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Andrew Srisuwananukorn, MD, discusses the main findings from research of an artificial intelligence-powered machine learning algorithm which evaluated digital whole-slide images of diagnostic bone marrow biopsies and accurately differentiated prefibrotic primary myelofibrosis from essential thrombocythemia.

Utilizing Interpretable AI to Distinguish prePMF From ET

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

Innovative AI Approaches to Cancer Screening and Risk Assessment

Sanjay K. Juneja, MD, hematologist & medical oncologist at Mary Bird Perkins Cancer Center, discusses how artificial intelligence is transforming early cancer screening.

 But where I also get really excited is this multi-modality approach, where, instead of having this kind of hard set like male, female, this is your age, having AI’s understanding. Remember, it is just prediction, when you feed AI longitudinal data like these are all the variables. These are all the metrics. This is what ended up happening to people by the 1000s, like hundreds of 1000s, and then you can kind of ascertain what characteristics may be at higher risk. When you say multimodal, that means you consider their molecular stuff, if it is precancerous, or even if it is like germline, meaning, like the stuff you were inherited with. You might think, how much does metabolic syndrome matter? Any of these things that you could conceive they can help really delineate what is the risk factor for an individual, rather than a person of a certain age, and that's super exciting.

 Again, take a multimodality approach, but then also, you have all these kinds of tests coming out that are able to check for pre cancer mutations at a very what is called high sensitivity, meaning before you could even potentially see it on an image. You may be able to tell that there are some precancerous lesions that are classic to say, cervical cancer or colon cancer, or even early cancer itself.

Now, a lot of people say, Well, how would you know where it is and what do you do with it? But that's when you can look at, you know, things called theranostics, to where you could actually inject things that say are metabolized, that are fuel sources for rapidly growing tumors. It is kind of like a PET scan, but you are checking based on metabolic activity of something else other than glucose. So, those things are getting much more defined, and earlier as well. Another one is also with endoscopy.

So, if you think about it, you are putting a camera down to check. For example, when you have AI technology embedded, it can consider all the things that maybe you do not have as a gastroenterologist in your local area, like if you happen to have an Indian patient or a patient of Indian descent or Jamaican descent, and they have certain turmeric-based diets, then suddenly what you are looking for and the idiosyncrasies about that very early, you know, polyp lesion, you know, may not be top of mind. But now they have technologies where you input those variables, and it can kind of pull up all of the things that are more unique or classic about that person with a turmeric- or curry-based diet, or what medications they are on, or what—maybe you know—those idiosyncrasies for them specifically, and it can kind of just flag on the screen like, hey, I know we went by this, but there is something that is XYZ that is relevant to maybe having a little higher degree of concern. That is where you are able to detect polyps at a higher rate as well, and that can go both from upper and lower scopes.

So these are all things that do not replace, you know, physicians by any means, or some of our diagnostic tests, but certainly leverage and kind of, you know, maybe one day add a log, like, actually, just logarithmically help the utility or use case for these imaging and molecular- or blood-based screenings that we do.

Sanjay K. Juneja, MD, discusses how artificial intelligence is transforming early cancer screening.

A 52-year-old, postmenopausal woman had a history of grade 2, node-negative invasive ductal carcinoma (IDC).

Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27

Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.

Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).

Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.

The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.

Required 1 dose reduction to 400 mg ribociclib due to neutropenia.

Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.

She noted mild increase in lower back pain​.

Circulating tumor DNA (ctDNA) analysis confirmed an 

Fulvestrant + a different CDK 4/6 inhibitor 

 Using fulvestrant plus a different CDK4/6 inhibitor would not be an unreasonable choice if the patient didn't have an 

 mutation. Fulvestrant alone isn’t a [definite] option for a patient like this. I probably wouldn't use exemestane plus everolimus [Afinitor] here because I don't think this patient has definitively endocrine-resistant disease. Likewise, I probably wouldn't give single-agent chemotherapy. So I would agree with the participants and give elacestrant [Orserdu].

 I absolutely agree. I think elacestrant would be a preferred option.

 But there are some other circumstances where somebody doesn't have access to elacestrant. The 

 mutation would drive me towards a selective estrogen receptor degrader over an aromatase inhibitor combination. So thinking about fulvestrant is also a reasonable option, but I think elacestrant [is a recommended] option.

 The patient received ribociclib in the first-line setting—if she got palbociclib [Ibrance], would you consider, if she didn't have any sort of mutation, fulvestrant plus ribociclib based on the MAINTAIN trial [NCT02632045]?

 I think [we take into account] the MAINTAIN data.

 They are certainly compelling. I have done that very thing in patients who lack other targetable mutations, had a good run on first-line palbociclib, and just have a small amount of progression. We did see data that ribociclib plus fulvestrant was better than fulvestrant alone in that population. I would consider that, remembering that phase 2 hypothesis-generating study.

 mutation, what comes first? How do you deal with that?

 It's a very good question. It's a data-free zone, but I think given the toxicity profile, I probably would lean towards elacestrant.

 I think this depends on the patient in front of you and the volume of their disease. Are they symptomatic, and are we feeling comfortable with single-agent endocrine therapy knowing that we still have the ability to target the PIK3CA pathway at the subsequent progression? I think in the absence of data, it's an art-of-medicine decision. I think there's a place for single-agent endocrine therapy, given the constellation of risk-benefit balance.

 When you look at SOLAR-1 [NCT02437318], the benefit with alpelisib [Piqray] was pretty significant.

 We just don't know the answer right now. And I think you're absolutely right, it depends on the patient.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 2.2024. Accessed June 6, 2024. 

2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. 

. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392

3. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. 

. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011

During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, looks at options for a patients with hormone receptor–positive, HER2-negative breast cancer and an ESR1 mutation in the second article of a 2-part series.

Second-Line Targeted Options Considered in ESR1-Mutated Breast Cancer

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?

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.

Andrew Srisuwananukorn, MD

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