Dr. Mary Samplaski discusses online resources regarding male infertility.

Speaking of Urology Podcast 

Decipher Prostate, a 22-gene microarray-based genomic classifier, was clinically validated as a predictor of overall survival (OS) in men with biochemically recurrent prostate cancer after radical prostatectomy (RP), according to an ancillary study of the pivotal phase 3 NRG/RTOG 9601 trial.

The outcome on the genomic classifier, known as the Decipher Score, was independently associate with OS, prostate cancer–specific mortality, and risk of metastasis.

"Identifying which patients with recurrent disease are most likely to benefit from hormonal therapy will improve our ability to extend patient survival, while minimizing unnecessary toxicity for a large group of men with prostate cancer," lead author Felix Feng, MD, vice chair of radiation oncology at University of California, San Francisco, stated in a press release. "Decipher Prostate RP improves upon clinical and pathological risk stratification methods and informs the use of hormonal therapy, making it a reasonable and recommended component of the prostate cancer standard of care."

The ancillary study used RP specimens obtained in the practice-changing NRG/RTOG 9601 (NCT00002874) randomized clinical trial. These specimens from that phase 3 placebo-controlled study were collected between March 1998 and March 2003. The double-blind NRG/RTOG 9601 study included 760 patients with recurrent pT3N0 prostate cancer after RP and pelvic lymphadenectomy.

 Patients were randomized to receive radiation therapy with either antiandrogen therapy (24 months of daily bicalutamide) or placebo tablets daily during and after radiation therapy. OS was the primary end point.

In NRG/RTOG 9601, the OS rate at 12 years was 76.3% in the bicalutamide arm versus 71.3% in the placebo arm, translating to a 33% reduction in the risk of death (HR, 0.77; 

 = .04). Prostate cancer–related death at 12 years occurred in 5.8% versus 13.4% of the 2 arms, respectively (

For the ancillary study, the researchers used specimens from 352 men randomized to either placebo or hormone therapy in NRG/RTOG 9601. The median age of these men was 64.5 years (range, 60-70) and 89.2% were White. Statistical modeling showed that Decipher was independently associated with distant metastasis (HR, 1.17; 

 = .006),prostate cancer–specific mortality (HR, 1.39; 

"This is very exciting, as the study validates Decipher Prostate as the first independent predictor of overall survival and shows how predicting metastatic risk with the Decipher test can be utilized to better guide treatment decisions in men with a prostate specific antigen recurrence," Tina S. Nova, PhD, president and chief executive officer of Decipher Biosciences, stated in the press release.

1. Decipher Test Clinically Validated as a Predictor of Overall Survival in Men with Prostate Cancer. Published online February 11, 2021. Accessed February 25, 2021. https://prn.to/3pZ3X7X.

2. Feng FY; Huang H-C, Spratt DE, et al. Validation of a 22-gene genomic classifier in patients with recurrent prostate cancer: an ancillary study of the NRG/RTOG 9601 randomized clinical trial [published online ahead of print February 11, 2021]. 

3. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. 

. 2017 Feb 2;376(5):417-428. doi: 10.1056/NEJMoa1607529

Articles

The outcome of the Decipher Prostate test was independently associated with overall survival, prostate cancer–specific mortality, and risk of metastasis.

Analysis validates 22-gene genomic classifier in biochemically recurrent prostate cancer

Findings from cohort 2 of the EV-201 trial showed that enfortumab vedotin (Padcev) achieved a 52% confirmed objective response rate (ORR) in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had prior exposure to a PD-1/PD-L1 immune checkpoint inhibitor.

The noncomparative phase 2 EV-201 trial included 2 cohorts. Previously reported data from cohort 1 of the study led to the December 2019 FDA accelerated approval of enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

“What I'll discuss today are data from cohort 2, which specifically focused on cisplatin-ineligible patients who received immunotherapy in the frontline setting, and who were ineligible for cisplatin-containing chemotherapy at the time of study enrollment,” Arjun V. Balar, MD, said when presenting the findings during the 2021 Genitourinary Cancer Symposium.

