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Within the past decade, there has been a surge in terms such as value-based care, patient-centered care, shared decision-making, and more at the macro level of health care delivery in the US.

Building a Patient-Centered Ecosystem Leads to Better Care

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

Polatuzumab vedotin ± rituximab ± bendamustine

What therapies would you consider for a patient like this? ​

Who is involved in the decision making?​

 More than half of you would think about tafasitamab [Monjuvi] plus lenalidomide [Revlimid] and then a little bit more than a third would consider the polatuzumab [Polivy] combination [with bendamustine and rituximab (Rituxan)], and some would consider a gemcitabine-based regimen.

It sounds like nearly all of you would treat this patient within the context of your practice …while waiting for cell therapy as opposed to referring for a clinical trial or [stem cell] transplant. I’d love to hear from somebody who chose the polatuzumab option. It gives you a lot of plus/minuses there. Would you add rituximab or bendamustine to this [regimen], and how would you use that combination?

 I voted for that. What I’ve seen our transplanters prefer is to do polatuzumab/rituximab without the bendamustine pending collection.

 So you base that on your prior experience with the CAR T-cell therapy group that you work with and that being their preference. What’s your experience with using that? How comfortable are you with it? How well does it work to control disease?

 It’s reasonably tolerated. It’s not clear that the bendamustine adds much besides toxicity. In my limited experience, it’s helped people and it’s gotten people to CAR T-cell therapy. It’s been OK.

 It does what you’re expecting it to do.

 Let’s go on to someone who uses a tafasitamab/lenalidomide regimen; does anyone want to comment on your experience with that?

 I’ve used tafasitamab/lenalidomide in this setting. The main reason is because I find it easy to manage in terms of adverse events. It mostly seems to be driven by the lenalidomide which we can easily dose modify, and we’re used to doing that with not just lymphoma but myeloma, etc.

 What dose of lenalidomide do you find you end up giving most of those patients?

 I feel like my patients don’t tolerate the lenalidomide as well as what I see typically in the trials. I’m often going down to 10 mg for a lot of my patients…that’s what I’ve been seeing.

 There is nothing [unusual] about your practice. Patients don’t tolerate lenalidomide at the starting dose [of 25 mg] that they’re using in most of the trials.

 I agree with Dr Arjunan. Lenalidomide is the 1 I always adjust. I’m using [closer to] 15 mg lenalidomide. Ten milligrams is even better [tolerated] but I push 15 mg.

 I agree with my colleagues. I like the idea that you can give tafasitamab for a limited period of time and then continue on lenalidomide. There’s a lot of familiarity with lenalidomide from other malignancies, and we know how to dose adjust and what to monitor for.

 Does anybody worry about giving a CD19-directed therapy with tafasitamab before giving a CD19-directed CAR T-cell therapy?

 I’ve talked to my transplant specialists and CAR T cell specialists about it…and they seem comfortable. I don’t know why, but they feel very comfortable with tafasitamab/lenalidomide prior to CAR T-cell therapy as a bridging therapy.

 That’s true. There was some concern about the CD19, but I don’t think they’re worried about it.

 There has been a continual concern about giving CD19-directed therapy before another CD19-directed therapy in either direction, giving CAR T-cell therapy before tafasitamab/lenalidomide or giving tafasitamab/lenalidomide or loncastuximab tesirine [Zylonta] before giving CAR T-cell therapy.

There have been retrospective observational studies presented at national meetings that show it can be done successfully, and that you can still get good responses from the second CD19 therapy in both directions.

 In those patients who relapse on the lenalidomide/tafasitamab combination, have they looked at what their CD19 status is?

 The studies that I’ve mentioned are all small studies and in relatively few patients that have gone on to subsequent therapy. CD19 as an antigen is tricky to look at, too, because there are multiple ways that you can have CD19 loss in terms of the ways it affects its expression. We know about CAR T-cell therapy and CAR T-cell failure and that CD19-low is one of the pathways for CAR T-cell failure in about 25% to 30% of patients.

 And there’s a concern that if you give a CD19 therapy before another CD19 therapy that you might have CD19 loss as a mechanism, but that pathway has not been studied.

: In the trial, bridging chemotherapy was forbidden. So I don’t know how one would apply those data if you’re going to use some chemotherapy, which sometimes we end up having to do if steroids don’t seem to be enough. But those are usually patients who have a very aggressive disease with high lactate dehydrogenase and so on. So what is your assessment of that, what we do in the community as opposed to what was done in the trial?

 You are correct, there are some challenges there. One is the practicality of getting a patient to CAR T-cell therapy; getting all the insurance approvals can be challenging and making sure that those are in place, so the patients can go on to therapy. There oftentimes is a need for therapy to get a patient to the CAR T cells. There are patients who can get the CAR T cells more quickly or can have just simple steroids as a therapy.

I think 1 of the things that we did have concerns about early on is that if you gave steroids, that they would inhibit the ability of CAR T cells to work. We now know that’s not true and that bridging with steroids was a reasonable and effective approach in the axicabtagene ciloleucel [Yescarta] randomized trials, the ZUMA-7 trial [NCT03391466], and in other studies.

We’ve also found from our University of Texas MD Anderson Cancer Center group led by Chelsea C. Pinnix, MD, PhD, that bridging radiation can be quite an effective therapy, particularly when the disease is in a relatively limited area.

