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Ron Bose, MD, PhD, discusses the rationale for a trial of neratinib plus alpelisib for patients with HER2-positive breast cancer.

Exploring Resistance to HER2-Targeted Therapy for Breast Cancer

Ron Bose, MD, PhD, discusses the challenge of drug resistance due to mutations for patients with HER2-positive breast cancer.

Addressing Drug Resistance Due to Mutations in HER2+ Breast Cancer

Ron Bose, MD, PhD, discusses the importance of computer simulations to develop treatments for patients with HER2-positive breast cancer as established by a recent study. 

Computer Simulations Predict Treatment for HER2-Mutated Breast Cancer

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

The FDA has granted a fast track designation to the investigational agent lasofoxifene for the treatment of women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who have an 

The agent is currently being investigated in a phase II trial in this setting.

"Lasofoxifene's fast track designation highlights the significant unmet medical needs of patients who have ER-positive/HER2-negative breast cancer with an 

mutation," said David Portman, MD, the CEO of Sermonix, in a statement. "Fast track will allow us to more quickly complete our development program and, if successful, make lasofoxifene available to patients sooner."

Lasofoxifene is a nonsteroidal selective estrogen receptor modulator that is being considered a potential precision medicine treatment for women with breast cancer who have 

mutations as the agent has demonstrated activity against mutations of the estrogen receptor. 

mutations are commonly found in the metastatic setting in breast cancers, especially among women who have progressed on prior endocrine therapies, which is why this is considered an area of high unmet need in oncology.

"We are very encouraged to receive fast track designation, a recognition of lasofoxifene's potential promise as a precision medicine for [patients] with ER+ metastatic breast cancer," Anthony H. Wild, PhD, chairman of Sermonix, said in a statement.

The open-label, randomized, multicenter phase II ELAINE trial is exploring the use of lasofoxifene in comparison with fulvestrant (NCT03781063). The trial is enrolling up to 100 postmenopausal women with locally advanced or metastatic ER-positive, HER2-negative breast cancer with an acquired 

mutation, as detected by a cell-free circulating-tumor DNA liquid biopsy test, who have progressed on an aromatase inhibitor in combination with a CDK4/6 inhibitor. Eligible patients must have received 1 prior chemotherapy regimen in the neoadjuvant or adjuvant setting and have an ECOG score of 0 or 1.

The primary endpoint of the study is progression-free survival and secondary endpoints include clinical benefit rate, objective response rate, duration of response, time to response, overall survival, and safety. An exploratory analysis will also explore the presence of select mutations, including 

Preclinical findings for lasofoxifene will be presented at the 2019 ASCO Annual Meeting.

According to the abstract, lasofoxifene demonstrated greater efficacy than fulvestrant at inhibiting metastasis in xenograph models. In addition, in a study of lasofoxifene or fulvestrant in combination with palbociclib (Ibrance) in mice, the combination of lasofoxifene and palbociclib demonstrated greater reduction of primary tumor growth. The study showed that lasofoxifene can disrupt the active conformation of the ER-alpha Y537S ligand-binding domain.

As a result of the fast track designation, Sermonix is looking to potential breakthrough and priority review designations for a future new drug application for the agent.

1. Sermonix Receives FDA Fast Track Designation for Investigational Drug Lasofoxifene [news release]. Columbus, OH: Sermonix Pharmaceuticals LLC; May 28, 2019. Accessed May 28, 2019. 

2. Laine M, Fanning SW, Greene M, et al. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer.

The FDA has granted a fast track designation to the investigational agent lasofoxifene for the treatment of women with estrogen receptor-positive, HER2-negative metastatic breast cancer who have an ESR1 mutation. The agent is currently being investigated in a phase II trial in this setting.

FDA Grants Fast Track Designation to Lasofoxifene for ER+, ESR1-Mutant Metastatic Breast Cancer

In October 2016, a 57-year-old black man was referred to the urology department with a PSA (prostate-specific antigen) of 6.8 ng/mL. His medical history included seizures that were controlled with oxcarbazepine. His mother and sister had a history of breast cancer, and his brother had a history of pancreatic cancer. A multiparametric MRI scan showed a 58 cc index lesion to his left prostate zone, and prostate imaging reporting and data system showed it to be 4/5, 1.8 cm. 3 months later, he had a robotically assisted radical prostatectomy and extended lymph node dissection. 6 weeks post operation, the patient had a PSA of 0.15 ng/mL and baseline serum testosterone of 420 ng/mL.

Androgen deprivation therapy (ADT) was initiated with leuprolide depot at 45 mg. The patient returned in August 2019. His PSA doubling time (PSA-DT) was 8.6 months with a PSA of 1.2 ng/mL. In October 2019 he was restaged, and bone scans showed he was negative for metastatic disease with an ECOG performance status of 0. In October 2020, the patient’s PSA was 3.81 ng/mL.

