 Will Pizii 

The combination of neratinib (Nerlynx) and trastuzumab (Herceptin), with or without fulvestrant (Faslodex), demonstrated beneficial clinical activity in patients with heavily pretreated hormone receptor (HR)-positive, HER2-negative, HER2-mutant metastatic breast cancer (MBC). Komal Jhaveri, MD, FACP, presented these data along with the effectiveness of HER2-directed antibody-drug conjugates (ADCs) in patients with HER2-mutant breast cancer at the 21st Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource, LLC (PER®) in New York, New York.

Results from the SUMMIT basket study (NCT01953926) revealed encouraging results with the triplet regimen in patients with HR-positive/ HER2-negative MBC compared with other variations and monotherapies of the 3 drugs.

The study also assessed the use of neratinib and trastuzumab alone among patients with triplenegative breast cancer (TNBC).

Patients with HR-positive MBC with prior CDK4/6 inhibition who received the triplet (n = 51) had an objective response rate (ORR) of 35.3% (n = 18), whereas patients who received fulvestrant plus trastuzumab or fulvestrant alone had no responses before crossing over to receive the triplet. Of the 18 responses with the triplet combination, 17 patients had partial response (PRs) and 1 patient had a complete responses (CR). Best overall responses, whether confi rmed or unconfirmed, to treatment with the triplet occurred in 25 patients (49.0%). The triplet regimen also had a median duration of response (DOR) of 14.3 months (95% CI, 6.4–not estimable [NE]) and a clinical benefit rate of 47.1%. The median progression-free survival (PFS) for patients receiving neratinib, trastuzumab, and fulvestrant was 8.2 months (95% CI, 4.7-12.7) compared with 3.9 months (95% CI, 1.9-4.1) with fulvestrant plus trastuzumab before crossover and with 4.1 months (95% CI, 1.6-4.1) . with fulvestrant monotherapy before crossover.

The phase 2 SUMMIT trial had a Simon 2-stage design. The primary end point was ORR in patients with HR-positive tumors and ORR at fi rst assessment for patients with TNBC. The secondary end point was confirmed ORR per investigator review.

The most common any-grade adverse events (AEs) among patients with HR-positive disease who received the triplet were diarrhea (90.2%), nausea (72.5%), vomiting (52.9%), and fatigue (43.1%). The most common grade 3 AEs in this group were diarrhea (51.0%), vomiting (7.8%), decreased appetite (7.8%), and fatigue (5.9%). Two grade 4 AEs were also reported: coma (n = 1) and muscle weakness (n = 1).

The neratinib/trastuzumab doublet also showed beneficial results among patients with TNBC (n = 18). The ORR was 33.3% (n = 6), with 1 CR (5.6%) and 5 PRs (27.8%). The best overall response rate was 38.9%. The median DOR was NE and the clinical benefit rate was 38.9%. The median PFS was 6.2 months (95% CI, 2.1-8.2). The median duration of treatment was 4.4 months (range, 0.3-15.4).

The most common any-grade AEs in patients with TNBC who received the doublet regimen were diarrhea (88.9%), nausea (50.0%), vomiting (50.0%), and constipation (38.9%). The most common grade 3/4 AEs were diarrhea (16.7%) and fatigue (16.7%). Thirteen patients (72.2%) discontinued treatment because of disease progression.

Jhaveri, an associate attending in the Breast Medicine and Early Drug Development Service, section head of the Endocrine Therapy Research Program, and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, explained the value of ADCs in HER2-mutant tumors. “What we’re beginning to learn with these novel [ADCs], which have a higher drug-to-antibody ratio of cleavable linker and novel payloads, is that they exhibit bystander effect. [This] is not only causing apoptosis of the cancer cell, but it [is] also [causing] killing of the neighboring cancer cells.”

The DESTINY-Breast04 (NCT03734029) trial is a phase 3 multicenter, randomized, open-label, active-controlled trial study of trastuzumab deruxtecan (T-DXd; Enhertu) vs treatment of physician’s choice in patients with unresectable or metastatic disease and low HER2 expression (IHC1+ or IHC2+/ISH–).

 Investigators randomly assigned patients to receive T-DXd 5.4 mg/kg once every 3 weeks (n = 373) or physician’s choice of either capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane; n = 184). The primary end point was PFS in the HR-positive population, and the secondary end points were PFS in all patients, overall survival (OS), ORR, and DOR.

