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Spotlight

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Authors

Meredith McKean, MD, is a medical oncologist at the Sarah Cannon Research Institute in Nashville, TN. 

Meredith McKean, MD, discusses a longer-term follow-up study investigating fianlimab and cemiplimab immunotherapy in advanced melanoma. 

Melanoma Treatment Advances: Fianlimab and Cemiplimab Show Promise

Meredith McKean, MD, discusses a novel mRNA therapy for the treatment of solid tumors. 

Understanding JZP898: A Breakthrough mRNA Therapy for Solid Tumors

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

Adagrasib (Krazati), compared with docetaxel, provided significantly better results for patients with previously treated 

 G12C-mutated non–small cell lung cancer (NSCLC), even when they had existing brain metastases (BM). These findings are consistent with the overall benefits observed in all patients participating in the phase 3 KRYSTAL-12 trial (NCT04685135).

The findings, which were presented at the 

, demonstrated that among patients with baseline brain metastases, the median intracranial time to progression was 18.6 months (95% CI, 9.6-not evaluable [NE]) in the adagrasib arm and NE (95% CI, 4.2-NE) in the docetaxel arm (HR, 0.60; 95% CI, 0.26-1.40). Additionally, the intracranial progression-free survival (PFS) hazard ratio for patients with brain metastases was 0.93 (95% CI, 0.50-1.73).

 G12C–mutated locally advanced/metastatic NSCLC who had been previously treated with platinum-based chemotherapy and anti–PD-(L)1 therapy and who were randomized 2:1 to receive 600 mg of oral adagrasib twice daily or 75 mg/m2 of docetaxel every three weeks intravenously.

Patients with treated, neurologically stable brain metastases at baseline were eligible for participation, and 114 patients (25.2%) had baseline brain metastases (78 in the adagrasib arm, 36 in the docetaxel arm).

At a median follow-up of 7.2 months, median PFS was 4.4 months (95% CI, 3.1-5.8) in the adagrasib arm and 2.9 months (95% CI, 2.0-6.2) in the docetaxel arm among patients with brain metastases; 5.9 months (95% CI, 4.8-7.2) in the adagrasib arm and 3.9 months (95% CI, 2.4-5.6) in the docetaxel arm in patients without brain metastases.

Furthermore, the objective response rate (ORR) was higher in the adagrasib vs docetaxel arm among patients both with (26.9% vs 2.8%) and without (33.6% vs 11.2%) baseline brain metastases, as was the median duration of response (DOR) for patients with (7.4 vs 5.4 months) and without (8.3 vs 5.4 months) baseline brain metastases.

Treatment-related adverse effects (TRAEs) were also reported to be comparable across treatment arms and irrespective of the presence of baseline brain metastases. Among patients with brain metastases, 94% of patients in the adagrasib arm and 86% of patients in the docetaxel arm experienced a TRAE, while among patients without brain metastases 94% and 87% of patients in the adagrasib and docetaxel arms, respectively, experienced a TRAE. There were 5 total treatment-related deaths, 4 among patients in the adagrasib arm without brain metastases and 1 in the docetaxel arm with brain metastases.

“Adagrasib demonstrated an improved intracranial efficacy over docetaxel in patients with treated, neurologically stable baseline brain metastases,” Professor Fabrice Barlesi, MD, PhD, thoracic oncologist, Paris Saclay University and chief executive officer of Gustave Roussy Institute, in France, said in a presentation of the findings. “Systemic overall response rate, duration of response and PFS were numerically greater with adagrasib compared to docetaxel, regardless of the presence of brain metastases, the safety profiles of adagrasib and docetaxel were comparable in patients with and without brain metastasis, and were consistent with all randomized patients. Overall, these results clearly reinforce adagrasib as an efficacious treatment option for patients including with baseline brain metastasis with previously treated 

Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib (ADA) vs docetaxel (DOCE) in patients (pts) with KRASG12C-mutated advanced NSCLC and baseline brain metastases (BM): Results from KRYSTAL-12. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA57.

Adagrasib demonstrated superior outcomes to docetaxel in patients with previously treated KRAS G12C-mutated non-small cell lung cancer, even among those with baseline brain metastases.

Conference News

Canonical

Adagrasib Outperforms Docetaxel for Pretreated KRAS G12C-Mutant Non–Small Cell Lung Cancer

The patient is a 62-year-old man in Florida.

He presented to his primary care physician (PCP) with symptoms of fatigue, night sweats, and increased bruising.

