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Authors

Brittany N. Bohinc, MD, Division of Endocrinology, Duke University, discusses the potential to use LGR5 as a biomarker in papillary thyroid cancer.

Using the LGR5 Protein as a Biomarker in 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. 

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 48-year-old woman with T1N1 triple-negative breast cancer (TNBC) received adjuvant dose-dense doxorubicin, dose-dense cyclophosphamide, and paclitaxel, which she tolerated well. Eight months after completion of adjuvant therapy, she reports worsening fatigue. ​

Labratory results: alanine aminotransferase 1.5x upper limit of normal, aspartate transaminase 1.5x upper limit of normal

CT showed 1 liver and 2 left lung lesions​.

Biopsy of the liver lesion confirmed recurrent metastatic TNBC ​(mTNBC).

Brain MRI: negative for brain metastasis ​

Genetic panel testing: negative for detectable mutations​

PD-L1 on immune cells (IHC 22C3 pharmDx): 0%​

No significant comorbidities; otherwise healthy​

: What was the FDA indication for sacituzumab govitecan-hziy (Trodelvy) leading to its approval for use in patients with breast cancer?

 For patients with mTNBC, they must have received 2 or more prior systemic therapies, and at least 1 of the therapies [must have been] for metastatic disease.

 Patients can be on second-line treatment, had 1 in the metastatic setting, and the second one could have been in the adjuvant setting.

It’s tricky because I would love to give this particular patient sacituzumab up front. Technically that’s not really the way the indication is from the FDA label because you must have had at least 1 line of therapy in the metastatic setting. Although, I think that many people may argue that, if someone is recurring so soon after capecitabine, they probably had metastatic disease while receiving the capecitabine. But that’s not the way the label is written. If you decided to use sacituzumab in that particular case, you would have to see if insurance would approve it, and how savvy they would be about the nuances of the label.

Microtubule inhibitor (eribulin, vinorelbine)

Initially sacituzumab got an accelerated approval based on their phase 1 basket data.

They got the full indication once they had the full ASCENT trial [NCT02574455] data. Initially, they had an indication for the third line and beyond, and then more recently, they were given an indication where patients just had to have 2 treatments and at least 1 of which was from metastatic disease so [the approval] in fact moved it up to the second-line setting.

Could you describe the study design of the phase 3 ASCENT trial?

The ASCENT trial took patients who had metastatic disease. Patients had to have had 2 chemotherapies for advanced disease, but they counted as 1 chemotherapy if patients had an early relapse. There were some patients who were second line because they had an early relapse, but the rest were third line and beyond. They were randomized to get sacituzumab or treatment of physician’s choice therapy. The trial’s primary end point was progression-free survival [PFS], and secondary end points included overall survival [OS], overall response rate [ORR], duration of response [DOR], and time to response [TTR].

What were the characteristics of the patient population of the ASCENT study of sacituzumab?

[Reflecting the real-world population], only about 7% of patients had known germline 

 mutations. There were about 30% of patients who had estrogen receptor [ER]–positive disease at the time of their initial diagnosis, but when they recurred in the metastatic setting, they were triple negative. We certainly do see this clinically but they did have that mix of patients.

This is a population with predominantly visceral metastases. About 70% of patients had received 2 or 3 lines of prior systemic chemotherapy, and all had received prior taxane. Most patients had prior anthracycline, platinum, and capecitabine. There were 7% of patients who had a prior PARP inhibitor, who were the patients with the 

 mutations. There were about 30% of patients who had had prior [PD-1/PD-L1] checkpoint inhibitors.

 So, [this population was] not unlike our modern-day population.

What were the survival outcomes observed in the study?

What I think is remarkable is that the PFS for sacituzumab is just under 6 months [95% CI, 4.3-6.3].

 But when you look at the control arm, you see that the PFS for treatment of physician’s choice is [1.7] months [(95% CI, 1.5-2.6) HR, 0.41; 95% CI, 0.32-0.52; 

 < .001]. This is really telling because it shows you how poorly we do with standard chemotherapy for mTNBC, that the PFS is very short.

If you look at the OS, you see it almost doubles with sacituzumab, going from 6.7 months [95% CI, 5.8-7.7] to [12.1] months [(95% CI, 10.7-14.0) HR, 0.48; 95% CI, 0.38-0.59; 

< .001]. So [sacituzumab was associated with] very dramatic improvement, not just in PFS, but also in OS.

What were the outcomes for different treatment options given as treatment of physician’s choice in the control arm?

The choices were, eribulin [Halaven], vinorelbine [Navelbine], capecitabine, and gemcitabine. The PFS and OS were similar across all the different agents. Numerically, gemcitabine had the highest PFS compared with eribulin, vinorelbine, or capecitabine. But it was 2.7 months compared with around 2 months and all of them do not do well.

Did the survival outcomes observed vary by different subgroups?

If you look at the subgroups, every subgroup benefits [from sacituzumab]. Whether or not patients had ER–positive disease at their initial diagnosis, prior to recurring, whether they had liver metastases, whether or not they had prior checkpoint inhibition, the benefit is remarkably similar.

 mutation status. Sacituzumab does better than treatment of physician’s choice therapy in the patients with germline 

 mutations as well. So, [that is] not a reason to choose or not choose sacituzumab based on mutation.

What was the response rate seen in the study?

There was a 35% response rate for sacituzumab, compared with just 5% for chemotherapy.

 I think this is very important when having discussions with patients about the benefits of chemotherapy in pre-treated mTNBC because it tells us that, to be honest with our patients, we have to tell them that the average response rate is only 5% and the average PFS for chemotherapy is just under 2 months. So, again, patients do not do very well with standard chemotherapy outside the first-line setting. 

What was the significance of the outcomes of patients with and without brain metastases in the study?

The trial was designed in an interesting way, where [the investigators] took the PFS in the patients who did not have brain metastases as baseline. So PFS in patients without brain metastases was the primary end point. However, they did an analysis of the full population, which included patients who had a history of brain metastases. What that means is, people could have had stable brain metastases and go on the study. In fact, when you add in those patients, you still see the same hazard ratio, so in this case it was 1.7 months versus 4.8 months, for the overall population.

 So, benefits were seen in the whole population as well.

What adverse events were reported in the study?

During a live virtual event, Sara Tolaney, MD, discussed the results of the ASCENT trial of sacituzumab govitecan in patients with triple-negative breast cancer.

Brittany N. Bohinc, MD

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