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Christopher Y. Park, MD, PhD, hematopathologist, Memorial Sloan Kettering Cancer Center, discusses some of the biggest challenges in myelodysplastic syndromes (MDS). 


Biggest Challenges in MDS

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

The Targeted Pulse: FDA Approvals in HCC and CRC, Promise for SCLC, and More

FDA Greenlights Potent Nivolumab/Ipilimumab Combo for First-Line Use

The FDA granted approval for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as a first-line treatment for adults with unresectable hepatocellular carcinoma (HCC). This decision is supported by findings from the phase 3 CheckMate 9DW (NCT04039607) clinical trial.

In this study, 668 patients with unresectable HCC who had not received prior systemic therapy were randomized to receive either the nivolumab and ipilimumab combination or the investigator's choice of standard treatments. The results demonstrated a statistically significant improvement in median overall survival (OS) for patients receiving the combination therapy (23.7 months) compared with those receiving lenvatinib (Lenvima) or sorafenib (Nexavar; 20.6 months). The 24-month OS rates were 49% and 39%, respectively. For more details, access the full article 

FDA Approves Dual Immunotherapy for Frontline MSI-H/dMMR Colorectal Cancer

The FDA also approved the nivolumab plus ipilimumab for the first-line treatment of adult and pediatric patients aged 12 and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC). Alongside this, the FDA granted regular approval to nivolumab monotherapy for previously treated patients in this same group, converting its prior accelerated approval.

These decisions are supported by the phase 3 CheckMate-8HW (NCT04008030) trial. Results showed the nivolumab/ipilimumab combination significantly improved progression-free survival (PFS) compared with chemotherapy in the first-line setting. Median PFS was not reached with the combination vs 5.8 months with chemotherapy.

The trial also compared the combination against nivolumab monotherapy across all lines of treatment, finding superior PFS and a higher objective response rate (ORR) for the combination.

Experts note this dual immunotherapy addresses an unmet need for patients with this aggressive form of CRC. For more details, access the full article 

Tarlatamab Shows Overwhelming Survival Benefit

The phase 3 DeLLphi-304 (NCT03319940) trial demonstrated that tarlatamab-dlle (Imdelltra) significantly improved OS compared with standard-of-care chemotherapy in patients with small cell lung cancer (SCLC) that progressed after 1 line of platinum-based chemotherapy. This positive result met the trial's primary end point at a planned interim analysis. The safety profile of tarlatamab was consistent with previous findings.

These topline results from the global, randomized study, which enrolled 509 patients with SCLC, suggest a substantial clinical benefit and potentially establish tarlatamab as a new standard in this setting.

Tarlatamab, a bispecific T-cell engager, was previously granted accelerated approval by the FDA in May 2024 for this patient population based on earlier phase 2 data.

For more information, access the full article 

Next-Gen IORT: ZEISS INTRABEAM 700 Gains FDA Clearance

The ZEISS INTRABEAM 700 received FDA 510(k) clearance for enhanced intraoperative radiation therapy (IORT). This next-generation platform combines robotic precision, a digital-first workflow, and integrated connectivity, making it valuable for oncologic surgeons, particularly in neuro-oncology and breast cancer.

The system delivers robotic-assisted precision, enhancing control during IORT. Its SMART Stand allows for seamless transitions between approach and navigation modes, managed via touch controls. Precise applicator positioning, active vibration damping, and dynamic stabilization ensure consistent radiation delivery.

The INTRABEAM 700 emphasizes efficiency with single-use applicators, RFID-assisted management, and a user-friendly interface. Integrated Radiance™ software enables real-time radiation planning, improving preoperative assessment and intraoperative confidence. The system also integrates into surgical infrastructure and hospital information systems. Several clinical trials are investigating the INTRABEAM platform.

Larotrectinib Receives Full FDA Approval Following Promising Trial Results

Larotrectinib (Vitrakvi) has received full FDA approval for adult and pediatric patients with solid tumors that have an 

 gene fusion, lack known acquired resistance, are metastatic or where surgery would cause severe morbidity, and lack alternative treatments or have progressed after prior therapy.

