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Spotlight

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Authors

David Sallman, MD, discusses some of the innovative therapies and strategies being investigated in myelodysplastic syndromes studies.

Investigational Studies and Therapies in MDS 

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, explains the significance of the initial results from a recent phase 1B/2 trial combining APR-246 and azacitidine (Vidaza) in patients with TP53-mutant myelodysplastic syndrome and acute myeloid leukemia.

Phase Ib/II Results for TP53-Mutant MDS and AML

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

SEQUOIA Trial: Updates from ASH 2024 

Experts review the 5-year results of the phase 3 SEQUOIA trial evaluating treatment options for previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma at the 66th American Society of Hematology Annual Meeting and Exposition 2024.

Video Series

A 39-year-old premenopausal woman underwent bilateral mastectomy with reconstruction for ypT1b, ypN2a, grade 2 invasive ductal carcinoma (IDC), hormone receptor (HR) positive, HER2 positive (immunohistochemistry [IHC] 3+)

Germline testing results showed no actionable/pathogenic alterations​.

She received adjuvant TCHP (docetaxel, carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]) for 6 cycles, with trastuzumab/pertuzumab for 1 year; leuprolide plus aromatase inhibitor (AI) was initiated​.

Three years later: metastatic recurrence in the vertebral spine​

Bone biopsy confirms relapse, HR+, HER2+ (IHC 3+) IDC​

Next-generation sequencing: no actionable mutations identified ​

She received first-line THP (docetaxel, trastuzumab, and pertuzumab) for 6 cycles plus denosumab​.

Transitions to HP (trastuzumab plus pertuzumab)

What is your preferred frontline therapy for HR-positive, HER2-positive metastatic breast cancer (mBC)? ​

Are you using endocrine therapy for patients with HR-positive, HER2-positive mBC? ​

: This is a pretty straightforward case. What do people think? What's your usual practice for a patient who now has metastatic HER2-positive, HR-positive disease and have not received any other treatment for the metastatic setting?

I usually start out with THP in the first-line setting, and after finishing paclitaxel with HP, add something like ovarian suppression plus AI. If they have progressed on an AI, I consider fulvestrant.

Does anybody do anything different? Does anyone use a different chemotherapy? Does everyone use paclitaxel?

Both are very reasonable. The original study with HP [CLEOPATRA; NCT00567190] used docetaxel. Some of us have switched to use paclitaxel instead because, in some patients, it's a little better tolerated, but it does require more visits. But both are appropriate.

Does anybody not use chemotherapy up front? There are some data using endocrine therapy alone with HP with some good outcomes, but that hasn't been compared with chemotherapy.

 Given the fairly substantial survival benefit seen with THP for most patients, most physicians are using chemotherapy, at least as an induction.

Dr Madadi already talked about using endocrine therapy once you drop the chemotherapy. Does everybody tend to do that for an ER-positive, HER2-positive patient once you've stopped the chemotherapy?

The problem in this case is that the patient was already on AI. It doesn't hurt to add it if you want to stop or hold the chemotherapy, so to speak. But that's the only thing here. She was on AI, and she experienced progression. That's what makes me think, “Would there be any benefit here?” But it doesn't hurt. The downside is pretty low here in this case.

Yes, and as was brought up, you could use fulvestrant. If you wanted to do endocrine therapy, you could use fulvestrant if you were worried. It's a good point. This [disease] developed on AI. Are you going to get much mileage out of putting her back on an AI vs giving her fulvestrant? I think that's very reasonable. Unfortunately, this hasn't been tested in a definitive way, because the original CLEOPATRA trial did not allow any endocrine therapy. All the data we have on THP, at least right now, were in the absence of endocrine therapy. But for all the reasons you've all mentioned, it seems pretty reasonable. I think most of us end up doing it, whether it's an AI or fulvestrant, depending on the situation.

How do site(s) of progression and tumor burden factor into your decision making at this point?​ For example:

Progression limited to 1 or 2 small sites?​

What’s important to you? What sites would change your thinking on using trastuzumab deruxtecan [Enhertu; T-DXd] vs something else?

[It would be] concern about brain metastases because if there are extensive brain metastases, we have some data on the tucatinib [Tukysa] and capecitabine combination being more effective.

 Otherwise, systemically, I would say a majority of the time [I would use] T-DXd.

: Fair enough. What about the people who said doesn't matter? Why doesn't it matter? I am one of the people who says doesn't matter, and until recently, I would have said it does matter for the same reason that Dr Madadi just said. But some of the data that have come in more recently suggest that maybe it's not so important to use presence or absence of brain metastases in your treatment decision.

Are there any other site issues? It sounds like most of the importance was because of brain metastases. Are there any other factors, like comorbidities or safety issues; to whom would you not give T-DXd to in the second line?

 I would be concerned about someone who already has interstitial lung disease.

Yes, in somebody who already had pneumonitis. Would you think about trying something different [based on] performance status? This patient was doing well, but [what about] for somebody who was debilitated, with a lot of comorbidities? [What if they had], not necessarily lung issues, but were someone who's pretty limited.

I think that for somebody with a limited performance status, maybe we would be thinking something gentle, like vinorelbine plus trastuzumab, and neither the [tucatinib] nor T-DXd. But for me, somebody has to have pretty limited performance status to not want to at least try T-DXd, especially if I think their performance status is limited because of their disease burden.

Fair enough, and you also don't have to use full dose in that patient if you're concerned.

1. Arpino G, de la Haba Rodríguez J, Ferrero JM, et al. Pertuzumab, trastuzumab, and an aromatase inhibitor for HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer: PERTAIN final analysis. 

. 2023;29(8):1468-1476. doi:10.1158/1078-0432.CCR-22-1092

2. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. 

 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

3. Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. 

. 2023;34(suppl 2):S335-S336. doi:10.1016/j.annonc.2023.09.554

During a Case-Based Roundtable® event, Ian Krop, MD, and participants discussed considerations affecting first- and second-line treatment of metastatic HER2-positive breast cancer in the first article of a 2-part series.



Therapy Type and Site of Metastases Factor into HR+, HER2+ mBC Treatment

Polatuzumab vedotin ± rituximab ± bendamustine

What therapies would you consider for a patient like this? ​

During a Targeted Oncology case-based roundtable event, Christopher R. Flowers, MD, MS, discussed the choice of bridging therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who may receive CAR (chimeric antigen receptor) T-cell therapy. 

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

David Sallman, MD

Articles

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