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Howard A. &quot;Skip&quot; Burris, III, MD, president, Clinical Operations, chief medical officer and executive director of Drug Development, Sarah Cannon, talks about chemotherapy in the era of personalized medicine.

Dr. Howard A. Burris, III, on Modern Chemotherapy for Patients with HER2-Positive Breast 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

During a Targeted Oncology case-based roundtable event, Jeanne M. Palmer, MD, discussed the case of a patient with myelofibrosis whose platelet count declined during JAK inhibitor therapy.

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

Six months ago, a 72-year-old woman with a history of hyperlipidemia (controlled on rosuvastatin [Crestor]) and hypertension (controlled on amlodipine [Norvasc]), developed itching, bloating, loss of appetite, a notable 20 lb weight loss, drenching night sweats, and significant fatigue.

Abdominal examination revealed splenomegaly, spleen palpable 8 cm below the left costal margin without hepatomegaly. CT scans of the chest, abdomen, and pelvis revealed moderate mediastinal lymphadenopathy and splenomegaly.

A peripheral blood smear produced a leucoerythroblastic picture with nucleated threads and immature cells in the periphery. Next-generation sequencing showed a 

 mutation (allele frequency, 22%). Bone marrow biopsy showed megakaryocyte proliferation with atypia, 3+ reticulin fibrosis. Cytogenics were normal.

Laboratory values

A decision to initiate ruxolitinib (Jakafi) was made. ​There was initial symptom improvement in appetite, night sweats, and weight at a dose of 10 mg twice daily, and the dose was increased to 15 mg twice daily. One month later, platelet count decreased to 100,000/μL, and the dose was reduced to 10 mg twice daily. One month later, platelet count dropped to 32,000/μL, and the patient received a red blood cell transfusion. After another month, platelet count remained at 85,000/μL.

Repeat red blood cell transfusion and continue ruxolitinib 10 mg twice daily

Continue ruxolitinib at reduced dose (5 mg twice daily)

There is not a right or a wrong answer. [The majority of participants chose] pacritinib [Vonjo]. If you stop ruxolitinib and go directly to pacritinib, which you can do, then you should be OK, but if you stop the ruxolitinib and their platelets go back up, always remember that sometimes, you can convince [insurance providers] to give you pacritinib, even if the platelets are higher off the ruxolitinib.

Pacritinib 200 mg twice daily (off label)

How do you define ruxolitinib failure? ​

What are triggers for you intervene earlier versus later?​

What are triggers for you to change therapy?​

Alright, so one of the big questions that comes up, or I think that's going to be very important for the myeloproliferative neoplasms community to answer, is the definition of ruxolitinib failure, so what are the various things that may happen to a patient that would make you say the ruxolitinib is not working?

 I think if the patient has constitutional symptoms and is not improving, the spleen is not getting smaller, and then they are continue to require blood transfusions.

 Any other comments on what defines ruxolitinib failure for patients? And what triggers you to change therapy?

 The return of blood transfusion requirements, which will indicate progression of disease, and therefore, repeat bone marrow [biopsy].

 Three things: laboratory results, spleen [volume], and quality of life.

 That is the name of the game, isn't it? We have a very recurrent theme in those 3 things.

When they actually looked at what drove ruxolitinib discontinuation, based on the European database, lack of response is one, loss of response was another one of the big ones.

 Blast phase was actually almost a quarter of the patients. Allogeneic stem cell transplant and a favorable response. Ruxolitinib-related adverse events [AEs] was also slightly over a quarter of the patients, and then ruxolitinib-unrelated AEs, which was an interesting distribution.

Switching to another Janus kinase (JAK) inhibitor or other therapy?

How can switching from one JAK inhibitor to another be done safely?

What has been your experience with ruxolitinib interruption/discontinuation? With fedratinib?

Would you taper the ruxolitinib dosing for interruption or hold or discontinuation or switching to another JAK inhibitor? Do you usually taper ruxolitinib if you're going to switch to another JAK inhibitor, or do you just directly switch to another JAK inhibitor, and [what is] the setting where you've done that? For what it's worth, I generally try to taper down the ruxolitinib a little bit before I will switch them to another JAK inhibitor.

