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Spotlight

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Authors

Colin P.N. Dinney, MD, is the chairman of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center in Houston.

Colin P.N. Dinney, MD, provides some background on translational analyses from the BOND-003 and CORE-001 trials.


uGDB Predicts Response to Cretostimogene in BCG-Unresponsive NMIBC

Colin P.N. Dinney, MD, discusses updated translational analyses from the BOND-003 and CORE-001 trials.

Predicting Cretostimogene Grenadenorepvec Response With Urinary Genomics

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. 

https://tinyurl.com/fwhru4ft

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. 

https://tinyurl.com/4sryy6vh

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

This approval of belzutifan (Welireg) for the treatment of advanced renal cell carcinoma (RCC) is supported by findings from the phase 3 LITESPARK-005 study (NCT04195750).

Statistically significant and clinically meaningful improvements in progression-free survival (PFS) were observed with belzutifan.

This approval provides adult patients with RCC who progressed on immune checkpoint and anti-angiogenic agents with a new mechanism of action.

The FDA approved belzutifan for the treatment of adult patients with advanced RCC whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor (TKI) treatment.

This regulatory decision is supported by data from the 

in which the co-primary end point of PFS was met. Treatment with belzutifan reached a statistically significant and clinical meaningful improvement in PFS at the landmark 18 months analysis, as 22.5% of patients remained progression-free vs 9% with everolimus (Afinitor; HR, 0.74; 95% CI, 0.63-0.88). Belzutifan demonstrated a statistically significant improvement in PFS compared with everolimus (HR 0.75, 95% CI 0.63-0.90, one-sided 

=.0008). Kaplan-Meier analysis indicated non-proportional hazards, with similar median PFS estimates of 5.6 months (95% CI 3.9-7.0) for belzutifan and 5.6 months (95% CI 4.8-5.8) for everolimus.

A statistically significant improvement in the key secondary end point of overall response rate (ORR) was also observed with belzutifan vs everolimus. In the belzutifan arm, the observed ORR was 22.7% of belzutifan vs 3.5% in the everolimus arm.

LITESPARK-005 is an open-label, randomized, phase 3 study that randomized 746 patients with advanced RCC who progressed after treatment with anti-PD-1/PD-L1 and VEGF-targeted therapies to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily.

Investigators evaluated the coprimary end points of PFS and overall survival (OS).

 Secondary end points of the trial included ORR, duration of response, the number of patients who experience 1 or more adverse events (AEs), the number of patients who discontinued study treatment as a result of AEs, time to deterioration (TTD) of health-related quality of life (HRQOL), TTD in physical functioning, TTD in disease symptoms, change from baseline in HRQOL per the EORTC Core Quality of Life questionnaire C30 (EORTC QLQ-C30) items 29 and 30 score, change from baseline in physical functioning based on the EORTC QLQ-C30 items 1-5 score, change from baseline in disease symptoms according to the functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms items 1-9 score, and change from baseline in European Quality of Life 5 Dimensions per the 5-level Questionnaire Health Utility score.

Enrollment was open to patients with unresectable, locally advanced, or metastatic disease who had received no more than 3 prior systemic agents for locally advanced or metastatic RCC and had adequate organ function.

To date, there have been no statistically significant OS benefits seen with belzutifan compared with everolimus, though there is a signal for OS benefit (HR, 0.88; 95% CI, 0.73-1.07; 

=0.099). At 18 months, the OS rates are 55.2% and 50.6% for belzutifan and everolimus, respectively.

A complete response was observed in 3.5% of those treated with belzutifan vs none with everolimus. Both arms showed a similar median time to response at 3.7 months and 3.8 months, but the median duration of response was longer with belzutifan at 19.5 vs 13.7 months with everolimus.

For safety, both arms had similar grade 3 or worse AEs, but those that led to treatment discontinuation were seen in 6% of patients given belzutifan vs 15% of those given everolimus. The most commonly reported AEs included anemia and fatigue. Approximately 30% of patients in the belzutifan arm had grade 3 or worse anemia.

1. FDA approves belzutifan for advanced renal cell carcinoma. News release. U.S. Food & Drug Administration. December 14, 2023. Acccessed December 14, 2023. 

http://tinyurl.com/54xcm7f6 

2. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. 

. 2021;385(22):2036-2046. doi:10.1056/NEJMoa2103425

3. Merck announces Welireg® (belzutifan) phase 3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. August 18, 2023. Accessed December 1, 2023. 

https://tinyurl.com/5duv497t

4. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated August 1, 2022. Accessed December 1, 2023. 

https://tinyurl.com/3ejtc595

Belzutifan is now an FDA-approved treatment for adult patients with advanced renal cell carcinoma.

FDA Approves Belzutifan for Adult Patients With Advanced RCC

The FDA has approved belzutifan (MK-6482) for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery, according to a press release by the FDA.

Belzutifan is a novel and potent selective HIF-2a inhibitor. When the tumor-suppressor protein VHL is inactive, hypoxia-inducible factor proteins such as HIF-2a can accumulate in patients. When not properly regulated this protein stimulates several different cellular proliferation, angiogenesis, and tumor growth-associated oncogenes. This can lead to the growth of both malignant and benign tumors. The inactivation of VHL has been observed in majority, 90%, or RCC tumors.

The approval of this agent is based on a phase 2 study, which showed that the agent has long-term clinical activity in patients with VHL-associated RCC treated in the frontline setting.

Updated results for the study were presented during the 2021 American Society of Clinical Oncology Annual Meeting. Sixty-one patients with VHL disease who had at least 1 measurable RCC tumor, had not received any prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of 0 or 1 were evaluated. The primary end point of the study is objective response rate (ORR). Secondary outcomes include duration of response (DOR), time to response, progression-free survival (PFS), time to surgery, the number of participants experiencing adverse events (AEs), the number of patients experiencing a serious AE, belzutifan plasma concentration, and belzutifan metabolite plasma concentration.

At baseline, the majority of patients in the study (82%), had an ECOG score of 0 and the median number of prior tumor reduction procedures per patient was 5. Additionally, 33% of patients had lesions outside the kidneys.

At a median follow-up was 69 weeks the ORR was 49% ( 95% CI:36, 62). There were an additional 7 unconfirmed responses, all of which were partial. The DOR was not reached, but 56% of responders had DOR ≥ 12 months and a median TTR of 8 months.The median time to relapse was 31 weeks.

 Ninety-two percent of patients had some reduction in the sum of all tumor lesion diameter. The PFS rate at week 52 was 98%.

In the subgroup of patients with other VHL-associated non-RCC tumors, 24 patients with measurable central nervous system (CNS) hemangioblastomas achieved an ORR of 63% and 12 patients who had measurable pNET reached an ORR of 83%. The median DOR was not reached in these patients, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively.

In terms of safety, AEs were reported in 20% of the patient who received belzutifan. The most common AEs were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm.

1. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed August 13, 2021. 

2. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555

The FDA has approved belzutifan for the treatment of von Hippel-Lindau-associated renal cell carcinoma treated in frontline setting. 

Colin Dinney, MD

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