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Radiation Oncologist Dana-Farber Cancer Institute Assistant Professor of Radiation Oncology Harvard Medical School in Boston, MA

Increasingly, and with exponential pace, AI algorithms are finding their way into the oncology clinic. 

Steady Progress of AI Makes its Mark in the Clinic 

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

Intro and Overview of Bispecifics in Non-Hodgkin Lymphoma (NHL)  

Video content above is prompted by the following:

Provide a brief overview of the use of bispecifics antibiotics (BsAbs) in NHL

Please give a brief overview of the four bispecific antibodies cuused in NHL

Panelists discuss how bispecific antibodies are transforming the treatment landscape for non-Hodgkin lymphoma by enhancing T cell engagement and targeting malignant B cells effectively.

Aumolertinib Shows Potential in POLESTAR Trial

Aumolertinib (formerly almonertinib; HS-10296) showed an improvement in progression-free survival for patients with unresectable stage III non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 POLESTAR trial (NCT04951635). In the trial, patients were randomly assigned 2:1 to receive 110 mg of aumolertinib once daily or matching placebo. Trial data were presented at the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC).

Regarding safety, patients in the experimental arm experienced an increase in any-grade adverse events (AEs), leading to treatment interruptions, dose reductions, and discontinuations. The most common AEs included elevated blood creatinine phosphokinase levels, radiation pneumonitis, and decreased white blood cell count.

“These findings demonstrate aumolertinib [is] a novel treatment option for patients with unresectable stage III 

-mutated NSCLC after CRT [chemoradiation therapy],” lead study author Xiangjiao Meng, MD, of Shandong Cancer Hospital and Institute at Shandong First Medical University in Jinan, China, said in a presentation of the data.

Exploring the Rapid Changes in Endocrine Therapy for Breast Cancer

Erika Hamilton, MD, director of breast cancer research at the Sarah Cannon Research Institute, discussed the rapidly advancing treatment landscape of endocrine therapies for breast cancer in an interview with Targeted Oncology

. Oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs) provide additional treatment options especially in the post-CDK4/6 inhibitor setting. Hamilton also highlights several ongoing trials, including phase 1 trials evaluatingARV-471 both as a monotherapy and in combination with palbociclib (Ibrance).

“There are adjuvant trials for curative breast cancer [treatment] that may replace our traditional endocrine backbones. These trials come in 2 varieties: comparing the new agents up front with aromatase inhibitors and using a switch strategy after 2 to 5 years on an aromatase inhibitor. With all these trials ongoing, we will certainly have a rich dataset to improve our endocrine therapies,” Hamilton explained.

Ivonescimab Makes Waves By Besting Pembrolizumab in

Data from the primary analysis of the phase 3 HARMONi-2 trial (NCT05499390) indicated that ivonescimab reduced the risk of disease progression or death in PD-L1–positive advanced NSCLC compared with pembrolizumab (Keytruda). Data were presented at the 2024 International Association for the Study of Lung Cancer WCLC. The findings from the HARMONi-5 trial (NCT04900363) supported the design of the double-blind HARMONi-2 trial, which included 398 patients who were randomly assigned 1:1 to receive 20 mg/kg of ivonescimab every 3 weeks or 200 mg of pembrolizumab every 3 weeks.

“This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared with pembrolizumab in advanced NSCLC,” Caicun Zhou, MD, PhD, lead study author and director of the Department of Oncology at Shanghai Pulmonary Hospital in China, said in a presentation of the data.

Insights on AEs Associated With CAR T-Cell Therapy in Relapsed Multiple Myeloma

In this Case-Based Roundtable® event, Saad Z. Usmani, MD, FACP, MBA, reviews the case of a 60-year-old woman diagnosed with Revised International Staging System (R-ISS) stage II/R2-ISS stage III IgGκ relapsedmultiple myeloma. Usmani, a myeloma specialist & cellular therapist at Memorial Sloan Kettering Cancer Center in New York, New York, discussed third-line chimeric antigen receptor (CAR) T-cell therapy options, highlighting data from the KarMMa-3 (NCT03651128) trial. He also addressed the management of AEs associated with ide-cel (idecabtagene vicleucel; Abecma), including cytokine release syndrome (CRS).

