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Colton Ladbury, MD, a radiation oncologist and assistant clinical professor in the Department of Radiation Oncology at City of Hope.

Colton Ladbury, MD, discusses radiation therapy for hematologic malignancies, total marrow irradiation, and findings that were presented during the American Society for Radiation Oncology Annual Meeting.


Ladbury Discusses Advancements in Total Marrow Irradiation

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

Fedratinib (Inrebic) as a maintenance therapy following allogeneic hematopoietic cell transplant given at a 400 mg daily dose was determined to be safe and established as the maximum tolerated dose (MTD) for patients with myeloproliferative neoplasms (MPNs).

Findings come from a recent phase 1 trial where experts explored the potential of fedratinib, a JAK2 inhibitor already approved for pre-transplant myelofibrosis, as a post-transplant maintenance therapy to reduce relapse risk and mitigate graft-vs-host disease (GVHD).

, Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the department of bone marrow transplant and cellular immunotherapy, discussed the trial’s findings, the safety profile of fedratinib, and its evolving role in the post-transplant setting.

Targeted Oncology: Could you discuss the background of this study and what motivated the research?

 One of my areas of research is transplant for myelofibrosis and myeloproliferative neoplasms. While transplant can be curative, the cure rate, depending on the study, is generally in the 40% to 60% range. The main reason patients are not cured by transplant is largely the risk of relapse, which [occurs when] the cancer returns after the transplant. For those who do not relapse, there is also the risk of toxicity, such as GVHD, where the transplant attacks the patient's own body. There are many strategies in development, both for myelofibrosis and other cancers, to reduce the risks of relapse and GVHD.

One commonly used strategy to reduce relapse risk is maintenance therapy, which means finding a low-toxicity drug, generally an oral drug, that is continued after transplant to suppress the cancer and prevent relapse while the transplant ultimately takes over the bone marrow and cures the patient. In the case of myelofibrosis, one appealing class of drugs is called JAK2 inhibitors. We specifically chose fedratinib, which is FDA-approved for treating myelofibrosis in patients before transplant, to see if it could reduce the risk of post-transplant relapse in patients with myelofibrosis.

Secondarily, JAK2 inhibitors have been shown to be effective in treating GVHD, so we hoped that fedratinib could also reduce GVHD by blocking the JAK2 pathway, which is known to be involved in GVHD's pathophysiology.

What were the objectives, methods, and design of the trial?

This was a traditional phase 1, 3+3 dose escalation study. We started patients on half of the FDA-approved dose of fedratinib. The FDA-approved dose for pre-transplant patients is 400 mg per day, so in this study, the first 2 patients were given 200 mg per day. If that was well tolerated, we increased the dose to 300 mg per day for the next 3 patients, and then 400 milligrams per day for the next group, [which is the] standard dose. We did this because combining fedratinib with transplant might cause more toxicity than in patients who have not had a transplant, so we did not assume that the standard dose would be appropriate post-transplant.

Patients enrolled in the study had undergone their first allogeneic transplant for myelofibrosis or another MPN. We even included patients with myelodysplastic syndromes [MDS] and MPNs, which include conditions like chronic myelomonocytic leukemia and atypical chronic myelogenous leukemia. After recovering from the transplant and fully engrafting—meaning the transplant has taken hold in the bone marrow—patients started fedratinib between 60 to 100 days post-transplant. They continued on the drug for up to 1 year after the transplant.

We had a 30-day cycle: patients would come in for a checkup each month, and if they were doing okay, we'd refill the drug and continue. The primary end point was to determine the maximum tolerated dose, and the secondary end point was disease-free survival or progression-free survival, meaning the percentage of patients who were alive and had not relapsed.

How did the fedratinib safety profile compare with expectations? Were there any unexpected toxicities observed?

Typically, with fedratinib, the main toxicities are cytopenia, which is low blood counts, and [gastrointestinal] toxicity, such as nausea, vomiting, or diarrhea. Before the drug was widely recognized, there were reports of Wernicke's encephalopathy, which is a type of confusion due to a deficiency in vitamin B1. In this study, we were proactive about ensuring patients had adequate thiamine levels before starting fedratinib, [following the FDA's guidelines].

What we saw in terms of toxicity was mainly cytopenias. We did have some grade 3 cytopenias and even 1 patient with grade 4 thrombocytopenia, which required stopping the drug for that patient. But overall, it was fairly well tolerated. Nausea, vomiting, and diarrhea were generally mild—grade 1 or 2—and we did not see any other dose-limiting toxicities during the 30-day dose-limiting toxicity window. However, some patients did withdraw from the study early due to side effects, even though these weren’t severe enough to be classified as dose-limiting. Blood level changes, especially after a transplant, can be worrying for patients, and I realized this was psychologically difficult for some of them.

Did the data suggest that fedratinib maintenance therapy helped reduce the risk of disease relapse?

Yes, we treated 12 patients in total, and the dose level of 400 mg per day was determined to be the recommended phase 2 dose, meaning it was deemed safe. Now, in terms of relapse, we saw that 4 patients relapsed within the first year, which is probably on par with what you would expect for patients who are not in this study. However, when we looked closer, we saw a dose-dependent response. Three out of three patients at the lowest dose level (200 mg) relapsed, and 1 out of 3 patients at the middle dose (300 mg) relapsed. But at the highest dose level (400 mg), none of the 6 patients relapsed at the time of reporting.

