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Cedric Pobel, MD, is a medical oncologist, PhD student, Institut de Cancérologie, Gustave Roussy, Paris, France.

Cedric Pobel, MD, discusses the design and objectives of the phase 3 PEACE-1 trial for patients with de novo metastatic castration-sensitive prostate cancer. 

Behind the Design of the PEACE-1 Trial in mCSPC

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

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.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)​

History of low-volume, indolent metastatic clear cell renal cell carcinoma (ccRCC), status post‒left nephrectomy and adrenalectomy​

Based on low-volume, indolent disease, and patient preference – observation only​

At 1.5 years post-nephrectomy CT scan: ​

New paratracheal lymph node (2.0 x 1.5 cm) and more than 10 pulmonary nodules on CT​ scan

Lung biopsy confirmed metastatic ccRCC​.

Laboratory results: within normal limits​

Approximately what proportion of your patients with metastatic RCC are like this one with favorable risk?

How often do you see cases like this? Is this the [usual type of patient] coming into your referral base, or are they more [severe] type cases? What’s typical for you in your practice?

I would say about 25% of patients are like this; 75% are more aggressive.

I think that's fair. It's nice to see that in the community. In registries we've done, it's been somewhat less than that and I do worry if things are changing. It seems to me like I see more aggressive cases. Maybe that’s because [oncologists] are so good at managing these patients with favorable risk in the community setting, they don't come to us anymore.

I see more of these type of cases. I run the thoracic program at Cone Health Cancer Center, so most of these present as lung nodule and mediastinal lymphadenopathy. Initially, it could be lung cancer, and they tend to have metastatic renal cell carcinoma. These are the ones that I keep most of the time because I was the only medical oncologist there, so I try to handle it as much as I can.

That’s a great point. What happens is those with favorable risk stay with you for years and years, and you can forget about the intermediate- and poor-risk patients, because you get so many patients. But these patients keep coming back so you start thinking you have a lot of them.… you remember them because they're memorable cases. I don't keep strict statistics on this, but I think you're right. There are a lot of these cases that you're not actively managing; they have scans every 6 months or so, but they're out there.

To what extent is risk status a deciding factor in your first-line treatment decision making?​

What drives your selection of first-line therapy for favorable-risk, metastatic ccRCC? ​

I think quality-of-life data may be different for patients who are taking [immunotherapy (IO) plus tyrosine kinase inhibitor (TKI)] vs when they get nivolumab [Opdivo]/ipilimumab [Yervoy].

Some of the issues are how our immunotherapies are working in these sites like the brain or the liver, where we know we can get penetration with TKIs in there. And these are vascular lesions. I think some of that's a factor.

You don't see sarcomatoid much in favorable-risk patients. It tends to be more in intermediate- and poor-risk, but it's possible. There's exceptions to everything, so it's certainly something to consider.

What about quality of life and safety? How do people feel about the quality of life for these patients? These are long-term survivors. Do you feel one way or another about IO/TKIs vs IO/IO combinations?

I use both [types of] regimens. In general, I feel that the TKI component is definitely harder on patients, especially cabozantinib [Cabometyx] and axitinib [Inlyta] too, with significant fatigue and hand-foot syndrome as issues. If the patients do well with nivolumab/ipilimumab, they usually do not have a problem. If they do have a problem, that could be pretty intense, especially with adrenal insufficiency. I had a patient who ended up having insulin-dependent diabetes, a very rare, but definitely life-changing event for the patient.

I think it’s a good point. Unfortunately, when we get toxicities from nivolumab/ipilimumab, they tend to be durable as well. Some of them are permanent, and others can last weeks. We can run into real trouble. If you treat enough patients, you’re going to have some die from it; I have. You learn and know what to look for as early signs. You definitely have to be careful. And it's not always early on. Some of these toxicities happen in the third or fourth cycle. So, you're not out of the woods with that. Those are the tricky things. With the TKIs, the adverse events are more common, but they're also more reversible when you hold the TKI. It gives you an out for some of these patients, and that's important.

