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

Benjamin P. Saylor

Recently presented phase 3 data indicate that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the first-line treatment of advanced renal cell carcinoma (RCC) yields benefits that remain durable at 4-year follow-up compared with treatment with sunitinib (Sutent).

Investigators for study, which was presented at the 2020 European Society for Medical Oncology virtual congress,

 also reported that a subgroup of patients with 1 or more target kidney lesions experienced kidney tumor reduction and other benefits from the combination treatment.

“Nivolumab plus ipilimumab was the first immunotherapy combination to demonstrate an overall survival advantage over sunitinib in intermediate- and poor-risk patients with advanced renal cell carcinoma,” CheckMate-214 investigator Laurence Albiges, MD, PhD, said in a press release.

“Now, after 4 years, the durable efficacy seen in CheckMate-214 represents important progress towards the aim of changing survival expectations for these patients,” added Albiges, Head of Genitourinary Unit, Gustave Roussy Institute, Villejuif, France.

The randomized, open-label phase 3 CheckMate-214 trial evaluated the combination of nivolumab and ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC. Patients in the combination group (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg nivolumab every 2 weeks. Patients in the sunitinib group (n = 546) received 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Treatment was given until progression or unacceptable toxic effects.

Primary end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in an intermediate- to poor-risk patient population. In addition, non-prespecified, post hoc exploratory efficacy analyses were performed in a subgroup of study patients who had not undergone prior nephrectomy and who had 1 or more target kidney lesions.

In intermediate- to poor-risk patients treated with nivolumab/ipilimumab, median OS was 48.1 months, compared with 26.6 months in patients who received sunitinib (HR, 0.65; 95% CI, 0.54-0.78). The 4-year OS rate for the combination treatment and sunitinib groups was 50.0% and 35.8%, respectively. ORR was also higher in patients receiving combination treatment versus sunitinib, with more ongoing responses in intermediate- to poor-risk patients (65% vs 50%, respectively). Median duration of response was not reached in the combination treatment arm and was 19.7 months for sunitinib.

The benefits of nivolumab/ipilimumab treatment were also observed in an analysis of patients in the intention-to-treat (ITT) population with 48 months’ follow-up. Median OS was not reached for all patients in the combination treatment group vs 38.4 months in the sunitinib group (HR, 0.69; 95% CI, 0.59-0.81), with 4-year OS rates of 53.4% and 43.3%, respectively. ORR was higher in patients receiving nivolumab/ipilimumab, with more ongoing responses compared to patients receiving sunitinib (65% vs 52%). Median duration of response was not reached in patients treated with nivolumab/ipilimumab and was 23.7 months in the sunitinib group.

Looking at the subgroup of patients with 1 or more target kidney lesions, ORR was 34% in the nivolumab/ipilimumab group vs 15% in the sunitinib group. A 30% or greater reduction in target kidney lesion(s) was observed in 35% of patients receiving the combination treatment vs 20% in patients receiving sunitinib.

Treatment-related adverse events of any grade occurred in 94% of patients receiving combination treatment and 97.0% of patients receiving sunitinib, and no new safety signals emerged over the longer follow-up.

Nick Botwood, MD, vice president, interim head, Oncology Development, Bristol Myers Squibb, discussed the findings in a press release.

“We have now evaluated Opdivo plus Yervoy in multi-year phase 3 trials across RCC, melanoma, non-small cell lung cancer, and mesothelioma, and in all of these studies, we have seen improved survival compared to the existing standard of care. The 4-year results from CheckMate -214 build on our understanding of and leadership in addressing advanced RCC, reinforcing the potential for durable, long-term survival benefits with Opdivo plus Yervoy in the first-line setting. Taken as a whole, these data provide further evidence for the value of distinct but complementary dual checkpoint inhibition in the treatment of advanced cancers,” Botwood said.

Disclosures: The study was sponsored by Bristol Myers Squibb. Dr Albiges has received consulting fees from Pfizer, Novartis, Bristol Myers Squibb, Ipsen, Roche, MSD, AstraZeneca, Merck, Amgen, Astellas, Exelixis, Corvus Pharmaceuticals, and Peloton Therapeutics.

Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma 711P in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 711P.

Bristol Myers Squibb. Four-year data continue to show superior, long-term survival benefit with Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma. Press release. September 17, 2020. Accessed September 18, 2020. https://bit.ly/3mCwhwO.

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Investigators also reported that a subgroup of patients with 1 or more target kidney lesions experienced kidney tumor reduction and other benefits from the combination treatment.

Nivolumab/ipilimumab combo’s benefits durable at 4 years for treating advanced RCC

The FDA has granted fast track designation to EPI-7386, an oral, highly selective N-terminal domain inhibitor of the androgen receptor (AR), for treatment of metastatic castration-resistant prostate cancer (mCRPC) resistant to standard-of-care treatment, ESSA Pharma Inc announced.

