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Eric J. Sherman, MD, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, comments on the use of cabozantinib and vandetinib in medullary thyroid cancer.

Using Cabozantinib and Vandetanib in Medullary Thyroid 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. 

https://tinyurl.com/fwhru4ft

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. 

https://tinyurl.com/4sryy6vh

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

RP1 (vusolimogene oderparepvec) is a genetically engineered next-generation herpes simplex virus that is intended to lyse tumor cells, induce systemic anti-tumor immune response with enhanced T-cell activation, augment immunogenic cell death via the addition of the fusogenic GALV payload, while enhancing replication in tumor cells and not healthy cells. While T-VEC is the only approved oncolytic virus for melanoma, RP1 appears more potent in early data.

The IGNYTE trial (NCT03767348), a phase 1/2, dose-escalation and -expansion study, allowed injections into various sites, including visceral locations, in patients with advanced melanoma that progressed on immunotherapy. While no specific subgroup showed greater benefit, preliminary data indicated promising response rates in this refractory population.

“The virus is injectable, so you have to find a location where you can actually put the virus in. The nice thing about the study, the IGNYTE study, is that they allowed us to basically inject anywhere in the body. You could inject viscera like the liver. You can inject deep lymph nodes like the retroperitoneum. That was a very good part of that design, and it was mostly in patients who were progressing on immunotherapy,” Mohammed Milhem, MBBS, clinical professor at the University of Iowa Health Care, explained in an interview with 

The FDA received a biologics license application seeking the accelerated approval of RP1 plus nivolumab (Opdivo) in adult patients with advanced melanoma who have received previous treatment with a regimen containing a PD-1 inhibitor in November 2024. This submission was supported by safety and efficacy data from the anti-PD-1–failed melanoma cohort of the phase 1/2 IGNYTE trial.

Among the patients included in this cohort (N = 156) and at a median follow-up of 15.4 months (range, 0.5–55.5 months), the objective response rate (ORR) was 32.7%, including complete response (CR) and partial response (PR) rates of 14.7% and 17.9%, respectively.

 For the 82 patients who had received prior anti–PD-1 monotherapy, the ORR, CR, and PR rates were 37.8% 22.0%, and 15.9%., respectively Additionally, the respective rates for patients with prior exposure to both PD-1 and CTLA-4 inhibitors (n = 74) were 27.0%, 6.8%, and 20.3%.

Milhem highlighted RP1's potential to overcome tumor heterogeneity by acting as a beacon for the immune system, effectively turning "cold" tumors "hot." He also emphasized the rationale for combining RP1 with a PD-1 inhibitor like nivolumab to maintain immune system pressure.

In the interview, Milhem further discussed the oncolytic virus RP1 and the IGNYTE clinical trial for patients with melanoma that progressed on anti–PD-1 therapy.

: Could you briefly explain the mechanism of action of RP1 as an oncolytic virus in the context of melanoma?

It is a genetically engineered virus. It is attenuated. It basically replicates within the tumor, replaces the DNA of the tumor with its own DNA, and it has been spliced to actually make a drug called GM-CSF, which then is a beacon for white cells to come to the area. It is oncolytic, so it breaks up the cell and replicates in other cells as well. Of note, replication is restricted to tumors, so healthy tissue remains undamaged.

Are there any key differences between this and any other oncolytic viruses that are being investigated and used in melanoma?

There's only 1 oncolytic virus that's been approved, and that's T-VEC. RP1 seems to be more potent than the T-VEC virus, at least from the initial data that came out when comparing them together. RP1 expresses a fusogenic glycoprotein (GALV-GP-R-) that enhances immunogenic cell death and further activates innate and adaptive immune responses . They haven't really been compared head-to-head, but it does appear to be a little bit more powerful. There are other viruses, adenoviruses, smaller viruses that are being used for cancers, but nothing yet that has hit the FDA that's likely to get approved.

Delving into the IGNYTE study, could you just discuss a little bit of the methods, design, and background of this trial?

The trial is geared towards patients who are not responding very well to anti–PD-1 therapy. It is—in our world of immunotherapy—a desert, if you wish. There are no really good treatments to restore efficacy if your immunotherapy doesn't work; there's no way for us to make it work or wake it up. The design of the trial is in patients who are receiving immunotherapy with tumors that have progressed on immunotherapy, and they must have a site where you can at least inject the tumor.

The virus is injectable, so you have to find a location where you can actually put the virus in. The nice thing about the study, the IGNYTE study, is that they allowed us to basically inject anywhere in the body. You could inject viscera like the liver. You can inject deep lymph nodes like the retroperitoneum. That was a very good part of that design, and it was conducted in patients who experienced progression on immunotherapy.

What things are key to look out for regarding the study?

I think this is innovative. There's a mechanism in cancer called heterogeneity, which is very hard to control. Heterogeneity means each tumor type looks very different, genetically, epigenetically. Inside the body, tumors can escape the immune system. The immune system is agnostic to heterogeneity. It doesn't care as long as it recognizes the tumor. This is one way for us to inform the immune system that the tumor looks like this, please come and attack. And it sort of acts as a beacon.

This really changes the microenvironment of the tumor when you inject it. It allows for information to be discussed with the immune cells and allows for a different chance for us to improve outcomes in patients who don't respond to immunotherapy. The preliminary data that was already shared at ASCO and SITC in the past showed approximately a third of the patients were responding in some way, in people who were not responding previously. This is the first time we see such a nice, robust response in patients. I'd say overall response rates were really good, so [complete responses] and [partial responses] were really good.

