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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

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.

 Would you use dual immunotherapy or immunotherapy/TKI?

 If it’s a controlled setting, where the patient does not have [rapidly growing] disease, yes, I would use dual immunotherapy. But frequently, what I find happens with sarcomatoid histology is they are very sick; they’re sometimes even in the hospital and not doing so well. So typically, I end up having to use a cabozantinib/nivolumab type of regimen to get a quick enough response and be able to deliver the treatment to them quickly. Sarcomatoid can be a pretty aggressive histology, with very symptomatic patients.

 Is there advantage for TKI in sarcomatoid histology on top of the immunotherapy benefit?

 It’s pretty unknown at this point. But the non-immunotherapy–based regimens, at least, do not do well in sarcomatoid histology. So, if you use a single-agent TKI, you’re not going to get too much mileage. Combination with immunotherapy is critical. You could use dual immunotherapy depending on whether the patient can handle it, or you can use a [TKI-containing] combination.

 I once had a chromophobe patient—do you know if there’s any studies that have investigated that histology?

 No, those are the toughest to treat. But with that histology, even mTOR inhibitors have been shown to be more beneficial sometimes. For a patient with chromophobe [disease], it would depend on how aggressive their disease is. I would look at the risk characteristics and treat accordingly. [That is], unless you have a specific mutation, like the tuberous sclerosis complex mutations; [in that case], doing NGS [next-generation sequencing] to look at actionable mutations might be a critical piece.

 Is that the only histology you would look at NGS?

 Upfront, yes. That may change my management.

 Do you have any preference for patients with a brain metastasis?

 I tend to use a TKI-based regimen for brain metastases, because there are some reports of cabozantinib, lenvatinib, etc, showing a response in brain metastases. Ideally, you have to do the surgery, radiotherapy, whatever it takes to get the brain metastases in a semblance of control before you start systemic therapy, for the most part. The few patients to whom I’ve given dual immunotherapy after brain metastases are the ones who’ve been resected completely; [having] 1 or 2 metastases that have been resected, and they are free of disease in the brain afterward.

1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

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

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. 

 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. 

2021;27(1):78-86. doi:10.1158/1078-0432.CCR-20-2063

4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. 

2019;37(15_suppl):4500. doi:10.1200/JCO.2019.37.15_suppl.4500

5. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.

 2021;39(6_suppl):308. doi:10.1200/JCO.2021.39.6_suppl.308

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. 

Reviewing the Choice of First-Line Combinations for Clear Cell RCC and Other Histologies

A real-world study showed that treatment with zanubrutinib (Brukinsa) correlated with lower rates of switching agents and subsequent therapy vs other Bruton tyrosine kinase (BTK) inhibitors like acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

 showed that irrespective of whether patients were treated with a BTK inhibitor in the first or second line, the switching rate at 60 days or less and 61 to 89 days was lower for patients receiving zanubrutinib compared with those receiving acalabrutinib and ibrutinib (for both first and second line, 

In the first-line setting, the rate of patients switching therapies before 90 days was 10.2% for zanubrutinib (n = 157) compared with 20.5% for acalabrutinib (n = 1238) and 15.9% for ibrutinib (n = 1421). In the second-line setting, the switch rate before 90 days was 7.5% for zanubrutinib (n = 107), 13.2% for acalabrutinib (n = 672), and 21.1% for ibrutinib (n = 474).

“This study highlighted the real-world advantages of zanubrutinib compared [with] other BTK inhibitors in patients with CLL/SLL,” lead study author Javier Pinilla-Ibarz, MD, PhD, and colleagues, wrote in a poster presentation of the data. “Future studies with extended follow-up are necessary to facilitate evaluation of emerging therapies and to assess long-term real-world outcomes.”

Pinilla-Ibarz is a senior member and head of Lymphoma Section in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

The retrospective study utilized the Integra Connect database, which includes electronic medical records from community-based oncology practices, to evaluate real-world switching and sequencing to next-line therapies among patients with CLL or SLL initiating BTK inhibitors in the first-line or second-line setting.

The study period spanned from December 1, 2019, to March 31, 2023, with an index period between January 1, 2020, and February 28, 2023. Investigators gathered data for patients at least 18 years of age with CLL or SLL who initiated treatment with acalabrutinib, ibrutinib, or zanubrutinib during the index period.

On the study, a total of 2816 patients initiated first-line BTK inhibitor therapy; 1253 patients began second-line treatment. In the first-line setting, ibrutinib was the most frequently used BTK inhibitor (50.5%), followed by acalabrutinib (44.0%) and zanubrutinib (5.6%). In the second-line setting, acalabrutinib was most commonly used (53.6%), followed by ibrutinib (37.8%) and zanubrutinib (8.54%).

Demographic and clinical characteristics were assessed at baseline, and study authors noted that there were no significant differences in age, sex, payer type, or Rai stage among the 3 cohorts. The median follow-up duration in the first-line setting was 123 days (interquartile range [IQR], 63-335) for zanubrutinib, 406 days (IQR, 196-659) for acalabrutinib, and 637 days (IQR, 326-921) for ibrutinib (

 <.0001). In the second-line setting, median follow-up durations were 133 days (IQR, 62-385) for zanubrutinib, 503 days (IQR, 265-799) for acalabrutinib, and 524 days (IQR, 259-856) for ibrutinib (

Treatment switching was measured by identifying patients who initiated another treatment within the same line or advanced to the next line of therapy within 90 days. Sequencing to the next line of therapy was calculated using Kaplan-Meier analysis, and the proportion of patients receiving the next line of therapy at 180 days was reported.

Additional data showed the switching rates before 60 days in the first-line setting were 10.2% for zanubrutinib, 17.1% for acalabrutinib, and 13.1% for ibrutinib. The respective switching rates from 61 to 89 days were 0%, 3.4%, and 2.5%. In the second-line setting, the switching rates before 60 days were 7.5% for zanubrutinib, 10.7% for acalabrutinib, and 17.1% for ibrutinib. The switching rates from days 61 to 89 were 0%, 2.5%, and 4.0%, respectively.

The proportion of patients who received their next line of therapy at 180 days was lowest for those treated with zanubrutinib. In the first-line setting, 13.9% of patients treated with zanubrutinib received next-line therapy by day 180 compared with 24.5% of patients treated with acalabrutinib and 21.1% of patients treated with ibrutinib. In the second-line setting, these rates were 9.1% for zanubrutinib, 18.6% for acalabrutinib, and 29.2% for ibrutinib.

Authors noted that the study was limited by a United States–based population, which may not be applicable to all patient populations. They also explained data may be limited by the real-world nature of the study.

Pinilla-Ibarz J, Xue M, Wu E, et al. Real-world treatment switching and sequencing to next line of therapy of zanubrutinib, acalabrutinib, and ibrutinib in CLL/SLL. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, TX. Abstract CLL-354.

Findings from a real-world study showed that zanubrutinib was associated with lower rates of treatment switching and patients receiving subsequent therapy compared with acalabrutinib and ibrutinib in patients with CLL or SLL. 

Warner Kornberg

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