Benjamin P. Saylor is associate editor of Urology Times, an Advanstar Communications publication.

Benjamin P. Saylor

Investigators are evaluating the safety and efficacy of experimental combinations of investigational agents for advanced clear cell renal cell carcinoma (ccRCC) as part of a phase 1b/2 umbrella platform study, according to a poster shared during the 2021 American Association for Cancer Research Virtual Annual Meeting.

Substudy 03B (NCT04626518) will evaluate patients whose disease progresses after treatment with PD-1/PD-L1 inhibitors and VEGF-tyrosine kinase inhibitors (TKIs).

“PD-1/L1-based combination regimens are the standard of care for first-line treatment of advanced clear cell RCC; however, there is no standard of care in the post–immuno-oncology/post-VEGF patient population, resulting in a high-unmet need,” explained the investigators, led by Hans Hammers, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas.

The treatments to be evaluated in the study include the cytotoxic T-lymphocyte-associated protein 4 quavonlimab (MK-1308), belzutifan (MK-6482), lymphocyte activation gene 3 (MK-4280), immunoglobulin-like transcript 4 (MK-4830), pembrolizumab (Keytruda), and lenvatinib (Lenvima).

“Given the promising results in the RCC cohort of the phase 1b/2 trial (KEYNOTE-146; NCT02501096)

 and the recent phase 3 CLEAR study (NCT02811861),

 pembrolizumab in combination with lenvatinib will be used as the reference arm in substudy 03B,” wrote the investigators.

Adults aged 18 years or older with locally advanced or metastatic ccRCC, measurable disease per RECIST v1.1 criteria, disease progression on or after anti-PD-1/PD-L1 treatment, disease progression after VEGF-TKI therapy, and Karnofsky performance status of 70% or higher are eligible for the study.

The study will include a safety lead-in phase followed by an efficacy phase. Treatment arms in the safety lead-in phase will include pembrolizumab plus belzutifan and lenvatinib plus belzutifan cohorts. Patients will be assigned 1:1 to treatment in an experimental arm or the reference arm. Patients will continue treatment until radiographic disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of study treatment, or withdrawal of consent, according to the investigators.

Experimental arms in the efficacy phase will include quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W; MK-4280 800 mg and pembrolizumab 200 mg IV Q3W; pembrolizumab 200 mg IV Q3W plus MK-4830 800 mg IV Q3W; pembrolizumab 400 mg IV Q6W plus belzutifan 120 mg orally QD; and lenvatinib 20 mg orally QD plus belzutifan 120 mg orally QD. The reference arm will evaluate pembrolizumab 400 mg IV Q6W plus lenvatinib 20 mg orally QD.

“Primary end points for safety lead-in phase (if applicable) are safety and tolerability to establish [a recommended phase 2 dose]; co-primary end points for efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival, and clinical benefit rate per RECIST v1.1 (BICR), and overall survival,” according to the investigators.

Enrollment for the research is taking place at 27 sites in Australia, New Zealand, South Korea, Spain, and the United States.

1. Hammers H, Choueiri T, Plimack E, et al. A phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced renal cell carcinoma (RCC) who progressed on PD-1/L1 and VEGF inhibitors. Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT243.

2. Lee C-H, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). 

2020;38, no. 15_suppl:5008. doi:10.1200/JCO.2020.38.15_suppl.5008

3. Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

2021;384(14):1289-1300. doi:0.1056/NEJMoa2035716

Articles

Substudy 03B is enrolling patients with disease progression after treatment with PD-1/PD-L1 inhibitors and VEGF-tyrosine kinase inhibitors.

Umbrella study exploring novel combos in advanced RCC

 is looking to evaluate patterns of prostate cancer survivorship care among providers who manage patients with prostate cancer.

Discussing the impetus behind the survey, Stacy Loeb, MD, MSc, told 

®, “There are more than 3 million prostate cancer survivors living in the United States. Prostate cancer has a significant impact on quality of life, including urinary health, sexual function, and overall well-being.”

