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Morgan Bayer is an assistant editor for Targeted Oncology and Targeted Therapies in Oncology.

The FDA plans to conduct a speedy review of the supplemental new drug application for ivosidenib tablets as treatment of IDH1-positive, relapsed or refractory myelodysplastic syndrome. 

Ivosidenib Granted Priority Review by FDA for IDH1+ R/R Myelodysplastic Syndromes

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

A 64-year-old Asian woman presented with persistent dry cough and mild progressive dyspnea over last month, with unintentional weight loss of 8 lbs over the last 4 months​. She had a past medical history of hypertension and hypercholesterolemia​ and is a never-smoker​. Right lower lobe (RLL) auscultation revealed decreased breath sounds​. Her ECOG performance status was 1. A CT scan showed a 3.5-cm mass in RLL, small right pleural effusion with nodularity as well as mediastinal lymph nodes. ​PET/CT showed multiple bone metastases, including vertebrae and left scapula​. Brain MRI was negative for brain metastasis​. Mediastinal node endobronchial ultrasound led to diagnosis of non–small cell lung cancer (NSCLC); TTF1+ adenocarcinoma; stage IVB.

IO monotherapy or IO-IO combination therapy

So 60% of us [chose a] platinum-containing chemotherapy doublet; 20% of us said chemotherapy plus IO [immunotherapy] triplet, and 20% said other. In this case, I personally would choose platinum-containing chemotherapy doublet and I would like to hear the reasons from people who chose chemotherapy plus IO or other.

: I would say that…usually we get lucky and Guardant360 is back because of the proximity of their lab between 6 and 7 days. There are no circumstances for NSCLC where I don’t wait to see the 

 status. But if I wanted to wait, then I would pick the doublet without an IO as well. But for PD-L1 [positive disease], I get impatient.

You would wait for the EGFR and ALK testing results before adding the IO?

I would wait before starting therapy even if the patient is anxious.

This question does say that the patient is anxious, but we never said that she’s in visceral crisis or in a medical need to start therapy. Perhaps one of us who answered ‘other’ meant to just wait. That’s an option too. I also think that chemotherapy plus bevacizumab [Avastin] is not wrong. I don’t think there is harm in giving chemotherapy plus bevacizumab in a patient with unknown marker status in a setting of no brain metastasis, [with] no risk of brain bleed.

But we do want to avoid immunotherapy upfront when you don’t know the 

 mutation status, because if patients are given IO up front, and then you find out that this patient has 

 exon 19 deletion or EML4-ALK, you want to switch them to that therapy. But when you do switch, sometimes that can cause an increase in immune-related adverse events [AEs].

 Immune-related pneumonitis is well known for 

-mutated patients when they’ve been given PD-1 inhibitor up front, followed by an EGFR-TKI [tyrosine kinase inhibitor]. And for EML4-ALK, a similar thing happens, but it shows up more in the form of immune-related hepatitis for whatever reason.

In order to avoid these extra AEs, you want to try to wait until 

 results are back before you put them on IO. One might say, I don’t have to switch right away and that’s correct. You don’t have to switch right away even if the patient has 

[mutations]. If they were put on chemotherapy plus or minus IO or IO [alone] up front and it is working, then there might not be a need to switch right away. But eventually these patients are most likely going to progress, and eventually they’re going to need these TKIs. So you want to avoid exposure to PD-1 inhibitors upfront if at all possible, so that’s why I wouldn’t choose IO-containing regimens in this particular case when we don’t know that 

So are you suggesting in general, before we have the next-generation sequencing panel back, we should not start immunotherapy at all?

That is correct, and that is for the reason I just mentioned, especially for 

, if you do find mutations after you’ve already given them IO and then you put them on a TKI, it increases the risk of AEs. For example, what has been reported for 

 and pneumonitis is that the baseline pneumonitis rate with TKI is [approximately 3% to 4%].

 But that can increase up to 11% to 12% if a patient has been exposed to an immunotherapy agent prior to TKI, and it is also the reason why concurrent use is not recommended.

 Nobody should be getting immunotherapy and EGFR-TKI or ALK-TKI at the same time.

What if the patient was highly PD-L1 positive? My answer would be I would still wait and get the rest of the molecular profiling results because if the patient had an 

, I would not give an immunotherapy upfront.

That is correct. Especially with single-agent IO, their response rates are lower than the TKIs, so you do want to wait even if the PD-L1 is high.

The patient was started on chemotherapy doublet (cisplatin and pemetrexed)​. Tissue next-generation sequencing showed 

 exon 20 insertion mutation (V769_D770insASV)​. Four months after initiation of chemotherapy (with initial partial response), she reported worsening back pain and shortness of breath​. A CT scan showed disease progression​, and repeat brain MRI showed no metastases. She received amivantamab-vmjw (Rybrevant) as second-line therapy.

1. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. 

. 2019;30(5):839-844. doi:10.1093/annonc/mdz077

2. Lin JJ, Chin E, Yeap BY, et al. Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer. 

. 2019;14(1):135-140. doi:10.1016/j.jtho.2018.09.001

3. Tagrisso. Prescribing information. AstraZeneca; 2022. Accessed February 15, 2024. 

4. Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. 

. 2018;4(8):1112-1115. doi:10.1001/jamaoncol.2017.4526

During a Targeted Oncology™ Case-Based Roundtable™ event, Misako Nagasaka, MD, PhD, asked participants how they would approach therapy for a patient with metastatic non–small cell lung cancer when biomarker testing is not yet completed. This is the second of 2 articles based on this event.

Selection of First-Line NSCLC Therapy Influenced by Delayed Testing 

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.

Morgan Bayer

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