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Austin Richards is an attorney in the Columbus, Ohio, office of Reminger Co, LPA. He practices in the areas of professional liability, public entity liability and insurance litigation.

"All the components of the trial are designed to try to ensure that when the jurors depart for the deliberation room, they are inclined to find for the attorney’s side in the case," writes Austin Richards, Esq.

Malpractice Consult: What to know about closing arguments

"In the 21st century, expert witnesses serve a vital role in presenting evidence to a jury. A good expert will be able to distill complex information into digestible elements the jurors can understand," writes Austin Richards, Esq.

Malpractice Consult: What to know about direct examination of expert witnesses

"To form a connection between the witness and the jury and establish the witness’ credibility, the witness needs to be the star," writes Austin M. Richards, Esq.

Malpractice Consult: What to know about direct examination of lay witnesses

Here are some ways in which lawyers can remove potential jurors from a case.

Malpractice Consult: What you should know about jury selection 

The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

, provides an overview of the latest breakthroughs in non–muscle-invasive bladder cancer (NMIBC) and anticipates what may be on the horizon. This was highlighted in the recent publication, “Novel Delivery Systems and Pharmacotherapeutic Approaches for the Treatment of Non-muscle-invasive Bladder Cancer,” for which Guerrero-Ramos served as the lead author. Guerrero-Ramos is the coordinator of the urologic oncology unit and the bladder cancer unit at Hospital Universitario 12 de Octubre, in Madrid, Spain.

This transcription has been edited for clarity.

Could you describe the background for this work?

In the NMIBC setting, we've been using BCG and mitomycin for over 30 to 40 years. No new alternatives have been released. In the last decade, we've observed a high number of new alternatives within clinical trials, especially with intravesical delivery. We have some approvals from the FDA for BGC-unresponsive NMIBC, both systemic and intravesical. We have been learning that intravesical has similar or even increased efficacy with much less toxicity than systemic therapies. So, that's why we decided to give an overview of all the new alternatives with either final, preliminary, or still no results, so that readers can be up to date on what's going on and what's coming through in this field across all stages of NMIBC and with intravesical therapies.

You mentioned that there have been a few new recently approved therapies. Could you highlight those?

There are currently 3 approvals by the FDA. There was [an approval], some years ago, [for] intravenous pembrolizumab (Keytruda). It is important to highlight that these approvals are for carcinoma in situ (CIS) with or without papillary disease, but the patient must have CIS, which is BCG-unresponsive, as per the definition of the FDA or the EU or the [American Urological Association] guidelines. Pembrolizumab was the first approved agent with a 41% complete response rate at 3 months. Then the curve goes a little bit down for the response rate. I think it was at 18% at 3 years, which is the last [data that] was reported at the [European Association of Urology] Congress in Paris last April.

After that we had nadofaragene firadenovec (Adstiladrin) with a 3-month response rate of around 50% in these patients. [Nadofaragene firadenovec] is an intravesical virus that we put into the bladder.

The most recent approval has been Anktiva. Anktiva is a combination of BCG plus N-803, which is an interleukin 15 super agonist with a 71% complete response rate at any time, which is significantly higher than the former approvals and with a very favorable toxicity profile. So, these are the 3 agents that are currently approved by the FDA for the use in the United States for CIS with or without papillary disease that is unresponsive to BCG.

What are some things to consider when choosing between these therapies?

There are some limitations for these. Number 1 is that only the US FDA has approved these agents. No European or Asian agencies have approved these agents. So, I am based in Spain in Madrid, so I cannot use any of them outside of a clinical trial.

Another issue for the drugs is the cost. Pembrolizumab is not an expensive drug. [With] nadofaragene and especially Anktiva, there is an estimation of around $750,000 per treatment, which is quite a high cost for these drugs as compared to radical cystectomy, which is estimated to be at $150,000 at the first year. So, this is the main drawback I think for these therapies. However, in the near future, if they expand and are available for more people, I suppose that with higher manufacturing, the costs may decrease.

Could you highlight the therapies that are currently in development?

For the BCG unresponsive scenario, we have promising therapies. One of them is TAR-200, which is an intravesical releasing system that you put into the patient's bladder every 3 weeks. It's a sustained delivery of gemcitabine. The preliminary results that were reported at the 2024 American Urological Association Annual Meeting in San Antonio in May reported around an 83% complete response rate, which is higher even than Anktiva. This is one of the most promising drugs. They already have an FDA fast track designation as a breakthrough therapy. So, I suppose in the near future, we will have a new approval.

