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Eirwen M. Miller, MD, discusses novel biomarkers that she believes will be important for endometrial cancer in the future.

Miller Discusses Novel Targets in Endometrial Cancer

Adding immunotherapy to chemotherapy is the new standard-of-care treatment for advanced or recurrent endometrial cancer, according to Eirwen Miller, MD.

The Evolving Endometrial Cancer Treatment Paradigm

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

In practice, what is the most difficult disease feature to manage in primary myelofibrosis? Is it thrombocytopenia, anemia, splenomegaly, constitutional symptoms or other? For anybody who said anemia or thrombocytopenia, do you want to comment on why those are challenging?

I chose anemia. Usually, patients have more symptoms related to anemia than thrombocytopenia, so they probably come to our attention more than thrombocytopenia. Obviously, thrombocytopenia can be a challenge during the treatment…but it is the anemia that I find challenging, because usually once the patient hits low hemoglobin, they become symptomatic, and we try to avoid a transfusion if possible. I find that anemia is more challenging than thrombocytopenia at the beginning.

That's a great point. Anemia is something that's more likely to immediately impact quality of life from the symptoms that it causes, as well as the time spent in clinic.

For myself, especially in the patients that I have, thrombocytopenia tends to be the most challenging for us, because some of our patients’ [platelet counts] are [less than 20,000/μL] or sometimes even less than 10,000/μL and we struggle because transfusions don't work a lot, and a lot of them have other medical comorbidities…especially older patients. These are the challenges that we deal with, and thrombocytopenia is further complicating the picture. Anemia is potentially challenging, but thrombocytopenia is something that makes it difficult.

I've seen a few patients, but the last 2 patients have had issues with constitutional symptoms. Even though their numbers don't translate into that much anemia, and even though the numbers improved, [whether due to] the medicine [or] the disease itself, one of them keeps on asking for prolonging his disability or his time off from work.

So sometimes there's a disconnect between what the blood counts are showing with how the patients are feeling. I think that's pretty common. So that's a great point.

I picked constitution symptoms because fatigue [and others] are so subjective, and I feel those are difficult. Even for patients with profound thrombocytopenia and anemia, we have now drugs available to target those with pacritinib [Vonjo] and momelotinib [Ojjaara], but I feel constitutional [symptoms are challenging] for me. Some of them are younger patients [who] want to keep on a working schedule. Because that's so subjective, I feel that would be the hardest for me.

That's a wonderful point. Sometimes the JAK inhibitors really help with the constitutional symptoms, but they don't always work all the way and like [Dr Samdani] mentioned, sometimes the numbers don't tell the full story, and especially for our younger working patients, fatigue can be a really debilitating symptom that keeps people from working, especially those young patients that are still working.

What patient symptoms prompt you to initiate therapy for myelofibrosis? ​

What symptoms are the most important to control? ​

When do you start JAK inhibitor therapy?​

Do you choose your initial JAK inhibitor based on patient symptoms? ​

What are the symptoms that will prompt you to initiate therapy with myelofibrosis? How do you decide who needs to get started on therapy?

Symptoms will [make me] decide; if the patient has a lot of constituent symptoms, then I will initiate, plus the blood counts. The symptoms and the blood count issues, and sometimes they're related—if somebody has significant anemia, they might have hemoglobin of 9 to 10 g/dL, but they have a lot of constitutional symptoms, like night sweats, fever, and splenomegaly.

The first drug is determined by the blood count. Usually, if their platelet count above 50,000/μL, you can go with ruxolitinib [Jakafi]. If the hemoglobin is down, you can now use momelotinib for patient with significant anemia.

Does anybody have a different approach to initial therapy [besides looking at] blood counts and symptoms, and choosing a JAK inhibitor based on the blood counts?

I have a similar situation as well. I have 1 or 2 patients who have such an indolent disease, even though they do have cytopenias, but because of lack of symptoms, I didn't start them on treatment. I've been following them, but it's predominantly because of cytopenias.

This patient has the platelet count running in the low 20,000s [per μL], but they don't have symptoms for the last at least 5 years I've been following him. For someone like that, [I consider] their goals of care as well, if someone is extremely anxious, worried, and concerned, vs someone who might be weighing in the adverse events of the treatment, or weighing in the risk and benefit and decide that they're comfortable closely being followed. I think that’s part of the discussion that comes into play. When I do start treatment…platelet count is something that I do consider. Usually, my go-to is ruxolitinib, but I had someone recently with post essential thrombocythemia myelofibrosis where I considered fedratinib [Inrebic].

