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BTK Inhibitors: In-Focus

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Advances in the field have also led to the recognition of other clinical challenges, including unforeseen observations and complications associated with choosing the sequencing of appropriate therapeutic interventions as well as the management of drug-related complications.

Differentiating Pseudoprogression From Hyperprogression in Patients Treated With Immunotherapies

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.

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FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A 71-year-old woman reported symptoms of weight loss and increasing fatigue. She had a medical history of hypertension controlled with medication and takes over-the-counter proton pump inhibitor (PPI) tablets as needed for a “sensitive” stomach​. A physical examination revealed she had axillary lymphadenopathy. Her spleen was palpable and about 4 cm below costal margin. She was ill-appearing and continued only limited daily activity​.

Laboratory results​ showed a white blood cell count of 47,000, 76% lymphocytes, hemoglobin 8.7 g/dL, platelet count 115,000/mm3, absolute neutrophil count of 3,600/mm3, lactate dehydrogenase level of 250 U/L, and β2-microglobulin of 4.3 µg/L​. Flow cytometry showed she was CD5 positive, CD20 positive (dim), and CD23 positive with kappa restricted monoclonal B-cell population.

Fluorescence in situ hybridization assay discovered a deletion 11q mutation, but she was negative for a 11;14 translocation​ mutation. She was 

unmutated​. A bone marrow biopsy showed diffuse marrow infiltration by chronic lymphocytic leukemia (90%-95%)​.

What treatment would you select and what factors influence your recommendation for this patient?

What are the data and recommendations to guide therapy? ​

 I would choose acalabrutinib [Calquence] for her. She didn’t have any comorbidities that would preclude use of acalabrutinib. Hypertension is less with acalabrutinib than with ibrutinib [Imbruvica], and it’s controlled with medications.

. That’s what I would choose, and I usually do not give a CD20 antibody with Bruton’s tyrosine kinase [BTK] inhibitors. I know there are data that they inhibit each other a little bit. So, I think that ibrutinib inhibits the antibody-dependent cellular cytotoxicity [ADCC] or the BTK inhibitor inhibits the ADCC by the CD20 antibody.

 I think that as Dr Parrondo mentioned, there are the in vitro data showing that ibrutinib, through [inhibiting] inducible T-cell kinase, could really diminish the effect of the monoclonal antibody.

 However, the ALLIANCE A041202 trial [NCT01886872] didn’t show any advance of the reduction.

 We don’t know for sure [if this is an issue with] acalabrutinib, and I agree with Dr Parrondo. If I am going to use it, I use single agent because this potential issue still isn’t clear how clinically translated it could be, but it's definitely something to discuss.

 I chose ibrutinib, maybe because I’m more comfortable with it. I’ve seen that patients tolerate it well. This patient doesn’t have any comorbidities that would worry me. [I would consider] her age but it all depends on the [ECOG] performance status of the patient.

 I think it’s another very good alternative. I agree with [Dr Parrondo] that theoretically, [acalabrutinib] has less hypertension. We know that acalabrutinib is contraindicated [for PPI], but the question is why this patient is taking PPI.

 And there is no doubt, Dr Cruz-Amy, you have good previous experience with ibrutinib, which is something fundamental when we choose medications, in my opinion.

 In my experience giving BTK inhibitors in elderly patients, even if they don’t have comorbidities, it could be challenging in terms of infection risk and cardiovascular issues such as atrial fibrillation. Since this patient doesn’t have a 3p deletion or 17p deletion, I would go for a fixed duration therapy in that situation. Venetoclax [Venclexta] and CD20 inhibitor is an option. If you achieve minimal residual disease negativity, you can give a fixed duration therapy and then stop, but if you start ibrutinib, it’s not ending. You have to continue for a lifetime, until the disease develops growth effects or stops responding.

 I would choose acalabrutinib. I was thinking about adding obinutuzumab [Gazyva] with it. I’m impressed with the flattening of the [Kaplan-Meier] curves we’re seeing with that combination.

