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Martin E. Gutierrez, MD, director, Drug Discovery/Phase I Unit, and co-chief and medical oncologist, Divisions of Thoracic Oncology and Gastrointestinal Oncology, John Theurer Cancer Center, Hackensack University Medical Center, discusses the early findings for H3B-6527, an FGFR4 inhibitor, as a treatment of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma

H3B-6527 Demonstrates Tolerability in Phase I Trial for Patients With Advanced HCC 

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

KEY TAKEAWAYS FROM ADITYA BARDIA, MD, MPH​, FASCO

Trastuzumab deruxtecan and sacituzumab govitecan can be given to patients with metastatic HER2-low breast cancer after endocrine therapy and chemotherapy.

Progression-free survival and overall survival favor trastuzumab deruxtecan over chemotherapy in HER2-low disease.

The DESTINY-Breast06 trial showed similar outcomes for HER2-low and HER2-ultralow disease.

A 52-year-old postmenopausal woman underwent breast-conserving surgery plus radiation therapy for pT2 N1 invasive ductal carcinoma of the right breast, grade 2, estrogen receptor (ER)–positive, progesterone receptor–positive, HER2 1+ by immunohistochemistry (IHC); 21-gene recurrence score: 27​.

She received dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and completed 10 years of tamoxifen.​

Five years later, she presented with disease recurrence in the liver, hormone receptor–positive, HER2-low, no actionable mutations on tissue next-generation sequencing​.

She received first-line letrozole plus ribociclib​ (Kisqali).

​She went on to receive ​fulvestrant for 6 months to disease progression in the bone and liver, then everolimus plus exemestane for 4 months to disease progression, followed by capecitabine for 6 months until disease progression.

Repeat circulating tumor DNA next-generation sequencing at each progression showed no actionable alteration.

Targeted Oncology: Do you consider this patient with metastatic breast cancer (mBC) to be eligible for sacituzumab govitecan (Trodelvy)?

If you look at the label of sacituzumab govitecan, it says 2 prior lines of systemic therapy; it does not say which kind, so you can make a case that the endocrine-based treatment was also systemic therapy.

 But the TROPiCS-02 trial [NCT03901339], which led to approval, required 2 prior lines of chemotherapy. Purely from a trial perspective, you should give 2 lines of chemotherapy, but in routine clinical practice, after capecitabine, that's when we consider trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan.

Can you use T-DXd and sacituzumab one after another?

You can use them in sequence. There have been studies looking at the efficacy of one after the next,

 and there is some cross-resistance between these agents because they have similar payloads. In sacituzumab govitecan, SN38 is a topoisomerase-1 inhibitor. With T-DXd, deruxtecan is also a topoisomerase-1 inhibitor. But in some patients, it does work, and maybe in that setting, the disease progression is more because of the antigen, and so you're using a different antibody that works. But in some patients, you would see cross resistance.

If you look at our guidelines, you have both these drugs, T-DXd and sacituzumab govitecan. The guidelines would suggest T-DXd should be preferred for HER2-low disease.

 But if a patient is not a candidate for T-DXd, that's when you use sacituzumab. That could be either contraindication to T-DXd, or if a patient has HER2 IHC 0 mBC in that setting, you can use sacituzumab, and you can use them in sequence. If you start with one, you can use the other drug after that.

What data support the use of T-DXd in patients with HER2-low status?

This was based on DESTINY-Breast04 [NCT03734029], which looked at T-DXd vs standard chemotherapy for HER2-low, ER-positive breast cancer. It showed impressive improvement in both progression-free survival [PFS] and overall survival [OS]. We saw updated results last year, and essentially continue to see benefit with T-DXd vs a standard chemotherapy with median OS of about 24 months [vs 17.6 months for chemotherapy; HR, 0.69; 95% CI, 0.55-0.87].

 That's 2 years in the second line [and beyond] setting.

At least in DESTINY-Breast04, HER2 IHC 1+ vs 2+ didn't matter. We saw similar results, and in DESTINY-Breast04, any prior HER2-low specimen was allowed. That could be primary breast cancer. It could be the first metastatic [biopsy] specimen. Any prior specimen that was HER2-low was allowed, and they saw similar benefit. In terms of safety, the main adverse events [AEs] with T-DXd are neutropenia, alopecia, nausea, and then pneumonitis.