The median PFS for the primary end point was 10.1 months with T-DXd vs 5.4 months with physician’s choice (HR, 0.51; 95% CI, 0.40-0.65; 

 < .001). The median PFS across the whole patient population was 9.9 months with T-DXd vs 5.1 months with physician’s choice (HR, 0.50; 95% CI, 0.40-0.63; 

 < .001). The median OS for patients with HR-positive tumors was 23.9 months with T-DXd vs 17.5 months with physician’s choice of therapy (HR, 0.64; 95% CI, 0.48-0.86; 

 = .003). The median OS among all patients was 23.4 months with T-DXd vs 16.8 months with physician’s choice (HR, 0.64; 95% CI, 0.49- 0.84; 

 = .001). Patients with HR-negative and HER2-low tumors had a median PFS of 8.5 months with T-DXd vs 2.9 months (HR, 0.46; 95% CI, 0.24-0.89), and the median OS for this patient group was 18.2 months with T-DXd vs 8.3 months with physician’s choice (HR, 0.48; 95% CI, 0.24-0.95).

Any grade AEs in patients treated with T-DXd were most commonly nausea (73%), fatigue (48%), and alopecia (38%). The most common grade 3 AEs were neutropenia (14%), anemia (8%), and fatigue (8%). Jhaveri called special attention to drug-related interstitial lung disease (ILD)/pneumonitis and anygrade ILD/pneumonitis. This event occurred in 45 patients (12.1%), with 13 patients having grade 1, 24 as grade 2, 5 as grade 3, none as grade 4, and 3 as grade 5 events.

Activity with T-DXd was also reported in patients with HER2-low and HER2- negative MBC in the phase 2 DAISY trial (NCT04132960).

 Patients were stratified by HER2 status into 3 cohorts: HER2 overexpressing (cohort 1), HER2 low (cohort 2), and HER2 nonexpressing (cohort 3). The best ORR was 71% in cohort 1, 38% in cohort 2, and 30% in cohort 3. The median DOR was 9.7 months in cohort 1, 7.6 months in cohort 2, and 6.8 months in cohort 3. The median PFS was 11.1 months in cohort 1, 6.7 months in cohort 2, and 4.2 months in cohort 3. However, there was no HER2 immunohistochemistry scoring system optimized to distinguish a score of HER2 0 from HER2 1+. These results f rom the DAISY trial a re promising but require validation. 

1. Jhaveri K. What’s new for HER2-mutant and HER2-low metastatic breast cancers. Presented at: 21st Annual International Congress on the Future of Breast Cancer® East; July 15-16, 2022; New York, NY.

2. Oaknin A, Friedman CF, Roman LD, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: fi ndings from the phase 2 SUMMIT basket trial. 

. 2020;159(1):150-156. doi:10.1016/j.ygyno.2020.07.025

3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. 

. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

4. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS3-01.

Articles

Results from the SUMMIT basket study revealed encouraging results with a neratinib triplet regimen in patients with HR-positive/ HER2-negative metastatic breast cancer compared with other variations and monotherapies of the 3 drugs.

Clinical Activity Is Found With Triplet Combination and ADCs in HER2-Mutant MBC

Toripalimab (Tuoyi), a PD-1 inhibitor, with chemotherapy showed promising efficacy data as neoadjuvant treatment for patients with upper tract urothelial carcinoma (UTUC). These preliminary data were presented at the 37th Annual European Association of Urology Congress in Amsterdam, Netherlands, by Xingang Bi, MD, PhD of the Department of Urology at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences in Beijing, China.

Among 11 patients who enrolled, 8 completed treatment and were preliminarily analyzed. Three of the 8 patients (37.5%) had a pathological complete response (pCR). The downstaging rate was 75% (6/8), and the disease control rate was 100%. All patients were alive and tumor free at the median follow-up of 5.8 months.

In this phase 2 multicenter study (NCT04099589), investigators planned to enroll 34 patients to receive toripalimab plus a gemcitabine/cisplatin chemotherapy regimen. Toripalimab was administered in 240 mg doses on day 1, and gemcitabine and cisplatin were administered in 1000 mg/m

on day 1, respectively. Each treatment cycle lasted 21 days. Neoadjuvant therapy was followed by radical nephroureterectomy and pelvic lymphadenectomy.

The primary end point of the study is pCR, and the secondary end points include downstaging rate, objective response rate, 3-year disease-free survival, 3-year overall survival, and safety. Patients were eligible to enroll in the study if their ureteroscopic biopsy confirmed a diagnosis of UTUC, their tumor tissue was PD-L1 positive, they had no previous chemotherapy or immunotherapy, they had no tumors in the bladder, they were between the ages of 18 and 75, and they had an ECOG performance score of 0 or 1.

