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Meir Wetzler, MD, from Roswell Park Cancer Institute, discusses the potential impact of FLT3 inhibitors for the treatment of patients with acute myeloid leukemia.

The Impact of FLT3 Inhibitors for the Treatment of AML

Meir Wetzler, MD, chief, Leukemia Section, Department of Medicine, Professor of Medicine, Department of Medicine, Roswell Park Cancer Institute, discusses a phase I trial that studies the side effects and immune response to DEC-205/NY-ESO-1 fusion protein CDX-1401 and decitabine in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia 

CDX-1401 in Combination with Decitabine in Patients with MDS

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.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

The Targeted Pulse: Unlock Recent FDA Highlights in Leukemia and Prostate Cancer and An Interesting Vaccine Gaining Traction in Triple-Negative Breast Cancer

Imatinib, Now in Liquid Form, Receives Approval in Leukemia and Other Cancers

The first liquid form of imatinib (Imkeldi) oral solution has received FDA approval for certain forms of leukemia and other cancers. This liquid formulation of imatinib assists in dosing accuracy, accessibility, and treatment adherence and helps slow or prevent growth of chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative disease, and gastrointestinal stromal tumors.

“We are thrilled to offer an oral solution option for patients with leukemia and other cancers, [which is] a meaningful advancement for thousands in need,” said Sharon Cunningham, chief executive officer of Shorla, in a press release. “Oral solutions may ensure more precise and consistent dosing, offering a convenient alternative to compounding for patients who have difficulty swallowing or require dosing tailored to body surface area.”

A New Vaccine for Triple-Negative Breast Cancer Shows Interesting Potential

A phase 1 trial (NCT04674306) showed positive protocol-defined immune responses of an investigational breast cancer vaccine targeting triple-negative breast cancer. Data were presented at the 39th Annual Society for Immunotherapy of Cancer Meeting, stating that the α-lactalbumin vaccine demonstrated safety, tolerability, and immune activity across all its 3 patient cohorts. For the phase 2 trial, investigators plan to evaluate patients with newly diagnosed breast cancer in the neoadjuvant setting, with this phase set to begin in 2025.

“Triple-negative breast cancer is the form of the disease for which we have the least effective treatments," said G. Thomas Budd, MD, of Cleveland Clinic’s Cancer Institute and principal investigator of the phase 1 study, in a press release. “Long term, we hope this can become a true preventive vaccine that would be administered to individuals who are cancer-free to prevent them from developing this highly aggressive disease.”

Brexu-cel Appears to Stand theCentral Nervous System Test in R/RB-ALL

Brexucabtagene autoleucel (brexu-cel; Tecartus) demonstrated high rates of central nervous system (CNS) remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to data from the Real-World Outcomes Collaborative for Chimeric Antigen Receptor T in ALL (ROCCA) consortium. Ibrahim N. Muhsen, MD, a hematology and medical oncology fellow at Baylor College of Medicine, discussed his findings regarding the efficacy of brexu-cel in achieving CNS and systemic responses in adult patients with CNS involvement in relapsed/refractory B-ALL.

“When it comes to the safety of brexu-cel, [for] our patient population that has a very low rate of high-grade CRS, with only 1 patient experiencing grade 3 to 4 CRS. On the other hand, when it comes to immune effector cell-associate neurotoxicity syndrome [ICANS], we had a higher number of patients who had grade 3 to 4 ICANS. However, when we compared these numbers with those in the ROCCA consortium database—specifically patients without CNS involvement—the rates were similar,” Muhsen told Targeted Oncology

Darolutamide Starts its FDA Journey With a sNDA in mHSPC

The FDA has accepted the supplemental new drug application for darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC). This acceptance of the application is based on data from the phase 3 ARANOTE trial (NCT04736199), which were presented at the 

. In the trial, darolutamide plus ADT was compared with placebo plus ADT, showing a reduced risk of radiographic progression or death with the experimental combination.