What is the significance of the DESTINYBreast06 trial (NCT04494425) in mBC?

DESTINY-Breast06 also included HER2-ultralow, which is IHC 0+, so just some cells with HER2 expression. The other big difference was it did not require prior chemotherapy for metastatic disease. The comparator was capecitabine, which was 60% in this trial, or taxanes.

It showed results somewhat similar to DESTINY-Breast04, maybe a bit less in terms of HR, but still meaningful [in the HER2-low subgroup]. The HR was 0.62 [95% CI, 0.51-0.74; 

 < .0002] and a 5-month improvement in PFS [median, 13.2 months vs 8.1 months with chemotherapy].

Then if we combine both HER2-low and -ultralow, in the intent-to-treat population, there were very similar results [PFS HR, 0.63; 95% CI, 0.53-0.75; 

 < .0001]. In terms of OS, there was a trend towards improvement in OS [HR, 0.83; 95% CI, 0.66-1.05] but the results are not mature at this time.

If we just look at HER2-ultralow, there were very similar results, improvement in PFS with a delta of about 5 months [median, 13.2 months vs 8.3 months for chemotherapy; HR, 0.78; 95% CI, 0.50-1.21], and a trend towards improvement in OS as well [HR, 0.75; 95% CI, 0.43-1.29].

Then if you look at response rate, it was close to 60% overall response rate with T-DXd, even with HER2-ultralow. That’s why we feel that this drug works regardless of the amount of HER2 expression.

In terms of AEs, nausea is the most common, with alopecia, and some diarrhea as well. This is a setting where you should remember to get EKGs, because you can have decrease in left ventricle ejection fraction.

1. Trodelvy. Prescribing information. Gilead Sciences, Inc; 2023. Accessed November 13, 2024. 

2. Huppert LA, Mahtanai RL, Fisch SC, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): updated data and subgroup analyses by age, sites of disease, and use of intervening therapies. 

. 2024;42(suppl 16):1083. doi:10.1200/JCO.2024.42.16_suppl.1083

3. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2024. Accessed November 13, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

4. Modi S, Jacot W, Iwata H, et al. 376O - Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Updated survival results of the randomized, phase III DESTINY-Breast04 study. 

. 2023;34(suppl 2):S334-S335. doi:10.1016/j.annonc.2023.09.553

5. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

During a Case-Based Roundtable® event, Aditya Bardia, MD, MS, FASCO, discussed data from the DESTINY-Breast04 and DESTINY-Breast06 trials for HER2-low breast cancer in the second article of a 2-part series.

HER2-Low and -Ultralow Populations Benefit from T-DXd in HR+ mBC

A 77-year-old White woman presented to her primary care physician complaining of abdominal pain and fatigue.​ She had a history of cirrhosis due to heavy alcohol use; Crohn disease, controlled with infliximab [Avsola]; and a history of variceal bleeding, with banding 2 months ago​. Her ECOG performance status was 1​. A CT scan of her chest, abdomen, and pelvis with triphasic liver evaluation showed a 4.5-cm Liver Imaging Reporting and Data System 5 hepatic mass in the right lobe plus metastatic disease in the lung. She had a Child-Pugh score of A​ and an αfetoprotein level of 380 ng/mL. A biopsy was obtained and confirmed the diagnosis of hepatocellular carcinoma.

 I’d chose lenvatinib [Lenvima] because the patient [is receiving infliximab]. Otherwise, I probably would have used atezolizumab [Tecentriq] plus bevacizumab [Avastin].

 Anyone from the atezolizumab plus bevacizumab crowd? Why did you choose [that treatment]?

 I think it is the most preferred option. In this patient, there [was all that] plausible bleeding and Crohn disease, but it looks like everything is well controlled. The patient was banded recently and the risk of bleeding is lower, and it looks like the Crohn is well controlled too. It is not very clear, but I am assuming it is well controlled with infliximab. So the patient isn’t going to get a flare. One could use immunotherapy if they had colitis and didn’t respond to steroids, but you could use infliximab in those patients anyway. I feel like that patient is already on treatment and the autoimmune disorder is well controlled. If this patient doesn’t have a severe form of Crohn disease that is uncontrolled, immunotherapy is still an option.