Then there are 2 studies with a CG-0070, cretostimogene grenadenorepvec. One of them is the CORE-001, in which cretostimogene is combined with intravenous pembrolizumab. They reached response rates of around 88%. The BOND-003, which is [evaluating] just CG-0070, avoiding all the systemic toxicity of pembrolizumab, [and which achieved] around a 70% to 80% complete response rate. So, for me, this is another very promising agent.

If we focus still on the BCG-unresponsive scenario, we have also TAR-210, which is a similar design of TAR-200, but instead of gemcitabine, there's erdafitinib inside the device. This is for patients who only have papillary disease, because erdafitinib is a targeted agent for 

 mutations or fusions, and we know that CIS does not present in mutations or fusions of 

. So, that's a reason why this is only for papillary disease. They are using this device in an in-person human trial with 2 cohorts. There's 1 cohort for BCG-unresponsive papillary disease, where they reached very nice disease-free survival rates of 80% to 90%. This is a future option that may be available for those patients with papillary only disease for whom there is currently no approvals.

If we move to the intermediate-risk scenario, they are trying this device, [TAR-210,] in the intermediate-risk population as an ablative approach. There is a molecular screening prior to the inclusion in the clinical trial. If there are mutations or fusion for 

 either in during orientation, the patient is a candidate for the therapy, and you can put the device into the bladder. There's over 90% of complete response rates in these patients. In both of the cohorts, the toxicity is negligible.

What do you think the future holds for the NMIBC space?

There are 3 clear scenarios in non–muscle-invasive bladder cancer. One is the intermediate risk. There are mainly ablative approaches trying to avoid to TURBTs, but also some new trials with adjuvant therapies being compared with mitomycin. In the future, I believe those higher recurrent patients might be candidates for ablative therapies so that we avoid TURBTs and the cost of a TURBT: the inpatient, the hospital bed, and everything. We have, in fact, a nice figure in our paper showing the proposed future algorithm in case we have any approvals for intermediate risk.

If we go to the high-risk BCG-naïve scenario, we have clinical trials mainly assessing the efficacy of systemic immune checkpoint inhibitors with BCG maintenance or with BCG induction only. We have no data on these; we only have preliminary data of the BladderGATE trial (NCT04134000), which is a trial conducted in our center. It's a [phase 1b/2], 1 arm trial where patients receive both atezolizumab plus BCG with promising complete response rates, but with a limitation of being a small phase 1 trial. In the future, we are awaiting the results of the CREST (NCT04165317), POTOMAC (NCT03528694), and big phase 3 trials to see what happens with these. In this population as well, there's another trial with a slightly different design, which is the SunRISe-3 trial (NCT05714202), where there is an arm with no systemic therapy. We have the control arm with BCG, we have an interventional arm with TAR-200, and another interventional arm with TAR-200 plus intravenous cetrelimab. So, we will wait for the results of these, because if there's efficacy with TAR-200 alone, you can avoid systemic therapy for these patients.

Then finally, for the BCG-unresponsive scenario, several alternatives have been approved, as we previously said. But what we are learning––and this is my personal opinion, but it's a shared by many of my colleagues––is that the way to go is the intravesical therapy, because you do avoid toxicity. It's an easy route of administration for both urologists and nurses. Maybe those systemic therapies would be reserved for those patients who go to second- or third-line therapies who do not respond to the first-line intravesical therapy.

"In the last decade, we've observed a high number of new alternatives within clinical trials, especially with intravesical delivery," says Félix Guerrero-Ramos, MD, PhD, FEBU. 

Dr. Guerrero-Ramos on the evolving treatment landscape in NMIBC

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy.

During cystoscopy, a rim of calcification was seen along the right ureteric ridge (figure 1a). A biopsy of this area was taken with the pathology shown in figure 1b.

B. Squamous cell carcinoma of the bladder

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy. During cystoscopy, a rim of calcification was seen along the right ureteric ridge. What is the diagnosis?