The median age of the 8 patients was 64.5 years, and 62.5% (5/8) were men. Five of the 8 patients had ureteral cancer, 3 had renal pelvic cancer, and all 8 patients were considered high risk. All but 1 patient received 4 cycles of neoadjuvant therapy, and the remaining patient received 3 cycles. All patient tumors were unifocal. The median maximum tumor diameter was 2.5 cm (range, 1.5-5.1). Every patient had obstructed hydronephrosis. Multiparameter MRI confirmed clinical T staging, which found 7 patients were T3 and 1 patient was T2.

Seven patients had high-grade and 1 patient had low-grade urothelial carcinoma, according to the ureterorenoscopic biopsy. The median time from the end of neoadjuvant therapy to the start of radical nephroureterectomy was 7.3 weeks (range, 3.0-10.1).

Three patients (37.5%) had grade 3 chemotherapy-related adverse events (AEs) in the form of myelosuppression. No patients presented with grade 4 or grade 5 chemotherapy-related AEs. However, 2 patients had immune-related AEs in the form of grade 2 hypothyroidism and grade 2 adrenal insufficiency. No patients reported surgery-related complications, and the readmission rate was 0%.

The combination of toripalimab and chemotherapy displayed promising efficacy results. Safety was manageable, but immune-related AEs may occur and may result in prolonged treatment period.

1. Bi X, Shou J, Zhou A, et al. Neoadjuvant combined chemotherapy and immunotherapy for upper tract urothelial carcinoma: preliminary results of a phase II study. Presented at: 37th Annual European Association of Urology Congress; July 1-4, 2022; Amsterdam, Netherlands. Abstract A0301.

The combination of toripalimab and chemotherapy displayed promising efficacy results in a phase 2 study.

Toripalimab and Chemotherapy Combination Reveals Promising Efficacy for UTUC

The first patient was dosed with PT199, the anti-CD73 monoclonal antibody (mAb), for the treatment of multiple advanced tumors. This dose was administered in a phase 1 study (NCT05431270), announced by Phanes Therapeutics, Inc.

"The CD73 pathway represents a very promising target for addressing the immunosuppressive TME and we are pleased to open this study and bring this potential best-in-class mAb to cancer patients who have few treatment options." said Ming Wang, PhD, MBA, Founder and chief executive officer of Phanes Therapeutics.

 A Phase I, First-in-Human, Open-Label, Dose Escalation and Expansion Study of PT199 Administered Alone and in Combination With a PD-1 Inhibitor in Adult Patients With Advanced Solid Tumors

Ramzi M Melhem, MD 9168336928 ramzi.melhem01@phanestx.com

This phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT199 as a monotherapy and in combination with a PD-1 inhibitor for the treatment of patients with locally advanced or metastatic solid tumors who have progressed after standard therapy. Participants 18 years or older with measurable disease with at least 1 lesion amenable to response assessment per RECIST 1.1 criteria, adequate organ function, and ECOG performances stats of 0 or 1 are eligible for enrollment.

The phase 1 trial has a monotherapy dose escalation part (A), a combination therapy dose escalation part (B), and a combination therapy dose expansion part (A). In part A, the starting PT199 dose is 10 mg/kg weekly and will increase to 20 mg/kg once weekly, 30 mg/kg once weekly, and 30 mg/kg every 3 weeks. Part B will evaluate PT199 at 20 mg/kg weekly and include the PD-1 inhibitor at 200 mg once every 3 weeks. Part C will search for the maximum tolerated dose of the combination therapy.The primary end point of the study is the maximum tolerated dose, and the secondary end points include preliminary efficacy and pharmacodynamics.

In an abstract presented at the 2022 American Association of Cancer Research Annual Meeting, investigators reported that anti-CD73 therapeutic antibodies have largely subdued clinical activity and unfavorable characteristics, including incomplete enzyme inhibition, know as the “hook effect”, but their research supported on PT199 bound to a unique site on CD73 which bypassed and corrected the clinical flaws with the first generation of anti-CD73 mAbs. PT199 inhibits soluble shed CD73 and membrane-bound CD73 to completion without the “hook effect”. Research showed that PT199 exhibited no clinical observations up to the dose of 300 mg/kg weekly repeated dosing, and it had a very favorable PK profile. These results from a preclinical study support the phase 1 clinical trial.