What has been your experience with discontinuation or interruption of ruxolitinib? [Have you had] patients who just decided they were just going to stop it, or start to go down on the doses a lot without discussing?

My patient on pacritinib developed liver toxicity, so we held the medication, she improved, we'd rechallenge her, she again got liver function [tests with] ALT [alanine transaminase] being very high, so we had no choice but to stop completely without tapering, but she went onto pacritinib, and she seemed to be OK.

1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. 

. 2020;126(6):1243-1252. doi:10.1002/cncr.32664

When to Stop or Switch JAK Inhibitor Therapy in Myelofibrosis

He presented to his primary care physician (PCP) with symptoms of fatigue, night sweats, and increased bruising​.

His medical history includes type 2 diabetes, hypercholesterolemia, and hypertension.

“Normal” physical and blood work 1 year ago​

His PCP noticed lower hemoglobin (11-9.5 g/dL) and platelet count (350,000/μL-195,000/μL)​ from the previous year’s physical.​

He was referred to hematology/oncology; first available appointment in 2 months

At the appointment, exam findings include spleen 5 cm below left costal margin, worsening fatigue and night sweats, and bone pain.

He has a history of squamous cell carcinoma of the skin.

Blood: 1% blasts by manual count/flow cytometry

White blood cells: 19 × 109/L; hemoglobin: 9.1 g/dL; platelets: 135,000/μL; lactate dehydrogenase: 330 U/L

Bone marrow biopsy showed blasts less than 5% and grade 2/3 fibrosis

Karyotype was 46,XY [20], and next-generation sequencing panel showed a 

 V617F mutation with variable allele frequency of 53%

What patient symptoms prompt you to initiate therapy for MF? ​

What symptoms are the most important to control? ​

When do you start JAK inhibitor therapy?​

Do you choose your initial JAK inhibitor based on patient symptoms? ​

I'm curious to hear how you approach this in your practices, because it's probably a little bit different than what we that what we see here at University of Michigan in the academic setting. We tend to see patients a bit later.

In your practice, what patient's symptoms or findings would prompt you to initiate therapy for a patient with like this with a new diagnosis of myelofibrosis?

: Probably constitutional symptoms [such as] fever and night sweats, and splenomegaly. That usually tells me that I have to do something. That is what usually pushes me to start treatment if the patient is otherwise stable with stable [blood cell] counts.

The JAK inhibitors shrink the spleen…I only consider JAK inhibitors for patients with significant splenomegaly.

What do you think that JAK inhibitors leave to be desired?

To me, the reversal of bone marrow fibrosis is critical in managing myelofibrosis. So far, besides interferon, we don't have any drug that reverses or halts bone marrow fibrosis.

: If the principal issue is anemia, then one could consider [erythropoietin-stimulating agents or] luspatercept [Reblozyl] because the JAK2 inhibitors don't raise the hemoglobin [level] very well. But if the principal problem is splenomegaly or constitutional symptoms, then they're a good candidate for the JAK2 inhibitors.

That's a very good point. We assumed that when you shrink the spleen…the hemoglobin will go up. But JAK inhibitors also cause anemia.

: That is true for the older therapy, but the newer agents [momelotinib (Ojjaara) and pacritinib (Vonjo)] will improve the hemoglobin and platelet [counts].

My impression is that they don't lower it as much, but they do not necessarily improve it.

Thrombocytopenia and anemia are common in patients with myelofibrosis. Thrombocytopenia at the time of diagnosis is present in approximately 25% of patients; severe thrombocytopenia in approximately 11%.

 It occurs in more than half of patients at some point during their disease course. Anemia is even more common than that at baseline. We see anemia in up to 40% of patients [at baseline] and then at some point during their course in almost all patients with myelofibrosis.

How often do you encounter baseline platelet counts less than 50,000 μL and/or baseline hemoglobin less than 10 g/dL in patients diagnosed with primary myelofibrosis?

During a Case-Based Roundtable® event, Kristen Pettit, MD, moderated a discussion on which disease features of myelofibrosis are most challenging and when to use JAK inhibitors in the first article of a 2-part series.

Howard A. Burris, III, MD

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