“If approved, this would expand the indication for NUBEQA in patients with mHSPC to include both combinations with and without chemotherapy, providing physicians and their patients with an additional treatment option in this setting. We are working closely with the FDA to bring this additional NUBEQA treatment option to patients as soon as possible,” said Christine Roth, executive vice president, global product strategy and commercialization and member of the Pharmaceuticals Leadership Team at Bayer, in a press release.

Ribociclib (Kisqali) in combination with a nonsteroidal aromatase inhibitor (NSAI) showed significant improvement for patients with high-risk, node-negative, early-stage breast cancer, according to an analysis of data from the phase 3 NATALEE trial (NCT03701334). Denise Yardley, MD, director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, discussed the positive data and outlined the next steps, which include identifying patients who could benefit from ribociclib and other therapies sparing chemotherapy.

“By focusing on a select high-risk group of node-negative patients, we were able to demonstrate that they also benefited from…the addition of ribociclib to their anastrozole or letrozole therapy. This broadens the group of early-stage breast cancer patients who stand to benefit from an agent like ribociclib added to their standard endocrine therapy,” Yardley told Targeted Oncology

in the interview. “The trial did show those that received only the current standard of care, which is endocrine therapy by itself, fared poorly compared with the group that had the NSAI and ribociclib combination.

Thank you for joining us for this week’s 

In case you missed it, here is last week’s 

The FDA accepted darolutamide’s application for metastatic hormone-sensitive prostate cancer, imatinib is now in liquid form, and ribociclib, combined with an NSAI, showed significant benefit in high-risk, node-negative early-stage breast cancer. Brexu-cel demonstrated CNS remission in relapsed/refractory B-ALL, and a new vaccine shows promise in breast cancer.

A man, aged 61 years with an active lifestyle, had a history of metastatic renal cell carcinoma (mRCC), and was post‒left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) with metastases in the adrenal​ gland. Four years later, he had a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, they had been present on scans for at least 2 years prior​. Based on low volume, indolency of disease, and patient preference​, he underwent observation. Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis (2.0 x 1.5 cm). His ECOG performance score was 0.

Vote in the polls below on what you would have chosen if this was your patient.

 This is where we stand with regards to the National Comprehensive Cancer Network [NCCN] guidelines for kidney cancer for favorable-risk disease: we have category 1 data for all 3 immuno-oncology [IO] plus VEGF–tyrosine kinase inhibitor [TKI] combinations that have demonstrated improvements in overall survival [OS].

 These include axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab. Then under other recommendations axitinib/avelumab [Bavencio] is listed, cabozantinib alone is listed with a category 2B designation, nivolumab plus ipilimumab [Yervoy], and then single-agent TKI.

 These can be options for patients with favorable-risk disease.

With checkpoint inhibitor combinations like nivolumab/ipilimumab, the data there support the long-term durability of the regimen with long-term PFS at five years at around 30%.

 The Achilles heel of the CheckMate 214 [NCT02231749] data is that the primary progressive disease rate is 18%.

 At the present time we don’t have biomarkers to help us with the selection between IO/IO versus IO/VEGF-TKI.

In that context it seems like no [participants at this roundtable event would] select single-agent TKI. More individuals selected nivolumab/ipilimumab as a potential option, and then some continuing to select the IO/VEGF-TKI combination.

 I changed my treatment from single TKI to a TKI/IO because of the more aggressive presentation likely in the liver as well as the lung. The cancer now is progressing more and likely it's going to progress [even] more. We’ll gain more control of it. Patients need a more active treatment.

 I selected nivolumab/ipilimumab because of the liver involvement and a clear cell morphology. All options, TKI plus nivolumab or pembrolizumab are absolutely acceptable options, but I chose this particular combination because of the aggressive pattern of metastases and liver involvement, which in this setting of RCC, tends to be a much more aggressive disease compared with pulmonary involvement.