Cisplatin-based chemotherapy is considered the standard of care in advanced disease and is associated with some survival benefit, but approximately half of all of patients are ineligible for cisplatin-containing chemotherapy. Objective responses occur in about 20% to 30% of patients unselected for PD-L1 expression.. After progression on immunotherapy, these patients have limited treatment options.

Eighty-nine patients were enrolled in cohort 2. They received 1.25 mg/kg enfortumab vedotin IV on days 1, 8, and 15 of each 28-day cycle. The primary end point was centrally confirmed ORR and the secondary end points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Eligible patients had locally advanced unresectable or metastatic urothelial carcinoma who were previously treated with a PD-1/PD-L1 inhibitor. These patients were ineligible for cisplatin-containing chemotherapy and had no prior exposure to platinum-containing chemotherapy in the locally advanced or metastatic setting. Exclusion criteria were ongoing or sensory motor neuropathy that was grade 2 or higher, active central nervous system metastases, and uncontrolled diabetes mellitus.

At the data cutoff of September 8, 2020, 91 patients had enrolled and 89 were treated, said Balar, who is director of the genitourinary medical oncology program at New York University Langone’s Perlmutter Cancer Center in New York. Eighty-two percent of patients discontinued treatment; the most common reason for discontinuing treatment was because of progressive disease in 51% of patients. The second most common reason was the development of an adverse event (AE) in 24% of patients.

Baseline characteristics showed that patients were a median age of 75, male (74%), and 15% were obese. Two-thirds (67%) of patients exhibited a moderate decrease in kidney function. Looking at the primary site of tumor, 43% had a tumor in the upper tract. “This is somewhat expected because these are patients who may have had prior surgery and also have kidney dysfunction,” Balar said.

Regarding metastatic sites, 79% had visceral disease and 24% had liver involvement, demonstrating the overall poor prognosis of patients enrolled in the trial, added Balar.

Levels of Nectin-4 overexpression were very high in the population, obviating the need for testing prior to treatment.

The confirmed ORR was 52%. “What’s notable is a 20% rate for complete responses and only 9% of patients had progressive disease as their best response to treatment,” Balar said.

Balar noted in the subgroup analysis that responses were observed across all subgroups including patients with primary tumor sites in the upper tract (ORR = 61%), with liver metastasis (ORR = 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR = 48%).

“We identified a trend toward better responses in patients who had previously done well and responded to immunotherapy, which suggests 2 potential hypotheses underlying this observation. One is simply that patients who respond to treatment are the ones who will then respond to the next course of treatment, which highlights those patients who have a generally good prognosis.

“The other, more tantalizing explanation for this observation, is that there might be the presence of synergy between both enfortumab vedotin and immunotherapy,” Balar said. “This is being actively explored in randomized studies that are currently ongoing.”

Regarding secondary end points, the median time to response was 1.81 months with some patients who have durable responses that extend beyond a year or more. Median DOR was 10.9 months.

At a median follow-up of 13.4 months, the median PFS was 5.8 months and median OS was 14.7 months.

In terms of safety, any grade overall treatment-related adverse events (TRAEs) occurred in 97% of patients and grade 3 or higher TRAEs occurred in 55% of patients. TRAEs led to discontinuations in 16% of patients, and peripheral sensory neuropathy was the most common in 4%.

Balar noted that there were 4 deaths that were considered to be treatment related by the investigator and these were a result of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

“The first 3 deaths occurred within 30 days of the first dose of enfortumab vedotin. The only common denominator that is jumping out right now is a body mass index of 30 or greater. All these patients were older than 75 years and had other comorbidities, which is very common in this population,” Balar said.