1. Phanes therapeutics announces first patient dosed in phase 1 study of PT199 for advanced solid tumors. Press release. PR Newsire; August 23, 2022. Accessed August 24, 2022. https://prn.to/3ckUB5R

2. Dose escalation/expansion study of PT199 (an anti-CD73 mAb) administered alone and in combination with a PD-1 inhibitor. ClinicalTrials.gov. Updated August 12, 2022. Accessed August 24, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05431270?term=NCT05431270&draw=1&rank=1&view=record

3. Jia H, Li J, Pei F, et al. PT199, a next generation anti-CD73 mAb that inhibits both membrane-bound and soluble CD73 activity to completion without “hook effect” [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4259. Accessed August 24, 2022. https://aacrjournals.org/cancerres/article/82/12_Supplement/4259/702856

Phase 1 Study of PT199 Begins for the Treatment of Solid Tumors 

The first patient was dosed in a phase 1 dose escalation study (NCT05360680) which is evaluating CUE-102, of the interleukin 2 (IL-2) series, as monotherapy for the treatment of patients with Wilms’ Tumor 1 (WT1)-positive recurrent/metastatic cancers. The study will focus on colorectal, gastric, pancreatic, and ovarian cancers, according to a press release from Cue Biopharma.

 “CUE-102 has the potential to activate the patient’s immune system against numerous WT1-expressing cancers, including solid tumors and hematologic malignancies, and has demonstrated selective and significant activation of WT1-specific T cells in preclinical studies. We believe that CUE-102 can play an important role in changing the treatment landscape for patients with WT1-positive cancers, by potentially delivering higher efficacy and lower toxicities than current available treatments, said Ken Pienta, MD, acting chief medical officer of Cue Biopharma, in a press release.

 A Phase 1, Open-Label, Dose Escalation and Expansion Study of CUE-102 Monotherapy in HLA-A*0201 Positive Patients With WT1 Positive Recurrent/Metastatic Cancers

 steven Margossian, MD, PhD 857-228-0636 smargossian@cuebio.com and Reena Lynam 617-949-2637 rlynam@cuebio.com

In a preclinical study of CUE-102 tested humans with peripheral blood mononuclear cells (PBMC) for cellular activity and specificity, while in vivo CUE-102 is testing in mice who are human leukocyte antigen HLA-A2 transgenic. Investigators found that CUE-102 both activates and expands WT1-specific CD8-positive T cells from PBMC of healthy donors. Similar to results seen with CUE-101, CUE-102 showed significant functional reduction of the IL-2 components.The in vivo study found CUE-102 expands polyfunctional WT1-specific CD8-positive T cells from mice who were naïve and previously immunized, but the treatment did not alter the frequencies of other immune lineages.The in vivo study also found the WT1-specific CD8-positive T cells had a polyfunctional response to peptide-loaded target cells and selectively killed WT1-presenting target cells.These results, along with a tolerable safety profile, support the initiation of the phase 1 trial of CUE-102.

This phase 1 study aims to find the dose-limiting toxicity and maximum-tolerated dose of CUE-102. The secondary end points include safety and tolerability, antitumor response rate, antitumor duration of response, antitumor clinical benefit rate, progression-free survival, and overall survival. The dose escalation portion of the trial will administer CUE-102 in intravenous doses of 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, and an experimental recommended phase 2 dose every 3 weeks for up to 2 years.

Eligible patients in this phase 1 study will include patients who have colorectal, gastric, pancreatic, or ovarian cancer who have an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, have a human leukocyte antigen (HLA)-A*0201 genotype as determined by genomic testing, and tumors who are WT1-positive. Patients will be deemed ineligible if patients with central nervous system metastases have been treated and be asymptomatic, have a history of prior allogeneic bone marrow, stem cell, or solid organ transplant, treatment with radiation therapy within 14 days before the first dose of CUE-102, and a history of clinically significant cardiovascular disease.

“Initiating this phase 1 clinical study of CUE-102 at a starting dose of 1mg/kg, a clinically active dose in our Phase 1 CUE-101 clinical trial for HPV+ head and neck cancer, is an important step forward in demonstrating the modularity of our Immuno-STAT™ platform and the broader clinical potential of our CUE-100 series of biologics,” said Dan Passeri, chief executive officer of Cue Biopharma, in the press release. “We believe, given the preservation of the core molecular framework between CUE-102 and CUE-101 with the primary exception of the tumor-specific epitope, initiating the dose escalation trial at 1 mg/kg will result in reduced time and cost to evaluate tolerability at therapeutically active doses.”

