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Maciej Michal Mrugala MD, PhD, MPH, chief of the Division of Neuro-Oncology, University of Washington

Dr. Maciej Michal Mrugala on the Efficacy and Further Uses of Temozolomide in Gliomas

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become 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 a press release.

“[Nivolumab] 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 [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

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 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. 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. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

Just 15 years ago, Tara Graff, DO, MS, set out conduct research at the Medical College of Wisconsin (MCW). MCW’s Froedtert Memorial Lutheran Hospital is where Graff began her fellowship and where admittedly, she had planned to retire one day. Life had other plans, according to Graff, a hematologist/oncologist and physician champion and lead, Mission Cancer Trials Program, at Mission Cancer + Blood.

Family led Graff to relocate to Des Moines, Iowa, and where she took on a role in the community practice.

“If you would have told me 15 years ago that I would be in Iowa, I wouldn’t have believed it. I think that everything that I've done up until this point, from graduate school to medical school to my fellowship training, has provided me with the tools and resources to do what I’m doing today,” said Graff in an interview with Targeted Oncology™.

Although the patients, region, and cancer types were different from what Graff was used to, her goal to make a mark on cancer research did not die. Graff said, “it evolved.” Today, Graff leads a community-based clinical trial program at Mission Cancer + Blood. The program is a collaborative effort between Mission Cancer + Blood, Iowa-Wide Oncology Research Association, Des Moines Oncology Research Association, and Mercy Cancer Research. Together, the organizations have more than 100 research studies and clinical trials that are being conducted on a national and international scale.

Graff explained that the program gives access to the newest therapies to underserved patients. This is one reason that community-based research is so important, she said.

“The patients usual start in the community. Seventy to 80% of them are in the community and then are referred to academic centers. We need to be able to offer those patients not what's been used over the last 15 plus years, but what's new and relevant today. Those patients are here, they're in our backyard, they're not 2 hours away. We need to be able to truly help our patients in the here and now. If we don’t, we'll lose our patients.”

 discusses her path to community oncology from academia, and hopes to continue to advance community-based research in the future.

Targeted Oncology: Are the start of your career, what were your main goals?

When I first became an oncologist, what I intended to do for the rest of my life was lymphoma and transplant. I was at a large academic institution, Medical College of Wisconsin, where I started my career and I planned to end my career. I was very happy and heavily involved in research. But, as life has it, there are curveballs and paths change. My change was my husband. I tried commuting back and forth from Des Moines to Milwaukee, but that didn't work out very well. It only worked for about a year. Then, I ultimately decided to join my husband in Des Moines, Iowa, where I joined, at that time, Medical Oncology/Hematology Associates, which is now Mission Cancer and Blood. It was a little bit different. I wasn't a homegrown Iowan, and I didn't intend to do community oncology. I was an academic, so I was a fish out of water.

It's amazing how quickly one has to adapt to their environment. Suddenly, I was seeing different cancers and things I didn't really think about a lot, and that was interesting.

What were your goals once you started working at Mission Cancer + Blood? What were your key challenges treating patients in Des Moines?

Over the next several years, I wanted to merge my 2 worlds. I started my career as a basic scientist, I have a master's degree in T-cell immunology, and I did cancer research at the bench for years before I went to medical school. My heart has always been in research. Research is basically scientific advancement for patient care, but I was always on the other side of it, and then becoming an oncologist, I got to kind of go from A to B, and then B to C, which I found very fulfilling. I needed to figure out how to build that niche in a community oncology world, which is not something you see every day, because community is community, and academia is where the research is done. But that isn’t true because there's a lot of community groups that do research. So, I decided to sort of make that my goal.

Over the next several years, I helped build up the clinical trials program. Just in the last few years, it has exploded. I've been able to bring the best of both worlds together. It also brought the best patient care we can offer because patients don't want to necessarily have to travel. They don't want to drive 2 and a half hours, or 4 hours for clinical trials and new therapies. They want to stay home. This is especially for people in the Midwest because they're busy farming and doing all sorts of other things that limits their ability to travel far distances. What I wanted to do was bring the latest and greatest therapies, right to their own backyard, and we've been able to do that.

What should oncologists know about your community-based clinical trials program?

We've had several clinical trials that keep patients here. They don't have to travel, and they get to stay with their families. That's really what it's all about. The treatment landscapes for all cancers, not just lymphoma, but also solid tumors, are developing and becoming more targeted every day. If we don't keep finger on the pulse and adapt to that with new medicines and new trials, we're not doing right by our patients. I've tried to make the goal of really getting more partners involved and getting community clinicians involved in research more. We haven't just opened several lymphoma trials, we've are opening several breast cancer trials, lung cancer trials, we're starting our phase 1 research program, and a theragnostic program. We are going to be a central hub for all these patients so they can get the latest and the greatest, which is really what it's all about.

How have your goals changed over the past 15 years?

When you're in academics, it's all about research and funding and trials, whereas now my focus and goal is to be able to give my patients the best access to care. But I couldn't do that without the tools from my past. I don't think my goals have changed, but they have evolved.