TRAEs specific to enfortumab vedotin include skin reactions, peripheral neuropathy, and hyperglycemia. Median onset for skin reactions and hyperglycemia was 15 days, with median onset of peripheral neuropathy at 2.4 months.

“We observed in this study and in clinical practice that dose reduction and interruptions can lead to resolution and improvement of symptoms. What we also find particularly helpful is physical therapy to help with these toxicities. In general, these AEs are quite management,” Balar said.

Based on the data from cohort 2 of EV-201, a supplemental Biologics License Application has been filed with the FDA to expand enfortumab vedotin’s approval to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.

1. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6).394. doi: 10.1200/JCO.2021.39.6_suppl.394

2. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. Press release. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3aYylKk

Based on these findings, an application has been filed with the FDA to expand enfortumab vedotin’s approval to include cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor.

Enfortumab Vedotin highly active in cisplatin-ineligible urothelial cancer

Thomas E. Hutson, DO, PharmD, Texas Oncology‐Baylor Charles A. Sammons Cancer Center, discusses findings from the phase 3 CLEAR trial, in which frontline therapy with pembrolizumab (Keytruda) plus lenvatinib (Lenvima) reduced the risk of death by 34% versus sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC). The combination also improved progression-free survival (PFS) and response compared with sunitinib. In the trial, it was also demonstrated that combining lenvatinib and everolimus improved PFS and objective response rate but not OS versus sunitinib in this setting (

. 2021; 39[suppl6]:269. doi: 10.1200/JCO.2021.39.6_suppl.269).

Videos

The immunotherapy/TKI combination significantly improved overall survival versus sunitinib. 

Dr. Thomas E. Hutson on results of phase 3 CLEAR trial of pembrolizumab/lenvatinib in RCC

discusses findings from the study, “Association of the clinical cell-cycle risk score with metastasis after radiation therapy and identification of men with prostate cancer who can forgo combined androgen deprivation therapy,” which was presented at the 2021 Genitourinary Cancers Symposium. Tward is a professor of radiation oncology at the University of Utah, Salt Lake City.

“I find [the Prolaris test] to be a very helpful clinical tool,” says Jonathan D. Tward, MD, PhD.

Prolaris test aids in decision making on multimodal therapy in prostate cancer

Results of the phase 2 SWOG 1500 study presented during the 2021 Genitourinary Cancers Symposium showed that cabozantinib (Cabometyx) significantly improved progression-free survival (PFS) versus sunitinib (Sutent) in patients with metastatic papillary renal cell carcinoma (pRCC).

The median PFS with cabozantinib was 9.0 months versus 5.6 months with sunitinib, translating to 40% reduction in the risk of disease progression or death (HR, 0.60; 

The agent also led to a significantly higher response rate relative to sunitinib, at 23% versus 4.0%, respectively, in this population (

 = .010). Complete responses were only observed among those who were given cabozantinib. Moreover, although sunitinib was also compared with crizotinib (Xalkori) and savolitinib (AZD6094), those arms of the study were terminated prematurely in a futility analysis, as neither showed benefit in PFS relative to sunitinib.

“Although discordances were observed in subtype classification, cabozantinib had a homogeneous effect across treatment groups,” presenting author Sumanta K. Pal, MD, FASCO, who is also a medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in an oral presentation of the data. “With this in mind, cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC.”

Papillary RCC is a rare malignancy, accounting for 15% of all RCC cases. VEGF-targeted therapies, such as sunitinib, have previously comprised the standard of care in these patients; however, the estimates of efficacy of these options vary, noted Pal. Response rates for these therapies across retrospective and prospective series, range from 0% to 24%, and PFS has ranged from 1.6 months to 8.0 months.

“To date, there have been no randomized data specifically in [patients with] papillary RCC showing an advantage of 1 systemic therapy over another,” Pal noted.

Multiple studies have suggested that the 

 proto-oncogene may be a potential driver of papillary RCC. Although it is more common in type I compared with type II disease, the 

 mutation and copy number alteration occur in a proportion of both subtypes. In the SWOG 1500 trial, investigators sought to determine whether different MET inhibitors could improve clinical outcome relative to sunitinib in patients with metastatic papillary RCC.

