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Saeed Rafii, MD, PhD, MRCP, discusses the phase Ib JAVELIN solid tumor trial. The trial looks at the anti-PD-L1 antibody avelumab in patients with locally advanced or metastatic breast cancer.

Dr. Saeed Rafii on the Phase Ib JAVELIN Trial Examining Avelumab in Breast Cancer

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

Subcutaneous daratumumab (Darzalex Faspro) significantly reduced the risk of disease progression or death and was associated with an improved overall survival rate vs active monitoring in patients with intermediate- or high-risk smoldering multiple myeloma, according to primary results from the phase 3 AQUILA study (NCT03301220).

The findings, which were presented at the 

, showed that the greatest benefit with the subcutaneous formulation was seen among patients with high-risk disease.

“We believe that with these data, patients with high-risk smoldering myeloma may benefit from immediate treatment with daratumumab, and that observation for this particular subset of patients may not be an adequate option,” Meletios-Athanasios Dimopoulos, MD,professor and chairman, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra General Hospital, in Athens, Greece, said during a press briefing at the meeting.

After a median follow-up of 65.2 months (range, 0-76.6), the median PFS was not reached (NR) with daratumumab monotherapy compared with 41.5 months with active monitoring. Further, 60-month PFS rates were 63.1% and 40.8%, respectively, reducing the risk for disease progression or death by 51% (HR, 0.49; 95% CI, 0.36-0.67; 

“Furthermore, there were fewer patients in the daratumumab arm who progressed with CRAB criteria [12 vs 34, respectively] and with SLiM criteria [50 vs 65]. So not only [did] daratumumab [delay] progression, but [patients who received this agent] also avoided a clinically obvious and important type of progression,” Dimopoulos explained.

In total, 15 patients in the daratumumab arm (7.7%) and 26 patients in the active monitoring arm (13.3%) died. The 60-month OS rates were 93.0% with daratumumab compared with 86.9% with active monitoring, reducing the risk for death by 48% (HR, 0.52; 95% CI, 0.27-0.98). “The majority of deaths were due either to progressive disease during or after the study,” Dimopoulos added.

In addition, daratumumab monotherapy demonstrated a superior overall response rate (ORR) of 63.4% compared with 2.0% with active monitoring (

 < .001), with an improved median time to first-line treatment for active myeloma (NR vs 50.2 months, respectively; [HR, 0.46; 95% CI, 0.33-0.62; 

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 40.4% of patients in the daratumumab arm compared with 30.1% of those undergoing active monitoring, with the most common being hypertension (5.7% vs 4.6%, respectively). The most common serious TEAE was pneumonia (3.6% vs 0.5%, respectively).

“There were no new safety signals from what we know,” Dimopoulos said. “There was somehow an increased risk of infection, but these were well treated and reversible.”

Eleven patients discontinued daratumumab treatment due to TEAEs, whereas 90 patients underwent dose modifications as a result.

Although observation is the current standard of care for this patient population, Dimopoulos suggested that therapeutic intervention may benefit patients with high-risk disease.

At the ASH meeting, Dimopoulos presented on the primary analysis results from the phase 3 AQUILA study after 36 months of daratumumab monotherapy compared with active monitoring, aimed at assessing the effect of early intervention to prevent end-organ damage and progression to active disease.

“This is the largest phase 3 trial conducted in patients with high-risk smoldering myeloma,” Dimopoulos noted.

In the open-label, multicenter, randomized phase 3 trial, investigators randomly assigned patients 1:1 to receive either subcutaneous daratumumab monotherapy (n = 194) or active monitoring (n = 196) for 36 months or until confirmation of disease progression, whichever occurred first. Daratumumab was administered at a dose of 1800 mg on a weekly basis in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter in 28-day cycles.

Following treatment, patients underwent efficacy follow-up until progression by SLiM-CRAB criteria, with survival follow-up conducted every 6 months until the end of the study.

Patients were enrolled at 124 sites across 23 countries between December 10, 2017, and May 27, 2019.

Patients were eligible for the trial if they were 18 years of age or older; had received a confirmed diagnosis of smoldering multiple myeloma, in accordance with International Myeloma Working Group criteria, in the past 5 years; had measurable disease; had an ECOG performance status of 0 or 1; and were required to be at high risk for progression to active myeloma. High risk was identified with a percentage of clonal plasma cells in bone marrow of at least 10% and the presence of at least 1 of the following risk factors: serum M-protein level of at least 30 g/L, IgA disease, immunoparesis with reduced levels of 2 uninvolved immunoglobulin isotypes, serum involved/uninvolved free light chains between 8 and 100, or clonal plasma cells in bone marrow of more than 50% to less than 60%.

