine whether cytoreductive nephrectomy can influence patient outcomes when combined with an immunotherapy-based combination. Preclinical data indicate immunotherapy-based combination therapy increases the chances of response, Vaishampayan concludes.

Ulka Nitin Vaishampayan, MBBS, discusses the intent of the phase 3 PROBE trial in advanced renal cell carcinoma.

Ulka Nitin Vaishampayan, MBBS

Articles

Dr Vaishampayan on the Rationale For the SWOG-1931/PROBE Trial in Advanced RCC

Dr Vaishampayan on the Use of Talazoparib and Enzalutamide in Patients With HRR Gene–Mutated mCRPC

Dr Vaishampayan on Cabozantinib Plus Atezolizumab in RCC

Dr Vaishampayan on the Impact of TKI Combination Therapies in the Treatment of RCC

Dr. Vaishampayan on the PROBE Trial in Advanced RCC