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Senthil Damodaran, MD, PhD, discusses data from a phase 2 trial of futibatinib  in patients with metastatic HR-positive/HER2-negative breast cancer with FGFR1 amplifications.

Futibatinib Shows Promise in Breast Cancer With FGFR1 Gene Amplifications

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

Multiple novel agents with diverse mechanisms of action are currently in development to overcome resistance to endocrine therapy (ET) and CDK4/6 inhibitors in hormone receptor–positive breast cancer. This ongoing research, highlighted in a session by Hope S. Rugo, MD, at the 42nd Annual Miami Breast Cancer Conference, aims to address the significant unmet clinical need in this patient population.

“We stand here at the brink of a precipice. There’s going to be a whole lot of these drugs approved in the future. We’re going to need to understand how to use them alone or in combination. They’re oral agents, and that’s huge for our patients,” said Rugo, professor of medicine and Winterhof Professor of Breast Oncology, director, Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center. “I think that this is a really exciting advance. We’ve seen some great data in the past couple of years.”

The first agents to kick off this sea change in managing resistant HR-positive breast cancer were the oral selective estrogen receptor degraders (SERDs), which work best in those with the 

resistance mutation. In 2023, the FDA approved the first of these agents, elacestrant (Orserdu), for patients with estrogen receptor (ER)–positive, HER2-negative, 

-mutated advanced or metastatic breast cancer following progression on at least 1 prior line of ET. This approval was based on data from the phase 3 EMERALD trial (NCT03778931).

 which enrolled patients with or without 

 mutations, the progression-free survival (PFS) was significantly prolonged with elacestrant compared with standard of care ET (HR, 0.70; 95% CI, 0.55-0.88; 

mutations, the benefit in PFS was even more pronounced with elacestrant compared with standard of care (HR, 0.55; 95% CI, 0.39-0.77; 

A follow up analysis further found that response to prior therapy could be used to help select which tumors would be more sensitive to treatment with elacestrant.

 For those who received ET plus CDK4/6 inhibition for 12 months or greater, the median PFS was 8.61 months (95% CI, 4.14-10.84) with elacestrant compared with 1.91 months (95% CI, 1.87-3.68) with standard of care (HR, 0.41; 95% CI, 0.26-0.63).

The ability to predict sensitivity led to the next question of whether combinations could be effective, Rugo noted. The ELECTRA (NCT05386108) and ELEVATE (NCT05563220) trials sought to examine this question by combining elacestrant with the CDK4/6 inhibitor abemaciclib (Verzenio). Data from a pooled analysis from the studies for patients pretreated with ET and CDK4/6 inhibitors were presented at the 2024 San Antonio Breast Cancer Symposium showing an intriguing efficacy.

 the objective response rate (ORR) with the combination was 18%, which included 5% who had a complete response. There were 66% of patients beyond this who also had stable disease, for a clinical benefit rate (CBR) of 84%. In all patients, the median PFS with elacestrant plus abemaciclib was 8.7 months. In those who received prior ET/CDK4/6 treatment for 12 months or longer, the median PFS was 16.6 months with elacestrant plus abemaciclib.

“We saw an encouraging clinical benefit rate,” said Rugo. “Then we also looked at our response and many of these patients are staying on treatment for a long period of time, which is really encouraging.”

Other investigational SERDs are also currently being explored as treatments for patients with ET and CDK4/6 resistance, potentially offering an abundance of choices soon. The phase 2 SERENA-2 trial (NCT04214288) was recently published showing efficacy for the SERD camizestrant vs fulvestrant (Faslodex) for patients with ER-positive, HER2-negative advanced breast cancer.

 The median PFS with fulvestrant was 3.7 months (90% CI, 2.0-6.0) compared with 7.2 months (90% CI, 3.7-10.9) with a 75-mg dose of camizestrant (HR, 0.59 vs fulvestrant) and 7.7 months (90% CI, 5.5-12.9) with a 150-mg dose (HR, 0.64 vs fulvestrant).

Recent data from the phase 3 SERENA-6 trial (NCT04964934) also showed utility for camizestrant in the first-line setting in combination with a CDK4/6 inhibitor.

 The data from the study have not yet been released but a statement said that the study met its primary end point of improved PFS with the combination compared with standard of care aromatase inhibition plus CDK4/6 inhibition. AstraZeneca, the company developing camizestrant, said the data would be presented at an upcoming medical meeting and shared with global regulatory authorities.

