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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 75-year-old man presented with fever, a 7-lb unintentional weight loss, and occasional chest pain.

Medical history: hypertension, medically controlled; cardiac failure; atrial fibrillation 

Physical exam: appeared tired; palpable bilateral cervical lymphadenopathy

Immunohistochemistry panel: CD10+ and CD20+ confirmed diffuse large B-cell lymphoma (DLBCL).

Fluorescence in situ hybridization: negative for rearrangements of BCL6, BCL2, and MYC

Whole body PET/CT scan showed activity in multiple lymph nodes above and below the diaphragm (largest node, 3.9 cm) and evidence of subcutaneous tissue involvement.

MRI of the brain showed no evidence of lesions.

Staging: stage IV; International Prognostic Index, high risk; Ann Arbor stage III/IV

The patient received 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), which was well tolerated.

PET scan at the end of treatment showed complete remission.

One year later, the patient presented with diffuse lymphadenopathy, confirmed by PET/CT scan.

The patient was considered ineligible for transplant due to older age and high risk.

Polatuzumab vedotin/bendamustine/rituximab

: What do you think of the treatment choices for this patient?

Loncastuximab tesirine-lpyl [(Zynlonta) may be a good choice of therapy for this patient]. I participated in the trials of the first iteration of CD19 antibody-drug conjugate [therapy for diffuse large B-cell lymphoma (DLBCL)]. We initially used the monomethyl auristatin analog, the same cytotoxic agent used in brentuximab vedotin [Adcetris]; however, the analog we used had the ability to diffuse out so that it [not only] killed the cancer cells but also affected other [cells] around it.

[With this approach], we were seeing some thrombocytopenia [and bone] marrow toxicity, so we eventually moved to using the pyrrolobenzodiazepine [PBD] linker, [which is what is used in] loncastuximab. I don’t know if [Seagen Inc] purchased the PBD linker from Seattle Genetics or if they developed their own PBD linker with their own CD19 antibody. [But, based on my experience] using loncastuximab and [its good] safety and tolerability profile, I would consider it a good choice for this patient. Tafasitamab [Monjuvi] plus lenalidomide [Revlimid] would be equally relevant. I've certainly used lenalidomide a lot in relapsed/refractory [R/R] DLBCL. I don’t know whether tafasitamab/lenalidomide plus rituximab [Rituxan] would be better than tafasitamab/lenalidomide dual therapy.

10 or more years ago suggesting that tumor responses to lenalidomide weren’t [based] simply on [activated B-cell or germinal center B-cell (GCB) subtype]. Rather, it seemed to be those patients with interferon regulatory factor 4 [IRF4]- or multiple myeloma oncogene 1 [MUM1]-positive [tumors] derived a greater benefit from lenalidomide in terms of direct cytotoxicity, so I tend to use lenalidomide in patients with MUM1- or IRF4-positive tumors.

How could selinexor (Xpovio) be used for this patient’s treatment?

Selinexor [Xpovio] is a great drug, but [patients experience] a lot of nausea and fatigue with it. It’s a potent histone deacetylase [inhibitor], and it works to bring about stable disease and sometimes partial responses [PRs], but [it can be challenging] to manage the fatigue and nausea associated with it. In some cases, I’ve used atypical antipsychotics to help patients through. I think if selinexor were partnered with another drug, such as bortezomib [Velcade], or one of the newer proteosome inhibitors, or [perhaps a kinase inhibitor, such as] ibrutinib, the dose could be reduced, and it would be better tolerated.

Polatuzumab vedotin [Polivy] plus bendamustine [Treanda] and rituximab [pola-BR] is another good treatment choice for relapsed DLBCL. [However,] the challenge with using loncastuximab or polatuzumab, [particularly in the setting of relapsed disease], is that multidrug efflux pumps [push the drug out]. We often see this with inotuzumab [Besponsa], used to treat acute lymphocytic lymphoma. The more heavily pretreated someone is, the more you run into difficulty with drug efflux pumps pumping the drug out and [thereby reducing its] antilymphoma activity.

What are the data behind using loncastuximab for treatment of R/R DLBCL?

Loncastuximab is a CD19-directed antibody drug conjugate, which uses the PBD linker as its [cytotoxic] payload. Loncastuximab binds to the CD19 [antigen and] then is internalized within the tumor cell where it releases the drug. [Thus], loncastuximab is [essentially] a cytotoxic chemotherapy.

The phase 2 LOTIS-2 trial [NCT03589469] evaluated loncastuximab for treatment of R/R DLBCL.