Those are the kinds of approaches that we think about when you want to limit what’s given for bridging therapy. But, oftentimes, you do need to pursue another regimen. What I typically recommend is the use of polatuzumab without bendamustine as an off-label approach for being able to treat patients and to get them to CAR T-cell therapy [without] giving a CD19-directed therapy. But we have also seen that people get regimens like tafasitamab/lenalidomide as a bridging therapy or get a chemoimmunotherapy regimen as a bridging therapy. I think all of those are potential approaches in real life that can get people to CAR T-cell therapy.

1. Thapa B, Caimi PF, Ardeshna KM, et al. CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy. 

 2020;4(16):3850-3852. doi:10.1182/bloodadvances.2020002587

2. Caimi PF, Ardeshna KM, Reid E, et al. The antiCD19 antibody drug immunoconjugate loncastuximab achieves responses in DLBCL relapsing after antiCD19 CAR-T cell therapy. 

 2022;22(5):e335-e339. doi:10.1016/j.clml.2021.11.005

3. Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. 

 2020;38(27):3095-3106. doi:10.1200/JCO.19.02103

4. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. 

2022;386(7):640-654. doi:10.1056/NEJMoa2116133

5.Pinnix CC, Gunther JR, Dabaja BS, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. 

2020;4(13):2871-2883. doi:10.1182/bloodadvances.2020001837

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. 

Bridging Options for CAR T-Cell Therapy in R/R DLBCL

The patient is a 61-year-old man who is married with 2 grown children and 5 grandchildren who live nearby. He has an active lifestyle including daily walks and golfing regularly. He has a history of metastatic renal cell carcinoma (mRCC) and had a left nephrectomy and adrenalectomy due to clear cell RCC (ccRCC) with metastases in the adrenal​ gland.

Four years later, he has a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, this had been present on scans for at least 2 years prior​. He was observed based on low volume and indolency of the disease and patient preference​.

Eighteen months later, there is continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis that is 2.0 x 1.5 cm. He has an ECOG performance status of 0.​

Would your choice of therapy change in based on the number of metastases? Why or why not?

 I initially chose lenvatinib [Lenvima] plus pembrolizumab [Keytruda] because [the CLEAR study; NCT02811861] had the highest progression-free survival compared with other trials.1 But in my practice, I’ve seen cabozantinib [Cabometyx] plus nivolumab [Opdivo] has been tolerated better than lenvatinib/pembrolizumab, so I usually start patients on cabozantinib/nivolumab. I think that if you look at long-term data on doublet immunotherapy, 30% to 35% of patients still had a good response after many years.2 So, if patient has more organ involvement or more metastatic sites, I decided to change to ipilimumab [Yervoy] plus nivolumab.

 I chose the lenvatinib/pembrolizumab [in both cases] because of the recent data, and also because I had a patient on axitinib [Inlyta] plus pembrolizumab who progressed and had lymph node metastases in his neck. I changed to lenvatinib/pembrolizumab, and the lymph node metastases completely went away. The problem I have is he developed all these mouth sores, and so we had to stop it for a while, and I don’t know what’s going to happen. He has had it for 7 years now, so he’s had a lot of these other things that are [difficult]….But, that’s why I chose that [combination], because it worked on this patient that failed the other one, even though the pembrolizumab was the same. But then, on the other hand, I had problems with adverse events with both of those.

 What proportion of patients do you typically see with 2 or more sites of metastases?

 I think maybe 30% to 40% might have widespread [disease]; I’ve seen patients with 2 areas, maybe [in 1 or 2 sites] in the lung and 1 in the adrenal. But, to have extensive liver and lung metastases, would probably be more symptomatic.

 Yes, that’s usually [indicative of] more advanced stages.

What factors affect your choice of therapy?

 The data look quite robust [for all 4 regimens]. What is your favorite regimen do you use in your practice, for a patient with favorable risk?

 I am split between ipilimumab/nivolumab and cabozantinib/nivolumab or axitinib/pembrolizumab. I put it in my mind as immunotherapy-only regimens versus the TKI [tyrosine kinase inhibitor]/immunotherapy regimens. More and more, I have switched to cabozantinib/nivolumab recently, especially for patients with bulky disease and high disease load, because you need a quick response, and long-term outcomes are pretty similar across the board with all of these agents.

The reason for my preference for dual immunotherapy is more because it was there first. We have much longer, robust follow-up, which we don’t have with these newer regimens, especially the lenvatinib/pembrolizumab. But all of the data look like they are pointing in that similar direction to showing adequate overall survival improvement. But again, it’s early, and that’s the only reason I still use ipilimumab/nivolumab.

Should there be any preference for particular agents in patients with different disease histology?

 I had a recent case for non–clear cell papillary subtype RCC. I would favor cabozantinib up front, with or without immunotherapy combination, as opposed to the other agents.

 What would most of you do for sarcomatoid histology?

 Yes, I think it needs to be an immunotherapy-based regimen, that much is clear for CheckMate 214 [NCT02231749] and the axitinib/pembrolizumab study, KEYNOTE-426.

 They have looked at specifically the sarcomatoid subgroup, similarly, for cabozantinib/nivolumab.

 And across the board, with an immunotherapy-based regimen, the sarcomatoid subgroup does much better.

 So, it’s pretty clear that if you see any sarcomatoid histology in the pathology report, you should use an immunotherapy-based regimen.

During a live virtual event, Ulka N. Vaishampayan, MBBS, discussed the choice of first-line therapy for clear cell renal cell carcinoma and whether the approach to treatment would change with other disease histologies. 

Arva Patel

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