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The past decade has seen the FDA approve a handful of new targeted therapies for chronic lymphocytic leukemia that are prompting a move toward chemotherapy-free treatment of the disease.

10 Years in CLL: Top Advances From 2012-2022 

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 presented to her primary care physician with rib pain after a fall and reported increasing shortness of breath and fatigue. She had no history of smoking. Imaging showed a right hilar mass, rib metastases, and adrenal metastases, but a brain MRI was negative for brain metastases. She had an ECOG performance score of 1 and was diagnosed with stage IV lung adenocarcinoma.

Molecular testing of lymph node tissue showed a 

 exon 14 skipping alteration. We have a lot of options but unfortunately not a lot of guidance in terms of sequencing. So what would you do next? Capmatinib [Tabrecta], or tepotinib [Tepmetko], or crizotinib [Xalkori] are the 3 available type 1 

 inhibitors; chemotherapy would be chemoimmunotherapy; an immune checkpoint inhibitor alone; or other, which we can assume is a clinical trial.

 The first in market, capmatinib, captured the largest share of the poll. That’s very interesting. Tepotinib has 2 votes and crizotinib has 2 votes, and none would use chemotherapy. Who would use the immune checkpoint inhibitor? It’s not wrong, but I’d just be just curious what the thought process was. Is it the label, is it that it’s not exclusive, like we had seen with the EGFR and other inhibitors?

 I voted for that because I didn’t know the other agents that well.

 That’s why we’re here, so that’s a good thing. Aside from a [billable] standpoint, MET, unlike EGFR and ALK [inhibitors]—there’s nothing that speaks against immune checkpoint inhibitors in the first-line setting, with or without chemotherapy. Looking at the guidelines, I think we had a pretty good distribution between the targeted inhibitors and the checkpoint inhibitor. Who voted for the crizotinib? Did you care to comment? Is it a sequencing approach, where you do crizotinib first and use one of the newer MET inhibitors second?

 Well, I voted for crizotinib, and the reason is that I’m familiar with the drug, and I’ve used it in other patients with other mutations. These patients that we’re discussing here are so uncommon that I’m not as familiar with the other agents as maybe I should be.

 Familiarity with the drug is certainly a big factor for treatment. Crizotinib has multiple approvals in the settings of 

 Exactly, so that probably drove my decision to use crizotinib.

 That sounds very reasonable. Any thoughts on capmatinib vs tepotinib?

 I chose capmatinib, like most of the people in the group, because based on the phase 2 trial, the first line and second line, the response rate of the first line was pretty high compared with a chemoimmunotherapy, if you take any trial of a chemoimmunotherapy. Based on that, and also [considering that] the PFS was higher, too, I chose capmatinib. Tepotinib could be a choice; I didn’t choose it because while there’s no [direct] comparison, I think tepotinib has a lower response rate numerically, whether the patient received prior chemotherapy or not, compared with capmatinib—a higher response rate in treatment-naive patients, around 70%. So that’s why I chose capmatinib.

 We’re fortunate to have, in a relatively small space, 3 approved agents for the mutation, 2 being highly selective with good response rates, and a very similar safety profile. There are some differences in terms of dosing and convenience, but from a performance standpoint, I think we have 2 very good choices.

 exon 14 skipping mutation discovered before first-line therapy, the 2 preferred agents [by the National Comprehensive Cancer Network] are capmatinib or tepotinib; crizotinib is an additional option.

 Then, basically in acknowledgment of the guidelines and the FDA labels, also the standard non-driver mutation regimens can be utilized in the first-line setting, with a recommendation upon progression to move back into one of the MET inhibitors. If you discovered the 

 exon 14 mutation after initial treatment initiation, it becomes very difficult to decide how to switch, because there’s no real good data how to do that, whether you do it at progression, arbitrarily, or immediately upon the discovery of the mutation.

I think that the capmatinib and tepotinib data are a little bit cleaner than crizotinib, and mostly the paradigm of targeted therapy before chemoimmunotherapy, especially in this subtype. [

 mutation that is not as responsive to immunotherapy. I think I see a reasonable recommendation summary of the data. Has anybody used tepotinib yet in the first line, in the setting of 

 It seems to be similar to capmatinib. I don’t see a major difference. We’re very biased because we don’t know which one is better. They were approved in different studies. Traditionally, we use capmatinib first, because it’s approved first, and now we have tepotinib later, also.

 on-target effects there, and the edema is probably the main handling issue. A little bit of hypoalbuminemia, sometimes a little bit of increase in kidney function, or liver function test abnormalities, but it’s pretty balanced. I think that’s the non-selective nature of 

The FDA approval [of tepotinib] came earlier this year on February 3.

 Metastatic non–small cell lung cancer, any histology, with a MET exon 14 skipping alteration.

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2021. Accessed November 8, 2021. https://bit.ly/3025IKZ

2. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA. Published February 3, 2021. Accessed November 8, 2021. https://bit.ly/2YuQA86

At a live virtual event, Martin Dietrich, MD, PhD, discusses treatment options for a patient with non–small cell lung cancer when molecular testing shows a MET exon 14 skipping mutation. 

Part 2: Choosing a Treatment for NSCLC with MET Exon 14 Skipping Mutation

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.

Sonya Collins

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