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Peter R. Galle, MD, discusses the findings that came from the phase III IMbrave 150 clinical trial, which evaluated the combination of atezolizumab plus bevacizumab versus the standard of care, sorafenib, as frontline treatment of patients with unresectable hepatocellular carcinoma.

Combination Atezolizumab Plus Bevacizumab Improved Quality of Life in HCC

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

Adding ruxolitinib (Jakafi) to standard graft-vs-host disease (GVHD) prophylaxis reduced incidence of acute and chronic GVHD while maintaining survival rates in patients with myelofibrosis undergoing hematopoietic cell transplantation (HCT), according to data presented at the 2025 Transplantation & Cellular Therapy Meetings.

The phase 2 prospective study (NCT04384692) conducted at Fred Hutchinson Cancer Center showed grade II to IV acute GVHD occurred in 32% of patients receiving peri-transplant ruxolitinib, whereas it occurred in 71% in a pre-transplant ruxolitinib group of a similar preliminary study. The percentage of patients with chronic GVHD at 1 year with peri-transplant ruxolitinib 12%, whereas it was 25% with pre-transplant ruxolitinib. These rates of GVHD also coincided with high overall survival (OS) rates at year 1 and 2 of 100% and 87%, respectively, in the peri-transplant ruxolitinib trial.

“The incidence of acute and chronic GVHD was markedly reduced without the expense of non-relapse mortality, relapse, or survival. It doesn't appear that infections or transfusion needs were increased,” Rachel B. Salit, MD, associate professor at Fred Hutchinson Cancer Center, said in her presentation.

Janus kinase (JAK) inhibitors prevent activation of the JAK domain by binding to the kinase, in turn preventing STAT phosphorylation and translocation of the nucleus. This process reduces the production of pro-inflammatory cytokines. GVHD pathogenesis has shown to be affected by the JAK-STAT pathway, and JAK signaling is key in the process leading to tissue damage and inflammation.

In previous trials of ruxolitinib, such as COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544), this JAK inhibition showed significantly better results in reducing symptoms and splenomegaly compared with best available therapy in patients with myelofibrosis. Additionally, the REACH1 (NCT02953678), REACH2 (NCT02913261), and REACH3 (NCT03112603) trials demonstrated significantly improved response with ruxolitinib vs best available therapy when treating patients with acute and chronic GVHD.

The preliminary study (NCT02251821) of ruxolitinib pre-transplant showed improved survival in this patient population. With a median time of 7 months on ruxolitinib, 38% of patients had more than a 10% decrease in spleen size and 36% were stable. In patients with symptoms prior to ruxolitinib, 55% had stable or improved symptoms by the time of HCT.

Patients who received pre-transplant ruxolitinib (n = 61) and patients from historical data (n = 167) had similar rates of grade II to IV GVHD at 71% and 68%, respectively, and had similar rates of grade III to IV GVHD at 19% and 18%. In the ruxolitinib arm, the 2-year survival rate was 79% vs 60% according to historical data. The 5-year survival rate for patients given ruxolitinib was 74% compared with historical data at 57%. Relapse in these groups was similar between the 2 groups.

In the phase 2 trial investigating GVHD prevention in 25 patients with myelofibrosis undergoing HCT, the primary end point was determining whether adding ruxolitinib to standard tacrolimus and methotrexate GHVD prophylaxis would decrease incidence of grade II to IV GVHD at day 100. Secondary end points included whether a decrease in chronic GVHD would be observed without compromising relapse, non-relapse mortality, and OS when adding ruxolitinib to standard prophylaxis in these patients.

Ruxolitinib was given 8 weeks or more before HCT and was tapered 2 weeks before transplants. Myeloablative conditioning starting 7 days before transplant with cyclophosphamide and 4-day busulfan or reduced-intensity conditioning starting 5 days before transplant with fludarabine and melphalan were given to patients. By day 4 prior to HCT, ruxolitinib had to be tapered to 5 mg twice daily. Tacrolimus was given the day prior to HCT until day 220 after HCT, and methotrexate was given on days 1, 3 6, and 11 after HCT. Ruxolitinib was continued through cell infusion until 2 months after discontinuing tacrolimus.

