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BTK Inhibitors: In-Focus

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Authors

Management of relapsed or refractory disease is a highly relevant topic for patients with mantle cell lymphoma and the clinicians who treat them.

Novel Treatment Approaches in Relapsed/Refractory Mantle Cell Lymphoma

David Bond, MD, discusses 2 key findings from a recent study investigating the risk of developing a second cancer in patients with chronic lymphocytic leukemia treated with a BTK inhibitor.

Factors Identified for Risk of Second Cancer in CLL Following BTK Inhibition

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

Phase 3 PEACE-3 Study of Enzalutamide + Ra-223: Design

Video content above is prompted by the following:

Please review the design and objectives of the phase 3 PEACE 3 study of ENZA + Ra-223 for ARPI-naïve naive mCRPC.

Evan Y. Yu, MD, discusses the design and objectives of the phase 3 PEACE 3 study, which evaluates the combination of enzalutamide (ENZA) and radium-223 (Ra-223) in androgen receptor pathway inhibitor (ARPI)–naive metastatic castration-resistant prostate cancer (mCRPC), focusing on its aim to assess the potential synergistic effects of this combination in improving patient outcomes, including overall survival and bone health.

Case Based Peer Perspectives

Video Series

Guideline-Directed Treatment Options: mCRPC

What are the therapeutic options included in the NCCN guidelines for this patient (eg, ABI, ENZA)? For example:

Evan Y. Yu, MD, discusses the therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) included in the  National Comprehensive Cancer Network (NCCN) guidelines, such as abiraterone (ABI) based on the COU-AA-301 trial and enzalutamide (ENZA) based on the AFFIRM trial, highlighting the evidence supporting their use and how these therapies align with the most current NCCN recommendation.

A 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin plus cyclophosphamide with paclitaxel (ddAC-paclitaxel), which she tolerated well. Eight months after completion of adjuvant therapy, she reported worsening fatigue. ​Laboratory results showed 1.5 times elevated levels of alanine transaminase and aspartate transaminase above the upper limit of normal, and a CT scan showed 1 liver lesion and 2 left lung lesions. A biopsy of the liver lesion confirmed recurrent metastatic TNBC. A brain MRI was negative for brain metastases.

Genetic panel testing was negative for all detectable mutations. PD-L1 expression on immune cells was 0%. The patient was otherwise healthy with no significant comorbidities and had an ECOG performance score of 0.

Following recurrence at 8 months from treatment, the patient received first-line gemcitabine plus carboplatin with a documented partial response lasting 6 months​. After 6 months of therapy, she reportd worsening fatigue. Imaging revealed disease progression in the liver with new and enlarging metastases​. Her ECOG performance score is now 1.

Microtubule inhibitor (eribulin, vinorelbine)

Which therapeutic option would you seriously consider? ​

If you chose chemotherapy or other in the polling question, what agent/regimen are you most likely to recommend? ​

 I was thinking about doublet chemotherapy. I think more about the degree of transaminitis and thinking about whether we need to debulk faster.

But it sounded like her symptom burden was minimal, and the degree of elevation was mild. I don’t think it’s wrong to give this person a single agent and escalate if needed if you’re not seeing control pretty quickly.

A practical question that often comes up is if you’re going to give a single agent is how [closely] do you want to follow the patient? We have weekly regimens versus some that are every 2, or 3, or 4 weeks. In a patient like this, if I was going to give a weekly regimen, or if I was going to give a single agent, I’d want to watch her closer. You don’t want her cut loose for 3 weeks at a time if you don’t know what direction her liver dysfunction’s going to go. So, maybe this is a good person, if you’re going to get a single agent, to give weekly paclitaxel, vinorelbine [Navelbine], or something like that.

 Yes, I think there might be a little pushback for weekly paclitaxel if she’s recurred within 8 months of getting her adjuvant paclitaxel.

 I mean some weekly agent where you’re going to be seeing her laboratory results with some degree of regularity as opposed to a patient who’s doing really well, who has minimal disease, whose laboratory results look good, [or] who has maybe radiographic progression. Something that’s every 3 or every 4 weeks, from a quality-of-life [perspective], may be more appealing in that scenario.

 Yes, I agree. Does anybody else want to give some general thoughts about how they approach these patients with an early recurrence?

 I had picked carboplatin/gemcitabine in this scenario, even though it was a doublet. But [I favor] the idea of bringing a platinum agent; it’s a different agent. I’m not a big fan of capecitabine in TNBC, unless it was about an [issue with] the toxicity profile or the idea of taking it orally. I think I would jump on to sacituzumab govitecan [Trodelvy] after carboplatin/gemcitabine.