Residents Corner

Quiz: Sandy patch on cystoscopy

Max D. Sandler discusses findings on patient preference toward humor or professionalism in urologists

Study: Humor-centric approach to ED care may not resonate with all patients 

 highlights the background and key findings from the study, “Prospective Patient Preferences for Humor in Urologists Treating Erectile Dysfunction: A Survey Study,” for which he served as the lead author. Sandler is a third-year medical student at the University of Miami Miller School of Medicine in Miami, Florida.

Could you describe the background for this study?

First, just wanted to thank you for the opportunity to speak with you today. At least in my experience, urologists tend to be some of the funniest and most approachable physicians in the hospital. So, I thought it would be interesting to see how those traits made patients feel, especially for patients who might have a stigmatized condition like erectile dysfunction. So, unfortunately, there's not a lot of research on humor. It's hard to standardize; it's hard to study. So, I couldn't find that much literature out there, but I was able to find one study by an author named [Elisabeth] Sartoretti, and they found that women who received a funny business card during a routine mammogram screening tended to remember the radiologist's name better, they tended to rate the encounter as more positive overall. That's the background that helped guide me when I started thinking about how I wanted to do this project.

We created 5 pairs of mock business cards. They were for physicians; the business cards were physician business cards. In each pair, one was a humorous card, and one was a professional card. The funny card alluded to erections. For example, had a symbol of a diamond and the caption was "harder is better" on the business card, while the professional card just advertised expertise in health care, and didn't mention ED or anything. We posted an anonymous survey online to a website where respondents completed short tasks like surveys. Our survey basically asked them to imagine that they had erectile dysfunction and they're seeking a urologist to help them. Then they were asked which urologist they'd rather see based on the business cards of Dr. Smith or Dr. Jones, which were just the names that we assigned to the funny or the professional business card in each question. Respondents were able to pick Dr. Smith, Dr. Jones, I wouldn't care if I saw either urologist, or neither––they don't want to see either of them.

We had almost 1000 participants. The results showed a preference for the professional card in almost all questions. Across the whole survey, an average of 66% preferred the professional card. The highest rate of selection of the humorous card in a single question was only 38.4%. So, honestly, it was a bit of a surprise to us. We had a suspicion that participants would enjoy or appreciate a little bit of humor. We thought maybe it'd be more enjoyable for participants to seek out a physician who embraces humor, which would be similar to the results of the radiology study that I mentioned earlier. But something to keep in mind is that the participants in our study were prospective patients. So, they might not really have erectile dysfunction. They were completing tasks online, and they were being compensated, so efficiency might be a goal of theirs. We thought maybe they just might have seen this as a medical themed survey. So, they might have just chosen a professional card due to medicine's inherent ties to expertise. We think that the results of this study perhaps would be pretty different if it was conducted in a real clinic [with] real patients who actually have a stigmatized condition like erectile dysfunction, because they feel a stigma. People with a stigma may better appreciate humor to break the ice and create a trustworthy atmosphere with physicians.

“Across the whole survey, an average of 66% preferred the professional card. The highest rate of selection of the humorous card in a single question was only 38.4%,” says Max D. Sandler.  

Dr. Bjurlin on “Efficacy of inpatient, evidence-based tobacco use treatment of patients with bladder cancer after radical cystectomy.”

Dr. Bjurlin discusses inpatient tobacco treatment program post cystectomy

 describes the background and notable findings from the AUA 2024 abstract “Efficacy of inpatient, evidence-based tobacco use treatment of patients with bladder cancer after radical cystectomy.”

Please describe the background for this study.

We know that cigarette smoking is the leading modifiable cause of bladder cancer and that smoking cessation has been associated with a number of improved outcomes in our bladder cancer population who smoke. We've also learned that the diagnosis of bladder cancer in our patients who smoke is really a teachable moment to harness the power of smoking cessation. And there are some supporting data that suggest not only is the time of diagnosis a teachable moment, but perhaps the time of surgery may be a teachable moment. So with that in mind, we developed a 1-year prospective longitudinal study of inpatient post radical cystectomy patients who smoke to be evaluated by our tobacco treatment program. And then we looked at several outcome measures over the subsequent course of their hospital stay, and then a 1-month follow-up to ultimately see if we can support our patients with bladder cancer.

What were some of the notable findings? Were any of them surprising to you and your coauthors?

