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Alexander Zukiwski, MD, CEO, Arno Therapeutics, Inc., discusses the efficacy of onapristone (ONA) in progesterone receptor (PR)-expressing tumors.


Efficacy of Onapristone in PR-Expressing Tumors

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

A 68-year-old woman presented to her physician with symptoms of mild fatigue.

Spleen was palpable 6 to 7 cm below the left costal margin

Past medical history: no known comorbidities

Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis

Dynamic International Prognostic Scoring System: intermediate-2

Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients: intermediate risk

Initiate ruxolitinib ± refer for stem cell transplant

Initiate momelotinib ± refer for stem cell transplant

Initiate pacritinib ± refer for stem cell transplant

 We know this patient's profile; we know they have intermediate-2 risk. We know that they have moderate anemia with a hemoglobin level of 9.7 g/dL. If I read this correctly, observation is not selected because we have a symptomatic patient who has an enlarged spleen with intermediate-2 risk disease. There may be various barriers for patients to go on clinical trials that you see every day in your practice. [So] we would start treatment on this patient and not just refer them for stem cell transplant. The outcome could be improved if we help this patient from a spleen size perspective.

If we alter it just slightly, still a patient with intermediate-2 risk but the patient has a hemoglobin level of 7.8 g/dL, would this alternate scenario change your approach to this patient?

I chose momelotinib [Ojjaara] twice [for both polls], but I was on the fence before. I always think if I get the chance to get ruxolitinib [Jakafi] in, as long as the platelets are still OK, I should use it. I would [likely] use ruxolitinib with the other scenario and momelotinib now.

That's essentially what I chose; ruxolitinib and then momelotinib. Ultimately, the way things are perceived by each one of you is going to be colored by your experience.

I picked ruxolitinib because of the familiarity and the survival benefit. [In the scenario of] severe anemia, I changed to momelotinib.

How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting JAK (Janus kinase) inhibitor therapy?​

Other than selection of JAK inhibitor, are there other things that you would do for either of these patients in terms of supporting erythropoiesis?

I would consider erythropoietin-stimulating agents [ESAs]. Especially if the EPO [serum erythropoietin] level is low up front, I would consider adding an ESA to the JAK inhibitors.

What cutoff do you use for the EPO level?

I have also used luspatercept [Reblozyl].

I have heard about anabolic steroids like danazol. I have not used it so I can't really comment.

Danazol is a medication that's listed in the supportive care for anemia with this disease. I've used it a limited amount. Generally, it's been hard for me to tell if I was able to improve a patient's erythropoiesis. Several patients I've used it on remain transfusion dependent in spite of danazol therapy. It was tough to realize the exact benefit.

When do you typically intervene with ruxolitinib for intermediate- or high-risk patients?

If the patient has minimal or no symptoms or intermediate grade, I might hold. I don't know if [such a patient] will qualify for intermediate grade, but if there are no cytopenias, I might just watch and initiate it once I see some symptoms or spleen enlargement.

I think it's a great point, Dr Anwar. Intermediate risk is nonspecific. Intermediate risk can be intermediate-1 or intermediate-2. As the risk profile increases for the patient, the symptoms increase, so it is rare to encounter an intermediate-2 or high-risk patient who's completely asymptomatic. At intermediate-1, we more often see patients who are asymptomatic. The struggle is, do you start JAK inhibitors for those patients, or do you wait? Most of us start regardless, and I think that there's some credence in either approach. In a completely asymptomatic patient, careful monitoring of spleen and symptoms to see where the natural history of the disease is going is a legitimate way of handling this. But one could make an argument [we should] treat that patient right off the bat. As we get to intermediate-2 or higher-risk patients, we have [a lower] comfort level for watching and actively surveying the disease.

 We have patients with some adherence issues who have asthenia and fatigue, and sometimes they don't take [ruxolitinib] twice a day. Do you think you get the same benefit if it was [taken] daily?

That’s a hard one to answer. I rarely get down to dose reductions that would require me to use it once daily with myelofibrosis. The pharmacokinetics of the drug would suggest that even if you're getting down to low dosages, 5 to 10 mg on a daily basis, the drug is designed to be given twice daily, so those patients may not be experiencing the full benefit. The other thing that I would wonder about is, is there potentially some risk during of reducing ruxolitinib levels so much in those patients that they get a rebound cytokine release. If they take it at 9 AM, then by 9 PM or in the middle of the night, [they might] start to experience some adverse symptoms that could be somewhat related to ruxolitinib withdrawal.

Before momelotinib was approved, even if a patient's hemoglobin level was less than 7 g/dL, I would use ruxolitinib, because that was the only option to try and get a response while doing supportive care with transfusions, ESA, or whatever is needed. It changes now with the availability of momelotinib. I might prefer that more than ruxolitinib based on the comparative data for hemoglobin improvement.

 There were no known relevant disclosures by the participants.

During a live event, Mark J. Fesler, MD, and participants discussed selection and timing of initiation of JAK inhibitor therapy for myelofibrosis.

Starting Therapy for Intermediate-Risk Myelofibrosis Based on Hemoglobin

Mike is a 60-year-old man diagnosed 6 years ago with IgG-κ multiple myeloma; 60% plasma cells; translocation 14;20

Most recent labs show recurrence of M-protein (0.6 g/dL) and imaging shows a new hypermetabolic lytic lesion.

Medical history: hypertension controlled with lisinopril

He normally works in his garden and walks 2 miles daily; he noticed a progressive decline in his stamina where he needs to take breaks more often and has shortened his walking route.

He previously received daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone; autologous stem cell transplant; and lenalidomide maintenance with a complete response (CR) and time to relapse of 5.5 years.

: What are the options for this patient with multiple myeloma after first relapse?

 In the NCCN guidelines, there are a lot of options for the first to the third line of relapse.

 Carfilzomib [Kyprolis] base with daratumumab is an option, or with pomalidomide [Pomalyst]. We can also go back to bortezomib, because the patient was not really on bortezomib when he relapsed. So you can go back to bortezomib and combine that with daratumumab or even pomalidomide.

CAR [chimeric antigen receptor] T-cell therapy with cilta-cel [ciltacabtagene autoleucel, Carvykti] is also approved at the first relapse when someone is lenalidomide refractory, so he would technically qualify for early CAR T.

Other options include selinexor [Xpovio]-based regimens. I don't know how many people use selinexor, but you can combine that with bortezomib and the first relapse setting or beyond, based on the BOSTON study [NCT03110562], Elotuzumab [Empliciti] as a base is also an option. I'm not really a big fan of elotuzumab, so I try not to use that, especially if they've had daratumumab before, but that's also an option.

Mike and his oncologist have discussed his treatment options based on his response to his initial therapy.

As he is lenalidomide-refractory his options include:

During a live event, Jack Khouri, MD, discussed options for patients with multiple myeloma after relapse and choices to consider before CAR T-cell therapy.

Alexander Zukiwski, MD

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