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Over the past few years, remarkable advances have been achieved in the field of CLL by rationally targeting pathways overexpressed and used by the malignant clone for proliferation and survival. These developments have been achieved by a better understanding of the underlying biology and the disease process.

CLL in the Era of Targeted Therapies

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 52-year-old, postmenopausal woman had a history of grade 2, node-negative invasive ductal carcinoma (IDC).

Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27

Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.

Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).

Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.

The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.

Required 1 dose reduction to 400 mg ribociclib due to neutropenia.

Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.

She noted mild increase in lower back pain​.

Circulating tumor DNA (ctDNA) analysis confirmed an 

Fulvestrant + a different CDK 4/6 inhibitor 

 Using fulvestrant plus a different CDK4/6 inhibitor would not be an unreasonable choice if the patient didn't have an 

 mutation. Fulvestrant alone isn’t a [definite] option for a patient like this. I probably wouldn't use exemestane plus everolimus [Afinitor] here because I don't think this patient has definitively endocrine-resistant disease. Likewise, I probably wouldn't give single-agent chemotherapy. So I would agree with the participants and give elacestrant [Orserdu].

 I absolutely agree. I think elacestrant would be a preferred option.

 But there are some other circumstances where somebody doesn't have access to elacestrant. The 

 mutation would drive me towards a selective estrogen receptor degrader over an aromatase inhibitor combination. So thinking about fulvestrant is also a reasonable option, but I think elacestrant [is a recommended] option.

 The patient received ribociclib in the first-line setting—if she got palbociclib [Ibrance], would you consider, if she didn't have any sort of mutation, fulvestrant plus ribociclib based on the MAINTAIN trial [NCT02632045]?

 I think [we take into account] the MAINTAIN data.

 They are certainly compelling. I have done that very thing in patients who lack other targetable mutations, had a good run on first-line palbociclib, and just have a small amount of progression. We did see data that ribociclib plus fulvestrant was better than fulvestrant alone in that population. I would consider that, remembering that phase 2 hypothesis-generating study.

 mutation, what comes first? How do you deal with that?

 It's a very good question. It's a data-free zone, but I think given the toxicity profile, I probably would lean towards elacestrant.

 I think this depends on the patient in front of you and the volume of their disease. Are they symptomatic, and are we feeling comfortable with single-agent endocrine therapy knowing that we still have the ability to target the PIK3CA pathway at the subsequent progression? I think in the absence of data, it's an art-of-medicine decision. I think there's a place for single-agent endocrine therapy, given the constellation of risk-benefit balance.

 When you look at SOLAR-1 [NCT02437318], the benefit with alpelisib [Piqray] was pretty significant.

 We just don't know the answer right now. And I think you're absolutely right, it depends on the patient.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 2.2024. Accessed June 6, 2024. 

2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. 

. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392

3. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. 

. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011

During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, looks at options for a patients with hormone receptor–positive, HER2-negative breast cancer and an ESR1 mutation in the second article of a 2-part series.

Second-Line Targeted Options Considered in ESR1-Mutated Breast Cancer

A 68-year-old man presented with fatigue, back pain, and lymphadenopathy​, and had a prior medical history of medically controlled hypertension. A ​physical exam showed a 1.5-cm left posterior cervical node, a 2.5-cm right anterior cervical node, and a 2.0-cm left supraclavicular node. PET-CT scans showed multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 x 3.1 cm​. A biopsy confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal center (non-GC). Immunohistochemistry was positive for CD20, BCL-6, BCL-2 (50% of cells), MYC (greater than 90% of cells), Ki67 85%, MUM1, but was negative for CD10​. Fluorescence in situ hybridization was negative for translocations involving MYC, BCL2, BCL6​.

Laboratory results showed normal complete blood count, elevated lactate hydrogenase. He received a diagnosis of stage III DLBCL with IPI high-intermediate risk and ECOG performance score of 1. R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated for 6 cycles and back pain was resolved​. Post-treatment PET demonstrated a complete response with Deauville score of 2, and the patient was observed​.

Eight months after completion of therapy, he complained of fever, night sweats, and back pain. A palpable lymph node in left groin was discovered on physical examination​.

PET and CT scans showed a new left inguinal lymph node, an increase in size of a residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​. DLBCL was confirmed by biopsy.

The patient was referred to nearest transplant and cellular therapy center for evaluation, but ultimately opted not to pursue CAR (chimeric antigen receptor) T-cell therapy​.

Polatuzumab vedotin ± bendamustine ± rituximab

What factors influence your choice of treatment for this patient?

 For patients who you feel would not go through transplant and wouldn’t go through CAR T-cell therapy, the options are GemOx [gemcitabine/oxaliplatin], polatuzumab vedotin [Polivy] with or without bendamustine and rituximab, tafasitamab [Monjuvi] plus lenalidomide [Revlimid], or probably some other [options]. What would you do in this setting?