 I just started. I want to see how it goes.

Sounds great. It is approved in first line, so it's not a wrong choice for sure, and it's OK to try it there, even though we're all probably more familiar with ruxolitinib.

His choice was because of the dosing. It's once a day dosing with fedratinib, compared with twice a day [ruxolitinib], and he's someone who works in construction for long hours, so he preferred it once a day.

1. Inrebic. Prescribing information. Bristol-Myers Squibb; 2023. Accessed August 14, 2024. 

2. Jakafi. Prescribing information. Incyte Corporation; 2023. Accessed August 14, 2024. 

During a Case-Based Roundtable® event, Gabriela S. Hobbs, MD, surveyed physicians on the disease features that are most challenging in primary myelofibrosis in the first article of a 2-part series.

Cytopenias and Symptoms Prompt Imitation of JAK Inhibitors in MF 

During the American Society of Clinical Oncology (ASCO) Annual Meeting, Asal Pilehvari, PhD, et al

 looked at the financial benefit of adding a CDK4/6 inhibitor to hormone therapy in women with metastatic estrogen receptor (ER)-positive breast cancer treated in the community setting.

 Using average monthly drug and nondrug costs, the CDK4/6 arm had costs of $12,524 and $2278, respectively, vs $322 and $4265 in the hormone-only arm. Investigators concluded that it was financially beneficial for a 3.2-month progression-free survival (PFS). I will discuss some of my concerns with this study, starting with what incremental cost-effectiveness ratio (ICER) is and how it is calculated. 

ICER and quality-adjusted life-year (QALY) are used to calculate the value of a particular intervention.

 ICER tends to be a little more straightforward, with the difference in cost between 2 therapies divided by the difference in benefit, usually measured in years. QALY can often bring in other costs, including more subjective metrics such as quality of life. As for which benefit to use, the most common and easiest is overall survival (OS) because it is binary. Many governmental entities, such as the National Institute for Health and Care Excellence in the United Kingdom, rely on ICER to determine whether to cover the drug with public funds.

 Typically, most groups who use ICER recommend a maximum willingness-to-pay threshold that can range from $50,000 to $150,000 for every year of life gained. To accurately determine the ICER, the cost of the therapy, how long on average it was taken, and the OS benefit are needed. In analyzing the abstract, I used the 

(M-3; NCT02422615) trial of fulvestrant (Faslodex) vs fulvestrant plus ribociclib (Kisqali) to calculate and compare ICERs.

I'm choosing this study for several reasons, but the most important is reported OS benefit. In the ASCO abstract findings, the monthly cost for hormone therapy alone was $322, but with generic aromatase inhibitors costing $20, the closest drug at that price during the study period was fulvestrant. The 3.2-month PFS improvement is much lower than in findings from first-line studies using a CDK4/6 inhibitor, where it is for a year or more. Within the M-3 study findings, there were patients who received this therapy after first-line hormone therapy alone who had a 5.5-month PFS. M-3 study findings showed the PFS for fulvestrant was 9.1 months and 14.6 months for the combination, with an OS improvement of 7.7 months or 0.64 years. If we use the monthly drug cost from the abstract on the M-3 study data, the combination arm costs an extra $179,920, giving an ICER of $281,125 for each extra year of life. Adding in the respective monthly nondrug costs, the ICER is $272,472, or approximately $22,700 per month. Compared with a published article evaluating QALY from MONALEESA-7 (NCT02278120) findings, I'm not far off.

Although the abstract doesn't state overall PFS or OS, there is a hint. The investigators mentioned that the total drug cost in the combination arm was $195,487, and at $12,524 per month, the PFS comes out to 15.6 months vs 12.4 months in the hormone arm. When combining the drug and nondrug costs, this comes out to $554,970, or $46,248 per month. The authors claim that adding a CDK4/6 inhibitor is cost-effective, using a willingness-to-pay threshold of $65,000 or $780,000 per extra year of PFS. There is no mention where they got this range, and it is much higher than what most have published as reasonable. To equal the ICER determined in M-3 study findings, they would have to have seen a 6.6-month improvement in PFS. I commend the authors for looking at real, community-based data to see whether using CDK4/6 inhibitors is cost-effective, but there are too many holes in the data to accurately derive a solid conclusion and the results are far above a reasonable threshold. Many patients taking these drugs require dose modifications due to toxicity, but these often don't interfere with efficacy.

