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David J. Stewart, MD, head, Division of Medical Oncology, University of Ottawa/The Ottawa Hospital, discusses a study that investigated the impact of delaying approval on overall survival.

Dr. Stewart on the Impact of Delaying Approval on Overall Survival

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 man, aged 61 years with an active lifestyle, had a history of metastatic renal cell carcinoma (mRCC), and was post‒left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) with metastases in the adrenal​ gland. Four years later, he had a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, they had been present on scans for at least 2 years prior​. Based on low volume, indolency of disease, and patient preference​, he underwent observation. Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis (2.0 x 1.5 cm). His ECOG performance score was 0.

Vote in the polls below on what you would have chosen if this was your patient.

 This is where we stand with regards to the National Comprehensive Cancer Network [NCCN] guidelines for kidney cancer for favorable-risk disease: we have category 1 data for all 3 immuno-oncology [IO] plus VEGF–tyrosine kinase inhibitor [TKI] combinations that have demonstrated improvements in overall survival [OS].

 These include axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab. Then under other recommendations axitinib/avelumab [Bavencio] is listed, cabozantinib alone is listed with a category 2B designation, nivolumab plus ipilimumab [Yervoy], and then single-agent TKI.

 These can be options for patients with favorable-risk disease.

With checkpoint inhibitor combinations like nivolumab/ipilimumab, the data there support the long-term durability of the regimen with long-term PFS at five years at around 30%.

 The Achilles heel of the CheckMate 214 [NCT02231749] data is that the primary progressive disease rate is 18%.

 At the present time we don’t have biomarkers to help us with the selection between IO/IO versus IO/VEGF-TKI.

In that context it seems like no [participants at this roundtable event would] select single-agent TKI. More individuals selected nivolumab/ipilimumab as a potential option, and then some continuing to select the IO/VEGF-TKI combination.

 I changed my treatment from single TKI to a TKI/IO because of the more aggressive presentation likely in the liver as well as the lung. The cancer now is progressing more and likely it's going to progress [even] more. We’ll gain more control of it. Patients need a more active treatment.

 I selected nivolumab/ipilimumab because of the liver involvement and a clear cell morphology. All options, TKI plus nivolumab or pembrolizumab are absolutely acceptable options, but I chose this particular combination because of the aggressive pattern of metastases and liver involvement, which in this setting of RCC, tends to be a much more aggressive disease compared with pulmonary involvement.

 That’s absolutely correct that those with liver metastases can behave more aggressively than those without those sites of metastases.

 I picked lenvatinib plus pembrolizumab based on data from the CLEAR trial [NCT02811861]. I know that it has the longest response seen for any of the mRCC trials with a 71% objective response rate [ORR].

 The reason I didn’t go with cabozantinib plus nivolumab is that this patient did not have any bone metastases and we know cabozantinib/nivolumab is especially good in that subset of patients.

 I picked the pembrolizumab/lenvatinib based on the complete response rate, quicker response, and personal experience. I have a few patients that did really well on this combination and having the disease in the liver, it's probably more aggressive. Also, if the patient is symptomatic, doing TKI with immunotherapy probably reasonable.

A Black woman, aged 59 years, was diagnosed with a left renal mass ​and underwent left radical nephrectomy in December 2019​. Her diagnosis was ccRCC, T3aN0Mx, Fuhrman Grade 3​. Nine months later, she developed metastatic disease to the liver and retroperitoneal lymph nodes. Her radiographic diagnosis was stage IV RCC, with metastases to liver and retroperitoneum​. Her Karnofsky performance status was 90%. Her hemoglobin level was 11.1 g/dL​, and corrected calcium, neutrophils, and platelets were within normal limits.

A fair bit of participants would choose nivolumab/ipilimumab, some lenvatinib/pembrolizumab, some nivolumab/cabozantinib. There were not many people selecting pembrolizumab/axitinib or single-agent cabozantinib.

In the updated NCCN guidelines for treatment for patients with poor- and intermediate-risk disease, all the IO/VEGF-TKI combinations are fair game and so is nivolumab/ipilimumab.

[We can compare] the granular data regarding OS, progression-free survival, and ORR for the intermediate- and poor-risk population compared with the intent-to-treat population across these trials. I would keep in mind the number of patients with poor-risk disease that were enrolled across all of these trials, but based on topline data, every single one of these regimens is effective for patients with intermediate- and poor-risk disease.

Looking at the hazard ratio [HR] for OS, with the long-term follow-up of 67.7 months for nivolumab/ipilimumab is holding steady at 0.68 and for pembrolizumab/axitinib, 0.63.

 For cabozantinib/nivolumab, the HR for the intermediate-risk patients is 0.74; for the poor-risk patients it is 0.45.

 Then similarly for lenvatinib/pembrolizumab, the HR for intermediate-risk patients is 0.72 and for poor-risk patients is 0.39, so these are highly effective regimens.

 The ORR in the intermediate- and poor- risk patients, range from over 50% with the IO/VEGF combinations and 72% with lenvatinib/pembrolizumab, whereas for nivolumab/ipilimumab it's 42%.

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, 2.2023. Accessed August 23, 2022. https://bit.ly/2TAx1m3

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab vs sunitinib in patients with advanced renal cell carcinoma. 

. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

4. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

5. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib vs sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. 

 Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib vs sunitinib for patients with advanced renal cell carcinoma. 

2022;40(suppl 6):350. doi: 10.1200/JCO.2022.40.6_suppl.350

7. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab vs sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021; October 7-8, 2021; Philadelphia, PA. Abstract E41. Accessed August 23th, 2022. https://bit.ly/3yRcxMx

Participants of a live, virtual case-based event discussed different scenarios for treatment of a patient with previously untreated clear cell renal cell carcinoma. Vote in the polls on what you would have chosen if this was your patient.

POLL: What Frontline Treatment Would You Choose for Favorable- and Intermediate-Risk RCC?

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.

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

David J. Stewart, MD

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