 Is polatuzumab approved as second line? Or first line?

 Not really [either]. It’s part of the NCCN guidelines—you can usually get polatuzumab in second line.

 But when you look at the label, it would say 2 or more regimens prior.

None of you would use GemOx. GemOx was often used as a treatment for the unfit, older patients who didn’t go for transplant. But, I agree, I haven’t used it in a long time.

This patient is 68 years old, has hypertension, and relapsed after 8 months. Now what do you discuss with that type of patient; what is the clinical goal? How do you discuss the options?

 My goal would be to guess the longest response with a novel agent, such as tafasitamab plus lenalidomide. You can give treatment to disease progression with tafasitamab plus lenalidomide. My goal is to get the maximum response and duration of response.

 I think that that’s a valid point. When I see patients referred to us in our tertiary center, they trust you in the community when they ask “What are my shots? What should I go for?” These discussions are important for them, and your view on this is very important. So which are the factors that influence your recommendations for a patient with a kind of lymphoma that would relapse within 12 months?

 I work in a rural part of Virginia, and this sounds like a very common issue I deal with. Patients don’t want to travel for CAR T-cell therapy or stem cell transplant. We do have an older population, so patient preference or goals would be a very important factor for me, especially in choosing the regimen of tafasitamab plus lenalidomide versus polatuzumab. I would take the number of times they have to come to the cancer center for infusion, especially in this day and age with COVID-19, into consideration. None of my patients are older, but once healthy 70-year-olds start treatment, their age really shows. With their multiple comorbidities, I try to pick the lesser toxic regimen, but with longer response.

 I keep thinking about what I can do to keep the disease under control without necessarily damaging the stem cells, or affecting the immune system as much. So, for that, I think using something that is like a novel agent, since patients may need other drugs in the future. The subtype of the DLBCL, GC versus non-GC, can really be important in the selection.

After discussing the treatment options, tafasitamab plus lenalidomide was initiated​.

This regimen has been around for only a short time, and, this is a bit of a unique patient. Anybody willing to share their experience with the regimen?

 It seems to be better tolerated, similar to rituximab. I admit that I have used it in malignant pancytopenia to watch for some mild reactions in each, but otherwise, pretty well tolerated.

 I agree. [I have seen patients who were] progressing through CAR T-cell therapy, or [autologous stem cell] transplant, or allogeneic [stem cell] transplant go on tafasitamab plus lenalidomide and come in with disease shrinking or no disease. So it is definitely effective.

 My experience is similar to what you both mentioned. I think tafasitamab is like rituximab, but it just attacks different antigen on the B cells. So, you know, it is very similar to if many of you have had experience with R2[rituximab plus lenalidomide], and so this is very similar in terms of that. When you look at the L-MIND study, [it is given on] days 1 and 4, but the first week of tafasitamab, I usually skip day 4 and just do weekly tafasitamab for the first 3 months, and then switch to every other, as per the label.

What is your reaction to the efficacy data for combination tafasitamab plus lenalidomide? ​

 The duration of response [DOR] is very impressive, much better than the CAR T-cell therapy, if I have to put those data side-by-side. It is very well tolerated, and there are many complete responses, so I think these are the very impressive end points. Although it is a phase 2 trial, it is still very impressive.

 It is a little bit difficult to compare it with CAR T-cell therapy because they didn’t have all of the patients [such as] the primary refractory patients. I agree, it surprised me that they were able to generate such long term DOR. Any other feelings about these data sets from the L-MIND study [NCT02399085]?

 The data seems quite impressive. How long can they be given lenalidomide?

 Then [after 1 year] tafasitamab is continued as a maintenance. We’ve seen that prior in literature where in mantle cell lymphoma, they use rituximab maintenance until progression. And so they’ve designed this study the same way, that they used the tafasitamab maintenance until progression. I am not sure how much the tafasitamab maintenance plays a role, but if you want to follow the data, you will follow that. In some of our patients we didn’t continue for the whole duration until progression. They opted to hold it after some time because they were in remission.

 The reason I asked is because I wanted to see which was more cost effective: CAR T-cell therapy, or this regimen.

 It’s a good question, and the CAR T cell price tag is huge. Again, I am sure any of these treatments will be very expensive. That is a great question for health care economist, but I can’t answer that well.

 Can you comment on the lenalidomide dose? In my limited experience, I find that the 25 mg dose quite myelosuppressive.

During a live virtual event, Jakub Svoboda, MD, discussed with participants the choice of therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who would not receive stem cell transplant or chimeric antigen receptor therapy.

Kanti R. Rai, MD, Jacqueline C. Barrientos, MD

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