Please discuss your experiences with sacituzumab govitecan​ including toxicity and management.

 I had a patient that I inherited from another provider who received neoadjuvant ddAC-paclitaxel, and progressed through that. I was able to get sacituzumab approved for her; I was able to convince the insurance company that because she progressed through both doxorubicin and then a taxane, that was essentially 2 regimens for metastatic disease. She went on sacituzumab and did extremely well for about a year. So, I was incredibly impressed with it as my first time out, notwithstanding some of the issues in terms of the alopecia. She was…responding to something in a situation where we have seen other patients like this crash and burn fairly quickly in that setting.

 I have a patient on it that has been doing very well for over a year. She interacts with other women who are on the drug, she’s aware of how other patients are doing, and she is clearly among the better ones. As long as it works, I think it’s very well tolerated. The diarrhea can be easily managed, in this case, with diet. I am pleased to have this, and I’ll be interested to see if this has applications in the estrogen receptor–positive population, where there are studies going on right now.

 It’s been generally well tolerated. We’ve definitely run into problematic challenges with cytopenia more than anything else, particularly in patients that have been heavily pretreated. But with regard to some of the other things that we’ve been talking about, I think it’s been fairly easy to manage.

 How do you counsel your patients receiving sacituzumab, with respect to adverse events [AEs] that they might experience? Dr Donnelly, it sounds like you are optimistic; what do you tell your patients they might anticipate?

 The diarrhea’s an issue, and my first patient ended up having constipation because of the anti-emetic drugs that she received. Fortunately, it was in the summertime, and I went back to some of the dietary recommendations [such as] using fresh fruits and vegetables from the farm stands, which turned out to [make it] be a lot more palatable than a lot of drugs. So, by using those kinds of things, I think the diarrhea is manageable. Neutropenia can be an issue, but I have not found it to be overwhelming.

Please discuss the outcomes of the phase 3 ASCENT trial (NCT02574455) in the context of other therapies that have been most commonly used in the setting of relapsed/refractory mTNBC.​

 [For] the outcomes of the phase 3 ASCENT trial…my first thought was, “Wow, the efficacy of sacituzumab is so much better than chemotherapy.” It is chemotherapy, but [better than] other agents. How do you think this fits in with the game-changing treatments we’ve seen in TNBC over the last couple years?

 I find the control arm essentially showing how pathetic the options are for this group and keeping a low bar for sacituzumab to do better. It’s an antibody-drug conjugate [ADC], and hopefully in every cancer we’ll have more ADCs. Although, this one does work like chemotherapy, and the AEs are somewhat like chemotherapy would be: cytopenias and diarrhea. But, in general, I would second everyone’s comments about it being generally well tolerated. We are able to manage and fine-tune these AEs.

But, to the progression-free survival, I’m more impressed by the overall survival [OS], which is significantly better.

 That OS, as Dr Donnelly mentioned about her patient who has been receiving it for a year, is very reflective of how those who do respond tend to have the durability of response, and that’s what I’m excited about.

1. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

During a live virtual event, Elizabeth Ann Mittendorf, MD, PhD, discussed the case of a patient with triple-negative breast cancer whose disease progressed following adjuvant dose-dense doxorubicin plus cyclophosphamide with paclitaxel, then frontline gemcitabine and carboplatin. 

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

Exploring Sacituzumab Govitecan and Other Second-Line TNBC Therapies

A 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin plus cyclophosphamide with paclitaxel (ddAC-paclitaxel), which she tolerated well. Eight months after completion of adjuvant therapy, she reported worsening fatigue. ​Laboratory results showed 1.5 times elevated levels of alanine transaminase (ALT) and aspartate transaminase (AST) above the upper limit of normal, and a CT scan showed 1 liver lesion and 2 left lung lesions. A biopsy of the liver lesion confirmed recurrent metastatic TNBC. A brain MRI was negative for brain metastases.

Would your choice of treatment differ for progression after 24 months versus 8 months? Why?

 Does she has liver dysfunction from her disease?

 Yes, her AST and ALT were 1.5 times the upper limit of normal.

 I think that’s the more challenging aspect, to some extent, rather than the duration. Does she have end organ dysfunction, and some degree of impending visceral crisis? In my mind, that is driving more than the elapsed time in terms of how we would want to think about this.

During a Targeted Oncology case-based roundtable event, Elizabeth Ann Mittendorf, MD, discussed with participants their choice of treatment after progression for a patient with triple-negative breast cancer treated with adjuvant dose-dense doxorubicin plus cyclophosphamide with paclitaxel.

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

David Bond, MD

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