Notably, SWOG 1500 (NCT02761057) is the first randomized trial to exclusively enroll patients with metastatic papillary RCC and complete accrual. To be eligible for enrollment, patients had to have a histologically confirmed diagnosis of papillary RCC and measurable disease. Patients were permitted for inclusion if they had received 0 to 1 prior lines of therapy, provided they had not received previous treatment with sunitinib. Additionally, patients had to have a Zubrod performance status ranging from 0 to 1.

Patients were randomized 1:1:1:1 to the sunitinib, cabozantinib, crizotinib, or savolitinib arms. Participants were stratified based on disease subtype (type I vs II vs not otherwise specified [NOS] per local review) and number of prior therapies (0 vs 1). The primary end point of the study was PFS, while key secondary end points included overall survival (OS), response rate, adverse effects (AEs). Exploratory evaluations of 

A central component of the overall study design was the use of a coordinated central pathologic review, Pal noted. Images of tissues reviewed locally were secondarily reviewed by 3 central pathologists, and classified as either type I pRCC, type II pRCC, or pRCC NOS. Mixed features in specimens were deemed pRCC NOS, and any disagreements in specimen type were classified by majority opinion. If no agreement was reached, specimens were either re-reviewed or classified as pRCC NOS, explained Pal.

Notably, the study design permitted dose reduction for each agent used. In the trial, oral sunitinib was delivered on the conventional 4-weeks-on, 2-weeks-off schedule, at a daily dose of 50 mg, with dose reductions to 37.5 mg and 25 mg permitted. Oral cabozantinib was delivered at a daily dose of 60 mg, with dose reductions to 40 mg and 20 mg allowed. Moreover, oral crizotinib was given at a twice-daily dose of 250 mg, with reductions to twice-daily 200 mg and once-daily 250 mg permitted. Lastly, oral savolitinib was administered at a daily dose of 600 mg, with dose reductions to 400 mg and 200 mg allowed.

Investigators’ key assumptions were that PFS for sunitinib would be approximately 6 months, with comparator arms achieving a PFS of 10.5 months. As is standard for a randomized phase 2 study, investigators explored a 1-sided a of 0.1 with a b of 85%. With these considerations in mind, 41 patient per study arm would be required, for a total of 164 patients overall. In accounting for 10% ineligible patients, investigators assumed they would need to accrue an additional 4 patients per study arm, for a total of 180 patients.

Additionally, a prespecified futility analysis was implemented after 15 PFS events were reported in each of the experimental arms and 20 PFS events occurred in the sunitinib arm. If the PFS HR was greater than 1 for a MET inhibitor versus sunitinib, the arm was recommended for closure.

From April 2016 to December 2019, a total of 152 patients were enrolled to the SWOG 1500 trial at 65 cancer centers across the United States and Canada. As a result of the futility analysis, the savolitinib and crizotinib arms were closed in December 2018.

Patients had a median age of 66 years (range, 29-89), and the majority were male (75%) and white (77%). Few patients had received prior systemic therapy (7%), and as anticipated by investigators, a minority of patients had type I histology, ranging from 17% to 20% across study arms. Additionally, the majority of patients had intermediate risk by International Metastatic RCC Database Consortium Risk Group criteria (61%). Moreover, 61% had a performance status of 0, while 39% had a status of 1. Mixed histologies were observed in 15% to 24% of patients and over 70% of patients had prior nephrectomy. Few patients had central nervous system metastases (less than 1%).

A preliminary assessment of discordances based on pathologic subtype was also presented. Thirteen patients were categorized by local assessment with type I disease and they were noted to have type 2 disease on central assessment, Pal said. In contrast, 3 patients with type II disease per local assessment were characterized to have type I by central assessment.