What was the rationale for combining RP1 with nivolumab?

The mainstay in our thinking is to maintain an anti–PD-1 backbone of treatment that you still need. PD-1 biology is sort of interrupted when you are doing something else that still brings in the T cells that allow the T cells to stay functioning longer. I think that the only reason it stayed is it's one of the drugs that actually does help the immune system if you can reverse the environment around it to make it work much better, which I think RP1 does do that as a single agent. I don't see it doing as much without the anti–PD-1 backbone, and I think that is the key in a lot of these new injectables that are coming out, is to maintain some sort of pressure on the immune system through the PD-1, nivolumab, pembrolizumab, etc.

From a practical standpoint, what are some of the challenges or considerations that you would kind of inform oncologists on regarding administering oncolytic viruses like this in a clinical setting?

It is going to be very similar to the previous oncolytic virus that was accepted. This is a live virus. It does carry the risks of being an attenuated live virus, so you have to be careful in which patients you are going to put it in. You have to have the right setup to actually deal with viruses. Most academic centers tend to have the better setups to try to make the virus and put it into the vials. It is safe and there is biosafety data outlining that.

My only advice would be, this is one of the better formulations in that it is a shorter course of treatment. It is just 8 doses. That is what was in the trial, and it is given every 2 weeks. Generally, a good ultra-sonographer and interventional radiologists would be needed if they wanted to inject deeper tissue and targets, so that needs to be in place.

But make sure that you partner with an academic center, I would say for community oncologists, if they can't get access to it. It's a shorter course, and then you continue the anti–PD-1 after that. Generally, patients do very well. If they respond, then they can continue at least their therapy in the community. Generally, it is very safe. The adverse event profile is just when you give the injection itself; some people develop fever, chills, aches but grade 3 or 4 toxicities are less than 10%. Some people have had low blood pressure, needing fluids. We give some drugs to control some of those symptoms, but generally, it abates within 24 to 48 hours right after, it's a well-tolerated agent.

What are your hopes for future roles of oncolytic viruses like this in the treatment paradigm for melanoma?

I think the future is that we should expand into other tumor types. There are lots of tumors. I mean, there is this coined phrase that came out from the immune therapy community saying tumors were cold vs tumors becoming hot. You can change the microenvironment to make them more inflamed. This inflammatory response would allow the immune system to be reorganized, if you wish, or allow for some or more information to be shared with that immune system. Changing cold tumors to hot tumors would be what an oncolytic virus could do. Other cancers, cutaneous squamous cell carcinoma and your sarcomas, tumors that are very difficult to reach, colorectal cancers, I must say, high MSI tumors. RP-2 is being studied in uveal melanoma. There are, I think, applications that can be done if we can, if this is something that hits the community where we could see it morphing and going into other tumor types that are cold and changing that environment.

Are there any ongoing clinical trials involving RP1 that you are particularly excited about?

There is one that I am very excited about. It is angiosarcoma. We are seeing very good responses in angiosarcoma. In cutaneous angiosarcoma, we are seeing robust responses, especially in patients who have failed anti–PD-1. It seems to work. It hasn't been tried yet in the upfront setting, where you give it right away. That might be something that could happen in the future in melanoma and your sarcoma and other tumors. But it seems to work well in patients who are not responding to the initial immune therapy. Angiosarcoma is a very difficult disease to treat and has a very poor outcome, to see things happen like that, that to me is very exciting.

We are using it in other settings, but I'm not sure. I don't think we, as a site in Iowa, are not participating in each other's RP1 studies. We do have some RP2 studies in uveal melanoma. They are making different viruses that can make different substances. That's also exciting because that gave us a chance to modify the virus to do what we'd like it to do, secreting certain types of substances that might change that microenvironment to make tumors more readily accessible to the immune system.

Do you have any other advice for community oncologists who are interested in learning more about RP1?

Partner with an academic institution. Generally, that's the better way to do this, in my mind. In the community, it's good to have—they have the setup already—just to run scenarios by people who have had experience with injectables. In my experience, what I think about in terms of injecting is, inject as many tumors as you can, as much as you can, whenever you can, in any place that you can. The more you inform the immune system, the better and more robust your response would be with I guess that would be my take-home point.

1. Our pipeline. Replimune. Accessed April 30, 2025. 

https://replimune.com/pipeline/

2. Wong MKK, Sacco JJ, Robert C, et al. Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial. 

. 2024;42(suppl 16):9517. doi:10.1200/JCO.2024.42.16_suppl.9517 

4. Replimune receives breakthrough therapy designation for RP1 and submits RO1 biologics license application to the FDA under the accelerated approval pathway. News release. Replimune Group, Inc. November 21, 2024. Accessed April 30, 2025. 

https://tinyurl.com/3uh38cxu

Mohammed Milhem, MBBS discussed the mechanism of action of RP1, the design and preliminary findings of the IGNYTE trial in melanoma.

RP1 and the Future of Oncolytic Therapy in Melanoma

A patient with diffuse large B-cell lymphoma (DLBCL) relapsed after first-line therapy and received chimeric antigen receptor (CAR) T-cell therapy as a second line. ​​

During a live event, Krish Patel, MD, surveyed participants on using bispecific T-cell engagers vs loncastuximab in a patient with relapsed diffuse large B-cell lymphoma who had prior CAR T-cell therapy. 

Eric J. Sherman, MD

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