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An overview of the data and rationale that led to the approval of nivolumab and&nbsp;pembrolizumab for NSCLC, with an emphasis on specific patient&nbsp;populations likely to benefit from this approach and future&nbsp;directions for clinical research in this area.

PD-1 Checkpoint Inhibitors in Pretreated Non-Small Cell Lung Cancer

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

During a Targeted Oncology case-based roundtable event, Jeanne M. Palmer, MD, discussed the case of a patient with myelofibrosis whose platelet count declined during JAK inhibitor therapy.

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

Six months ago, a 72-year-old woman with a history of hyperlipidemia (controlled on rosuvastatin [Crestor]) and hypertension (controlled on amlodipine [Norvasc]), developed itching, bloating, loss of appetite, a notable 20 lb weight loss, drenching night sweats, and significant fatigue.

Abdominal examination revealed splenomegaly, spleen palpable 8 cm below the left costal margin without hepatomegaly. CT scans of the chest, abdomen, and pelvis revealed moderate mediastinal lymphadenopathy and splenomegaly.

A peripheral blood smear produced a leucoerythroblastic picture with nucleated threads and immature cells in the periphery. Next-generation sequencing showed a 

 mutation (allele frequency, 22%). Bone marrow biopsy showed megakaryocyte proliferation with atypia, 3+ reticulin fibrosis. Cytogenics were normal.

Laboratory values

A decision to initiate ruxolitinib (Jakafi) was made. ​There was initial symptom improvement in appetite, night sweats, and weight at a dose of 10 mg twice daily, and the dose was increased to 15 mg twice daily. One month later, platelet count decreased to 100,000/μL, and the dose was reduced to 10 mg twice daily. One month later, platelet count dropped to 32,000/μL, and the patient received a red blood cell transfusion. After another month, platelet count remained at 85,000/μL.

Repeat red blood cell transfusion and continue ruxolitinib 10 mg twice daily

Continue ruxolitinib at reduced dose (5 mg twice daily)

There is not a right or a wrong answer. [The majority of participants chose] pacritinib [Vonjo]. If you stop ruxolitinib and go directly to pacritinib, which you can do, then you should be OK, but if you stop the ruxolitinib and their platelets go back up, always remember that sometimes, you can convince [insurance providers] to give you pacritinib, even if the platelets are higher off the ruxolitinib.

Pacritinib 200 mg twice daily (off label)

How do you define ruxolitinib failure? ​

What are triggers for you intervene earlier versus later?​

What are triggers for you to change therapy?​

Alright, so one of the big questions that comes up, or I think that's going to be very important for the myeloproliferative neoplasms community to answer, is the definition of ruxolitinib failure, so what are the various things that may happen to a patient that would make you say the ruxolitinib is not working?

 I think if the patient has constitutional symptoms and is not improving, the spleen is not getting smaller, and then they are continue to require blood transfusions.

 Any other comments on what defines ruxolitinib failure for patients? And what triggers you to change therapy?

 The return of blood transfusion requirements, which will indicate progression of disease, and therefore, repeat bone marrow [biopsy].

 Three things: laboratory results, spleen [volume], and quality of life.

 That is the name of the game, isn't it? We have a very recurrent theme in those 3 things.

When they actually looked at what drove ruxolitinib discontinuation, based on the European database, lack of response is one, loss of response was another one of the big ones.

 Blast phase was actually almost a quarter of the patients. Allogeneic stem cell transplant and a favorable response. Ruxolitinib-related adverse events [AEs] was also slightly over a quarter of the patients, and then ruxolitinib-unrelated AEs, which was an interesting distribution.

Switching to another Janus kinase (JAK) inhibitor or other therapy?

How can switching from one JAK inhibitor to another be done safely?

What has been your experience with ruxolitinib interruption/discontinuation? With fedratinib?

Would you taper the ruxolitinib dosing for interruption or hold or discontinuation or switching to another JAK inhibitor? Do you usually taper ruxolitinib if you're going to switch to another JAK inhibitor, or do you just directly switch to another JAK inhibitor, and [what is] the setting where you've done that? For what it's worth, I generally try to taper down the ruxolitinib a little bit before I will switch them to another JAK inhibitor.

What has been your experience with discontinuation or interruption of ruxolitinib? [Have you had] patients who just decided they were just going to stop it, or start to go down on the doses a lot without discussing?

My patient on pacritinib developed liver toxicity, so we held the medication, she improved, we'd rechallenge her, she again got liver function [tests with] ALT [alanine transaminase] being very high, so we had no choice but to stop completely without tapering, but she went onto pacritinib, and she seemed to be OK.

1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. 

. 2020;126(6):1243-1252. doi:10.1002/cncr.32664

When to Stop or Switch JAK Inhibitor Therapy in Myelofibrosis

SEQUOIA Trial: Updates from ASH 2024 

Experts review the 5-year results of the phase 3 SEQUOIA trial evaluating treatment options for previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma at the 66th American Society of Hematology Annual Meeting and Exposition 2024.

Video Series

A 39-year-old premenopausal woman underwent bilateral mastectomy with reconstruction for ypT1b, ypN2a, grade 2 invasive ductal carcinoma (IDC), hormone receptor (HR) positive, HER2 positive (immunohistochemistry [IHC] 3+)

Germline testing results showed no actionable/pathogenic alterations​.

She received adjuvant TCHP (docetaxel, carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]) for 6 cycles, with trastuzumab/pertuzumab for 1 year; leuprolide plus aromatase inhibitor (AI) was initiated​.

Three years later: metastatic recurrence in the vertebral spine​

Bone biopsy confirms relapse, HR+, HER2+ (IHC 3+) IDC​

Next-generation sequencing: no actionable mutations identified ​

She received first-line THP (docetaxel, trastuzumab, and pertuzumab) for 6 cycles plus denosumab​.

Transitions to HP (trastuzumab plus pertuzumab)

What is your preferred frontline therapy for HR-positive, HER2-positive metastatic breast cancer (mBC)? ​

Are you using endocrine therapy for patients with HR-positive, HER2-positive mBC? ​

During a Case-Based Roundtable® event, Ian Krop, MD, and participants discussed considerations affecting first- and second-line treatment of metastatic HER2-positive breast cancer in the first article of a 2-part series.



James Luke Godwin, MD

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