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David F. McDermott, MD, associate professor, Department of Medicine, Harvard Medical School/Dana-Farber Cancer Institute, discusses PD-L1 expression in non-clear cell kidney cancer.

PD-L1 Expression in Non-Clear Cell Renal Cell Cancer

David F. McDermott, MD, associate professor, Department of Medicine, Harvard Medical School/Dana-Farber Cancer Institute, discusses PD-L1 expression in kidney cancer and developing biomarkers for anti-PD-L1 agents.

PD-L1 Expression in Kidney Cancer

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

A post hoc analysis incorporating the use of subsequent therapy in censored patients on the ARASENS trial (NCT02799602) supported the overall survival (OS) benefit of adding darolutamide (Nubeqa) to androgen deprivation therapy (ADT) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to a poster presented at the 2024 ASCO Genitourinary Cancers Symposium.

In the post hoc sensitivity analysis, investigators counted subsequent systemic antineoplastic therapy in patients who were not available for assessment as an OS event. There was an HR of 0.47 favoring darolutamide vs placebo (95% CI, 0.40-0.54; 

 < .0001), with a median OS of 49.0 months (95% CI, 45.2–not estimable [NE]) with darolutamide vs 31.6 months (95% CI, 29.7-33.8) with placebo.

“Findings from this post hoc sensitivity analysis support the primary OS analysis,” said Neal D. Shore, MD, FACS, medical director for the Carolina Urologic Research Center, in his presentation of the poster.

The phase 3 ARASENS trial randomly assigned 1306 patients on a 1:1 basis to receive 600 mg of oral darolutamide or placebo twice daily plus ADT and 6 cycles of docetaxel.2 The primary end point was OS, assessed using a log-rank test with 95% CI calculated using the Cox model. Those on the trial with no documented death were censored at the data cut-off or the last known alive date, whichever occurred first.

The primary OS analysis was published in the 

 in 2022. At data cut-off of October 25, 2021, median follow-up was 43.7 months in the darolutamide group and 42.4 months in the placebo group. At this time, 229 of 651 patients (35%) in the darolutamide group and 304 of 654 patients (46%) in the placebo group had died, with a 32.5% lower risk of death in the darolutamide group (HR, 0.68; 95% CI, 0.57-0.80; 

 The median OS with darolutamide was NE (95% CI, NE-NE) compared with 48.9 months (95% CI, 44.4-NE) with placebo.

Investigators noted that 374 of 495 patients (75.6%) who entered follow-up in the placebo group received subsequent life-prolonging therapies, primarily different androgen receptor pathway inhibitors besides darolutamide. This had the potential to impact OS outcomes.

In the post hoc sensitivity analysis, 776 patients were counted as having an event, either death or censored patients receiving subsequent therapy, including 300 of 651 (46.1%) in the darolutamide arm vs 476 of 654 (72.8%) in the placebo arm.

Planned sensitivity analyses for OS were also performed. Log-rank test and Cox model without stratification showed an HR of 0.69 favoring darolutamide (95% CI, 0.58-0.82; one-sided 

 <.0001). In a log-rank test and Cox model using stratification factors collected from electronic case report forms, the HR was 0.68 (95% CI, 0.57-0.81; one-sided 

 <.0001). The log-rank test and Cox model using extent of disease stratification factors based on central imaging review resulted in an HR of 0.68 (95% CI, 0.57-0.81; one-sided 

At data cut-off, 299 of 651 patients in the darolutamide arm (46%) and 125 of 654 patients in the placebo arm (19%) continued receiving study treatment. Forty-eight percent in the darolutamide arm and 76% of those in the placebo arm were eligible for subsequent therapy, and 34% of the darolutamide arm and 60% of the placebo arm ultimately received subsequent systemic antineoplastic therapy. The time to first subsequent systemic antineoplastic therapy, which was a key secondary end point of ARASENS, was superior in the darolutamide arm (HR, 0.39; 95% CI, 0.33-0.46; 

In terms of safety, the median duration of treatment was 41.0 months in the darolutamide arm vs 16.7 months in the placebo arm.

 Overall incidence of treatment-emergent adverse events (TEAEs) was similar between the groups, with the cumulative incidence of TEAEs commonly associated with androgen receptor inhibitor therapy being low in both arms, particularly when adjusted for exposure. TEAEs led to discontinuation in 13.5% in the darolutamide group vs 10.6% in the placebo group.

“In conclusion, the results of the post hoc sensitivity analysis were consistent with and supportive of the ARASENS primary OS analysis,” said Shore. “These data reinforce combination of darolutamide with ADT and docetaxel as an effective and well tolerated standard-of-care option for early treatment intensification in patients with mHSPC.”

1. Shore ND, Tombal BF, Hussain M, et al. Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy. 

 2024;42(suppl 4):166. doi:10.1200/JCO.2024.42.4_suppl.166

2. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. 

. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

A post hoc sensitivity analysis that counted use of subsequent therapies in patients censored from primary overall survival follow-up favored darolutamide plus androgen deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer. 

Conference News

Analysis of Subsequent Therapies Confirms OS Benefit of Darolutamide in mHSPC

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. 

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. 

David F. McDermott, MD

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