“You are giving these revved up T cells to patients and asking them to become hyperactive as soon as they are exposed to that specific surface marker or antigen. So of course they are going to become active, release cytokines, and essentially make the patient feel like they have a bad flu. That is what, essentially, CRS is. When we were using CAR T cells 10 to 12 years ago, there was a concern that if you try to stop that process, you may not get the efficacy. But pretty soon we learned that if we let that go too long, patients may even die from it,” Usmani explained.

Discussing Advances With BCL-2 Inhibitors for CLL Treatment

According to John Seymour, MD, director of hematology at the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne, Australia, BCL-2 inhibitors are a key component to preventing apoptosis, or programmed cell death. In this article, Seymour discussed the emergence of combining BCL-2 inhibitors with Bruton tyrosine kinase (BTK) inhibitors or anti-CD20 antibodies to improve outcomes and reduce the probability of resistance.

“Another key finding was that with continued single-agent therapy, there is a significant risk of induction of resistance mutations that lead to outgrowth of resistant clones. That was the impetus to use combination therapy, either with BTK inhibitors or with an anti-CD20 antibody, to achieve deeper reductions but enable time-limited therapy.

The third paradigm that emerged was, if we use this time-limited therapy, it then retains disease sensitivity, so at progression, we can retreat with that same combination,” Seymour explained.

Thank you for joining us for this week’s 

Aumolertinib showed improved PFS in NSCLC and ivonescimab outperforms pembrolizumab in advanced cases. Plus, insights into CAR T-cell therapy and its associated AEs are discussed in relapsed multiple myeloma. 

The Targeted Pulse: Uncover the Latest From WCLC and Experts Insights Into Latest Advances Across Cancer Types

Endocrine therapies for breast cancer are rapidly evolving, with several promising agents emerging. According to Erika Hamilton, MD, oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs), in particular, are transforming the treatment landscape for breast cancer, especially in the post-CDK4/6 inhibitor setting.

Elacestrant (Orserdu) is an oral SERD that is FDA approved for patients with 

 mutations, and camizestrant, another SERD, has demonstrated superior efficacy compared with fulvestrant and may soon be available for broader use.

Additionally, PROTACs like vepdegestrant (ARV-471) offer a new mechanism for degrading the estrogen receptor (ER) and are currently being tested in combination with CDK4/6 inhibitors.

Several ongoing clinical trials are also exploring novel strategies, including first-line therapies combined with CDK4/6 inhibitors and treatment in adjuvant settings with curative intent. The results of these studies could potentially shift the current treatment paradigms.

“With all these trials ongoing, we will certainly have a rich dataset to improve our endocrine therapies,” explained Hamilton, director of breast cancer research at the Sarah Cannon Research Institute, in an interview with Targeted Oncology

In the interview, Hamilton discussed how these therapies offer new hope for patients with breast cancer by improving progression-free survival and potentially delaying the need for more toxic treatments like chemotherapy.

Targeted Oncology: What are some of the most promising emerging endocrine therapies in breast cancer?

There are quite a few emerging endocrine therapies. We have 1 FDA-approved oral SERD, elacestrant, that is restricted currently to patients with 

 mutations, but there are a lot more coming. The other to have randomized data was camizestrant. It essentially looked at 2 different doses of camizestrant, but it easily beat fulvestrant. I think we know we are going to see data in multiple settings with that drug coming.

One of the other classes that is getting talked about quite a lot are the PROTACs or proteolysis-targeting chimeras. It is a different way to degrade estrogen through proteasome and ubiquitination of the target the estrogen receptor. The one farthest along is ARV-471, and we have seen data from the phase 1 trial, as well as in combination with palbociclib [Ibrance], and that is also currently enrolling in registrational trials.

There are other newer agents coming, and then I like to call it the word salad of endocrine therapy. But we have CERANs, complete estrogen receptor antagonists; we have SERMs, newer selective estrogen receptor modulators; we have SERCAs, selective estrogen receptor covalent antagonists—a lot of different drugs coming to essentially work for patients.

How are novel endocrine therapies improving treatment for metastatic breast cancer?

What we are seeing is that CDK4/6 [inhibitors] are really the mainstay of our treatment. In the first line, they extended progression-free survival by almost a year, improving overall survival in many cases. However, post-CDK4/6 [inhibitor], drugs we used to [rely on], like fulvestrant, are not performing as well as they used to. Now, we have 2 randomized trials in that second-line, post-CDK4/6 [inhibitor] setting, where fulvestrant gives us a progression-free survival of less than 2 months, which is certainly not good enough for our patients.