ESSA Pharma is conducting a phase 1 trial (NCT04421222)

 trial of EPI-7386 that will evaluate the safety and tolerability of the agent and also examine its pharmacokinetic, biological, and anti-tumor effects.

"We are pleased with the FDA's decision to grant Fast Track designation for development of EPI-7386 to treat mCRPC patients resistant to standard-of-care treatments. This designation signifies recognition of the unmet medical need for new and effective treatments for this patient population. EPI-7386 may represent a promising novel treatment option for these patients and the designation offers the opportunity to interact more closely with the FDA during the development of EPI-7386,” David R. Parkinson, MD, Chief Executive Officer of ESSA Pharma, said in a press release.

®, J. Brantley Thrasher, MD, explained that EPI-7386 is part of a new class of AR-targeting compounds known as anitens.

“These compounds differ from currently available AR-blocking compounds because they bind to the N-terminal domain of the AR instead of the ligand binding domain. Due to its novel binding and mechanism of blocking the AR, it appears to work well in those patients who are progressing on current standard of care treatments,” said Thrasher, executive director of the American Board of Urology in Charlottesville, Virginia.

Added Thrasher, “I think this therapy will provide another agent in the armamentarium for mCRPC and will likely be used at first for those recalcitrant to standard therapies like enzalutamide [Xtandi] or abiraterone [Zytiga] but will quickly be tested to find out whether it works best in combination with one of these agents and what the best sequence of delivery will be.”

1. ESSA Pharma announces fast track designation granted by the FDA to EPI-7386 for the treatment of metastatic castration-resistant prostate cancer. Press release. Essa Pharma. September 14, 2020. Accessed Sept. 16, 2020. 

2. Oral EPI-7386 in patients With metastatic castration-resistant prostate cancer (EPI-7386). Updated September 16, 2020. Accessed September 16, 2020. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 

https://clinicaltrials.gov/ct2/show/NCT04421222

The FDA has granted fast track designation to EPI-7386, an oral, highly selective N-terminal domain inhibitor of the androgen receptor for treatment of mCRPC resistant to standard-of-care treatment.

FDA grants fast track designation for oral mCRPC agent

A new clinical guideline for microhematuria embraces a risk-stratified approach to evaluating patients.

The guideline was presented at the 2020 American Urological Association Virtual Experience by guideline panel co-chairs Daniel A. Barocas, MD, MPH, associate professor and vice chair of urology at Vanderbilt University Medical Center, Nashville, Tennessee, and Stephen A. Boorjian, MD, professor of urology at Mayo Clinic, Rochester, Minnesota.

The multidisciplinary panel included members of the AUA, Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction, American College of Obstetricians and Gynecologists, as well as a patient advocate from the Bladder Cancer Advocacy Network. The panel’s evidence base consisted of 5 systematic reviews and 91 primary literature studies.

In presenting the guideline, Barocas explained that hematuria is one of the most common urologic diagnoses, “by some estimates accounting for 25% or more of urologic evaluations.”

Barocas also discussed the variability related to microhematuria evaluation.

“There is quite a bit of variability across current guidelines and consensus statements regarding the definition of microhematuria, criteria for evaluation, and the components for evaluation, including the optimal imaging modality,” Barocas said.

With the guideline, Barocas said the panel sought to address the following issues: conflicting guidelines, a low overall yield of evaluation, harms of evaluation in terms of risks to patients and cost to the health care system, and poor adherence to existing guidelines.

The guideline panel defines microhematuria as “[greater than or equal to] 3 red blood cells per high-power field on microscopic evaluation of a single, properly collected urine specimen.”

The guideline further advises that clinicians not define microhematuria solely by positive dipstick testing alone but rather proceed to formal microscopic evaluation of the urine following a positive dipstick test.

“This is because a variety of factors, including myoglobinuria, dehydration, exercise, and beta dyeing, can produce false-positive dipstick results,” Barocas said.

Barocas also described statements of the guideline related to patients diagnosed with gynecologic or non-malignant genitourinary sources of microhematuria. For these patients, the clinician should conduct a repeat urinalysis following the resolution of the gynecologic or non-malignant genitourinary cause.

Following this, “If the hematuria persists or the etiology can't be identified, clinicians should perform a risk-based evaluation. By the same token, in patients with hematuria attributed to a urinary tract infection, clinicians should obtain a urinalysis with microscopic evaluation following treatment to ensure the resolution of the hematuria,” Barocas said.

During his presentation, Boorjian described the risk stratification components of the guideline.

“The development of a risk classification system represents a recognition on the part of the 

guidelines panel of the heterogeneity in risk among patients presenting with microscopic hematuria for underlying genital urinary malignancy and an effort to provide an individualized approach to evaluation,” Boorjian explained.