This approval is based on data from 3 open-label, single-arm trials. An analysis of 339 patients with unresectable or metastatic solid tumors harboring an 

 gene fusion showed an ORR of 60%, with a complete response rate of 24%. The median duration of response was 43.3 months.

The full approval follows an earlier accelerated approval in November 2018. For more information, access the full article 

Thank you for joining us for this week’s Targeted Pulse. Look out for more recaps to come.

The week marked several FDA approvals for drugs and devices, plus data continues to show tarlatamab’s benefit in small cell lung cancer.

Fixed duration ibrutinib (Imbruvica) with venetoclax (Venclexta) led to durable outcomes when used for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), even in patients with bulky disease at baseline, according to updated findings from the phase 2 CAPTIVATE study (NCT02910583).

In the phase 2 CAPTIVATE study, investigators assessed the combination of ibrutinib and venetoclax as a first-line, all-oral, once-daily regimen for patients with CLL/SLL.

 Two cohorts were explored: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and fixed duration (FD cohort).

With up to 5.5 years of follow-up, the FD regimen demonstrated durable progression-free survival and overall survival rates, even among high-risk patients with genomic features like del(17p) or mutated 

. Safety was also manageable, with grade 3 or greater adverse events (AEs) observed in around 60% of patients. Few patients discontinued treatment due to AEs.

“The findings are highly positive for general hematologists because they demonstrate the availability of an easy-to-administer treatment combination. Both ibrutinib and venetoclax are oral therapies, which simplifies administration after the initial debulking phase with ibrutinib,” explained Paolo Ghia, MD, PhD, in an interview with 

In the interview, Ghia, deputy director of the Division of Experimental Oncology in San Raffaele Scientific Institute in Milan, Italy, full professor of medical oncology, a group leader in the B-cell Neoplasia Unit, and the head of the Strategic Research Program on CLL at the Università Vita Salute San Raffaele, provided background on the CAPTIVATE trial in CLL/SLL treatment and further discussed data which were presented at the 2024 American Society of Hematology Annual Meeting and Exposition.

: Can you provide an overview of the CAPTIVATE trial and what investigators sought to evaluate?

The CAPTIVATE trial is a phase 2 international trial where we investigated the combination of ibrutinib, the BTK inhibitor, and venetoclax, a BCL2 inhibitor, in frontline patients with CLL. And in particular, this combination was given with 3 months of debulking with the ibrutinib only, and then 12 months of the combination between ibrutinib and venetoclax. The study involved only young patients below 70 years of age.

There were 2 different cohorts, not arms. They were not randomized to each other. One cohort was MRD driven, so at the end of the 15 months of treatment, patients were randomized based on the level of undetectable MRD. But more importantly, we had the so-called fixed-duration cohort, where patients after 15 months of treatment all stopped the treatment regardless of the level of undetected MRD. And that is actually the regimen that has been approved in Europe, and it can be used now as a standard regimen.

What findings from the trial have been particularly noteworthy?

The study helped us understand the benefits of a combination treatment for patients with chronic lymphocytic leukemia in the frontline setting. This combination has also been explored in a randomized phase 3 study called the GLOW study, which involved elderly patients around 65 years of age. These patients were either treated with venetoclax or chlorambucil, the standard chemotherapy for this patient group.

The combination treatment showed significant benefits. At the 5.5-year follow-up, data presented revealed that about two-thirds of patients had not experienced disease progression and were still responding to treatment. Of particular interest, patients with unmutated immunoglobulin genes, but without 

 abnormalities, showed similar progression-free survival outcomes. This suggests that the combination treatment is highly effective in high-risk patients, particularly younger patients with mutated immunoglobulin genes.

From a safety perspective, there was no notable increase in adverse events compared with previous treatments. The exception was diarrhea, which affected more than 50% of patients, but most cases were grade 1 or 2. All other adverse events occurred at frequencies similar to those seen with single-agent therapies, such as ibrutinib or venetoclax.

What from this study was presented at ASH 2024?

In an interview, Paolo Ghia, MD, PhD, discussed updated data from the phase 2 CAPTIVATE trial of ibrutinib and venetoclax in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Christopher Y. Park, MD

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