Patients enrolled on this trial had to have a diagnosis of primary or secondary myelofibrosis, intermediate-1, -2, or high-risk disease, HCT-specific Comorbidity Index of 5 or less, and basic organ function criteria. Donor options for these patients included human leukocyte antigen (HLA)-matched sibling donor, 10 of 10 HLA-matched unrelated donor, 1 allele-mismatched unrelated donor, and umbilical cord blood units, and peripheral blood was preferred over bone marrow.

After day 28 post-transplant, ruxolitinib could be increased to 10 mg twice daily if the patient had engrafted and were tolerating the 5-mg ruxolitinib dose. Ruxolitinib could also be decreased to 5 mg once daily if the 5-mg twice daily dose was not tolerated. The treating physician could be continue or discontinue/taper ruxolitinib if the patient developed GVHD of grade II or high and required systemic immune suppression. Ruxolitinib was continued if topical therapy only was required.

In terms of dose modifications, all patients were on 5 mg of ruxolitinib twice daily at 4 days before HCT. There were 6 patients who went from 5 mg twice daily to once daily between days 0 to 100 because of cytopenia. In that same time frame, 7 patients increased to 10 mg twice daily of ruxolitinib for cytopenia or other toxicity. One patient paused ruxolitinib and was given prednisone, then went back on ruxolitinib at 10 mg twice daily, continuing for 9 months.

Patients on this trial were a median age of 66(range, 42-71), and 64% were male. Sixty percent of patients had primary myelofibrosis and 40% had secondary myelofibrosis. There were 68% of patients who were JAK2 positive. Over half of the patients had Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 disease, 24% had DIPSS intermediate-1, 16% had DIPSS high, and 4% had DIPSS low. The average time on ruxolitinib was 6 months, although it was only necessary to be on ruxolitinib for 8 weeks, Salit noted.

No patients had received cord blood, but 76% had unrelated donors and 24% had related donors. Reduced-intensity conditioning was used for 68% of patients and the rest received myeloablative conditioning.

With a median time to engraftment of 20 days, no patients experienced primary graft failure, but 1 patient had poor graft function. All patients had CD3 and CD33 chimerism on day 28 and day 100.

Acute GVHD grade II to IV was observed in 32% of patients and acute GVHD of III to IV in 8%. At 1 year, 12% of patients had chronic GVHD and none of the patients had moderate to severe chronic GVHD. Relapse at 1 year was seen in only 4% of patients, and there were 8% who were mutation positive at day 28 post-transplant, which dropped to 4% who were mutation positive at day 100.

Most infectious adverse events (AEs) were grade 3, in 20 out of 25 patients, and 4 patients had grade 4 AEs. Non-relapse mortality was 12% at 1 year.

In a non-randomized comparison of the pre-transplant ruxolitinib trial and the phase 2 peri-transplant ruxolitinib trial, Salit described some of the differences in the cohorts. The patients were approximately 10 years older in the peri-transplant group, and there were no cord blood recipients compared with 10% in the pre-transplant group. Otherwise, demographics and outcomes such as engraftment days, engraftment failure rates, red blood cell and platelet transfusions, and chimerisms were the same, but with the peri-transplant cohort having approximately half as much incidence of GVHD.

“We're currently looking at translational studies of GVHD biomarkers, STAT signaling, and disease modification with post-transplant ruxolitinib and optimizing dose timing and the tapering of the peri-transplant ruxolitinib are aims of future clinical trials,” Salit concluded.

1. Salit RB, Ng K, Ratsamee N, et al. Phase II single center prospective study of ruxolitinib in addition to standard graft versus host disease prophylaxis in patients with myelofibrosis demonstrates encouraging outcomes. versus host disease prophylaxis in patients with myelofibrosis demonstrates encouraging outcomes. Presented at: 2025 Transplantation & Cellular Therapy Meetings; February 12-15, 2025; Honolulu, Hawaii. Abstract ID 38.

A phase 2 study evaluated the use of ruxolitinib plus standard GVHD prophylaxis in patients with myelofibrosis undergoing transplant.