The anonymous online survey, which Loeb said can be completed in approximately 5 minutes, is meant to gain information “from urologists about the current survivorship care that is provided for survivors of prostate cancer,” according to Loeb, professor of urology and population health at New York University Grossman School of Medicine, New York City.

Added Loeb, “Once the survey is completed, we will publish the results in a urology journal and disseminate them through social media. We will also use the information to identify gaps that we can address to improve future care for prostate cancer.”

The anonymous online survey, is meant to gain information “from urologists about the current survivorship care that is provided for survivors of prostate cancer,” according to Stacy Loeb, MD, MSc.

Survey to examine patterns of prostate cancer survivorship care

Researchers will evaluate the investigational intravesical BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) treatment CG0070 in a phase 3 trial following promising data from phase 1 and 2 studies of the agent.

According to CG Oncology, which is developing the treatment, CG0070 is “a selective oncolytic immunotherapy based on a modified adenovirus type 5 backbone that contains a cancer-selective promoter and a GM-CSF transgene, destroys bladder tumor cells through their defective retinoblastoma (Rb) pathway.”

Discussing the agent, investigator Edward Uchio, MD, clinical professor of urology at the University of California, Irvine, highlighted CG0070’s intravesical nature, as urologists are already familiar with administering intravesical treatments such as BCG.

“[Urologists are] very comfortable giving agents in the bladder, so [CG0070] really fits in line with what we give,” Uchio said.

In an abstract presented at the 2020 Society of Urologic Oncology annual meeting,

investigators outlined the BOND-003 trial (NCT04452591) of CG0070. BOND-003 is a single-arm study in which 110 patients with BCG-unresponsive NMIBC will be treated with CG0070 weekly x 6 followed by weekly x 3 maintenance indications at 3, 6, 9, 12, and 18 months. Patients will be enrolled across the US and Asia-Pacific regions.

“We anticipate we will complete enrollment globally over the next year and a half, and then publish the early data probably within 6 to 12 months thereafter,” study investigator James Burke, MD, chief medical officer of CG Oncology, said in December.

The study’s primary end point will be complete response at any time. Secondary end points include CR at 12 months, duration of response, progression-free survival, cystectomy-free survival, and safety.

CG0070 was previously evaluated in the V-0046 phase 1 study (NCT00109655) and BOND2 phase 2 study (NCT02365818). V-0046 evaluated 35 patients treated with CG0070. The agent demonstrated antibladder cancer activity, with the most common adverse events consisting of grade 1-2 bladder toxicities.

 The BOND2 trial evaluated 65 patients, with a 62% complete response rate at any time, with complete response maintained in 46% at 12 months.

In December 2020, CG Oncology also reported that the first patient had been dosed in a phase 2 clinical trial evaluating CG0070 in combination with pembrolizumab (Keytruda) for the treatment of BCG-unresponsive NMIBC.

1. CG Oncology announces first patient dosed in phase 2 clinical trial of CG0070, an oncolytic immunotherapy, in combination with Keytruda (pembrolizumab) for non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guerin. News release. CG Oncology. December 9, 2020. Accessed January 22, 2021. http://bit.ly/2Y5Kh76

2. Uchio E, Lamm DL, Shore N, et al. Phase 3 study of CG0070 in patients with non-muscular invasive bladder cancer (NMIBC) unresponsive to bacillus-Calmette-Guerin (BCG). Paper presented at: 2020 Society of Urologic Oncology annual Meeting. December 3-5, 2020; virtual. Accessed January 22, 2021. https://bit.ly/39cQPHz

3. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. 

2012;188(6):2391-2397. doi:10.1016/j.juro.2012.07.097

4. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. 

2018;36(10):440-447. doi:10.1016/j.urolonc.2017.07.005

“[Urologists are] very comfortable giving agents in the bladder, so [CG0070] really fits in line with what we give,” says investigator Edward Uchio, MD.

