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Hideho Okada, MD, PhD, director, Brain Tumor Immunotherapy Center, professor of Neurological Surgery, University of California, San Francisco, discusses a study exploring vaccination in patients with glioblastoma.

Exploring Immunotherapy Vaccines in Glioblastoma

Hideho Okada, MD, PhD, director, Brain Tumor Immunotherapy Center, professor of Neurological Surgery, University of California, San Francisco, discusses a study exploring vaccination in low-grade glioma aiming at prevention of high-grade transformation.

Exploring Vaccination in Low-Grade Glioma With the Aim of Preventing High-Grade Transformation

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 52-year-old, postmenopausal woman had a history of grade 2, node-negative invasive ductal carcinoma (IDC).

Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27

Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.

Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).

Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.

The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.

Required 1 dose reduction to 400 mg ribociclib due to neutropenia.

Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.

She noted mild increase in lower back pain​.

Circulating tumor DNA (ctDNA) analysis confirmed an 

Fulvestrant + a different CDK 4/6 inhibitor 

 Using fulvestrant plus a different CDK4/6 inhibitor would not be an unreasonable choice if the patient didn't have an 

 mutation. Fulvestrant alone isn’t a [definite] option for a patient like this. I probably wouldn't use exemestane plus everolimus [Afinitor] here because I don't think this patient has definitively endocrine-resistant disease. Likewise, I probably wouldn't give single-agent chemotherapy. So I would agree with the participants and give elacestrant [Orserdu].

 I absolutely agree. I think elacestrant would be a preferred option.

 But there are some other circumstances where somebody doesn't have access to elacestrant. The 

 mutation would drive me towards a selective estrogen receptor degrader over an aromatase inhibitor combination. So thinking about fulvestrant is also a reasonable option, but I think elacestrant [is a recommended] option.

 The patient received ribociclib in the first-line setting—if she got palbociclib [Ibrance], would you consider, if she didn't have any sort of mutation, fulvestrant plus ribociclib based on the MAINTAIN trial [NCT02632045]?

 I think [we take into account] the MAINTAIN data.

 They are certainly compelling. I have done that very thing in patients who lack other targetable mutations, had a good run on first-line palbociclib, and just have a small amount of progression. We did see data that ribociclib plus fulvestrant was better than fulvestrant alone in that population. I would consider that, remembering that phase 2 hypothesis-generating study.

 mutation, what comes first? How do you deal with that?

 It's a very good question. It's a data-free zone, but I think given the toxicity profile, I probably would lean towards elacestrant.

 I think this depends on the patient in front of you and the volume of their disease. Are they symptomatic, and are we feeling comfortable with single-agent endocrine therapy knowing that we still have the ability to target the PIK3CA pathway at the subsequent progression? I think in the absence of data, it's an art-of-medicine decision. I think there's a place for single-agent endocrine therapy, given the constellation of risk-benefit balance.

 When you look at SOLAR-1 [NCT02437318], the benefit with alpelisib [Piqray] was pretty significant.

 We just don't know the answer right now. And I think you're absolutely right, it depends on the patient.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 2.2024. Accessed June 6, 2024. 

2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. 

. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392

3. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. 

. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011

During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, looks at options for a patients with hormone receptor–positive, HER2-negative breast cancer and an ESR1 mutation in the second article of a 2-part series.

Second-Line Targeted Options Considered in ESR1-Mutated Breast Cancer

A 78-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago; his lymph node dissection (LND) was positive for nodal involvement. The patient declined complete LND and adjuvant systemic therapy. He remained active since his surgery and maintained regular follow-up appointments.

On routine follow-up, the patient presented with moderate asthenia that limited his daily activities. His ECOG performance status was 1, and his physical examination was unremarkable. Notable laboratory findings included lactate dehydrogenase (LDH) level of 380 U/L (reference range, 110-240 U/L). A full-body CT scan revealed pulmonary and hepatic nodules but no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma.

 If this patient was in your clinic with previously untreated metastatic melanoma, we have lots of choices. It’s a good problem to have as an oncologist treating melanoma these days. Based on the factors, this is a patient without brain metastases, but with distant visceral disease. I’m curious to see what you would offer this 78-year-old patient. It seems the choices were primarily split between the dual checkpoint inhibitor therapies, with some PD-1 inhibitor monotherapy.