 Trial patients received 150 μg/kg per body weight [on day 1] of the initial two 21-day cycles, and then the dose was [halved to] 75 μg/kg on subsequent cycles for up to a year.

 Patients who had a remission [could go on to maintenance therapy], administered every 12 weeks for up to another 3 years. Loncastuximab is a drug that [can be used as] maintenance therapy.

What were the results of the LOTIS-2 trial?

Most of the patients enrolled [in LOTIS-2] had DLBCL histology. Some patients were categorized as having high-grade BCL [HGBCL], which is part of the DLBCL categorization. HGBCL is that what we used to call B-cell lymphoma, not otherwise specified with features indeterminate between [Burkitt] lymphoma and DLBCL. A small percentage of patients in LOTIS-2 were categorized as having primary mediastinal B cell lymphoma.

Approximately 10% of patients had double- or triple-hit lymphoma, and 14% had double- or triple-expressor lymphoma. The trial included patients with transformed follicular lymphomas; overall, two-thirds of patients had advanced stage disease. Most [trial patients had] relapsed disease [68%], some had refractory disease [20%], and a few had had prior autologous stem cell transplant [14%] or allogenic stem cell transplant [1%], but most patients had received only chemotherapy.

The overall response rate [ORR] to loncastuximab was 48%. Among patients who responded, most had a response after 41 days, which would be after 2 cycles of loncastuximab. The mean number of loncastuximab cycles was around 4 [and a half], which provides some insight into the duration of remission [we might expect with loncastuximab].

 Response to loncastuximab was consistent across patient subsets [defined by age, tumor subtype, and prior therapy]. No group seemed to do considerably better or worse [than any other], and even prior transplant patients seemed to do well, although few were included in the trial.

 [Notably], 6 of 13 patients who had had prior chimeric antigen receptor [CAR]-T cell immunotherapy had a preserved response to loncastuximab, [which has implications for the] concept of CD19 antigen loss.

Among the 24% of patients who had a complete remission [CR], remission tended to be of long duration [median duration of remission (DOR), 12.6 months]. Among patients who had a PR, the DOR was much shorter [5.7 months]. The overall median DOR was approximately 10 months.

Trends in median progression-free survival [PFS] closely mirrored those of DOR. The first dip in PFS occurred after the second cycle of loncastuximab,

 [which may be because the trial conducted its] first response assessment at that time. The next dip in PFS occurred [approximately] 2 cycles after that, after which patients tended to do well because they were responding to therapy. Median overall survival [OS] in LOTIS-2 was 9.9 months,

 which is consistent with our expectations. Loncastuximab was associated with a CR in [approximately one-fourth of] patients, and half of patients had at least a PR to loncastuximab. So, data from this trial are quite encouraging. [Fifteen] patients received CAR T-cell therapy after [the trial], with an ORR of 46.7%; 9 patients went on to receive a stem cell transplant after [response to] loncastuximab.

What adverse events (AEs) are important to highlight from this treatment?

It's important to talk about AEs associated with loncastuximab. Peripheral edemas are a notable AE because it's something unique and it occurred in 20% of patients.

 Localized edema can also occur with loncastuximab but it is not as common as a peripheral edema. To manage edema, patients with a weight gain of 1 kg from day 1 received spironolactone. Elevated γ-glutamyl transferase occurred in some patients [17.2%], as did liver toxicity [20%]. As with any antibody drug conjugate, cytopenias [can occur with loncastuximab]. High-grade neutropenia [occurred in approximately one-fourth] of the patients, high-grade thrombocytopenia in [17.9%], and high-grade anemia in [10.3%]. Older patients did not experience greater toxicity to loncastuximab compared with younger patients, so it may be an option for older patients who don’t want or are not eligible to proceed to CAR T-cell or stem cell therapy.

1. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. 

. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493

2. Carlo-Stella C, Zinzani PL, Kahl B, et al. Initial results of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory diffuse large b-cell lymphoma. Presented at: European Hematology Association meeting; June 12, 2020; virtual. Accessed September 10, 2021. https://bit.ly/2VJiPhQ

3. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. 

. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

4. Caimi P, Ai WZ, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2. J

39(suppl 15):7546. doi:10.1200/JCO.2021.39.15_suppl.7546

5. Caimi P, Ai WZ, Alderuccio JP, et al. Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large b-cell lymphoma. Presented at: 62nd American Society of Hematology Annual Meeting and Symposium; December 5, 2020; virtual. Accessed September 10, 2021. 

During a live virtual event with other physicians, Bijal Shah, MD, MS, discussed treatment options for patients with diffuse large B-cell lymphoma and the data that backs up the efficacy for these options.

Percy Lee, MD

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