I have 16 partners, I have multiple colleagues, nurse practitioners. There are all these different people who don't necessarily all think alike, or have the same passions, or maybe aren't involved in research. One of my newer goals to get others to be as excited about research and advancements as I am, I don't expect everyone to be a scientist, but it’s good to have a research-oriented mind. But I've been able to get several of my partners involved in research and the opening of clinical trials.

If you would have told me 15 years ago that I would in Iowa, I wouldn’t have believed it. I think that everything that I've done up until this point, from graduate school to medical school to my fellowship training, has provided me with the tools and resources to do what I’m doing today. I’m grateful for the support our staff at Mission Cancer and Blood, and our administration. I have a wonderful team of nurses and nurse practitioners that I always say if they didn't do what they do, I couldn't do what I do. That support has allowed me to go out and to speak and educate. I want to be involved. I want us to have the latest and greatest right here, and I want our patients to have everything, including access to clinical trials. That's where my focus is, that's my goal is to keep is to keep making Mission Cancer and Blood is as great and as strong, world renowned as we possibly can be.

Can you explain the importance of community-based clinical trials?

The patients usual start in the community. Seventy to 80% of them are in the community and then are referred to academic centers. We need to be able to offer those patients not what's been used over the last 15 plus years, but what's new and relevant today. Those patients are here, they're in our backyard, they're not 2 hours away. We need to be able to truly help our patients in the here and now. If we don’t, we'll lose our patients.

What do you hope to do next in your position?

It’s not a new thing. I plan to keep growing this program. My wish is that we bring more partners on board, so that we can do big trials that are not typically available in the community setting. My second goal is to play a part in bringing limiting the lack of diversity, which is a big theme in research. In the Midwest, we have disparity based on geographic location. Our group has 22 outreach clinics. We service people who don’t have cars and don’t have the funds for transportation. It’s a different type of disparity that we have here, but it’s still a disparity. I hope to do everything I can to help provide access for those patients.

As you aim to expand the clinical trial program, what are the key challenges you expect?

Again, I think access to care will be an important challenge. Also, finding for clinical trials, drug cost, drug reimbursement and drug availability are expected challenges.

In terms of all research for all tumor types, I think it will be important to design trials that are going to allow patients to have potential cure. I'm kind of speaking broadly across all oncology but I think we're in a day and age where we're figuring out mutations and targeted therapies for those mutations, so that our patients aren't having to rely on multiple lines of chemotherapy. I think that's important to keep designing trials that are giving our patients chemotherapy-free treatment plans, and potentially a cure. That's what we're trying to strive for, and there are challenges to that. But I think bringing together those brilliant minds will allow us to prolong the life and quality of life of our patients through community-based clinical trials.

 of Highlands Oncology. What message do you have for these physicians?

I would just say congratulations and thank you for doing what you're doing and your regions. I think it takes those of us who are in community and who are research oriented to provide our patients with access to best care possible. My co-honorees and several colleagues of mine throughout the country are driven, so, I commend them, and I thank them. I am glad that there are several of us on this journey to doing just that for our patients.

Nominations for the Oncology Icons award program are accepted on a rolling basis throughout the year. To be eligible for the Q3 award that will September 15, 2023. To submit, please 

In an interview with Targeted Oncology, Q2 2023 Oncology Icons honoree, Tara Graff, DO, MS, discusses her path to community oncology from academia, and hopes to continue to advance community-based research in the future.

Tara Graff: ‘My Heart Has Always Been in Research’

A 59-year-old African-American woman presented with a left renal mass​. She underwent left radical nephrectomy in December 2019 revealing clear cell renal cell carcinoma (RCC)​. Nine months later, she developed nodules in both lungs, with mediastinal (35 × 38 mm), and retroperitoneal lymph nodes​. Lung biopsy confirmed stage IV RCC with clear-cell histology​. Her Karnofsky performance status was 90%​. Hemoglobin was 11.1 g/dL and ​corrected calcium, neutrophils, platelets were within normal limits. She was considered to have an International Metastatic RCC Database Consortium (IMDC) intermediate risk status.

: There is a higher rate of patients in the intermediate and poor [risk group] in the [CheckMate 214 trial; NCT02231749] of ipilimumab [Yervoy] plus nivolumab [Opdivo]. So even though the numbers look worse, I think that the population may be a bit different.

 If you look at the CLEAR trial [NCT02811861], the poor prognosis percentage is 9% against 17% in the [CheckMate 214 trial], so I [chose] ipilimumab/nivolumab.

 One of the other things that I take into consideration as a community oncologist is…how easy it is to give immunotherapy compared with adding a TKI [tyrosine kinase inhibitor] because the adverse events [AEs] are significant. Not always, but we need to do a lot of hand holding in terms of how we’re going to set the dose, and the timing of starting therapy because of pre-authorization process. I think that all the options are very valid, and I usually present all the options to the patients. But, in practicality, I like the idea of the ipilimumab/nivolumab and I’m more familiar with it, too.