 And it looks like patients are having long-term progression-free survival [PFS] on that combination. I think it’s an easy choice. I’m happy to give acalabrutinib.

 I chose venetoclax and anti-CD20, but I’m afraid to give anti-CD20 in light of the pandemic. We’ve had lots of patients end very badly after they’ve gotten rituximab [Rituxan] and they’ve died, and I think it’s because of the rituximab. It’s not clear if I would choose that at the moment, just because…this pandemic. If the pandemic is ending, then maybe we could go back to selecting the [those] choices.

Going back to that, I’m not sure what the right choice is; the 3 choices seem wonderful. It comes back to my preference and my experience in using venetoclax and anti-CD20 antibodies.

 I think you bring up an excellent point that we discuss very often about how the pandemic is modifying our current trends of therapies, and as you just pointed out, how our CLL population is very prone to get COVID-19. Unfortunately, as you have experienced, we have lost several patients after monoclonal antibodies because there is no real immunity for at least 18 months after the last dose of monoclonal antibody, so those patients may be at high risk.

 I chose acalabrutinib. But in real life, I discuss the options with the patient, including BTK inhibitor versus venetoclax, just because of the duration of the treatment. I am a fan of the stop date, because I don’t like to keep treatment going. But it’s something I discuss with the patient. If the patient wants to have a stop date, I will go with the venetoclax plus obinutuzumab. But if a patient does not want to stop, or they have no preference, I will go with acalabrutinib.

 How do you manage the PPI [issue], [given that it is associated with] around 40% to 45% reduction of efficacy?

 We know that PPI like this patient was taking will reduce the absorption of acalabrutinib, so how you will manage this patient?

 I can switch them to an anti-H2 antagonist.

 Yes, I think that is a good point. What we have done many times, when we believe that acalabrutinib is the right thing, we try to understand the reason the patient is taking the PPI.

 I have chosen acalabrutinib. And also, there’s a good point about the PPI. I think it’s good to know what the patient is taking…so you can do a good patient education, and you can put the patient on acalabrutinib. Also, the acalabrutinib combination with the second-generation anti-CD20 has good results. It has even better results than acalabrutinib with chlorambucil. So, the patient will benefit from that.

 You will choose the monoclonal antibody plus acalabrutinib, is that what you will favor in this case?

 Yes. Just because of the hypertension, I’ll go over acalabrutinib instead of ibrutinib. Maybe it’s not that high, but it will be better to have more control over the other risks that the patient has.

1. NCCN. Clinical Practice Guidelines in Oncology. chronic lymphocytic leukemia/small lymphocytic leukemia, version 2.2022. Accessed February 11, 2022. https://bit.ly/35VbY9J

2. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. 

 (2013) 122 (15): 2539–2549. doi: 10.1182/blood-2013-06-507947

3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. 

2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836

4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Elevate-TN four-year follow up. 

 2021;39(suppl 15):7509. doi:10.1200/JCO.2021.39.15_suppl.7509

5. Acalabrutinib (Calquence). Prescribing Information. AstraZeneca; 2019. Accessed February 11, 2022. https://bit.ly/3gFmJzm

During a live virtual event, Javier Pinilla-Ibarz, MD, PhD, discussed treatment options for chronic lymphocytic leukemia including ibrutinib, acalabrutinib, and venetoclax with obinutuzumab. 

Choosing Between Venetoclax or BTK Inhibitors in Frontline CLL

Accelerated approval has been granted to asciminib (Scemblix) by the FDA for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

At 48 weeks, the major molecular response (MMR) rate for asciminib was 68% (95% CI, 61%-74%) vs 49% (95% CI, 42%-56%) in patients on standard tyrosine kinase inhibitors (TKIs).

Asciminib dosing is recommended as either 80 mg once daily or 40 mg twice daily, administered consistently at the same times each day for optimal results.

The FDA has granted asciminib accelerated approval for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.