“Ultimately these didn’t appear to have a key bearing on the key finding from our study,” said Pal. “Irrespective of central and local assessment, patients with type I and type II disease appeared to have benefit with cabozantinib.”

OS will continue to be followed among studies arms, but in a preliminary assessment, no significant differences were seen between the arms examined, said Pal. Notably, however, there is a slight trend toward improved OS in the cabozantinib arm relative to the sunitinib arm, at 20.0 months versus 16.4 months, respectively.

Grade 3/4 AEs were reported in 68% of patients in the sunitinib arm, 74% of patients in the cabozantinib arm, 37% of patients in the crizotinib arm, and 39% of patients in the savolitinib arm. Toxicities seen with the agents in SWOG 1500 were similar to those reported in larger studies, noted Pal. Moreover, the rate of treatment discontinuation due to AEs linked with study medication was highest with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%), and savolitinib (10%). Sixteen patients remained on protocol at the time of last follow-up.

Grade 3/4 laboratory toxicities with sunitinib, cabozantinib, crizotinib, and savolitinib occurred in 68%, 74%, 37%, and 39%, of patients, respectively. One grade 5 effect was observed in the cabozantinib arm, secondary to a thromboembolic event, concluded Pal.

1. Sumanta K. Pal, Catherine Tangen, et al. Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study. 

. 2021;339(suppl 6):270. doi:10.1200/JCO.2021.39.6_suppl.270

Papillary renal cell carcinoma (RCC) is a rare malignancy, accounting for 15% of all RCC cases. 

Cabozantinib significantly delays progression in papillary RCC

Incidentally discovered adrenal mass

Localized, high-risk prostate cancer with oligometastasis at diagnosis

Hear from key opinion leaders in the urology space as they discuss 2 complex cases across the multidisciplinary approach for an incidentally discovered adrenal mass and localized, high-risk prostate cancer with oligometastasis at diagnosis.

Around the Practice: February 17, 2021

What are legal standards used to define medical malpractice? How do judges and juries decide which medical errors entitle a patient to bring a lawsuit? If a plaintiff alleges medical malpractice, what must he or she prove to recover damages? This article will provide an overview of what must be present for a malpractice claim to exist.

The idea that physicians are responsible for avoidable injuries to patients is nearly as old as the practice of medicine. The Code of Hammurabi sets out penalties for medical errors: “If the doctor has treated a gentleman with a lancet of bronze and has caused the gentleman to die…cut off his hands.” Thankfully, our system for addressing medical errors has changed significantly since Babylonia’s 3800 years ago.

The foundation for the modern approach to addressing medical malpractice was set in ancient Rome, where a person injured by a doctor could seek monetary compensation for economic losses and pain and suffering. The Roman system was the basis for English common law, which was the basis for the American legal system.

To win a malpractice case, a patient is required to prove 4 elements:

• the existence of a duty of care owed to the patient by the doctor

• a breach of this duty in the form of a departure from the standard of care

• a causal tie between the breach and an injury to the patient, and

• damages in the form of monetary costs, physical pain, and mental suffering.

To prevail, a plaintiff must show that it is more likely than not that each element is present.

With the first element, a doctor must exercise reasonable care in providing treatment to the patient. This is typically the most straightforward element for a plaintiff to establish. Although there are some exceptions, a duty is generally presumed to exist when a doctor treats a patient.

To establish a breach of duty, a plaintiff must offer testimony from a qualified expert to explain the standard of care required and how the defendant failed to meet that standard. The definition of 

 can vary. In general terms, it refers to the care that a doctor is reasonably expected to provide under the circumstances in the case. Importantly, the standard of care requires that treatment decisions are reasonable. Meeting the standard of care does not require that decisions are made with foresight and perfect accuracy. Doctors may disagree about what treatment option is best. Such disagreements do not mean that 1 treatment option is within the standard of care and the other is not.