Phase 3 trial will evaluate oncolytic immunotherapy for BCG-unresponsive NMIBC

Investigators appear to have found molecular signatures that could identify patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) who are likely to have long-term benefit from treatment with apalutamide (Erleada) plus androgen-deprivation therapy (ADT).

The findings, presented at the 2021 Genitourinary Cancers Symposium,

 were derived from an exploratory analysis of patients from the phase 3 randomized, placebo-controlled SPARTAN trial (NCT01946204). At the final analysis of SPARTAN, treatment with apalutamide plus ADT increased median overall survival by 14 months versus placebo plus ADT in patients with nmCRPC.

 Based on initial data from the SPARTAN trial, the FDA approved apalutamide in 2018 for use in this setting.

For the current study, investigators characterized patients in the biomarker population of SPARTAN as either long-term responders (LTRs) or early progressors (EPs). Patients from the apalutamide plus ADT and placebo plus ADT groups were placed in quartiles based on the number and timing of metastatic events. Patients without progression or who reached a metastatic event after the third quartile were considered LTRs, whereas patients who had a metastatic event in the first quartile were considered EPs.

“Because patients in the placebo group had previously progressed on androgen deprivation therapy alone, our analysis focused only on the long-term responder population treated with apalutamide plus androgen-deprivation therapy,” said study investigator Felix Y. Feng, MD, professor of radiation oncology, urology, and medicine at the University of California, San Francisco and director of the Benioff Initiative for Prostate Cancer Research at Helen Diller Family Comprehensive Cancer Center.

The SPARTAN biomarker population comprised 233 tumors collected at radical prostatectomy or during diagnostic biopsies. “Gene expression profiling was used to identify molecular subtypes within the cohort, based on a selected number of predefined signatures representing distinct biological pathways or processes relevant in prostate cancer,” Feng said.

test method was used to analyze differential expressions in the LTR and EP groups. Signatures that showed nominal statistical significance were identified. In parallel, a Cox proportional hazards model was applied to the entire biomarker population to determine whether these signatures were associated with metastasis-free survival (MFS). The investigators then looked at signatures that were associated with response to treatment by both analyses. Signatures that were both differentially expressed in LTRs versus EPs and had a treatment-specific impact on clinical outcome were identified as predictive biomarkers of response to treatment, Feng said.

“Among patients treated with apalutamide, molecular signatures indicative of increased immune activity, decreased vascularization, or decreased proliferative capacity at baseline were each independently associated with long-term response. None of these signatures was associated with long-term response to placebo,” Feng reported.

In the placebo group, increased hormonal independence and metastatic capacity at baseline were associated with early progression.

Feng reported that signatures associated with long-term response to apalutamide plus ADT were also associated with increased MFS by Cox regression.

“Specifically, signatures of T cell proliferation and T cell stimulation at baseline were elevated in patients with long term response,” Feng said.

The investigators also found that patients with basal tumors with higher levels of T cell proliferation appeared to derive a similar benefit from apalutamide plus ADT compared with patients with luminal tumors.

1. Feng FY, Aguilar-Bonavides C, Lucas J, et al. Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC). 

. 2021;39(suppl 6):8. doi: 10.1200/JCO.2021.39.6_suppl.8

2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. 

2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

“Among patients treated with apalutamide, molecular signatures indicative of increased immune activity, decreased vascularization, or decreased proliferative capacity at baseline were each independently associated with long-term response,” reported Felix Y. Feng, MD.

Benjamin P. Saylor

Articles

Umbrella study exploring novel combos in advanced RCC

Survey to examine patterns of prostate cancer survivorship care

Phase 3 trial will evaluate oncolytic immunotherapy for BCG-unresponsive NMIBC

Molecular signatures linked to long-term apalutamide benefit in nonmetastatic CRPC