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Targeted agents are routinely used to treat many cancers and have improved outcomes for patients with solid tumors and hematological malignancies alike. Recently, targeted therapies made their way into the armamentarium for acute myeloid leukemia, representing the first therapeutic advances for AML in decades.

Targeted Therapies End the Dry Spell in AML Drug Development

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 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin and cyclophosphamide (ddAC) plus paclitaxel, which she tolerated well. Eight months after completion of adjuvant therapy, she reported worsening fatigue. Laboratory results: alanine aminotransferase, 1.5x upper limits of normal (ULN); aspartate aminotransferase, 1.5x ULN. A CT scan showed 1 liver and 2 left lung lesions.Biopsy of the liver lesion confirmed recurrent metastatic TNBC, and her brain MRI was negative for brain metastasis. Genetic panel testing was negative for detectable mutations. PD-L1 on immune cells (SP142 Ventana assay) was 0%. There were no significant comorbidities, otherwise healthy. She had an ECOG performance status of 0.

Vote in the polls below on what you would have chosen if this was your patient.

 If you chose chemotherapy or other, what agent or regimen are you most likely to recommend?

I was between a clinical trial and capecitabine but she's going to be difficult to treat chemotherapy wise, so clinical trials reasonable. She has ECOG performance status 0, and I don't know how long she'll stay that way. For that reason, I think for quality-of-life issues, capecitabine would be my choice to give her maybe some time that was reasonable.

 I also chose capecitabine. I think all of them are very reasonable choices, but for tolerability and efficacy, I would probably choose capecitabine first line in someone who’s PD-L1 negative.

If there's any clinical trial available, that would be my preference.

If not, oral capecitabine is probably what I would choose outside the clinical trial setting.

 So let me ask the question, another way, is there anyone who chose I single agent chemotherapy that wants to speak up and just give you a rationale for that route, as opposed to keep sight of being in the situation?

 I chose intravenous [IV] chemotherapy. I would choose sacituzumab govitecan [Trodelvy]. It's a new drug and response rates are really good with that drug as opposed to other single-agent chemotherapy regimens.

 Do you mind telling us what you chose in the first scenario and how you changed your response for this, if you did?

 I chose clinical trial for both answer. This one and the previous one. To me, the 24 months did not change my thinking. I was confused about the sacituzumab thought because I think it's approved for 2 prior lines of therapy and 1 can be within the adjuvant setting.

 It is approved after [at least] 1 line of therapy for the metastatic setting. If you could get for sacituzumab, it sounds like that's something that you may have been interested in.

 Yes, I agree with the earlier speaker. I have used the therapy in patients with this disease and at this stage, and I agree there have been some really great responses. I have a woman who's 65 years old, presented very similar to the pattern that you had [in this case]; she had earlier-stage disease 2 years ago, adjuvant therapy, late recurrence, and significant amount of disease on the chest wall. Sacituzumab has been relatively well tolerated except for some fatigue a single-agent IV and has healed the skin wound issues well.

 In the situation where a patient recurs after 8 months of treatment in the adjuvant setting, my general thought is we're dealing with a patient who has quite resistant disease. I don't think there's a right or wrong answer in terms of non–clinical trial-based chemotherapy. She seems to be relatively asymptomatic except for mild fatigue. She didn't have a huge burden of visceral disease. I probably would have used capecitabine in that situation.

Then similarly, I think treatment is palliative, even in the 24-month range. Afterwards, she's not symptomatic or overly symptomatic. I don't think there's a right or wrong answer. But capecitabine would be a reasonable approach there as well. If I were going to use IV chemotherapy, I would be more inclined to consider it in the first scenario where the patient had a very short disease-free interval just knowing that that patient isn't likely to do well with her disease recurring so quickly.

The patient received frontline carboplatin with a documented partial response lasting 6 months. After 6 months of therapy, she reported worsening fatigue. Disease progression and new metastasis in the liver was discovered. Her ECOG performance status is now 1.

Microtubule inhibitor (eribulin, vinorelbine)

 I want to ask you for your input in terms of how you're making this decision. If you chose chemotherapy or if you chose something other than sacituzumab in the first-line or second-line situation, are you using a different agent? Please address the ideal therapeutic sequence for these patients with triple-negative disease who are PD-L1 negative. This is a considerable population of the patients; we have about 40% of patients that have PD-L1–positive disease but there's a fair percentage of them that are negative, so how are you approaching these situations?

Usually in patient with PD-L1­–negative disease, it is based on the amount of disease that we're dealing with, what they have received before, and tolerability. Usually, if you have had a lot of disease, starting with [starting with an oral agent is] not a bad idea, especially if the patient is extremely symptomatic. If a patient is doing is relatively OK, doesn't have high burden of disease, I tend to start with single agent, and we can also use Doxil (doxorubicin), which is easy to tolerate. I try to balance what I need to do for the patient to make them feel better and improve the quality of life, what they can tolerate, and what is available.

If PD-L1 [expression was] negative, I would think mostly of the new medication sacituzumab, and Doxil as my colleague said….I think it is a good path, but it's again, what's available, what the patient wants, considered toxicities, and proceed that way.