The guideline directs clinicians to categorize patients presenting with microhematuria as being at low, intermediate, or high risk for genitourinary malignancy. Criteria for risk stratification are outlined in the guideline and include age, smoking status, degree of microhematuria, persistence of microhematuria, history of gross hematuria, and additional urothelial cancer risk factors.

In patients categorized as low risk, the guideline recommends a shared decision-making process to choose between repeating urinalysis within 6 months or proceeding with cystoscopy and renal ultrasound. Low-risk patients who choose not to undergo initial cystoscopy or upper tract imaging but are found to have microhematuria after repeat urine testing should be reclassified as intermediate or high risk and should then undergo cystoscopy and upper tract imaging.

Cystoscopy and renal ultrasound are recommended in patients with intermediate-risk microhematuria.

“The panel wants to emphasize that the overwhelming majority of genitourinary malignancies diagnosed among patients with microscopic hematuria are bladder cancers, and therefore cystoscopy represents an absolute cornerstone to the evaluation of microhematuria patients,” Boorjian said.

In patients categorized as being at high risk for malignancy, the guideline recommends that clinicians perform cystoscopy and axial upper tract imaging.

The guideline also covers urinary markers: “Recognizing the insufficient data existing to date on the incremental additive value to detect bladder cancers, the recommendation of the guidelines is that clinicians should not use urine cytology for urine-based tumor markers in the initial evaluation of patients with microhematuria, acknowledging that clinicians may obtain urine cytology for patients with persistent microhematuria after a negative workup who have irritative voiding symptoms or risk factors for carcinoma in situ,” Boorjian said.

Regarding follow-up after a negative microhematuria evaluation, the panel says clinicians may obtain a repeat urinalysis within 12 months, and that in patients with a prior negative evaluation and subsequent negative urinalysis, clinicians may discontinue further evaluation for microhematuria. For patients with a prior negative microhematuria evaluation who have persistent or recurrent microhematuria at repeat urinalysis, the panel advises shared decision-making regarding the need for further evaluation.

“Importantly, patients who experience a change in their clinical status should have further evaluation. Specifically, patients who develop gross hematuria, patients who develop new urologic symptoms, or an increase in their degree of microhematuria should initiate further evaluation,” Boorjian said.

1. Barocas D, Boorjian S, Alvarez R, et al. Microhematuria: AUA/SUFU guideline. Presented during 2020 AUA Virtual Experience. June 27-28, 2020

A multidisciplinary panel outlines criteria for stratifying risk for genitourinary malignancy in patients with microhematuria.

Microhematuria guideline emphasizes risk-stratified approach

The FDA approved an additional recommended dosage of 400 mg every 6 weeks for the anti-PD-1 therapy pembrolizumab (Keytruda), across all adult indications, including monotherapy and combination therapy, Merck reported.

This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials. This new dosage option will be available in addition to the current dose of 200 mg every 3 weeks, according to Merck.

53% of CIS patients achieve complete response with nadofaragene

Pembrolizumab has a number of genitourinary cancer indications. It is indicated for:

• the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status

• the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

• the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Pembrolizumab, in combination with axitinib, is also indicated for the first-line treatment of patients with advanced renal cell carcinoma.

“The important social distancing measures for COVID-19 have created a number of challenges for people with cancer, including keeping to planned treatment schedules,” said Roy Baynes, MD, PhD, of Merck Research Laboratories. “[The] approval of an every 6-week dosing schedule for KEYTRUDA gives doctors an option to reduce how often patients are at the clinic for their treatment.”

Commenting on the announcement, Arjun Balar, MD, told 

The newly approved dosing provided additional flexibility and convenience for patients, especially for those who have already achieved disease control with treatment and can now enjoy extended times between treatment visits.

“The safety and efficacy profile of every 6 weeks and every 3 weeks dosing should be identical. Therefore, whether you’re choosing every 6 weeks or 3 weeks dosing, it’s important to recognize that vigilance and monitoring for immune-related toxicities should be no different. Keeping in close contact with patients and early intervention for immune-related toxicities is particularly critical,” advised Balar, of NYU Langone Health.

Disclosures: Balar is a consultant/adviser for Genentech, Incyte, Janssen, Merck, Pfizer, AstraZeneca/Medimmune, Nektar, and Seattle Genetics. He has received institutional funding from Genentech, Merck, AstraZeneca/Medimmune, Seattle Genetics, and Immunomedics.

Benjamin P. Saylor

Articles

Nivolumab/ipilimumab combo’s benefits durable at 4 years for treating advanced RCC

FDA grants fast track designation for oral mCRPC agent

Microhematuria guideline emphasizes risk-stratified approach

FDA approves additional recommended dosage for anti-PD-1 therapy