Patients were stratified by the number of risk factors for progression to multiple myeloma (more or less than 3).

PFS served as the primary end point, and secondary end points included ORR, time to first-line treatment for myeloma, PFS on first-line treatment for myeloma, and OS.

Median age was 64 years (range, 31-86), and 40.5% of patients were classified as having high-risk disease in accordance with the Mayo 2018 risk criteria. The median time from initial diagnosis of smoldering myeloma to randomization was 0.74 years.

By the clinical cutoff (May 1, 2024), 65.5% and 40.8% of patients in the daratumumab and active monitoring arms, respectively, completed 36 months of treatment. The most common reason for treatment discontinuation across both arms was progressive disease (21.8% vs 41.8%, respectively).

In November 2024, a supplemental biologics license application was submitted to the FDA, and an extension of indication application was submitted to the European Medicines Agency, for subcutaneous daratumumab to treat adult patients with high-risk smoldering multiple myeloma based on results from this trial.

“I believe it is important to have an approved therapy, and then based on the practice of the physician and the patient they can make a joint decision whether [the patient] will get the treatment,” Dimopoulos said.

1. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Phase 3 Randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the Aquila study. 

. 2024;144(supplement 1):773. doi:10.1182/blood-2024-201057

2. DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) shows 51 percent reduction in risk of progression to active multiple myeloma for patients with high-risk smoldering multiple myeloma. Johnson & Johnson. Published: December 8, 2024. Accessed: December 8, 2024. 

Primary results from the phase 3 AQUILA study showed that subcutaneous daratumumab elicited a significant improvement in PFS compared with active monitoring in patients with smoldering multiple myeloma.

Conference News

Subcutaneous Daratumumab Significantly Delays Progression in Smoldering Myeloma

The FDA has accepted a biologics license application (BLA) and granted priority review for glofitamab (RG6026), an investigational CD20xCD3 T-cell engaging bispecific antibody, for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy.

The basis of the BLA and priority review come from findings from the pivotal phase 1/2 NP30179 study (NCT03075696) in which glofitamab led to durable response rates in patients with heavily pre-treated LBCL. Patients enrolled achieved a 40% complete response (CR).

“Unfortunately, people with relapsed or refractory large B-cell lymphoma have a poor prognosis and desperately need additional therapies that are immediately available at the time of relapse,” said Levi Garraway, MD, PhD, chief medical officer and head of global product development of Roche, in the press release. “Even for patients whose cancer is rapidly progressing, glofitamab given for a fixed duration has shown impressive efficacy and long-term durability, with patients continuing to experience a complete remission after treatment has concluded.”

In the phase 1/2 multicenter, open-label, dose-escalation, and dose-expansion NP30179 study, investigators aim to determine the safety, efficacy, and pharmacokinetics of glofitamab in patients with R/R LBCL.

Patients included in the trial are those 18 years and older and must have previously received multiple courses of therapy. Patients must have measurable disease, an ECOG performance status of 0-1, a life expectancy of 12 weeks or greater, adequate liver, hematological, and renal function, resolved to grade 1 or less adverse events from prior anti-cancer therapy, and provide a fresh biopsy.

Among those enrolled, 85.1% of patients were refractory to their most recent therapy and 33.1% of patients had received prior chimeric antigen receptor T-cell therapy. 

The primary end point of the trial is CR rate by an independent review committee and secondary end points include overall response rate, duration of response, progression-free survival, safety, and tolerability.

Findings showed that among the 155 included in the trial, 40.0% (n = 62) achieved a CR and 51.6% (n = 80) achieved an objective response. The median follow-up time was 13.4 months. Additionally, of patients who achieved a CR, 73.1% continued to experience a response at 12 months. The median duration of CR was not reached but the median duration of response was 18.4 months.

Earlier cut-off of data from the study were 

presented at the American Society of Hematology 2022 Annual Meeting

in December 2022. Data revealed that when glofitamab was administered as a fixed-duration treatment, patients had early and durable CRs and most patients who had achieved a CR at the end of treatment experienced durable responses.

Based on data from a phase 1/2 study, a  biologics license application has been accepted for glofitimab and the product has been granted priority review to for relapsed/refractory large B-cell lymphoma.

Saeed Rafii MD, PhD, MRCP

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