I chose the M-3 study because of the way the manufacturer has priced and dosed ribociclib, where dose reductions will lead to lower costs. If lowering the dose cuts the drug cost in the M-3 study by 25%, the ICER is $188,000 and is getting very close to the $150,000 upper threshold. Because dose reductions in findings from studies referred to in the package insert range from 32% to 45%, this may be a conservative assumption.

 It is also why we, as treating physicians, need to encourage manufacturers to both determine what the minimum effective dose is and price their drugs where lower doses or fewer pills cost less.

Leslie Busby, MD, is chair of the US Oncology Pharmacy & Therapeutics Committee, and a medical oncologist and hematologist at Rocky Mountain Cancer Centers, Boulder, Colorado.

1. Pilehvari A, You W, Kimmick G, Bonilla G, Anderson R. Unveiling the cost-effectiveness of CDK4/6 inhibitors in treating patients with HR+/HER2- metastatic breast cancer: A closer look at nonmedication expenses. 

. 2024; 42(suppl 16; abstr 1532). doi: 10.1200/JCO.2024.42.16_suppl.1532

2. Institute for clinical and economic review. Value Assessment Framework. Updated September 25, 2023. Accessed July 10, 2024.

3. Sanders GD, Neumann PJ, Basu A, et al. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. 

. 2016;316(10):1093-1103. doi:10.1001/jama.2016.12195

4. Claxton K, Martin S, Soares M, et al. Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold. 

5. Burke J. Should Progression-Free Survival Be the Primary End Point for Registration of Oncology Drugs? 

6. Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. 

. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149

7. Jeong E, Wang C, Wilson L, Zhong L. Cost-Effectiveness of Adding Ribociclib to Endocrine Therapy for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Among Premenopausal or Perimenopausal Women. 

. 2021;11:658054. Published 2021 May 7. doi:10.3389/fonc.2021.658054

8. Ismail RK, van Breeschoten J, Wouters MWJM, et al. Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer. 

. 2021;60:263-271. doi:10.1016/j.breast.2021.11.013

At the ASCO Annual Meeting, Asal Pilehvari, PhD, and colleagues presented a study evaluating the financial benefit of adding a CDK 4/6 inhibitor to hormone therapy for women with metastatic estrogen receptor-positive breast cancer in community settings.

Publications

Exploring the Financial Advantages of Adding a CDK 4/6 Inhibitor to ER-Positive Breast Cancer

A 4-year follow-up of the phase 3 GAIA/CLL13 study (NCT02950051) sought to directly compare venetoclax (Venclexta)-based combinations for the treatment of patients with chronic lymphocytic leukemia (CLL). These included venetoclax with obinutuzumab (Gazvya), venetoclax/obinutuzumab/ibrutinib (Imbruvica), and venetoclax/rituximab (Rituxan). 

patients receiving venetoclax/obinutuzumab

 (85.5%; 97.5% CI, 79.9%-91.1%) or venetoclax/obinutuzumab/ibrutinib (81.8%; 75.8%-87.8%) had significantly longer progression-free survival (PFS) vs patients receiving venetoclax/rituximab (70.1%; 63.0%-77.3%) or chemoimmunotherapy (62.0%; 54.4%-69.7%). While there was no significant PFS difference between venetoclax and obinutuzumab with or without ibrutinib, there were more adverse events associated with the triplet regimen. 

This study suggests that venetoclax combined with obinutuzumab demonstrated a significant advantage in terms of PFS in previously untreated patients with CLL compared with standard chemoimmunotherapy or venetoclax with rituximab. However, the potential benefits of adding ibrutinib need to be weighed against the increased toxicity.

, Moritz Fürstenau, MD, University of Cologne, discussed the findings and implications of this follow-up study.

Targeted Oncology: What is the current standard-of-care in CLL?

Moritz Fürstenau, MD, discussed a follow-up of the GAIA/CLL13 study exploring venetoclax combinations vs chemoimmunotherapy for the treatment of chronic lymphocytic leukemia. 

Eirwen Miller, MD

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