I think the unmet clinical needs are for these patients whose tumors remain endocrine sensitive. We need better endocrine therapy so they can remain on endocrine therapies or endocrine combinations and delay having to move to other treatments with more toxicities, such as chemotherapy.

What upcoming developments in the space are you most excited about?

There are a lot of trials ongoing. First, there are multiple companies developing novel endocrine agents, and they are diversifying their approaches. The area that will likely be actionable first is the second-line, post-CDK [inhibitor] space. However, there are also ongoing trials in the first-line setting in combination with CDK4/6 inhibitors as a switch strategy for positive [circulating tumor DNA (ctDNA)], with results expected to read out relatively soon.

Additionally, there are adjuvant trials for curative breast cancer [treatment] that may replace our traditional endocrine backbones. These trials come in 2 varieties: comparing the new agents up front with aromatase inhibitors and using a switch strategy after 2 to 5 years on an aromatase inhibitor. With all these trials ongoing, we will certainly have a rich dataset to improve our endocrine therapies.

Can you describe the different classes of endocrine therapies and how they compare to one another?

Tamoxifen [Soltamox] is our oldest endocrine agent, and that is a SERM, a selective estrogen receptor modulator. We also have aromatase inhibitors. This is our mainstay of endocrine therapy, I would say. Then there is fulvestrant, which is an intramuscular injection form of a SERD. We now have new SERDs coming, and they are different because they are oral, not intramuscular, and have better activity. One of them is approved, elacestrant, for patients with 

 mutations, and there are many more oral SERDs on the way.

Additionally, we have PROTACs, which work by using an E3 ligase molecule to bind the target—in this case, the estrogen receptor. This leads to the ubiquitination of the estrogen receptor, marking it for degradation by the proteasome. I tell my patients it "chews up" the estrogen receptor and "spits it out.”

We also have a novel SERM called lasofoxifene [Fablyn], which is a tamoxifen-like drug. It offers some advantages in terms of adverse effects because it does not act as a full antiestrogen throughout the body—it acts as a proestrogen in some areas and an antiestrogen in others.

Finally, there are CERANs, SERCAs, and other new agents, all of which essentially work to block estrogen's interaction with cancer cells. They either lower estrogen levels so there is nothing to bind, get rid of estrogen receptors on the cell surface, or block estrogen receptors so that estrogen cannot bind to them.

How do you approach treatment after progression on first-line therapy in hormone receptor-positive breast cancer?

It is way more complicated than it used to be. There are a few actionable things. Does the patient have an 

 mutation? If so, they are eligible for elacestrant, our oral SERD. Do they have a 

 mutation? Then they are eligible for fulvestrant in combination with alpelisib [Piqray]. We also still have PARP inhibitors that are actionable for patients with 

For those with what I call a "bland profile," where there are no actionable mutations, we are not very happy with what fulvestrant alone offers. So, we have the option of using fulvestrant with everolimus, an older combination, or we have more data from the postMONARCH trial [NCT05169567] suggesting there may be a benefit to continuing CDK4/6 inhibitors in the second line. Specifically, in a switch strategy, if someone received palbociclib or ribociclib [Kisqali] in the first line, you might consider abemaciclib [Verzenio] in combination with fulvestrant in the second-line setting. What used to be pretty straightforward, where many patients got fulvestrant, has become much more complicated in recent years.

How important is it to continue targeting estrogen receptors after progression on endocrine therapy?

It is really important. There are many patients whose tumors continue to be sensitive to endocrine agents. One of the biggest unmet clinical needs right now is that we do not have a reliable way to predict which patients fall into this category. Some patients post-CDK4/6 [therapy] may not benefit from further endocrine therapies, even though their tumors are still ER positive. They may or may not have an 

 mutation, but we lack a strong assay to determine whose tumor remains endocrine sensitive and whose does not.

From my experience working with all these classes of agents through clinical trials at Sarah Cannon, I have seen patients stay on these novel agents for up to 2 years. It is hard to argue against trying additional endocrine therapies, with close follow-up, because some patients achieve meaningful disease control for a significant amount of time without having to move on to more toxic treatments like chemotherapy.

In an interview with Targeted Oncology, Erika Hamilton, MD, discussed emerging endocrine therapies that are advancing breast cancer treatment.

Benjamin H. Kann, MD

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