 I think that’s a great point. First of all, when you look at [the 4 frontline trials,] there are different breakdowns for the different IMDC risk populations within the trial. Interestingly, the patients who have intermediate and poor risk tend to do better in these trials. I think that having a lower percentage of poor-risk patients is a disadvantage to that regimen because the favorable-risk patients do well almost regardless of what you give them. But I think the second point is accurate. All these regimens are 100% appropriate, but to choose one based on the ease of administration is completely reasonable.

I think we’ve been giving ipilimumab/nivolumab for the longest time of all these regimens because it was approved first. It has the longest follow-up, and when you look at the 5-year follow-up, approximately 50% of patients are still alive and approximately 30% are still progression-free.

 We’re comfortable giving it. It doesn’t require a TKI and [so] I give it as well.

 I voted for lenvatinib [Lenvima] and pembrolizumab [Keytruda]. The reason behind that is…patients like to see a little quicker response, so adding a TKI always give you a little quicker response than just IO [immunotherapy] plus IO. I have used all 4 regimens. I had a bad experience with axitinib [Inlyta] and pembrolizumab. The patient had a hypertensive crisis and was admitted to the hospital with seizures and delusions. We still do not know whether he had a posterior reversible encephalopathy versus just a hypertensive crisis. We had to discontinue axitinib and he is doing fine on pembrolizumab alone. Lately I've been using cabozantinib [Cabometyx] or lenvatinib/pembrolizumab, and I’m very comfortable with the combinations. I just have to do little dose adjustments. I’m in a community practice, so…I look at the risk factors but I’m not bound by the risk factors [for choosing which] combination I use. So far, I have not got pushback from the insurance companies. I have a few patients on lenvatinib/pembrolizumab and I’m very comfortable with that combination; they’re all doing very well.

 Great. It’s interesting to hear how much personal experience plays a role in decision making. If somebody has a bad experience with, let’s say, cabozantinib and nivolumab—in the context of having 3 other regimens approved, they’re not going back to it. So it’s interesting to hear that you have that experience with axitinib/pembrolizumab and you tried other regimens [and you were] comfortable with them.

 I’ve used axitinib/pembrolizumab and ipilimumab/nivolumab in this patient population, and both of these regimens have significant potential AEs. I have had patients on ipilimumab/nivolumab with significant AEs where I have to drop immunotherapy or at least 1 of the drugs, which made me a little bit reluctant to give it to patients whom I thought will do OK on axitinib and pembrolizumab. Having said that, I had patients with significant AEs with axitinib and had to either drop it or significantly dose reduce it. I use both of these regimens with caution, and the risk factors…but also clinical judgment is key. I use both of the regimens with excellent results and with patients who’ve had significant AEs.

 Is there a reason you would use axitinib/pembrolizumab over lenvatinib/pembrolizumab or cabozantinib/nivolumab or is it just you have the experience with axitinib/pembrolizumab?

 I definitely have much more experience with axitinib and pembrolizumab. For that very reason I don’t think I’ve ever use lenvatinib and pembrolizumab in metastatic RCC because I’m so much more familiar with the other regimens. I’ve used lenvatinib in other cancers and that can be a challenging drug, too.

 The lenvatinib/pembrolizumab looked like the best [drug] for progression-free survival, but…[the trial] had…very few patients with poor prognostic factors.

 I think comparing cross trial is not a good idea, in my opinion, because they do not have the same population enrolled. Personal experience is more important than this trial.

 I think the note that I would caution on is when you look at the subgroup analyses in these trials, the benefit is more significant in the patients who have intermediate and poor risk. So, one would expect that for a trial that has less than 10% of patients with poor risk, the outcomes would be a little bit worse than the other trials.

 I found lenvatinib the most difficult of these TKIs to manage out of all the TKIs that we have here. I have tended to use lenvatinib/pembrolizumab in patients who are very fit and very symptomatic since the objective response rate seems to be a bit higher.

 I have more experience with axitinib because at the Cleveland Clinic, we had the trial published by Brian Rini, MD, and we adopted it pretty fast.

 But, if somebody is at high cardiovascular risk, where TKIs would be very high risk, I have gone towards the IO/IO combination.

 Because we had a good chunk of patients on the trial and Dr Rini was here, we shifted to axitinib/pembrolizumab quickly when it got approved. And now there’s more of a smattering of different agents being used now that we have more approvals.

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126


2. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

2021;32(suppl_5):S678-S724. doi: 10.1016/annonc/annonc675

3. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

During a Targeted Oncology case-based roundtable event, Moshe Ornstein, MD, MA, discussed the factors influencing the choice of frontline therapy for a patient with stage IV clear cell renal cell carcinoma whose risk status was intermediate. 

IO/IO Versus IO/TKI Frontline Therapy for Intermediate-Risk RCC

Polatuzumab vedotin ± rituximab ± bendamustine

During a Targeted Oncology case-based roundtable event, Christopher R. Flowers, MD, MS, discussed the choice of bridging therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who may receive CAR (chimeric antigen receptor) T-cell therapy. 

This is the second of 2 articles based on this event. 

Maciej Michal Mrugala MD, PhD, MPH

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