Continue androgen deprivation therapy as monotherapy

How critical are quality-of-life issues in decision-making?

Why would you reach for a first-generation antiandrogen?

 I did pick a first-generation antiandrogen, and the reason for that is mainly pragmatic reasons.

In this nonmetastatic recurrent disease, you have a drug that is effective, it is inexpensive, and it has hardly any adverse events [AEs]. So, I tend to use that in these settings, and I [have success] with it for a year or 2. And then once they [progress], I go to the next generation, mainly because of the cost.

 So, you would use something like bicalutamide [Casodex] due to the [low] cost and not having a lot of AEs?

What factors influence your selection of a novel hormonal agent?​

 Which [novel hormonal agent] one would you select? Dr Jafari, let us say you used bicalutamide already and the PSA is still rising through [the treatment period], and you restage the patient. Still no metastases on CT or bone scan. Would you pick abiraterone [Zytiga], apalutamide [Erleada], darolutamide [Nubeqa], or enzalutamide [Xtandi] for this patient?

 I picked apalutamide because that is the first one to get approved for this specific indication of nonmetastatic castrate-resistant prostate cancer [nmCRPC].

 [I have] experience since I have been using it for the past year and more.

 I picked enzalutamide because I am familiar with it. That is the only reason.

 [Dr Agarwal’s reason] was that apalutamide was first to be approved in this setting…and enzalutamide was the first to be approved for metastatic CRPC, post-chemotherapy, and then pre-chemotherapy.

 I prefer darolutamide for a slightly better tolerability, and fewer interactions between this drug and others.

 I chose enzalutamide. I was between darolutamide and enzalutamide. Enzalutamide was more tolerable, and I have seen it more.

 [I chose abiraterone for] similar reasons to [Dr Sui]. I am familiar with the abiraterone in the metastatic setting. And I am familiar with the AE profile, so I think I can manage them.

 Yes. Does that affect your choices, Dr Wong?

 I do not have any clinical experience with it causing seizures, but supposedly enzalutamide can lower the seizure threshold.

 Yes, it is not high. It is [around] 0.6% to 0.9% in their early studies.

 Then subsequent earlier-stage studies are only 0.1%.

 But again, those trials excluded patients with a seizure history, and this patient already has a seizure disorder. Did you pick abiraterone, then?

 I picked darolutamide because although they were not directly compared, it seemed to have the lowest rate of AEs compared with placebo.

 Darolutamide has a different biochemical structure than enzalutamide or apalutamide, and there are data to show that there is less crossing in the blood-brain barrier with darolutamide.

 So, the interesting thing is that the darolutamide clinical trials did not exclude patients with seizure history or seizure risk.

 It is the only agent that does not have a contraindication [or warning] for patients with seizures.

Now, abiraterone does not have any issue with seizures either, but it is not an androgen receptor antagonist. Although there are great phase 2 data, there has not been a randomized phase 3 trial with abiraterone in this setting.

So I think you hit the nail on the head there. If you are looking for FDA-approved answers for a patient with a history of seizures, darolutamide would be the best agent for this patient.

 So, [the SPARTAN trial (NCT01946204) of] apalutamide also excluded patients with seizure history?

 Yes. Enzalutamide and apalutamide were created in the same lab. There is just a small change in the nitrogen side chain. So, they are essentially almost the same biochemical structure.

Abiraterone is not approved for treatment of nmCRPC. It is apalutamide, darolutamide, and enzalutamide [that are approved by the FDA].

For abiraterone, there is only the phase 2 [IMAAGEN] study [NCT01314118]. The data looked great. If they ran a phase 3 study, it probably would work as well. It is just that abiraterone went generic, so nobody was going to back a phase 3 study in this situation.

After shared decision-making, darolutamide was initiated.​

How would a PSA doubling rate of 15 months affect your choice?

What if the PSA doubling was not 8 months, but was 15 months? Does that change your decision making at all?

 Yes, I think that makes difference if the doubling time is 6 months, 8 months, or 12 months, it makes a difference. If it were 15 months, I would think about it. If, for example, the PSA went from 1 ng/mL to 2 ng/mL, with a doubling time of 15 months, I may not change the regimen.

 You might just watch them for a while. Alright, that sounds good. Dr Shao, what would you do if the PSA doubling time was 15 months here?

 [There are] 2 choices. Either we watch for a while, or we can continue the hormone that he is [receiving] right now.

 Dr Sun, would you treat this patient, or would you observe, still just on ADT?

 I would just continue the monotherapy. I wouldn't add another agent in this situation. Fifteen months doubling time can be monitored. Once the doubling time shortens you can initiate at that point.

During a live virtual event, Evan Yu, MD, discussed the choice of novel hormonal agent for a patient with nonmetastatic castration-resistant prostate cancer. 

Ron Bose, MD, PhD

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