 I would probably use nivolumab [Opdivo] plus ipilimumab [Yervoy]. I think that’s still the preferred regimen, but I may consider, from his age, using low-dose ipilimumab with higher-dose nivolumab.

 There are some data now that show you can use nivolumab/relatlimab [Opdualag] once they fail nivolumab/ipilimumab.

 It gives you a second-line option. That’s the way I would probably approach it. I’ve used more of the alternate dosing because of age, but I still think nivolumab/ipilimumab is the preferred [regimen].

 I [would choose] nivolumab/relatlimab because the data are similar compared with nivolumab/ipilimumab and the tolerability is slightly better.

 If I use nivolumab/ipilimumab, which I think is a good choice and the first choice, I would use nivolumab/relatlimab in the second line. But I tend to lean towards it more because…compared with nivolumab/ipilimumab, the data are similar or better.

That’s a great point, weighing the relative benefit and toxicity and certain patient factors.

 I have usually used nivolumab/ipilimumab in the past, but now seeing the approval of nivolumab/relatlimab I [would] switch over. The tolerability is, in my experience, a lot better than the nivolumab/ipilimumab combination. I rarely have any patient have any significant adverse event like diarrhea or severe colitis that require [hospital] admission. So far, [my patients] all seem to get pretty good responses, including 1 who had a complete response. So far, it’s a very good experience for me.

 I will primarily use nivolumab/ipilimumab. There are some data also that you can restage the patient after 2 cycles.

 If there hasn’t been a response, you can drop the ipilimumab because the likelihood of response will be a lot less. But I will give a chance to nivolumab/ipilimumab based on the [slightly] superior response rate [vs nivolumab/relatlimab], and more maturity of the data.

 Good points. I think everyone’s made the points that we’re all thinking about, trying to weigh risk and benefit when we’re making decisions in clinic.

 mutation, what factors influence the first-line selection of immune monotherapy versus dual immunotherapy in a patient such as this?

 It seems like this is a group that is in favor of a dual checkpoint inhibitor therapy. What are the factors that go into your decision making for monotherapy vs dual immunotherapy? We’ve listed some things that we take into account, but how you make these decisions?

In my own practice, it certainly mirrors what many people here have talked about, favoring dual checkpoint inhibitor therapy…. The group that we now treat with monotherapy has become less and less common, based on some of the data. Although I think there are certain situations where monotherapy still may be warranted. Comorbidities…for example, underlying autoimmune disorders or other things where we might be worried about an increased risk of adverse events, depending on site of disease and extent of disease. Age of the patient can sometimes influence that. I’ve personally treated a few patients well into their 90s, and that’s an extreme example. Those are patients where I may be more likely to use monotherapy vs dual checkpoint inhibitor therapy.

: In the past, in patients who are frail, I would lean toward monotherapy, like pembrolizumab [Keytruda]. I think nivolumab/relatlimab is, from my experience, very tolerable so I’m leaning toward that direction now.

 [With] high LDH or higher tumor burden, I’m even more willing to do dual immunotherapy. Also, I think if they have the 

 mutation, they seem to do better if they have dual immunotherapy. There are some data saying that.

 Yes, there are [data] on different subgroups.

 So if they’re wild-type, have low LDH, have low tumor burden, or they’re older, you might consider monotherapy more in that type of patient. But in general, default is the doublet unless somebody needs monotherapy for those other reasons that you state [such as] comorbidities.

 That’s a great point. We could talk for hours on why there’s not a biomarker for selecting immunotherapy, [but] I don’t use PD-L1 or LAG-3 expression in melanoma. PD-L1 expression is predictive, but it’s not adequate to select 1 type of therapy over another. It sounds like most [physicians] are not using that, which is good to hear.

1. Lebbe C, Meyer N, Mortier L, et al. Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: Three-year results of CheckMate 511. 

. 2021;39(suppl 15):9516. doi:10.1200/JCO.2021.39.15_suppl.9516

2. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

 2022;386(1):24-34. doi:10.1056/NEJMoa2109970

3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. 

. 2022;40(2):127-137. doi:10.1200/JCO.21.02229

During a Targeted Oncology™ Case-Based Roundtable™ event, April K.S. Salama, MD, discussed treatment approaches for a 78-year-old patient with metastatic melanoma discovered 12 years after surgical resection. 

Hideho Okada, MD, PhD

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