A departure from the standard of care is legally insignificant without an injury. To establish the third element of a malpractice claim, a plaintiff must show a direct tie between a breach of the relevant standard and an injury. Expert testimony can usually establish that an injury would not have occurred “but for” the identified breach of the standard of care.

Finally, a plaintiff asserting a malpractice claim must show that the injury incurred is compensable. There are 2 recognized types of injury, or damages. First, there are economic damages, the monetary costs resulting from an injury. This includes the cost of subsequent medical care and lost wages. The other component is a plaintiff’s noneconomic damages, which comprise the pain and mental suffering associated with an injury. This type of loss is much more difficult to evaluate. What is the dollar amount that compensates someone for discomfort? What is the monetary value of the anxiety a patient experiences? The answers to these questions are entirely subjective. Ultimately, if a plaintiff can show that the other elements of their claim are present, a jury will determine the amount that represent fair compensation for an injury.

The framework explained in this article is designed to balance society’s interest in compensating persons wrongly injured by medical errors against the need to ensure that doctors are not held to an impossible standard of perfection. This system has been developed over thousands of years. It is unclear if we will ever find the perfect way to respond to medical complaints, but we can be certain that the justice system will continue to evolve.

 is an attorney in the Columbus, Ohio office of Reminger Co., LPA. He specializes in malpractice defense and insurance litigation. Please contact him at KSteele@reminger.com with any feedback or comments on this column.

Required elements to prove a claim include breach of duty and damages.

How is a medical malpractice claim defined?

Patient dosing has started in the PHYOX4 trial, which is evaluating nedosiran in patients with primary hyperoxaluria type 3 (PH3), according to Dicerna Pharmaceuticals, the company developing the RNAi drug.

Nedosiran is a once-monthly subcutaneous injection under investigation for all 3 types of PH, a rare, inherited condition characterized by recurrent kidney and bladder stones. Each PH type results from a mutation in a different gene. Dicerna noted in a press release that there are about 4100 patients in the United States with PH3; accordingly, the study’s target enrollment is only 6 patients. 

In the PHYOX4 study (NCT04555486), patients aged ≥6 years with PH3 will receive a single dose of nedosiran. The primary end point is safety, with secondary end points including plasma pharmacokinetics and response, defined as having a ≥30% decrease from baseline in 24-hour urinary oxalate (Uox) on 2 consecutive visits. Initial study results are anticipated in mid-2021.

“PH3 is the most recently characterized genetic subtype of primary hyperoxaluria and represents an area of significant unmet need,” Shreeram Aradhye, MD, executive vice president and chief medical officer at Dicerna, stated in the press release. “With dosing in our PHYOX4 PH3 trial underway, we have achieved another important milestone on our path to develop nedosiran as a potential treatment for all 3 genetically defined PH subtypes.”

Dicerna’s PHYOX clinical trial program consists of multiple nedosiran clinical studies, including PHYOX1, PHYOX2, PHYOX4, the PHYOX-OBX natural history study of patients with PH3, and the ongoing open-label PHYOX3 extension trial. Upcoming studies will also explore nedosiran in end-stage renal disease (PHYOX7) and in patients aged ≤6 years (PHYOX8).

The company recently announced that enrollment has been completed in the pivotal PHYOX2 trial exploring nedosiran in patients with PH1 and PH2.

Those patients enrolled in any PHYOX trial, including PHYOX4, who complete their treatment are eligible to enroll in the PHYOX3 extension trial. Results from an interim analysis of PHYOX3 were shared during the American Society of Nephrology’s Kidney Week 2020 annual scientific conference. The findings showed that regardless of PH subtype, all patients receiving nedosiran reached either normalization or near-normalization of Uox by day 180.

Normal Uox excretions at 1 or most visits were achieved by all 10 PH1 patients who reached day 180 of the interim analysis, and by 2 of the 3 PH2 patients who reached day 180. Further, nearly two-thirds (62%) of all patients achieved normal Uox excretions on 3 or more consecutive visits.