 I'm definitely hearing decision making is informed by IV versus oral, shared decision-making, and toxicities that that they may have had in the past. In this scenario of the patient having recurred within 24 months versus 8 months, what you do in the second line? Does that does that recurrence, the timing of the initial recurrence, change how you look at that patient going forward? Or are you following this algorithm that once you start, it really doesn't matter when the patient had a recurrence?

If it's the first recurrence—for example, if she would have progressed 8 months after a ddAC—I would go with single-agent carboplatin because it's chemotherapy with different mechanism of action. If they are young and/or fit, I'd like to save the capecitabine for later, keep it in my back pocket in case they become less fit. That's a better tolerated treatment.

If she would have progressed within 24 months initially, we'll go back to single-agent taxane. But then, in the relapse after first line, for second line metastatic disease, I would go with sacituzumab regardless. I like to cycle the chemotherapy with a different mechanism of action.

Participants of a live, virtual case-based event discussed different scenarios for treatment of a patient with BRCA and PD-L1 negative, metastatic triple-negative breast cancer. Vote in the polls on what you would have chosen if this was your patient.

POLL: What Treatment Would You Choose for BRCA-, PD-L1- Metastatic TNBC?

In practice, what is the most difficult disease feature to manage in primary myelofibrosis? Is it thrombocytopenia, anemia, splenomegaly, constitutional symptoms or other? For anybody who said anemia or thrombocytopenia, do you want to comment on why those are challenging?

I chose anemia. Usually, patients have more symptoms related to anemia than thrombocytopenia, so they probably come to our attention more than thrombocytopenia. Obviously, thrombocytopenia can be a challenge during the treatment…but it is the anemia that I find challenging, because usually once the patient hits low hemoglobin, they become symptomatic, and we try to avoid a transfusion if possible. I find that anemia is more challenging than thrombocytopenia at the beginning.

That's a great point. Anemia is something that's more likely to immediately impact quality of life from the symptoms that it causes, as well as the time spent in clinic.

For myself, especially in the patients that I have, thrombocytopenia tends to be the most challenging for us, because some of our patients’ [platelet counts] are [less than 20,000/μL] or sometimes even less than 10,000/μL and we struggle because transfusions don't work a lot, and a lot of them have other medical comorbidities…especially older patients. These are the challenges that we deal with, and thrombocytopenia is further complicating the picture. Anemia is potentially challenging, but thrombocytopenia is something that makes it difficult.

I've seen a few patients, but the last 2 patients have had issues with constitutional symptoms. Even though their numbers don't translate into that much anemia, and even though the numbers improved, [whether due to] the medicine [or] the disease itself, one of them keeps on asking for prolonging his disability or his time off from work.

So sometimes there's a disconnect between what the blood counts are showing with how the patients are feeling. I think that's pretty common. So that's a great point.

I picked constitution symptoms because fatigue [and others] are so subjective, and I feel those are difficult. Even for patients with profound thrombocytopenia and anemia, we have now drugs available to target those with pacritinib [Vonjo] and momelotinib [Ojjaara], but I feel constitutional [symptoms are challenging] for me. Some of them are younger patients [who] want to keep on a working schedule. Because that's so subjective, I feel that would be the hardest for me.

That's a wonderful point. Sometimes the JAK inhibitors really help with the constitutional symptoms, but they don't always work all the way and like [Dr Samdani] mentioned, sometimes the numbers don't tell the full story, and especially for our younger working patients, fatigue can be a really debilitating symptom that keeps people from working, especially those young patients that are still working.

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

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? ​

What are the symptoms that will prompt you to initiate therapy with myelofibrosis? How do you decide who needs to get started on therapy?

Symptoms will [make me] decide; if the patient has a lot of constituent symptoms, then I will initiate, plus the blood counts. The symptoms and the blood count issues, and sometimes they're related—if somebody has significant anemia, they might have hemoglobin of 9 to 10 g/dL, but they have a lot of constitutional symptoms, like night sweats, fever, and splenomegaly.

The first drug is determined by the blood count. Usually, if their platelet count above 50,000/μL, you can go with ruxolitinib [Jakafi]. If the hemoglobin is down, you can now use momelotinib for patient with significant anemia.

Does anybody have a different approach to initial therapy [besides looking at] blood counts and symptoms, and choosing a JAK inhibitor based on the blood counts?

I have a similar situation as well. I have 1 or 2 patients who have such an indolent disease, even though they do have cytopenias, but because of lack of symptoms, I didn't start them on treatment. I've been following them, but it's predominantly because of cytopenias.

This patient has the platelet count running in the low 20,000s [per μL], but they don't have symptoms for the last at least 5 years I've been following him. For someone like that, [I consider] their goals of care as well, if someone is extremely anxious, worried, and concerned, vs someone who might be weighing in the adverse events of the treatment, or weighing in the risk and benefit and decide that they're comfortable closely being followed. I think that’s part of the discussion that comes into play. When I do start treatment…platelet count is something that I do consider. Usually, my go-to is ruxolitinib, but I had someone recently with post essential thrombocythemia myelofibrosis where I considered fedratinib [Inrebic].

 I just started. I want to see how it goes.

During a Case-Based Roundtable® event, Gabriela S. Hobbs, MD, surveyed physicians on the disease features that are most challenging in primary myelofibrosis in the first article of a 2-part series.

Christin L. Melton

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