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Kelly Paulson, MD, PhD, a fellow at Seattle Cancer Care Alliance, discusses single-cell RNA sequencing in merkel cell carcinoma during&nbsp;The Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting.

Single-Cell RNA Sequencing in Merkel Cell Carcinoma

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.

News

Clinical

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

A post hoc analysis incorporating the use of subsequent therapy in censored patients on the ARASENS trial (NCT02799602) supported the overall survival (OS) benefit of adding darolutamide (Nubeqa) to androgen deprivation therapy (ADT) plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to a poster presented at the 2024 ASCO Genitourinary Cancers Symposium.

In the post hoc sensitivity analysis, investigators counted subsequent systemic antineoplastic therapy in patients who were not available for assessment as an OS event. There was an HR of 0.47 favoring darolutamide vs placebo (95% CI, 0.40-0.54; 

 < .0001), with a median OS of 49.0 months (95% CI, 45.2–not estimable [NE]) with darolutamide vs 31.6 months (95% CI, 29.7-33.8) with placebo.

“Findings from this post hoc sensitivity analysis support the primary OS analysis,” said Neal D. Shore, MD, FACS, medical director for the Carolina Urologic Research Center, in his presentation of the poster.

The phase 3 ARASENS trial randomly assigned 1306 patients on a 1:1 basis to receive 600 mg of oral darolutamide or placebo twice daily plus ADT and 6 cycles of docetaxel.2 The primary end point was OS, assessed using a log-rank test with 95% CI calculated using the Cox model. Those on the trial with no documented death were censored at the data cut-off or the last known alive date, whichever occurred first.

The primary OS analysis was published in the 

 in 2022. At data cut-off of October 25, 2021, median follow-up was 43.7 months in the darolutamide group and 42.4 months in the placebo group. At this time, 229 of 651 patients (35%) in the darolutamide group and 304 of 654 patients (46%) in the placebo group had died, with a 32.5% lower risk of death in the darolutamide group (HR, 0.68; 95% CI, 0.57-0.80; 

 The median OS with darolutamide was NE (95% CI, NE-NE) compared with 48.9 months (95% CI, 44.4-NE) with placebo.

Investigators noted that 374 of 495 patients (75.6%) who entered follow-up in the placebo group received subsequent life-prolonging therapies, primarily different androgen receptor pathway inhibitors besides darolutamide. This had the potential to impact OS outcomes.

In the post hoc sensitivity analysis, 776 patients were counted as having an event, either death or censored patients receiving subsequent therapy, including 300 of 651 (46.1%) in the darolutamide arm vs 476 of 654 (72.8%) in the placebo arm.

Planned sensitivity analyses for OS were also performed. Log-rank test and Cox model without stratification showed an HR of 0.69 favoring darolutamide (95% CI, 0.58-0.82; one-sided 

 <.0001). In a log-rank test and Cox model using stratification factors collected from electronic case report forms, the HR was 0.68 (95% CI, 0.57-0.81; one-sided 

 <.0001). The log-rank test and Cox model using extent of disease stratification factors based on central imaging review resulted in an HR of 0.68 (95% CI, 0.57-0.81; one-sided 

At data cut-off, 299 of 651 patients in the darolutamide arm (46%) and 125 of 654 patients in the placebo arm (19%) continued receiving study treatment. Forty-eight percent in the darolutamide arm and 76% of those in the placebo arm were eligible for subsequent therapy, and 34% of the darolutamide arm and 60% of the placebo arm ultimately received subsequent systemic antineoplastic therapy. The time to first subsequent systemic antineoplastic therapy, which was a key secondary end point of ARASENS, was superior in the darolutamide arm (HR, 0.39; 95% CI, 0.33-0.46; 

In terms of safety, the median duration of treatment was 41.0 months in the darolutamide arm vs 16.7 months in the placebo arm.

 Overall incidence of treatment-emergent adverse events (TEAEs) was similar between the groups, with the cumulative incidence of TEAEs commonly associated with androgen receptor inhibitor therapy being low in both arms, particularly when adjusted for exposure. TEAEs led to discontinuation in 13.5% in the darolutamide group vs 10.6% in the placebo group.

“In conclusion, the results of the post hoc sensitivity analysis were consistent with and supportive of the ARASENS primary OS analysis,” said Shore. “These data reinforce combination of darolutamide with ADT and docetaxel as an effective and well tolerated standard-of-care option for early treatment intensification in patients with mHSPC.”

1. Shore ND, Tombal BF, Hussain M, et al. Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy. 

 2024;42(suppl 4):166. doi:10.1200/JCO.2024.42.4_suppl.166

2. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. 

. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

A post hoc sensitivity analysis that counted use of subsequent therapies in patients censored from primary overall survival follow-up favored darolutamide plus androgen deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer. 

Kelly Paulson, MD, PhD

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