There is 1 patient still on fedratinib who has not completed the full 1-year follow-up, so it is not confirmed whether he’ll relapse, but overall, the data suggest that higher doses might be more effective at preventing relapse.

Were any quality of life assessments conducted during the study?

No formal quality of life assessments were conducted. However, GVHD in general is a major contributor to reduced quality of life. We did see a dose-dependent response in terms of GVHD as well. At the lowest dose level, we had 1 patient with moderate-to-severe chronic GVHD, but no patients at the higher dose levels had moderate-to-severe GVHD. This suggests that fedratinib may help improve quality of life by reducing GVHD. That said, we did not assess quality of life formally, though some patients who withdrew from the study early cited adverse events like nausea and blood level changes as factors in their decision.

Based on these findings, how do you see fedratinib’s role evolving for patients with MPNs?

My hope is that fedratinib can become a standard maintenance therapy. These results suggest that it warrants further investigation. While we have only treated 12 patients, the promising results justify larger trials. The next step would be a phase 2 trial with a larger patient population, and if that is successful, we could move on to phase 3, where patients are randomized to receive fedratinib or not as part of maintenance therapy.

We will need to be selective about which patients benefit most. Not all MPN patients will respond to maintenance therapy. For example, myelofibrosis patients seemed to have a better response to fedratinib than chronic myelomonocytic leukemia patients, with lower relapse rates in the former. Additionally, patients with a 

 mutation seem to have a better response, so we might focus on those patients moving forward. Ultimately, I could see fedratinib becoming a maintenance therapy for 

-positive patients, especially those who are at high risk for relapse post-transplant.

For the community oncology audience, what would you say are the key takeaways from this research?

The key takeaway is that fedratinib in the post-transplant setting is safe, well-tolerated, and shows potential to prevent both relapse and chronic graft-vs-host disease. Importantly, while the study was conducted at a large cancer center, fedratinib is a drug that can be prescribed and managed in the community setting. Many patients have their transplant at a major center like Moffitt, but then return to their local oncologists for follow-up care. So, this drug could be used by community physicians to manage these patients post-transplant.

Elmariah H, Kim J, Hornfeck E, et al. Safety of fedratinib as a maintenance strategy after allogeneic hematopoietic cell transplant for myeloproliferative neoplasms. Blood. 2024;144(suppl 1):1048. doi:10.1182/blood-2024-210830

Hany Elmariah, MD, discussed the safety profile of fedratinib and its evolving role in the post-transplant setting for patients with myeloproliferative neoplasms.

Fedratinib Shows Safety, Potential as Post-Transplant Therapy in MPNs 

Molecular oncology is reshaping how oncologists understand, diagnose, and treat cancer. In contrast to traditional methods, which primarily rely on histopathological examination, molecular oncology delves deeper, identifying the genetic and molecular changes that fuel tumor growth.

By sequencing a patient’s tumor and mapping its unique genetic alterations, clinicians can tailor treatments to the individual, leading to more precise and effective outcomes.

“For many years, cancer was completely defined by what it looked like under the microscope. We still do that, but now we have additional information that we can get by sequencing these tumors and learning what causes them to be the genetic drivers. It can tell us things about how they are going to respond to therapies and it can make them be able to use certain therapies that are targeted to these specific mutations,” explained Alec Kimmelman, MD, PhD, in an interview with 

Molecular profiling has already led to several successes across cancer types, resulting in targeted therapies that are changing the standard of care. In cancers like lung, breast, and colorectal, molecular testing has allowed for more precise identification of mutations and alterations that can be targeted by specific treatments.

In non–small cell lung cancer (NSCLC), genetic testing has identified mutations in the 

 gene. In patients with these mutations, targeted therapies like erlotinib (Tarceva) and gefitinib (Iressa) have improved survival rates by focusing on the specific genetic cause of the cancer.

“In lung cancer therapy, it is basically part of everyone's cancer treatment pathway to have this baseline testing done when they have advanced disease,” Sarah Kerr, MD, a pathologist at Allina Health, told 

Both erlotinib and gefitinib are FDA-approved as targeted therapies for patients with 

-mutant NSCLC, based on findings from the IPASS (NCT00322452), EURTAC (NCT00446225), and OPTIMAL (NCT00874419) trials.

 mutation testing has become a standard part of the diagnostic pathway for patients with advanced NSCLC.

In breast cancer, molecular profiling has also yielded success with the identification of the HER2 gene. Agents like trastuzumab (Herceptin) now specifically target HER2-positive tumors, offering a precision approach that has transformed breast cancer treatment, particularly for advanced or metastatic cases.

Clinical trials, including HERA (NCT00045032), CLEOPATRA (NCT00567190), and NCCTG N9831 (NCT00004067; NCT00005970),

 have demonstrated significant improvements in overall and progression-free survival for patients with HER2-positive breast cancer. Additionally, newer therapies like pertuzumab (Perjeta) and trastuzumab deruxtecan (Enhertu) have improved outcomes, providing more options for patients.

Molecular oncology is revolutionizing cancer care by using genetic profiling to tailor personalized treatments, improving efficacy, minimizing adverse events, and paving the way for advanced therapies.

Colton Ladbury, MD

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