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Susan M. Domchek, MD, director of the Basser Center for BRCA at Penn Medicine, discusses the role biomarkers have in the treatment of patients with breast cancer. Identifying biomarkers in patients early on, such as knowledge of estrogen receptor status, can lead to better treatment plans, Domchek says.

The Role of Biomarkers in Patients with Breast Cancer

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

Mark Agulnik, MD, discusses the intricacies of desmoid tumors that can be recognized before starting treatment for patients.

Understanding When to Choose Systemic Treatment for Desmoid Tumors

Mark Agulnik, MD, professor of Clinical Medicine, Vice Chair for Faculty Development, Department of Medicine, and Section Chief of Sarcomas & Melanoma at the Keck School of Medicine of USC, discusses the intricacies of desmoid tumors that can be recognized before starting treatment for patients.

Desmoid tumors are complex conditions with a pattern of growth and regression, necessitating careful monitoring of their longitudinal progression, according to Agulnik. Initial treatment typically does not start unless there's an urgent medical need, focusing instead on evaluating the natural history of the disease.

Treatment is considered if the tumor causes significant pain, impairs function, or negatively impacts the patients’ quality of life. Standard therapy now favors drug treatments over surgical resection due to the high recurrence risk associated with surgery. Agulnik says this shift reflects improved understanding of the disease's behavior, leading to more patient-beneficial systemic therapies.

 Desmoid tumors are very complex. There's a very unique process to this condition. There is a ‘wax and wane’ type of quality, and so patients can have growth of the tumor, and then they can have subsequent regression of the tumor. So, one needs to be very aware of what's happening. They have to understand the longitudinal process of the disease, and also, they have to understand what are the inherent needs at the time that the patients are seen.

 If a patient is seen for the first time, there likely is not a need to start treatment unless there is an impending medical emergency, but for the most part, these patients need to be evaluated, and then a longitudinal evaluation needs to be done to understand the natural history of the disease. If the disease or the tumor grows over time or is causing significant problems for the patient with respect to pain, disruption of ability to function [or] their activities of daily living, or affecting quality of life, then it is reasonable to start patients on a therapy. Currently, the standard first-line therapies would be drug therapies for most patients. Many years ago, the standard treatments would have been for surgical resection. But that has changed over time because we have a better understanding that these diseases do come back after surgical resections for many patients, and therefore, if we could take a path to systemic therapy or drug therapy, that is in the patient's best interest.

A 68-year-old man presented with fatigue, back pain, and lymphadenopathy​, and had a prior medical history of medically controlled hypertension. A ​physical exam showed a 1.5-cm left posterior cervical node, a 2.5-cm right anterior cervical node, and a 2.0-cm left supraclavicular node. PET-CT scans showed multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 x 3.1 cm​. A biopsy confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal center (non-GC). Immunohistochemistry was positive for CD20, BCL-6, BCL-2 (50% of cells), MYC (greater than 90% of cells), Ki67 85%, MUM1, but was negative for CD10​. Fluorescence in situ hybridization was negative for translocations involving MYC, BCL2, BCL6​.

Laboratory results showed normal complete blood count, elevated lactate hydrogenase. He received a diagnosis of stage III DLBCL with IPI high-intermediate risk and ECOG performance score of 1. R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated for 6 cycles and back pain was resolved​. Post-treatment PET demonstrated a complete response with Deauville score of 2, and the patient was observed​.

Eight months after completion of therapy, he complained of fever, night sweats, and back pain. A palpable lymph node in left groin was discovered on physical examination​.

PET and CT scans showed a new left inguinal lymph node, an increase in size of a residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​. DLBCL was confirmed by biopsy.

The patient was referred to nearest transplant and cellular therapy center for evaluation, but ultimately opted not to pursue CAR (chimeric antigen receptor) T-cell therapy​.

Polatuzumab vedotin ± bendamustine ± rituximab

What factors influence your choice of treatment for this patient?

 For patients who you feel would not go through transplant and wouldn’t go through CAR T-cell therapy, the options are GemOx [gemcitabine/oxaliplatin], polatuzumab vedotin [Polivy] with or without bendamustine and rituximab, tafasitamab [Monjuvi] plus lenalidomide [Revlimid], or probably some other [options]. What would you do in this setting?

 Is polatuzumab approved as second line? Or first line?

 Not really [either]. It’s part of the NCCN guidelines—you can usually get polatuzumab in second line.

 But when you look at the label, it would say 2 or more regimens prior.

None of you would use GemOx. GemOx was often used as a treatment for the unfit, older patients who didn’t go for transplant. But, I agree, I haven’t used it in a long time.

This patient is 68 years old, has hypertension, and relapsed after 8 months. Now what do you discuss with that type of patient; what is the clinical goal? How do you discuss the options?

 My goal would be to guess the longest response with a novel agent, such as tafasitamab plus lenalidomide. You can give treatment to disease progression with tafasitamab plus lenalidomide. My goal is to get the maximum response and duration of response.

