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Glenn J. Hanna, MD, discusses the results of a study investigating nivolumab  as treatment for proliferative leukoplakia leading to oral cancer.

Nivolumab Reduces Transformation of Precancerous Leukoplakia to Oral Cancer

Glenn J. Hanna, MD, discusses proliferative leukoplakia and risk of oral cancer.



Proliferative Leukoplakia and Oral Cancer Transformation

Squamous cell carcinoma of the head and neck (SCCHN) is an immunosuppressive disease, as its patients often demonstrate immune dysregulation that correlates with poorer outcomes. Trials are underway combining chemoradiotherapy with immune checkpoint inhibitors.

Integrating Immunotherapy With Chemoradiation in the Treatment of Head and Neck Cancer

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

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.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

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?

Are these common things that you're dealing with in your practice? Are you seeing more of the patients with [enlarged] spleens and terrible symptoms, and not so much with the cytopenias?

: I don't see low platelets that often, and I keep looking to see if I can use this agent on it. I don't have very many patients with under 50,000/μL, [although I don’t] have that many patients.

I would echo the same thing. I see more anemia than low platelets as a problem. I have had patients where I've had high platelet count [with] essential thrombocythemia transforming to myelofibrosis. I have [patients with] high platelets and low hemoglobin; that's been a problem for me.

That's helpful to know, and demonstrates that this disease is all over the spectrum. There aren't necessarily 2 patients or 2 practices that are going to be the same.

1. Reynolds SB and Pettit K. New approaches to tackle cytopenic myelofibrosis. 

2022;1:235-244. doi:10.1182/hematology.2022000340

2. Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. 

. 2012;87(1):25-33. doi:10.1016/j.mayocp.2011.11.001

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.

Challenging Disease Features of Myelofibrosis Lead to Use of JAK Inhibitors

The combination of selinexor (Xpovio) with ruxolitinib (Jakafi), in both 40mg and 60  mg doses, demonstrated encouraging efficacy with a manageable safety profile in patients with myelofibrosis (MF) who were previously treated with ruxolitinib, according to preliminary findings from a phase 2 trial. These data were presented at the 2024 ASH Annual Meeting.

Selinexor with ruxolitinib demonstrated encouraging efficacy with a manageable safety profile in patients with myelofibrosis who were previously treated with ruxolitinib.

Glenn J. Hanna, MD

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