His past medical history includes type 2 diabetes, hypercholesterolemia, and hypertension.

Normal physical and blood work 1 year ago

His PCP noticed lower hemoglobin (11-9.5 g/dL) and platelet count (350,000/μL-195,000/μL) from the previous year’s physical.

He was referred to hematology/oncology; first available appointment in 2 months

At the appointment, exam findings include spleen 5 cm below left costal margin, worsening fatigue and night sweats, and bone pain.

He has a history of squamous cell carcinoma of the skin.

Blood: 1% blasts by manual count/flow cytometry

/L; hemoglobin: 9.1 g/dL; platelets: 135,000/μL; lactate dehydrogenase: 330 U/L

Bone marrow biopsy showed blasts less than 5% and grade 2/3 fibrosis

Karyotype was 46,XY[20], and next-generation sequencing panel showed a 

V617F mutation with variable allele frequency of 53%

Peers & Perspectives in Oncology: Which tools can be used to assess risk status for a patient such as this?

The PASS tool looks at the prognosis, anemia and thrombocytopenia, systemic symptoms, and splenomegaly and related symptoms.

Looking at the MIPSS70+ [Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis], certain [prognostic variables] stand out.

type 1 mutation [is a risk factor. This means] if you have [the mutation], it’s a very good thing. If you don’t, [you are at higher risk]. High-risk molecular mutations [also increase risk]. If we compare the MIPSS70+ with some of the older models we had, the [overall survival (OS)] curves were a lot closer together previously. With the newer models, the curves are spreading out pretty nicely, similar to the models for myelodysplastic syndrome. It’s not just that they are cytopenic, but the degree of cytopenia, how many mutations they have, [the] karyotype, [the] molecular [status], and the number of circulating blasts by flow cytometry [are all factors]. I use the MIPSS70+ all the time. For patients with secondary myelofibrosis, we have other models that capture similar factors. Dividing these patients up the best we can is important.

What are the challenges of using these scoring systems?

[This patient has] moderate anemia, constitutional symptoms, and absence of the 

mutation. The constitutional symptoms are a tough [challenge]. Are they related to something else? The reality is you are seeing a lot of patients in clinic with a variety of different illnesses, so when you start to talk about symptom scores, it’s very difficult. I know several of my colleagues have very simple tools that we might be able to use to capture this. It’s difficult when you’re doing retrospective review on these patients to capture constitutional symptoms accurately if risk scores aren’t done as they are published, which, to be honest, is exceedingly difficult for anyone who is in the practice as busy as all of us have.

It’s a big [question] that we have to tease out to discern: Are they feeling poorly from their disease [or other reasons]? [Should we suspect] fatigue is from anemia if the anemia is not that bad? Is it fatigue from the proinflammatory state that they have? There’s a lot of overlap within this PASS criteria.

Night sweats, bone pain, and fever are very common, in my experience. Often, these patients will have fevers associated with their disease, and sometimes they’ll end up in the hospital for long periods of time because we want to rule out infections and the like, especially if they’re on therapies that might increase the risk of infection. There is abdominal discomfort and early satiety [that is] typically spleen related but not always. Some patients whose spleens are improving [in size experience worsening] pain because they have a splenic infarct or something else. Conversation is important as we decide what to use and how well something might be working, which predicts outcomes for some agents.

How do trial data support the use of pacritinib (Vonjo) in patients with thrombocytopenic myelofibrosis?

I [focus on] the PERSIST-2 [NCT02055781] data on first- and second-line therapy for patients with thrombocytopenia. Even though the [approval] is for those with a platelet count under 50,000/μL, the trial that led to that approval was for patients [whose platelet count was] under 100,000/μL.

 The dose that we all use, as it relates to safety and efficacy, is pacritinib 200 mg twice daily. The primary end points were splenic volume reduction [SVR] and total symptom score [TSS] at [more than] 50% improvement at the 24-week mark against best available therapy [BAT].

These are patients who were on a variety of therapies, which even included thalidomide…. Lenalidomide [Revlimid] is used more now in some of these patients, but the reality is immunomodulatory imide drugs have a role here, albeit increasingly limited with the development of these newer agents. These patients generally had intermediate-1 and higher-risk disease. A good number had intermediate-2 and high risk, approaching 80% of the patients with those higher-risk categories. A significant number had hemoglobin under 10 g/dL, [59% in the experimental arm and 57% in the BAT arm]. We think about this trial as one for patients with thrombocytopenia, but anemia was demonstrated there.