Overall, the treatment paradigm for hyperoxaluria is rapidly evolving. In November 2020, the 

 as the first drug for the treatment of patients with PH1. The drug is approved for both adult and pediatric patients.

1. Dicerna Initiates PHYOX™4 Trial of Nedosiran for Primary Hyperoxaluria Type 3. Published on February 11, 2021. Accessed February 26, 2021. 

2. Dicerna Announces Enrollment Completion of PHYOX™2 Pivotal Trial of Nedosiran for Treatment of Primary Hyperoxaluria. Posted online January 4, 2021. Accessed February 9, 2021. https://bwnews.pr/3q7FvSP.

The RNAi drug nedosiran is a once-monthly subcutaneous injection under investigation for all 3 types of primary hyperoxaluria. 

Nedosiran explored in primary hyperoxaluria type 3

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

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

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) as a frontline treatment for patients with advanced renal cell carcinoma (RCC).

The recommendation was based on findings from the phase 3 CheckMate-9ER trial (NCT03141177). Study results showed that the combination reduced the risk of disease progression or death by 49% versus sunitinib (Sutent) in treatment-naïve patients with advanced RCC, with a median progression-free survival of 16.6 months versus 8.3 months, respectively (HR, 0.51; 

Additional findings showed that, at a median follow-up of 18.1 months, the median overall survival was not reached in either arm, and there was a 40% reduction in the risk of death with the combination (HR, 0.60; 

The European Commission will now review the CHMP recommendation and make a final decision in the next few months on whether to approve the combination.

“Today’s news is welcomed by physicians treating people living with advanced renal cell carcinoma,” sCristina Suárez, MD, medical oncologist at the Vall d´Hebron University Hospital, Barcelona, Spain, and a lead investigator on the CheckMate -9ER trial, stated in a press release. “The positive CHMP opinion brings us 1 step closer to the promise of a new approach that combines improved treatment outcomes, a favorable tolerability profile and superior health-related quality of life for patients.”

In the international, randomized, phase 3 CheckMate-9ER trial, 651 patients with advanced RCC received the combination of nivolumab and cabozantinib (n = 323) or sunitinib (n = 328) in the first-line setting. Patients must have had previously untreated advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

The combination demonstrated a benefit across numerous subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

The objective response rate (ORR) was also doubled with nivolumab/cabozantinib in this setting compared with sunitinib, at 55.7% versus 27.1%, respectively (

 <.0001). In the combination arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were not evaluable or not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Moreover, 13.7% of patients had PD and 17.1% of patients were not evaluable or not assessed.

Regarding safety, the incidence of the most common, any-grade and high-grade treatment-related adverse events (TRAEs) were similar in both arms. More than 50% of patients on the combination required dose reductions of cabozantinib due to adverse effects (AEs). TRAEs led to treatment discontinuations in 15.3% of those in the nivolumab/cabozantinib arm and in 8.8% of those on sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib due to AEs, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.

The overall rate of serious AEs was similar between the 2 groups; however, liver toxicity was more common with cabozantinib/nivolumab. Nineteen percent of patients on the combination required corticosteroids due to immune-related AEs, 4% of whom needed corticosteroids for at least 30 days.

nivolumab/cabozantinib was approved by the FDA

on January 22, 2021, as a frontline treatment for patients with advanced RCC.

1. Ipsen Receives Positive CHMP Opinion Recommending Cabometyx® in Combination With Opdivo® as First-line Treatment for Patients Living With Advanced Renal Cell Carcinoma. Posted online February 26, 2021. Accessed February 26, 2021. https://bwnews.pr/3r0eZeB.

2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.

The European Commission is reviewing data from the pivotal phase 3 CheckMate-9ER trial.

Nedosiran explored in primary hyperoxaluria type 3

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

Nivolumab/cabozantinib combo nears EU approval for frontline kidney cancer