 That’s absolutely correct that those with liver metastases can behave more aggressively than those without those sites of metastases.

 I picked lenvatinib plus pembrolizumab based on data from the CLEAR trial [NCT02811861]. I know that it has the longest response seen for any of the mRCC trials with a 71% objective response rate [ORR].

 The reason I didn’t go with cabozantinib plus nivolumab is that this patient did not have any bone metastases and we know cabozantinib/nivolumab is especially good in that subset of patients.

 I picked the pembrolizumab/lenvatinib based on the complete response rate, quicker response, and personal experience. I have a few patients that did really well on this combination and having the disease in the liver, it's probably more aggressive. Also, if the patient is symptomatic, doing TKI with immunotherapy probably reasonable.

A Black woman, aged 59 years, was diagnosed with a left renal mass ​and underwent left radical nephrectomy in December 2019​. Her diagnosis was ccRCC, T3aN0Mx, Fuhrman Grade 3​. Nine months later, she developed metastatic disease to the liver and retroperitoneal lymph nodes. Her radiographic diagnosis was stage IV RCC, with metastases to liver and retroperitoneum​. Her Karnofsky performance status was 90%. Her hemoglobin level was 11.1 g/dL​, and corrected calcium, neutrophils, and platelets were within normal limits.

A fair bit of participants would choose nivolumab/ipilimumab, some lenvatinib/pembrolizumab, some nivolumab/cabozantinib. There were not many people selecting pembrolizumab/axitinib or single-agent cabozantinib.

In the updated NCCN guidelines for treatment for patients with poor- and intermediate-risk disease, all the IO/VEGF-TKI combinations are fair game and so is nivolumab/ipilimumab.

[We can compare] the granular data regarding OS, progression-free survival, and ORR for the intermediate- and poor-risk population compared with the intent-to-treat population across these trials. I would keep in mind the number of patients with poor-risk disease that were enrolled across all of these trials, but based on topline data, every single one of these regimens is effective for patients with intermediate- and poor-risk disease.

Looking at the hazard ratio [HR] for OS, with the long-term follow-up of 67.7 months for nivolumab/ipilimumab is holding steady at 0.68 and for pembrolizumab/axitinib, 0.63.

 For cabozantinib/nivolumab, the HR for the intermediate-risk patients is 0.74; for the poor-risk patients it is 0.45.

 Then similarly for lenvatinib/pembrolizumab, the HR for intermediate-risk patients is 0.72 and for poor-risk patients is 0.39, so these are highly effective regimens.

 The ORR in the intermediate- and poor- risk patients, range from over 50% with the IO/VEGF combinations and 72% with lenvatinib/pembrolizumab, whereas for nivolumab/ipilimumab it's 42%.

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, 2.2023. Accessed August 23, 2022. https://bit.ly/2TAx1m3

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab vs sunitinib in patients with advanced renal cell carcinoma. 

. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

4. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

5. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib vs sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. 

 Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib vs sunitinib for patients with advanced renal cell carcinoma. 

2022;40(suppl 6):350. doi: 10.1200/JCO.2022.40.6_suppl.350

7. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab vs sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021; October 7-8, 2021; Philadelphia, PA. Abstract E41. Accessed August 23th, 2022. https://bit.ly/3yRcxMx

Participants of a live, virtual case-based event discussed different scenarios for treatment of a patient with previously untreated clear cell renal cell carcinoma. Vote in the polls on what you would have chosen if this was your patient.

POLL: What Frontline Treatment Would You Choose for Favorable- and Intermediate-Risk RCC?

Polatuzumab vedotin ± rituximab ± bendamustine

What therapies would you consider for a patient like this? ​

During a Targeted Oncology case-based roundtable event, Christopher R. Flowers, MD, MS, discussed the choice of bridging therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who may receive CAR (chimeric antigen receptor) T-cell therapy. 

This is the second of 2 articles based on this event. 

Meir Wetzler, MD

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