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Holmen says that utilizing targeted therapies could potentially be the answer, though clinically-tested combinations have historically not done as well as clinicians had hoped.

Dr. Sheri Holmen on Finding the Appropriate Treatments for Brain Metastases in Melanoma

Sheri Holmen, PhD, discusses treating metastases in melanoma. Holmen says the treatment of metastases in melanoma is currently the cancer's biggest unmet clinical need, specifically brain metastases. 

Dr. Sheri Holmen on Brain Metastases in Melanoma

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 54-year-old man with a history of metastatic renal cell carcinoma (mRCC) had undergone a left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) and metastases in his adrenal gland. Four years later, the patient had a recurrence of his cancer. A biopsy showed lung nodules consistent with ccRCC. In retrospect, it had been present on scans for at least 2 years prior.

The patient was observed based on the low volume and indolence of the disease and on his preference. Eighteen months later, a reexamination showed continued indolent growth on scans, with an increased total tumor burden, and a new paratracheal lymph node (2.0 × 1.5 cm). A decision was made to initiate systemic therapy with pembrolizumab (Keytruda) plus axitinib (Inlyta).

On follow-up, the patient’s disease was stable. The patient reported moderate diarrhea (well controlled with antidiarrheal medication) and mild fatigue. After cycle 6, he developed fatigue, mild shortness of breath, and mild cough without chest pain.

At approximately week 18, a chest CT scan confirmed grade 3 pneumonitis. Pembrolizumab treatment was held, and intravenous steroids were administered. Pembrolizumab then was discontinued, and the patient continued on axitinib.

Fourteen months after the initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain. Imaging confirmed disease progression: the paratracheal lymph node had been 20 × 15 mm and was now 25 × 28 mm; there were new mediastinal and hilar nodal involvement, new retroperitoneal nodes, and new lytic lesions. He had an ECOG performance status of 1.

The patient was given 60 mg of cabozantinib (Cabometyx) once a day. Four months later, disease progression was documented. The patient wanted to continue active therapy.

What do you consider when choosing the next line of therapy for a patient like this?

 As far as I know, there is no study showing that if you fail one TKI [tyrosine kinase inhibitor], then you are going to fail the other ones. I am looking at it like you look at multiple myeloma with immunomodulatory drugs or proteasome inhibitors. Do we know that if you have failed one particular TKI that that necessarily means that you are not going to be using that class of therapy?

 No. In fact, the data would suggest the opposite, that there is efficacy. The first line therapies were all TKI, pazopanib [Votrient], sunitinib [Sutent], and then cabozantinib got approved with the METEOR study [NCT01865747], for example. That is one TKI given right after another and there is efficacy there. Similarly, with lenvatinib [Lenvima] plus everolimus [Afinitor], it was post TKI. There is well established efficacy, though maybe not as good in the later lines as if you give it up front. But most of these drugs have second-line data to support their use. You don’t exclude the class.

[Additionally], there’s a rare patient where, if you cycle through enough therapies, you can sometimes go back to the first one and get a response on occasion. That is probably because the spectrum is very different across the kinases that it [targets], and you [may] rescue some of the resistance by switching. That’s one of the nice things about having lots of options because you can cycle through them, even though they are in the same class.

Single-agent TKI (eg, sunitinib, pazopanib)

 [I chose] ipilimumab [Yervoy] plus nivolumab [Opdivo]. There are multiple studies that have shown a 15% to 20% significantly durable response rate post–single-agent TKI or single-agent checkpoint inhibitor in ccRCC.

 For a good performance status in a younger patient who is interested in more than what tivozanib [Fotivda] offers in a few months, I’d definitely discuss ipilimumab plus nivolumab if they haven’t had significant toxicity previously with pembrolizumab.

I agree with Dr Kuzel on the salvage ipilimumab plus nivolumab in second line and beyond. Response rates are low, [somewhere] in the 11% to 20% range,

 but if [the patient is] relatively asymptomatic and going for that long, durable response, it is reasonable as a careful discussion. There are not many complete responses [CRs]. Michael B. Atkins, MD’s study had CRs,

but the rest of the studies across the board didn’t have any CRs.

I picked other. I like lenvatinib plus pembrolizumab, based on a smaller study [KEYNOTE-146; NCT02501096] that showed lenvatinib plus pembrolizumab was able to rescue patients after frontline IO [immunotherapy] regimens.