How many of your patients are you treating if they have a history of autoimmune disease?

Are you comfortable treating those patients that have autoimmune disease that are potentially controlled?

 These are all questions that face us in the real-world practice because if you look at the trials of atezolizumab plus bevacizumab, they definitely excluded patients who had significant autoimmune diseases, or they had to have lower than physiologic doses of prednisone to be eligible for the study. So there were very fixed criteria for patients excluded from the trial. In real-world practice, how many people are using atezolizumab plus bevacizumab for patients with autoimmune conditions?

 Well controlled is when the specialist treating the patient says it’s well controlled. I am not a gastroenterologist, and I wouldn’t comment if somebody’s Crohn disease is well controlled, and the same with other autoimmune diseases. It should come from the subspecialists treating the patient. Also, symptom-wise, what kind of symptoms does the patient have? If they are symptomatic, obviously, they are not well controlled.

 I usually try to steer clear of immunotherapy when somebody is using an immunosuppressant if there is another option. I think there are active trials looking at these immunotherapies to see if they are acceptable in autoimmune diseases. Until we have more data, if there are other feasible options, I try to use them.

 I would say I am also conservative with this. In the IMbrave150 trial [NCT03434379] with atezolizumab plus bevacizumab, there were clearly defined exclusions. Our case is somewhat a high-risk patient because they are on an immune modulatory agent like infliximab that tells me, potentially, they were not able to be controlled by steroids. That is a little bit concerning for me. This is an ongoing area of research, particularly for patients with liver transplants on chronic immunosuppressants. Many of us wouldn’t necessarily treat them [with immune modulators] because early retrospective studies have shown high rejection rates. So I think it is very risky, but Dr. Chand I do understand your point about working with gastroenterology to make sure of what is defined as good control versus poor control. It’s a personal decision that is somewhat risky to [proceed with] because there can be significant toxicity when this is introduced in someone that is on immunosuppressants.

 What are your thoughts on bevacizumab? In which patients would you not use it? [With] portal hypertension that is systemic? How do you select it?

That is a very good question just because of the potential bleeding risk. In general, I would say I follow what was done in the trials. I do get endoscopy prior to starting treatment and I make sure that varices are treated. If someone has significant varices, particularly gastric varices that cannot be banded or eradicated and which traditionally have been very difficult to treat, I think that would potentially give me pause because those patients are at a very high risk for bleeding. Certainly, [I would not use bevacizumab] in someone who had an acute bleed prior to that. I would say that this in general applies for the tyrosine kinase inhibitors [TKIs] too.

In the National Comprehensive Cancer Network guidelines, atezolizumab plus bevacizumab is the preferred regimen for Child-Pugh A patients.

Other recommended regimens include sorafenib [Nexavar] and lenvatinib. Sorafenib includes Child-Pugh B7 patients and nivolumab [Opdivo] is useful in certain circumstances based off the CheckMate 459 study [NCT02576509] data for frontline therapy. Even though it wasn’t technically a positive study, it showed some benefit in terms of overall survival but not significant; however, FOLFOX is approved in China.

1. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 1.2022. Accessed April 3, 2022. https://bit.ly/3Ao3MZW

During a live virtual event, Daneng Li, MD, discussed the case of a 77-year-old woman with stage IV hepatocellular cancer and a Child-Pugh score of A. 

This is the first of 2 articles from this event. 

Considering Treatment for Patients with HCC and Autoimmune Disease

The phase 3 TROPION-Lung12 trial (NCT06564844) evaluating adjuvant treatment regimens for patients with stage I adenocarcinoma non–small cell lung cancer (NSCLC) has tested for eligibility its first patient with the investigational GRAIL NSCLC circulating tumor (ct) DNA assay.

This research, approved under an FDA Investigational Device Exemption (IDE) held by GRAIL, uses the biotechnology company's innovative targeted methylation platform to identify ctDNA. The method uses blood only, removing the need for tissue biopsies or custom panel creation and allows for seamless integration into pharmaceutical clinical trials.

The TROPION-Lung12 trial uses a circulating tumor DNA assay to preoperatively screen patients with non–small cell lung cancer for eligibility in post-surgical adjuvant treatment regimens.

Martin E. Gutierrez, MD

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