What were the outcomes for the primary end points?

Looking at the 200-mg twice-daily dosing for those patients with platelet count under 50,000/μL, you saw a 30% improvement in SVR with [patients who were] severely thrombocytopenic.

 That’s a very good number considering the fact that a good number of these patients would not have been able to dose escalate on alternative therapy. One thing I always remind people of is that these data are excellent as it relates to SVR, [but] it…takes a little more time to achieve the same response. Though we don’t see a great degree of thrombocytopenia associated with treatment, we might not see a rise, though we do in some patients. It doesn’t necessarily mean we’re not helping if the spleen is regressing. In these patients, you can see SVR at the baseline dose of 200 mg without dose modification.

TSS was clearly favoring pacritinib at the 200-mg twice-daily dosing. Interestingly, there was a [nearly] 50% change in the pruritus, which is tough [to manage]. Ruxolitinib [Jakafi] has always had a good track record there, and I think it’s on par with pacritinib. There was marked reduction in the night sweats, discomfort in the spleen, and the early satiety associated with it. Across the board, there are improvements.

What other data from the trials of pacritinib are relevant to this patient population?

I want to draw attention to the anemia response rates. Sixty percent [of those] enrolled in the PERSIST-2 trial at a standard dosing of 200 mg twice daily were anemic. The patients who were anemic at baseline had a substantially lower rate of transfusion need as treatment continued [

]. That continued to improve throughout the 24-week treatment course, where it was under 1 red blood cell unit per month, approaching only one-half of a unit per month across the group. There was some improvement over time in the platelet count, though sometimes there was a bit of a dip.

I have dose adjusted, but it is not standard for everyone. I have a lot of colleagues who will push through, but if it’s severe enough, I will push down. I have a handful of patients who do well on 100 mg twice daily. There are those few patients who require that, but overall, most of my patients are dose intensified on pacritinib. We either see stability of the platelet count or some rise over the course of time, but it works more slowly.

Achievement of transfusion independence is an important [end point]. Some 24% of patients treated with pacritinib in PERSIST-2 achieved transfusion independence [vs 5% with BAT; 

The group who [received] BAT included patients who were on erythropoietics. It speaks to the fact that the erythropoietin-stimulating agents don’t work that well for our patients, as is evidenced in PERSIST-2. [However], approximately one-quarter of patients on pacritinib will [achieve] transfusion independence as a conversion rate.

What toxicity concerns are there with pacritinib?

The [rate of] cytopenias was less than what we saw with ruxolitinib.

 These are patients who are generally thrombocytopenic to begin with, but it is something we have to be paying attention to. These patients are already in a state of marrow failure. We recognize these cytopenic patients with myelofibrosis. For any of the drugs, I start with weekly laboratory tests across the board for the first 8 weeks of therapy. It’s my standard routine, and then I start to space it out thereafter. Diarrhea of grade 3 or higher is very uncommon [4%]. I have had a lot of ruxolitinib and pacritinib use, and I don’t see a ton of diarrhea. I see mild diarrhea not infrequently. Within the first 2 weeks, most of these patients start to improve. The other gastrointestinal adverse events are fairly uncommon. For me, pacritinib has been a very well-tolerated agent.

If you look at ruxolitinib and the risk of viral infections, I tend to use acyclovir for prophylaxis. [The risk of] shingles is not small. Not all my colleagues do it but several do. Infections tend not to be a big problem with pacritinib, presumably because of the lack of JAK1 inhibition.

 Similarly, we start thinking about the secondary malignancies, nonmelanoma skin cancers being one of the more common, which favored pacritinib in this adverse event of interest compared with those who had BAT consisting of ruxolitinib [5 events with pacritinib vs 11 with ruxolitinib]. This was very intriguing when we looked at the very early pacritinib data, as they relate to the infection and secondary cancers. We’re having all these patients see a dermatologist regularly—6 months to 1 year—being evaluated for nonmelanoma skin cancers. It’s something we have to think about with most JAK inhibitors. Pacritinib seems to be one where it’s less of a concern.

What did the landmark survival analysis of PERSIST-2 show?

Looking at symptom responses and how it can predict for OS, those patients who had improvement in TSS—even 10% to 20%—had improvement in OS.

During a Case-Based Roundtable® event, James M. Rossetti, DO, discussed the role of risk scoring and stratification tools and treatment for a patient with declining hemoglobin and platelet counts due to primary myelofibrosis. 

Meredith McKean, MD

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