 I think that that’s a valid point. When I see patients referred to us in our tertiary center, they trust you in the community when they ask “What are my shots? What should I go for?” These discussions are important for them, and your view on this is very important. So which are the factors that influence your recommendations for a patient with a kind of lymphoma that would relapse within 12 months?

 I work in a rural part of Virginia, and this sounds like a very common issue I deal with. Patients don’t want to travel for CAR T-cell therapy or stem cell transplant. We do have an older population, so patient preference or goals would be a very important factor for me, especially in choosing the regimen of tafasitamab plus lenalidomide versus polatuzumab. I would take the number of times they have to come to the cancer center for infusion, especially in this day and age with COVID-19, into consideration. None of my patients are older, but once healthy 70-year-olds start treatment, their age really shows. With their multiple comorbidities, I try to pick the lesser toxic regimen, but with longer response.

 I keep thinking about what I can do to keep the disease under control without necessarily damaging the stem cells, or affecting the immune system as much. So, for that, I think using something that is like a novel agent, since patients may need other drugs in the future. The subtype of the DLBCL, GC versus non-GC, can really be important in the selection.

After discussing the treatment options, tafasitamab plus lenalidomide was initiated​.

This regimen has been around for only a short time, and, this is a bit of a unique patient. Anybody willing to share their experience with the regimen?

 It seems to be better tolerated, similar to rituximab. I admit that I have used it in malignant pancytopenia to watch for some mild reactions in each, but otherwise, pretty well tolerated.

 I agree. [I have seen patients who were] progressing through CAR T-cell therapy, or [autologous stem cell] transplant, or allogeneic [stem cell] transplant go on tafasitamab plus lenalidomide and come in with disease shrinking or no disease. So it is definitely effective.

 My experience is similar to what you both mentioned. I think tafasitamab is like rituximab, but it just attacks different antigen on the B cells. So, you know, it is very similar to if many of you have had experience with R2[rituximab plus lenalidomide], and so this is very similar in terms of that. When you look at the L-MIND study, [it is given on] days 1 and 4, but the first week of tafasitamab, I usually skip day 4 and just do weekly tafasitamab for the first 3 months, and then switch to every other, as per the label.

What is your reaction to the efficacy data for combination tafasitamab plus lenalidomide? ​

 The duration of response [DOR] is very impressive, much better than the CAR T-cell therapy, if I have to put those data side-by-side. It is very well tolerated, and there are many complete responses, so I think these are the very impressive end points. Although it is a phase 2 trial, it is still very impressive.

 It is a little bit difficult to compare it with CAR T-cell therapy because they didn’t have all of the patients [such as] the primary refractory patients. I agree, it surprised me that they were able to generate such long term DOR. Any other feelings about these data sets from the L-MIND study [NCT02399085]?

 The data seems quite impressive. How long can they be given lenalidomide?

 Then [after 1 year] tafasitamab is continued as a maintenance. We’ve seen that prior in literature where in mantle cell lymphoma, they use rituximab maintenance until progression. And so they’ve designed this study the same way, that they used the tafasitamab maintenance until progression. I am not sure how much the tafasitamab maintenance plays a role, but if you want to follow the data, you will follow that. In some of our patients we didn’t continue for the whole duration until progression. They opted to hold it after some time because they were in remission.

 The reason I asked is because I wanted to see which was more cost effective: CAR T-cell therapy, or this regimen.

 It’s a good question, and the CAR T cell price tag is huge. Again, I am sure any of these treatments will be very expensive. That is a great question for health care economist, but I can’t answer that well.

 Can you comment on the lenalidomide dose? In my limited experience, I find that the 25 mg dose quite myelosuppressive.

 You’re right. The majority of the patients were at 20 mg or higher. But, surprisingly, they were able to do 20 mg. I agree with you. When I use R2, hematological toxicities were the issue there. Grade 3 to 4 adverse events were definitely seen in those patients: neutropenia, anemia, thrombocytopenia, as expected, and I feel that is very comparable to the R2 data, just from the lenalidomide itself.

 I don’t really feel that the tafasitamab contributes to the cytopenias, personally. They did have a 10% rate of febrile neutropenia. There was 1 patient with grade 4 agranulocytosis.

 How important do you feel that maintaining dose intensity with the lenalidomide is in this regimen?

 I don’t think it’s as important, to be honest. We did some very early studies with lenalidomide/rituximab at least 10 years ago, and we used 10 mg daily without 3 weeks on and 1 week off, and patients did very well. I feel that with these immunomodulatory agents, and other agents, the dose is not as critical as conventional chemotherapy.

1. NCCN. Clinical practice guidelines in Oncology. B-cell lymphomas, version 4.2022. Accessed June 17, 2022. https://bit.ly/3xylMAF

2. Polivy. Prescribing information. Genentech, Inc; 2019. Accessed June 17, 2022. https://bit.ly/39wfGsy

3. Monjuvi. Prescribing information. Morphosys US Inc; 2020. Accessed June 17, 2022. https://bit.ly/3A1wumn

4. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. 

During a live virtual event, Jakub Svoboda, MD, discussed with participants the choice of therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who would not receive stem cell transplant or chimeric antigen receptor therapy.

Susan M. Domchek, MD

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