 The [objective response rate at week 24] was 55% and the progression-free survival is probably rivaling lenvatinib plus everolimus, but with less toxicity without everolimus.

 Great thoughts. Maybe with the ipilimumab plus nivolumab, [there is] a low response rate, but potentially, if it is durable, it could be important to patients, especially if they are asymptomatic or have low symptoms. Then lenvatinib plus pembrolizumab is another good and interesting option. We [at the University of Chicago] were involved in that study, as well. It was a single-arm study, but it was pretty compelling.

 This is where I have a problem with [the National Comprehensive Cancer Network (NCCN) guidelines] because when you request an IO after an IO, we usually get denied. Insurers say no because the NCCN says if you had a prior IO then it makes it difficult to try another one, even if it was given first line and you are looking at third line.4 It makes it difficult to try any IO thereafter. We’ve tried and tried to look at ipilimumab plus nivolumab, but then they ask, does the patient have sarcomatoid [histology]? If we say no, [then we get denied], and you have to try something else. That’s one of the issues.

 I would say [ipilimumab/nivolumab] is not my go-to, even if it is a consideration for some patients. I don’t know if Dr Kuzel or Dr Tan are doing that in most patients, or if it [is for] selected patients. It’s mostly based on the response rate being relatively low, and that is probably why it is not in the guidelines. But if you are adhering to the guidelines, it’s never going to be 100% [appropriate for all cases] anyway. But I agree, that’s the nuance that’s missing in the guidelines.

 I don’t think that you could [dismiss ipilimumab plus nivolumab based on] the response rate. I think lenvatinib plus pembrolizumab [as subsequent therapy] is interesting. Ipilimumab plus nivolumab is on the NCCN guidelines as a regimen so that I have almost no pushback in terms of giving ipilimumab plus nivolumab in the salvage setting.

 The guidelines have lots of options that they delineate. Even lenvatinib plus pembrolizumab is on there [as useful in certain circumstances]. Those are on there, but it still may be harder to get approval. Insurance companies sometimes still deny.

 It looks like the old drug temsirolimus [Torisel] is coming back. [Do you have] any experience with that?

 I haven’t used it in a long time. I tend to give everolimus with lenvatinib when I give everolimus. But I don’t know if others have been using temsirolimus recently.

 I remember that from fellowship, but I haven’t used it as an attending, and that was 10 years ago. I remember it was [at the time] a category 1 option for patients with Memorial Sloan Kettering Cancer Center poor-risk disease, [but is now category 2B].

I used it on 2 patients over the last year. It was 1 patient with clear cell [histology] and 1 with a mixed histology, with partial response in both cases.

1. Yang Y, Mori SV, Li M, et al. Salvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma: a meta-analysis. 

. 2022;11(7):1669-1677. doi:10.1002/cam4.4587

2. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). 

 2022;40(25):2913-2923. doi:10.1200/JCO.21.02938

3. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. 

. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2

4. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2023. Accessed April 14, 2023. https://bit.ly/2TAx1m3

During a Targeted Oncology™ Case-Based Roundtable™ event, Randy F. Sweis, MD, discussed possible therapy options for a patient with metastatic renal cell carcinoma whose disease progressed on frontline therapy. 

Use of Immunotherapy Considered in Later Lines of RCC Therapy

The FDA has granted approval to the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) as treatment of advanced renal cell carcinoma in the frontline setting, announced the FDA in a press release.

Approval of the supplemental Biologics License Application for the combination was supported by results from the phase 3 CheckMate 9ER clinical trial (NCT03141177), in which nivolumab/cabozantinib demonstrated statistically significant improvements in progression-free survival (PFS), overall survival (OS) and good confirmed overall response rate (ORR).

“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib; progression-free survival, overall survival and objective response rate, while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate 9ER and quality of life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” said Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, in a statement.

 “With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer.”

In the study, 651 patients with advanced RCC were randomized 1:1 to receive either the frontline combination of nivolumab plus cabozantinib (n = 323) or sunitinib (n = 328). Nivolumab was administered by intravenous infusion at 240 mg every 2 weeks, and cabozantinib was given orally at 40 mg daily. In the control arms, sunitinib was administered orally at a dose level of 50 mg daily on a cycle of 4-weeks-on and 2-weeks-off. All study treatments were continued until disease progression or unacceptable toxicity.