[There is also] the fast onset with TKIs. I think that's key as well. For our intermediate- and poor-risk patients, safety and quality of life matter. But at the end of the day, this is still—even in the patients with favorable-risk metastatic disease—a lethal disease for the majority of patients looking out 5 to 10 years. It's not like our patients with chronic lymphocytic leukemia or indolent prostate cancer. This is still disease, even in the best of scenarios, that can progress and can be unpredictable. Certainly, these are patients we need to keep close tabs on.

During a Case-Based Roundtable® event, Daniel J. George, MD, discusses how often community oncology participants see patients with favorable-risk vs intermediate- or high-risk RCC, and how it changes their treatment options.

Considering How Favorable Risk Affects Treatment in ccRCC

KEY TAKEAWAYS FROM ADITYA BARDIA, MD, MPH​, FASCO

Trastuzumab deruxtecan and sacituzumab govitecan can be given to patients with metastatic HER2-low breast cancer after endocrine therapy and chemotherapy.

Progression-free survival and overall survival favor trastuzumab deruxtecan over chemotherapy in HER2-low disease.

The DESTINY-Breast06 trial showed similar outcomes for HER2-low and HER2-ultralow disease.

A 52-year-old postmenopausal woman underwent breast-conserving surgery plus radiation therapy for pT2 N1 invasive ductal carcinoma of the right breast, grade 2, estrogen receptor (ER)–positive, progesterone receptor–positive, HER2 1+ by immunohistochemistry (IHC); 21-gene recurrence score: 27​.

She received dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and completed 10 years of tamoxifen.​

Five years later, she presented with disease recurrence in the liver, hormone receptor–positive, HER2-low, no actionable mutations on tissue next-generation sequencing​.

She received first-line letrozole plus ribociclib​ (Kisqali).

​She went on to receive ​fulvestrant for 6 months to disease progression in the bone and liver, then everolimus plus exemestane for 4 months to disease progression, followed by capecitabine for 6 months until disease progression.

Repeat circulating tumor DNA next-generation sequencing at each progression showed no actionable alteration.

Targeted Oncology: Do you consider this patient with metastatic breast cancer (mBC) to be eligible for sacituzumab govitecan (Trodelvy)?

If you look at the label of sacituzumab govitecan, it says 2 prior lines of systemic therapy; it does not say which kind, so you can make a case that the endocrine-based treatment was also systemic therapy.

 But the TROPiCS-02 trial [NCT03901339], which led to approval, required 2 prior lines of chemotherapy. Purely from a trial perspective, you should give 2 lines of chemotherapy, but in routine clinical practice, after capecitabine, that's when we consider trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan.

Can you use T-DXd and sacituzumab one after another?

You can use them in sequence. There have been studies looking at the efficacy of one after the next,

 and there is some cross-resistance between these agents because they have similar payloads. In sacituzumab govitecan, SN38 is a topoisomerase-1 inhibitor. With T-DXd, deruxtecan is also a topoisomerase-1 inhibitor. But in some patients, it does work, and maybe in that setting, the disease progression is more because of the antigen, and so you're using a different antibody that works. But in some patients, you would see cross resistance.

If you look at our guidelines, you have both these drugs, T-DXd and sacituzumab govitecan. The guidelines would suggest T-DXd should be preferred for HER2-low disease.

 But if a patient is not a candidate for T-DXd, that's when you use sacituzumab. That could be either contraindication to T-DXd, or if a patient has HER2 IHC 0 mBC in that setting, you can use sacituzumab, and you can use them in sequence. If you start with one, you can use the other drug after that.

What data support the use of T-DXd in patients with HER2-low status?

This was based on DESTINY-Breast04 [NCT03734029], which looked at T-DXd vs standard chemotherapy for HER2-low, ER-positive breast cancer. It showed impressive improvement in both progression-free survival [PFS] and overall survival [OS]. We saw updated results last year, and essentially continue to see benefit with T-DXd vs a standard chemotherapy with median OS of about 24 months [vs 17.6 months for chemotherapy; HR, 0.69; 95% CI, 0.55-0.87].

During a Case-Based Roundtable® event, Aditya Bardia, MD, MS, FASCO, discussed data from the DESTINY-Breast04 and DESTINY-Breast06 trials for HER2-low breast cancer in the second article of a 2-part series.

Cedric Pobel, MD

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