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Jennifer H. Kuo, MD, director, Thyroid Biopsy Program, Columbia University, discusses a study looking at the incidence of thyroid cancer among breast cancer survivors.

The Incidence of Thyroid Cancer Among Breast Cancer Survivors

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

Seth Wander, MD, PhD, discusses approved and upcoming targeted therapies for patients with ESR1-mutated breast cancer.

Targeting ESR1 Mutations in Breast Cancer With Novel Therapies

Seth Wander, MD, PhD, a medical oncologist at the Massachusetts General Hospital and instructor in medicine at Harvard Medical School, discusses approved and upcoming targeted therapies for patients with 

Current options for these patients include elacestrant (Orserdu), a selective estrogen receptor degrader (SERD), and fulvestrant, a chemotherapy. However, Wander says fulvestrant’s effectiveness varies among 

 mutations. Some, such as Y537S, may have resistance to this therapy.

Recent trials including the phase 3 EMBER-3 trial (NCT04975308) investigating imlunestrant with or without abemaciclib (Verzenios) have shown potential in subpopulations of patients with ESR1 mutations. Imlunestrant is also a SERD but Wander notes that therapies such as selective estrogen receptor modulators, proteolysis targeting chimeras, and covalent estrogen receptor antagonists are also being looked at as single agents and in combination for use in this patient population.

 Patients who demonstrate endocrine sensitivity and then they develop the 

 mutation, they're good candidates for using elacestrant. There are many other drugs that are being developed right now for patients with 

-mutant breast cancer. Fulvestrant can work, although I would argue that the preconceived notion that fulvestrant works across the board for 

-mutant patients is not entirely true. Not all 

 mutations are created equally. Some of them probably have distinct neomorphic activities and may be more resistant to a drug like fulvestrant, for example, the Y537S mutation. We're still learning a lot about what these mutations do at the cellular biochemical level. So fulvestrant can be helpful in some cases. Elacestrant is FDA approved for 

-mutant breast cancer that's progressed on prior endocrine therapy.

 Now we have a number of newer drugs that we have phase 3 data coming online. We just saw phase 3 data from the EMBER-3 trial, looking at imlunestrant either as a single agent or with abemaciclib...that showed very similar results where there was activity as a single agent in the ESR1-mutant subpopulation of that study. Then we have other newer drugs coming up. We have lots of other oral SERDS. We have SERMs, selective estrogen receptor modulators. We have PROTACs, proteolysis targeting chimeras. We have SERCAs, covalent estrogen receptor antagonists. So lots of new mechanisms, new anti-estrogen agents being developed as single agents and also as combinations with various targeted therapies.

The remarkable intracranial efficacy of novel HER2-targeted therapies has established a new treatment paradigm, allowing oncologists to prioritize systemic therapies over local interventions for managing small, asymptomatic brain metastases in patients with metastatic breast cancer, noted Sara A. Hurvitz, MD, FACP, at the 42nd Annual Miami Breast Cancer Conference.

The newer agents that cross the blood-brain barrier for HER2-positive metastatic breast cancer include tucatinib (Tukysa) and fam-trastuzumab deruxtecan-nxki (Enhertu), with several other TKIs also showing promise. A meta-analysis of 97 studies found that HER2-targeted therapies significantly improved overall survival (OS) compared with non-targeted treatments for patients with HER2+ breast cancer with intracranial metastatic disease (HR, 0.47; 95% CI, 0.39-0.56).

"When we have a patient develop brain metastases, we should refer patients or work very closely with our multidisciplinary colleagues in radiation oncology and neurosurgery. There are a number of factors that will weigh into treatment decision-making in terms of extracranial disease, how symptomatic the patient is, the number and the location of lesions," said Hurvitz, head of the Division of Hematology/Oncology at University of Washington School of Medicine and senior vice president of Clinical Research Division at Fred Hutchinson Cancer Center in Seattle. "we are still in an era where we rely pretty heavily on locoregional therapy, but for HER2-positive central nervous system [CNS] disease, we now have the availability of systemic therapies that work."

Several studies have assessed TKI-based regimens for patients with brain metastases utilizing a variety of agents, each showing different levels of intracranial response. Hurvitz noted that intracranial responses in these studies have ranged from 8% to as high as 75%.

The phase 2 HER2CLIMB study (NCT02614794) examined capecitabine plus trastuzumab (Herceptin) combined with the TKI tucatinib or placebo for patients with HER2-positive metastatic breast cancer, including those with brain metastases. An updated exploratory analysis specifically looked at the 291 patients enrolled in the study with brain metastases.

 In those receiving tucatinib, the risk of developing a new brain lesion was significantly reduced compared with patients given placebo (HR, 0.55; 95% CI, 0.36-0.85).

The median OS was longer with the tucatinib regimen compared with placebo for patients with active brain metastases (21.4 months vs 11.8 months, respectively). Additionally, of the 66 patients enrolled with untreated brain metastases, the median OS was 19.7 months with tucatinib compared with 13.4 months with placebo.