According to the blinded independent central review committee, the median PFS observed with nivolumab plus cabozantinib was 16.6 months compared with 8.3 months in the sunitinib arm, (HR, 0.51; 95% CI, 0.41-0.64), at a median follow-up of 18.1 months. The median OS was not yet reached in either arm of the study (HR, 0.60; 95% CI, 0.40-0.89).

In terms of response, patients treated with nivolumab plus cabozantinib achieved a 55.7% ORR compared with 27.1% in the sunitinib arm. Responses in the combination arm included complete responses (CRs) in 8.0% of patients and partial responses (PRs) in 47.7%. In the sunitinib arm, only 4.6% of patients had CRs and 22.6% had PRs.

Adverse events (AEs) observed in the study subjects led to treatment discontinuation in 50%. The most common AEs (≥20%) included diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Treatment-related AEs (TRAEs) were also seen in the study and led to discontinuation of treatment in 15.3% of the nivolumab/cabozantinib arm versus 8.8% of the sunitinib arm. Overall, the most common TRAEs were similar between patients treated with the combination and those treated with sunitinib monotherapy.

Based on the safety data from CheckMate 9ER, the recommended dose is nivolumab 240 mg given every 2 weeks by 30-minute IV. Nivolumab can also be administered at a 480-mg dose every 4 weeks by 30-minute IV in combination with cabozantinib 40 mg given orally once daily without food. Treatment should continue until disease progression or unacceptable toxicity.

1. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA. January 22, 2021. Accessed January 22, 2021. 

2. Exelixis announces U.S. FDA approval of Cabometyx® (cabozantinib) in combination with Opdivo® (nivolumab) as a first-line treatment for patients with advanced renal cell carcinoma. New release. Exelixis. January 22, 2021. Accessed January 22, 2021. 

3. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. 

The FDA has granted approval to the combination of nivolumab and cabozantinib as treatment of advanced renal cell carcinoma in the frontline setting.










FDA Approves Nivolumab Plus Cabozantinib in Advanced Renal Cell Carcinoma

A 51-year-old man presented with pallor and worsening fatigue on exertion. Laboratory results showed that his hemoglobin was 9.2 g/dL, blood urea nitrogen/creatinine and calcium was within normal limits, and lactate dehydrogenase was within normal limits. Serum β2-microglobulin was 4.1 mg/L, serum albumin: 3.2 mg/dL, serum M-protein was 1.5 g/dL, and λ free light chains was 110 mg/dL.

A bone marrow biopsy showed 66% plasma cells. Fluorescence in situ hybridization showed a deletion 13q mutation. Urine protein electrophoresis showed a M-spike of 400 mg of λ free light chains in 24 hours. PET/CT scans showed lytic lesions in the ribs and L3 lymph node, and there was no increased standard uptake. Immunoglobulin G was positive in urine and serum free light chains. 

The patient had adequate liver and heart function and was rated at an ECOG performance status of 1. He was diagnosed with stage II (International Staging System [ISS] and Revised ISS) multiple myeloma at standard risk.

 The question was “What primary therapy are you most likely to recommend for this patient eligible for transplant?” VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone]; CyBorD [cyclophosphamide, bortezomib, dexamethasone]; KRd [carfilzomib (Kyprolis), lenalidomide, and dexamethasone], Dara-Rd [daratumumab (Darzalex), lenalidomide, and dexamethasone]; Dara-VRd [daratumumab, bortezomib, lenalidomide, and dexamethasone]; or other. So VRd was selected by 80% and Dara-VRd was 20%.

Some of you are convinced by the GRIFFIN [NCT02874742] data; others I suspect are waiting, understanding that GRIFFIN was a randomized phase 2 trial, and the primary end point was rates of stringent complete response [sCR] and the end of consolidation.

 So, I think that this is in line with what we’re seeing across the board, across the country. The triplet regimen remains king, but we’re starting to move towards the quadruplet regimen. And as the data mature, I think that we’ll all be considering going towards that direction.

What is the best approach (doublet, triplet, quadruplet) toward primary therapy? ​

What aspects of a therapy are most important to you in treatment of newly diagnosed transplant eligible patients with multiple myeloma?​

During a live virtual event, Douglas Sborov, MD, MS, discussed the possible treatment regimens for a patient with newly diagnosed multiple myeloma who is eligible for stem cell transplant. 

Sheri Holmen, PhD

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