Another SERD, imlunestrant, has also demonstrated promise with or without the addition of abemaciclib for patients with ER-positive, HER2-negative advanced breast cancer in the phase 3 EMBER-3 trial (NCT04975308).

 In data from the study, the median PFS was 5.6 months (95% CI, 5.3-7.3) with imlunestrant and 5.5 months (95% CI, 4.6-5.6) with standard therapy (HR, 0.87; 95% CI, 0.72-1.04; 

 mutations, the median PFS was 5.5 months (95% CI, 3.9-7.4) with imlunestrant compared with 3.8 months (95% CI, 3.7-5.5) for standard therapy.

The combination of imlunestrant plus abemaciclib was also compared with imlunestrant monotherapy in the study. The median PFS with the combination was 9.4 months compared with 5.5 months with imlunestrant monotherapy (HR, 0.57; 95% CI, 0.44-0.73; 

 mutations, the median PFS with the combination was 11.1 months (95% CI, 7.4-13.7) compared with 5.5 months (95% CI, 3.8-7.2) with monotherapy (HR, 0.53; 95% CI, 0.35-0.80).

“The only downside here is that there’s no comparison of imlunestrant/abemaciclib vs standard of care ET,” said Rugo. “It is difficult to assess the impact of the 

Another SERD, giredestrant, is also being examined in combination with palbociclib (Ibrance) plus letrozole in a phase 3 study labeled persevERA (NCT04546009).

 This trial is currently active but not recruiting, with an estimated primary completion date in October 2025.

Novel Agents for ER Targeting Under Investigation

The novel agent vepdegestrant (ARV-471) offers another method for approaching ET resistance. The agent is a proteolysis-targeting chimera (PROTAC), which act as protein degraders targeted to ER proteins. A phase 1b study (NCT04072952) assessed vepdegestrant in combination with palbociclib for patients with ER-positive, HER2-negative breast cancer following exposure to ET with or without CDK4/6.

 The CBR with the combination was 63% (95% CI, 47.6%-76.8%) in the overall population enrolled. For those with the 

 mutation, the CBR was 72.4% (95% CI, 52.8%-87.3%). The median PFS was 11.2 months (95% CI, 8.2-16.5) in the overall population and 13.7 months (95% CI, 8.2-not reached) in the 

In February 2024, vepdegestrant received a fast track designation from the FDA, a distinction that is meant to speed up the development of new medications. The phase 3 VERITAC-3 study (NCT05909397) is also assessing the agent with palbociclib compared with palbociclib and letrozole. The phase 3 VERITAC-2 trial (NCT05654623) is currently assessing vepdegestrant vs fulvestrant for patients with ER-positive, HER2-negative advanced breast cancer. The study indicates that it has fully recruited with results expected soon.

“These are very exciting drugs and many of them [are] still in development,” said Rugo. “The trial is fully accrued so we’re going to see the results relatively sooner.”

Another approach to ET resistance comes through the complete ER antagonist (CERAN) palazestrant (OP-1250). This agent was examined in combination with ribociclib (Kisqali) in a phase 1b/2 study (NCT05508906). In findings from the study,

 the median PFS was not reached. The 6-month PFS rate was 72% across all patients and 81% in those with 

Based on these findings, Olema Oncology, the company developing palazestrant, is launching the phase 3 OPERA-02 study to further assess the combination for patients with breast cancer. The FDA granted palazestrant a fast track designation in 2022.

Rugo received institutional research support from AstraZeneca, Daiichi Sankyo, Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., Lilly, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer, Stemline Therapeutics, OBI Pharma, and Ambryx; and served in a consulting/advisory role for Chugai, Sanofi, Napo, and Mylan.

Rugo HS. Emerging therapies: updates on oral SERDs for metastatic HR+ breast cancer. Presented at: 

 Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida.

Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. 

. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. 

. 2024;30(19):4299-4309. doi:10.1158/1078-0432.CCR-24-1073

Rugo HS, Tolaney SM, Chan N, et al. Elacestrant plus abemaciclib (abema) combination in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer (mBC). Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Poster PS7-07.

Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial. 

New agents targeting endocrine therapy and CDK4/6 resistance in hormone receptor–positive breast cancer are in development.


Senthil Damodaran, MD, PhD

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