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Robert L. Kirkman, MD, President and CEO, Oncothyreon, discusses the development of ONT-380, an oral HER2-specific inhibitor, for the treatment of patients with HER2-positive metastatic breast cancer.

The Development of the HER2-Specific Inhibitor ONT-380 for Breast Cancer

One year since the FDA’s Oncologic Drugs Advisory Committee (ODAC) 

voted in favor of using minimal residual disease

 (MRD) as an end point to support accelerated approval of drugs, changes are taking place in ongoing clinical trials and cancer research.

The groundbreaking decision led to new trials designed with MRD end points from the start and amendments to existing trial protocols that will enable these trials to report results and submit to the FDA for approval much more quickly.

“If the study is successful in showing higher rates of MRD negativity for a new therapy, that treatment could be approved based on accelerated approval, so patients can get access to new drugs 10 years sooner than just waiting for the clinical outcome. That's a huge step forward for the field and for all the patients,” 

Landgren, professor of medicine and chief of the myeloma division and the Myeloma Institute at the Sylvester Comprehensive Cancer Center at the University of Miami, led the research efforts to support the use of MRD for over a decade.

Additionally, in the past year, the ODAC vote sparked new interest for using MRD more actively in other disease types and improving MRD assays for patients.

MRD serves as a surrogate for clinical outcomes and can be assessed much more rapidly than progression-free survival (PFS). Investigators in ongoing trials have amended their protocols to use both MRD negativity and PFS as coprimary end points for accelerated approval. Investigational therapies that could be evaluated based on MRD include cell therapies, T-cell engagers, antibody-drug conjugates, and small molecule compounds.

“We have also seen that all the companies that have ongoing trials that used to have only PFS as the primary end point have…negotiated with the FDA to revise or amend their protocols to also include MRD as a coprimary end point,” said Landgren. “Everything is ongoing has been updated, and all the new trials have been including [MRD].”

Landgren and other researchers have also presented data to the European Medicines Agency. He said it may take longer for other regulatory agencies to review the data and authorize MRD as an approval end point.

Additionally, researchers in other disease types such as chronic lymphocytic leukemia and lymphoma have expressed interest in following the same path, though they will need to collect the data to support it.

Landgren and Sean M. Devlin, PhD, a biostatistician at Memorial Sloan Kettering Cancer Center in New York, published a review in 

 outlining the long process of developing supporting evidence, which led to the acceptance of MRD by the FDA.

 Two research groups, one from the National Cancer Institute and National Heart, Lung, and Blood Institute and the a second made up of other researchers, developed studies that provided evidence for the use of MRD.

The review noted the utility of overall response rate [ORR] as a meaningful end point in myeloma has decreased as current standard therapies are showing high ORRs comparable to investigational agents with superior PFS. Evaluating MRD during trials provides an alternative that can still yield results more rapidly than mature PFS. MRD at 10

 sensitivity—detecting 1 malignant cell in 100,000 cells—is supported by the FDA as the minimum threshold for MRD analysis, with 10

 sensitivity also being evaluated in trials.

They provided a set of meta-analyses showing MRD negativity was associated with superior PFS and OS outcomes and described their methodology for making meta-analyses to establish it as a surrogate end point for PFS or OS using both trial-level data and patient-level data. Collecting individual patient data was necessary to demonstrate the association between MRD and long-term outcomes was established regardless of patient population, disease setting, or treatment history. This required researchers to gather individual patient data from industry-sponsored trials.

To emphasize the impact of using MRD vs PFS for approval, Landgren and Devlin showed a trial in newly diagnosed multiple myeloma (NDMM) with a comparator arm that had an 84% 4-year PFS rate would require 11.5 years to read out a significant PFS difference with an HR of 0.7, as opposed to only 3.7 years to show a difference in MRD negativity.

There are more avenues to develop MRD in myeloma in the future. Landgren said there have been improvements in the use of bone marrow–based MRD assays as well as the development of blood-based assays and imaging-based technologies that could change how trials are performed.

Additionally, using MRD status to guide further treatment is another approach yielding results. The phase 3 ADVANCE trial (NCT04268498) is investigating the addition of daratumumab (Darzalex) to KRd (carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone) in NDMM. Patients could receive autologous stem cell transplant if they were MRD-positive and otherwise go directly to maintenance therapy. This trial’s outcomes will be presented at the 2025 American Society of Clinical Oncology Annual Meeting and European Hematology Association Congress.

Read the full interview with Dr Landgren on the changes taking place in myeloma research.

1. Cancer research in the wake of a key FDA decision on minimal residual disease. University of Miami. April 10, 2025. Accessed May 13, 2025. 

2. Landgren O, Devlin SM. Minimal residual disease as an early endpoint for accelerated drug approval in myeloma: a roadmap. 

. 2025;6(1):13-22. doi:10.1158/2643-3230.BCD-24-0292

In the last year, there has been excitement about the use of MRD in multiple myeloma trials and new approaches to assessing clinical outcomes in patients. 

Clinical

One Year After ODAC Decision: Myeloma Studies Move to Adopt MRD End Point

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.

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A 52-year-old, postmenopausal woman had a history of grade II, node-negative invasive ductal carcinoma (IDC).

Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27

Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.

Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).

Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.

The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.

Required 1 dose reduction to 400 mg ribociclib due to neutropenia.

Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.

She noted mild increase in lower back pain​.

Tissue-based next-generation sequencing (NGS)

Peripheral blood (plasma) circulating tumor (ct) DNA

Tissue-based NGS with ctDNA at progression

 It looks like most people in the first-line setting would do tissue-based next-generation sequencing [NGS], on its own.... Any thoughts on this?

 You can use a company that does both and it doesn't cost the patient anything extra. If [you] do both concurrently, even if you're one of the pilot sites like we are, you can use them concurrently. Certainly, why not just do both if it's not going to cost the patient anything extra? You may possibly get some information out of [either test] if their tissue doesn't come out inadequate.

 I like the speed with which we get an answer from ctDNA. With a newly diagnosed patient with metastatic breast cancer, I still want that tissue biopsy done to confirm their ER/PR/IHC [status]. But the molecular profiling I find takes a bit longer, so I tend to send off the ctDNA to get a quick answer, so I can start with my planning, but go ahead and send off the tissue-based NGS also.

During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, led a discussion on whether to order next-generation sequencing and/or circulating tumor DNA testing for a patient with hormone receptor–positive breast cancer after progression in the first article of a 2-part series. 

Robert L. Kirkman, MD

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