Findings from the ASC4FIRST trial (NCT04971226) support this regulatory approval of asciminib in newly diagnosed Ph+ CML in CP. For the primary end point of the study, the MMR rate at 48 weeks, the rate was 68% (95% CI, 61%-74%) in the asciminib arm and 49% (95% CI, 42%-56%) in the investigator-selected TKIs arm, making for a difference of 19% (95% CI, 10%-28%; 

 <.001). Within the imatinib (Gleevec) stratum, the MMR rate in the asciminib arm was 69% (95% CI, 59%-78%) compared with 40% (95% CI, 31%-50%) in the investigator-selected TKI arm, for a difference of 30% (95% CI, 17%-42%; 

For safety, the most common adverse effects observed in ≥20% patients with newly diagnosed and previously treated Ph+ CML in chronic phase included musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, and diarrhea. The most common laboratory abnormalities seen in ≥40% of patients with newly diagnosed Ph+ CML in chronic phase consisted of decreased lymphocyte count, decreased leukocyte count, decreased platelet count, decreased neutrophil count, and decreased calcium corrected.

The recommended dosage of asciminib is 80 mg taken orally once daily at approximately the same time of day or 40 mg taken orally twice a day at approximately 12-hour intervals.

 for patients with Ph+ CML in chronic phase who had been treated with 2 or more TKIs.

 Asciminib is among the newest available treatments for patients with CML.

ASC4FIRST is a multicenter, randomized, active-controlled, open-label trial. A total of 405 patients were randomized in a 1:1 fashion and given either asciminib or imatinib, nilotinib (Tasigna), dasatinib (Sprycel), or bosutinib (Bosulif).

 A total of 405 adult patients were enrolled across 111 locations.

In addition to the primary end point of MMR at week 48, the secondary end points included MMR at week 96, time to discontinuation of study treatment due to AEs, complete hematologic response, complete cytogenetic response, duration of MMR, time to first MMR, time to treatment failure, failure-free survival, event-free survival, progression-free survival, and overall survival.

1. FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. News release. FDA. October 29, 2024. Accessed October 29, 2024. 

2. FDA approves Novartis Scemblix® (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia. News release. Novartis. October 29, 2021. Accessed October 29, 2024. 

3. A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP. ClinicalTrials.gov. Updated May 3, 2024. Accessed October 29, 2024. 

https://clinicaltrials.gov/study/NCT04971226

Asciminib has gained accelerated approval from the FDA for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

FDA Approves Asciminib in Newly Diagnosed Ph+ CML in Chronic Phase

In a 2 to 10 vote, the FDA’s Oncologic Drug Advisory Committee (ODAC) voted that the risk-benefit assessment is not favorable for the use of checkpoint inhibitors (CPIs) in first-line advanced HER2-negative gastric and gastroesophageal junction (GEJ) adenocarcinoma in patients with PD-L1 expression less than 1.

The ODAC discussed this question through data supporting the current approvals of nivolumab (Opdivo) and pembrolizumab (Keytruda) plus chemotherapy, as well as the application of tislelizumab-jsgr (Tevimbra) plus chemotherapy, for this indication. 

“I agree based on the totality of the data that there was not a favorable risk-benefit [profile] for this PD–L1-low population,” said ODAC member Neil Vasan, MD, PhD, Columbia University Medical Center. “For me, it was clear that there was benefit in the [PD-L1 expression] greater than 10 and no benefit [with PD-L1 expression less than 1.] It is that intermediate range where we need clinical trials to help answer questions where we have levels of equipoise as with any continuous variable.”

Introductory remarks were delivered by Steven Lemery, MD, MHS, director of the Division of Oncology 3, Office of Oncologic Diseases. He presented the goals of the meeting as considering the class labeling of CPIs, maximizing risk-benefit balance, fostering consistent treatment, and creating a consistent drug developmental landscape. Lemery noted that while PD-L1 is a predictive biomarker, it is an imperfect one.

The FDA’s Oncologic Drug Advisory Committee voted against the use of checkpoint inhibitors in first-line advanced gastric cancer with PD-L1 expression less than 1.

Sara Rogers, PharmD

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