Conference News

Ruxolitinib Shows Promise in Preventing GVHD in Myelofibrosis

Targeted Pulse

Nivolumab/Ipilimumab Combination Moves Forward in dMMR/MSI-H CRC

The FDA has accepted the supplemental biologics license application (sBLA) for nivolumab (Opdivo) plus ipilimumab (Yervoy), marking a potential first-line treatment option. The indication includes adult and pediatric (≥12 years) patients with microsatellite instability–high or mismatch repair–deficient unresectable or metastatic colorectal cancer. The sBLA submission is supported by data from the phase 3 CheckMate 8HW study. The Prescription Drug User Fee Act (PDUFA) target date for this indication is June 23, 2025.

“CheckMate 8HW has been [ongoing] for several years now as we have gotten updates from the study’s maturation, [evaluating] the combination of nivolumab and ipilimumab,” 

. “It drives home the point of [identifying] biomarkers as early as possible, because if you can save a patient from chemotherapy, that is a wonderful thing to do,” Lewis is director of gastrointestinal oncology at Intermountain Health in Salt Lake City, Utah. For further information regarding this sBLA, access the full article 

Funding Freezes Put Cancer Research on Ice, Halting Progress

Gwen Nichols, MD, discussed the ramifications of a rapidly implemented policy, that froze and then cut funding. She addressed concerns over the potential impact these reductions in federal funding may have on both community and academic centers that rely on grants from the National Institutes of Health (NIH). Nichols is particularly concerned for young investigators who depend on these grants to establish their careers. She explained that these cuts could have a trickle-down effect, slowing the next generation of innovation in cancer research.

“The freeze affected community health centers funded by the NIH, forcing some to temporarily close their doors and stop seeing patients until funding was restored. These were unintended consequences of a rapidly implemented policy,” Nichols explained. “This isn’t about the Leukemia & Lymphoma Society (LLS) taking a stance on the policy itself, but rather about how quickly these changes occurred, without sufficient time to adjust and find alternative solutions. Nichols is executive vice president and chief medical officer of the LLS in Rye Brook, New York. To access this information, we ask that you share some details about yourself so we can better tailor our offerings. Begin 

Maintenance Fedratinib After Transplant Shows Potential in MPN

Hany Elmariah, MD, discussed recent data from a phase 1 trial evaluating fedratinib (Inrebic) as maintenance therapy for myeloproliferative neoplasms following allogeneic hematopoietic cell transplant. Fedratinib is a JAK2 inhibitor that is approved for pre-transplant myelofibrosis and is now being evaluated as a post-transplant maintenance therapy to potentially reduce relapse risk and graft-vs-host disease. In the trial, a daily dose of 400 mg of fedratinib, the established maximum tolerated dose, was determined safe.

“Importantly, although the study was conducted at a large cancer center, fedratinib is a drug that can be prescribed and managed in the community setting,” Elmariah told Targeted Oncology

. “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 is associate member at the Moffitt Cancer Center in the department of bone marrow transplant and cellular immunotherapy in Tampa, Florida. For more information about the data, access the full article 

Petosemtamab/Pembrolizumab Combo Gains Breakthrough Status in HNSCC

The FDA has granted priority review to the combination of petosemtamab and pembrolizumab (Keytruda) as a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma with a PD-L1 combined positive score of at least 1. Findings from phase 2 of a phase 1/2 trial (NCT03526835) are the basis for this development. In addition, the phase 3 LiGeR-HN1 trial (NCT06525220), is another study evaluating the combination in this patient population.

“One of the interesting things I’ve learned about these molecules is that responses can be seen quite early, which is unusual for checkpoint inhibitors—we typically have to wait longer,” 

 explained in an interview with Targeted Oncology

. “For unknown reasons, this antibody shows activity early in the treatment course, which is crucial for symptomatic patients. This is especially important for those with life-threatening disease in the immediate term, as we aim not to lose patients.” Perez is a hematologist and medical oncologist at Florida Cancer Specialists & Research Institute’s Lake Nona Cancer Center & Drug Development Unit. For information regarding this development, access the full article 

“Priority Review Illustrates Urgent Need” for Zongertinib in HER2-Mutant NSCLC

The FDA has granted priority review to zongertinib (BI 1810631) for patients with unresectable or metastatic non–small cell lung cancer harboring 

) mutations who have received prior systemic therapy. This decision is supported by data from the phase 1b Beamion LUNG-1 trial (NCT04886804). The PDUFA date is set for the last quarter of 2025.

The FDA advances in multiple cancer types, and researchers assess potential impacts of funding freezes on cancer research.

Peter R. Galle, MD

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