So just briefly to discuss how our implementation worked first, and then I'll get into a little bit of the data. Essentially, from June of 2022, to June of 2023, all of our patients with bladder cancer who smoked and underwent a radical cystectomy were then consulted by our in-house tobacco treatment program on post-operative date 2 or 3, to assess their smoking situation and to provide some support. Our tobacco treatment programs specifically did a telephone consultation; they did a standardized assessment of their nicotine dependence using this Fagerstrom test. They counseled our patients on tobacco cessation treatment strategies, as well as resources available, and then they offered them nicotine replacement. We looked at several outcomes. One of the primary measures was, were we actually able to implement this tobacco treatment consultation, and we compared that to our historical controls. And then we also looked at both inpatient nicotine replacement therapy use as well as outpatient nicotine therapy fill rates on 1-month follow-up. Some secondary measures that we looked at included the number of quit attempts. In the first month after discharge, we looked at the reduction in cigarette use. And then we looked at the actual quit rate at that 4 weeks post discharge, as well as some provider satisfaction and some patient satisfaction surveys. So I think the results that we got from this 1-year longitudinal study were actually quite interesting and perhaps profound. Prior to the start of our intervention, about 20% of our patients who underwent radical cystectomy who smoked were referred to our inpatient tobacco treatment program. After our intervention, we were able to ramp that up to 100% of our patients. In that 1 year, we did 63 radical cystectomies, and then 16 of those patients smoked and were enrolled in this trial. When we looked at nicotine replacement therapy, 40% of our participants accepted nicotine replacement while in the hospital. And we know when they take nicotine replacement in the hospital, it curbs their withdrawal, it helps them essentially on a road to quitting. And as a number of positive impacts and downstream quit attempts. On the 4-week follow-up, about 64% of our patients fulfilled their nicotine replacement therapy, which suggests that they're on the road to try to curb their smoking use. In terms of some of the secondary measures we looked at, we were able to decrease the amount of cigarettes that our participants smoked, from on average about 14 cigarettes per day down to just about 6 and a half cigarettes a day. So we're almost cutting their smoking in half, which was statistically significant. And perhaps some of the profound data we have is that 86% of our patients attempted to quit smoking during that 4-week time period, which I think is quite remarkable. This really shows that these patients are taking what they've learned and their motivation during their hospital stay and then transitioning that to their normal life when they leave the hospital. And our actual smoking quit rate was 29%, which suggests almost 1 out of 3 of our patients with bladder cancer who smoked were able to quit in the first 4 weeks after discharge. So I think a lot of provocative data in this smaller single-institutional study, but it really opened up an opportunity to provide support for our patients with bladder cancer who smoked in patient after that teachable moment of surgery.

This transcription was edited for clarity.

"It really opened up an opportunity to provide support for our patients with bladder cancer who smoked in patient after that teachable moment of surgery," says Marc Bjurlin, DO, MSc, FACOS.

Dr Stratton further discusses a phase 1B trial evaluating relugolix (Orgovyx) and enzalutamide (Xtandi) for high-risk prostate cancer

Expert discusses trial evaluating evaluating relugolix and enzalutamide in high-risk prostate cancer

 further discusses a phase 1B trial evaluating relugolix (Orgovyx) and enzalutamide (Xtandi) for high-risk prostate cancer. Stratton is an associate professor of urologic oncology at the University of Oklahoma, Oklahoma City.

This is a phase 1B study with no control arm. How will you compare the effectiveness of this regimen with standard treatment options? Are there plans for future comparative studies based on the results of this trial?

The primary aim is looking at the dose-limiting toxicity of this drug combination. We want to make sure that this is safe and effective. We have every reason to believe that this is going to be a highly effective combination. But we want to look at that specifically in this group of patients, because we do have good treatments for these patients. So before we change our practice, we want to evaluate that to ensure that patients are able to tolerate it and we feel like this is a beneficial drug combination. But going forward after this study, we hope to be able to expand and potentially look at patients undergoing either surgery or radiation therapy, and really try to determine the potential benefit. I think, with these studies already showing some signal for activity that if this is a positive study, it will just add to that body of work that shows that combined anti-androgen treatment is helpful in patients who are high risk and at risk for metastatic disease in the future.

"The primary aim is looking at the dose-limiting toxicity of this drug combination," says Kelly L. Stratton, MD, FACS. 

Austin Richards

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