Another TKI of interest for brain metastases is pyrotinib, Hurvitz noted. This agent showed activity when used in combination with capecitabine for patients with HER2-positive metastatic breast cancer. In the phase 2 PERMEATE study (NCT03691051),

 which was conducted in China, the intracranial response rate was 74.6% in those who had not received prior radiation therapy, and it was 42.1% in those who had received prior radiation. Pyrotinib is currently being explored in a variety of combinations and settings but is not yet approved in the United States.

Antibodies and Antibody-Drug Conjugates for Brain Metastases

Antibody therapies like pertuzumab (Perjeta) and trastuzumab have also been explored in combination as a treatment for brain metastases. As have their armored counterparts, the antibody-drug conjugates (ADCs) ado-trastuzumab emtansine (T-DM1; Kadcyla) and trastuzumab deruxtecan.

In the phase 2 PATRICIA trial (NCT02536339),

 the combination of pertuzumab plus high-dose trastuzumab showed a confirmed CNS response of 11% (95% CI, 3.0-25.4). The median CNS-PFS was 4.6 months, and the median OS was 27.2 months with this combination.

"The PATRICIA study is overlooked in a lot of cases," said Hurvitz. "I think these are notable data especially to keep in mind for our patients whose disease has progressed in the brain."

The first ADC for HER2-positive breast cancer, T-DM1, was explored for patients with brain metastases in the phase 3 KAMILLA study (NCT01702571).

 In this study, the best overall response rate was 21.4%, which included both CNS and non-CNS responses. There was a 30% or greater reduction in the sum of the largest brain lesions observed in nearly one-third of patients treated with T-DM1 after radiotherapy (32.7%). In those who received T-DM1 without prior radiotherapy, a 30% or greater reduction in brain lesions was seen in 49.3% of patients.

These data set the stage for trastuzumab deruxtecan, which has significantly disrupted the treatment of HER2-positive breast cancer across several settings. A few studies have shown significant improvement in brain metastases with trastuzumab deruxtecan, including the phase 2 TUXEDO-1 (NCT04752059) and DEBBRAH (NCT04420598) trials, and the retrospective, real-world ROSET-BM study (UMIN000044995) conducted in Japan, Hurvitz detailed.

The DESTINY-Breast trials were foundational in the establishment of trastuzumab deruxtecan for HER2+ breast cancer. A pooled analysis of the phase 2 DESTINY-Breast01 (NCT03248492), phase 3 DESTINY-Breast02 (NCT03523585), and phase 3 DESTINY-Breast03 (NCT03529110) studies examined the efficacy of the trastuzumab deruxtecan in patients with brain metastases.

 Across these studies, 148 patients with brain metastases received the ADC compared with 83 patients with brain metastases in the control arms.

In this pooled analysis, for those who had previously treated or stable brain metastases, the intracranial response rate was 45.2% with trastuzumab deruxtecan. In those with untreated or active asymptomatic brain metastases, the intracranial response rate was 45.4% with trastuzumab deruxtecan. In the comparison arms for these trials, which included T-DM1, lapatinib (Tykerb) plus capecitabine, and trastuzumab plus capecitabine, the intracranial response rates were 27.6% and 12% in the same patient groups, respectively.

"What is notable here is how bad the comparator arms [are] doing in the patients with untreated and active brain metastases," Hurvitz noted.

The most recent study showing a benefit for trastuzumab deruxtecan was the phase 3b/4 DESTINY-Breast12 trial (NCT04739761).

 The open-label study enrolled patients with or without brain metastases to compare outcomes between both groups. In those with baseline brain metastases, the median progression-free survival (PFS) was 17.3 months. The 12-month CNS PFS was 58.9%.

Intracranial tumor shrinkage was seen with trastuzumab deruxtecan in almost all patients with measurable brain metastases at baseline, with confirmed CNS responses for 62.3% of those with active brain metastases. Those with previously untreated brain metastases had an intracranial response rate of 82.6% with trastuzumab deruxtecan.

"I think we see clear evidence of activity in the brain with this molecule," said Hurvitz.

Next Steps for Systemic Treatment of Brain Metastases

For patients with HER2-positive metastatic breast cancer, the brain is the most common site of metastatic disease, with nearly half of patients developing this condition, Hurvitz noted. With such a high rate of brain metastases, guidelines have grappled with the notion of screening all patients with HER2-positive metastatic disease, regardless of symptoms. Although this is not the current standard of care, studies are underway to assess the long-term benefits of screening asymptomatic patients with HER2-positive metastatic breast cancer for brain metastases (NCT04030507, NCT05115474). With enough evidence, Hurvitz believes screening asymptomatic patients with metastatic breast cancer could be added to future guidelines.

The ideal candidate for systemic vs local therapy is one with no symptomatic mass effect, a single lesion less than 2 cm, or multiple lesions less than 2 cm. In many cases, the use of systemic therapies avoids the adverse effects associated with radiation; however, the use of these agents vs a local therapy does require careful consideration of a multidisciplinary team to arrive at the optimal treatment choice.

“There are ongoing studies that may address this important question of whether we should screen asymptomatic patients with HER2-positive breast cancer for brain metastases,” said Hurvitz. “Hopefully, there will be data forthcoming in the not-too-distant future.”

Novel HER2 therapies show strong intracranial efficacy, enabling systemic treatment over local therapy for small, asymptomatic brain metastases in metastatic breast cancer.



Jennifer H. Kuo, MD

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