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Spotlight

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Authors

Sheng F. Cai, MD, PhD, is a leukemia specialist and early drug development specialist at Memorial Sloan Kettering Cancer Center. 

Sheng F. Cai, MD, PhD, discusses the results of the BEAT AML master trial in patients with acute myeloid leukemia. 

Risk-Adapted Study Enhances Response to IDH2-Targeted Therapy for 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

Idecabtagene vicleucel (ide-cel; Abecma) has shown promise as a breakthrough therapy in relapsed/refractory (R/R) multiple myeloma. However, understanding the key factors influencing treatment outcomes, particularly regarding toxicity and durable responses, remains a critical focus for researchers and clinicians alike.

, Doris K. Hansen, MD, Moffitt Cancer Center discussed a comprehensive analysis of pretreatment biomarkers associated with these outcomes in patients receiving ide-cel therapy.

The study, which involved a retrospective analysis of 180 patients, uncovered important findings about the relationship between disease characteristics, immune responses, and patient outcomes.

Hansen also touched on her work comparing ide-cel to ciltacabtagene autoleucel (cilta-cel; Carvykti), another promising chimeric antigen receptor (CAR) T-cell therapy, providing valuable insights for the oncology community on how to optimize therapy for patients facing this challenging disease.

Targeted Oncology: What motivated this investigation into pretreatment biomarkers and their potential link to toxicity and lasting responses in ide-cel therapy for R/R multiple myeloma?

 This study looked at key pretreatment characteristics and biomarkers that may be associated with and predict toxicity, as well as durable responses or disease responses to this product. This was a retrospective analysis performed at Moffitt Cancer Center with a concentrated protocol. A total of 180 patients were included in this analysis. A high proportion of these patients had high-risk disease features. About a third had high plasma cell burden, a third had penta-class refractory disease, and 40% had high-risk genetics.

What were the findings from this analysis?

We identified that patients more likely to experience severe cytokine release syndrome [CRS] received a higher median of T cells. These patients were also more likely to experience greater toxicity, as well as have more advanced disease in terms of ISS staging. They had triple-class refractoriness, high plasma cell burden, and elevated baseline inflammatory markers such as ferritin and C-reactive protein.

We also found associations with certain cytokines and the development of grade 2 or higher cytokine release syndrome. We examined bone marrow immune cell profiling to identify associations with toxicity and response. We found that monocytopenic suppressor cells were associated with reduced T-cell expansion. Conversely, higher proportions of CD4/CD8 ratios and certain central nervous system-positive T cells were associated with responses, as well as cytotoxic natural killer cells.

We identified markers of exposure in patients with high plasma cell burden, including impaired activation, proliferation, and increased expression of inhibitory immune receptors, which contribute to tumor immune tolerance. It is important to note that our study identifies several cytokines, inflammatory markers, and immune cells that are associated with toxicity and response in myeloma patients receiving ide-cel. We hope this provides insight for managing toxicity and potential interventions or therapeutic optimization for high-risk patients, particularly those with non-durable responses.

What are the key takeaways for the community oncology audience?

I think the key takeaway is that while some of these findings are from research labs, there are also clinical biomarkers that can be easily measured in clinical laboratories. If we have patients with significantly high disease burdens based on pre-treatment bone marrow biopsies, we need to consider optimization strategies to reduce their disease burden. This may involve chemotherapy or bridging therapies. If a patient is at high risk for toxicity, we can consider prophylactic interventions or inpatient administration of the product. Additionally, for patients with non-durable responses, maintenance therapies or consolidation therapies may be necessary, particularly for high-risk patients.

Could you delve into the study that evaluated cilta-cel and ide-cel’s safety and efficacy in R/R multiple myeloma?

One of the other abstracts examines the comparative safety and efficacy of standard care and response idecabtagene vicleucel and ciltacabtagene autoleucel. This study addresses a gap due to the lack of prospective randomized controlled trials, as the studies included were single-arm studies with varied responses, toxicities, and survival rates. We used an inverse probability of treatment weighting approach, a form of propensity score matching, to balance confounders across treatment arms while preserving the sample size in this analysis—641 patients were leukapheresis and 586 were infused. We also performed sensitivity analysis.

What are the main take home points from this research?

We found that patients who received cilta-cel were more likely to experience certain toxicities, such as severe CRS, infections, delayed myelotoxicity, and slightly higher non-relapse mortality. However, these findings were not statistically significant. We did observe a trend for more [second primary malignancies], but this was also not significant.

These results should be interpreted with caution. In terms of responses, we identified that cilta-cel was associated with superior responses, particularly in depth of response, and significantly superior overall survival compared to ide-cel. We hope this study provides information for clinical decision-making, patient counseling, and product selection for patients receiving immunotherapies such as ide-cel.

Comprehensive analysis of pre-treatment biomarkers associated with toxicity and durable responses in idecabtagene vicleucel therapy for relapsed/refractory multiple myeloma. Presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, CA; Abstract 896.

Comparative safety and efficacy of ciltacabtagene autoleucel and idecabtagene vicleucel CAR T-cell therapies in relapsed or refractory multiple myeloma. Presented at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10; San Diego, CA; Abstract 936.

Doris K. Hansen, MD, discussed a comprehensive analysis of pretreatment biomarkers associated with outcomes in patients receiving idecabtagene vicleucel therapy

Biomarkers and Treatment Strategies in CAR T-Cell Therapy for R/R Multiple Myeloma 

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.

Sheng F. Cai, MD, PhD

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