1. Cue biopharma doses first patient in phase 1 study of CUE-102 for Wilms’ Tumor 1 (WT1) - expressing cancers. Press release. Cue Biopharma; August 22, 2022. Accessed August 23, 2022. https://www.cuebiopharma.com/investors-media/news/

2. Zhang C, Girgis N, Merazga Z, et al. 720 CUE-102 selectively activates and expands WT1-specific T cells for the treatment of patients with WT1+ malignancies. 

r. 2021;9:doi: 10.1136/jitc-2021-SITC2021.720

3. A phase 1 in patients with HLA-A*0201+ and WT1+ recurrent/metastatic cancers. ClinicalTrials.gov. Updated July 7, 2022. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05360680?term=NCT05360680&draw=2&rank=1&view=recor

Certain patients with Wilm's tumor-expressing solid tumors are eligible to be treated with an investigational agent in a phase 1 clinical trial. 

Phase 1 Trial of CUE-102 in WT1+ Solid Tumors is Now in Motion

Avapritinib (Ayvakit) displayed positive, top-line results in part 2 of the PIONEER trial (NCT03731260) in patients with non-advanced systemic mastocytosis (SM), according to a press release.

Investigators found clinically meaningful benefit across both primary and secondary end points. In response to these promising data, Blueprint Medicines plans to submit a supplemental new drug application to the FDA for avapritinib for non-advanced SM in the fourth quarter of the year and also present detailed data from the PIONEER study at an upcoming meeting.

Avapritinib achieved its primary end point with a significant difference of mean change in total symptom score (TSS) at 24 weeks compared to placebo (

 = .003). Patients in the avapritinib arm had a reduction of 15.6 points in mean TSS at 24 weeks and continued to decrease to 20.2 points at 48weeks in patients who rolled over to the part 3 open-label extension study. The control arm at 24 weeks had a reduction of 9.2 points in mean TSS.

The PIONEER trial compared once a day avapritinib at 25 mg plus best available care (n = 141) vs placebo plus best available care (n = 71). The primary end point was mean change in TSS, and the secondary end points were reduction in mean TSS, mean change in most severe symptom score, and reduction in serum tryptase. TSS was evaluated using the Indolent SM Symptom Assessment Form.

"As a physician and clinical researcher who has been treating non-advanced SM patients for over 25 years, I have been awaiting a therapy that decreases the abnormal mast cell burden and activation, improves a wide range of symptoms and ultimately provides an improved quality of life to patients," said Mariana Castells, MD, PhD, director, Mastocytosis Center, Brigham and Women's Hospital, and an investigator on the PIONEER trial, in a press release. "For patients with non-advanced SM, PIONEER is the first study to show significant clinical improvements over best available care across patient-reported symptoms and objective measures of disease, with a safety and tolerability profile supporting chronic treatment. The trial results suggest that if approved, Ayvakit would represent a practice-changing treatment, enabling important clinical benefits for a broad range of patients with non-advanced SM."

Patients treated with avapritinib had a significantly higher rate of at least 50% reduction of serum tryptase compared to no patients in the control arm: 53.9% vs 0%, respectively (

Overall, avapritinib was well tolerated and had a favorable safety profile. Ninety-six percent of patients treated with avapritinib completed 24 weeks of therapy vs 93% of patients in the control arm. AEs occurred in 90.8% of the avapritinib group and in 93% of the control group. Serious AEs occurred in 5% of patients in the avapritinib arm vs 11.3% of patients in the control arm. Treatment-related AEs (TRAEs) occurred in the form of headache (7.8% with avapritinib vs 9.9% with placebo), nausea (6.4% vs 8.5%, respectively) peripheral edema (6.4% vs 1.4%, respectively) and periorbital edema (6.4% vs 2.8%, respectively). Few patients discontinued treatment because of TRAEs, with 0.7% of patients discontinuing with avapritinib treatment vs 0% of patients in the control arm discontinuing.

"The PIONEER results showcase Blueprint Medicines' dedication to advancing the promise of precision therapy for patients with significant medical needs," said Becker Hewes, MD, chief medical officer at Blueprint Medicines. "AYVAKIT has the potential to be the first approved medicine for non-advanced SM, and the only treatment that would address the genetic root cause across advanced and non-advanced forms of the disease. Today's milestone represents a watershed moment for the systemic mastocytosis community and Blueprint Medicines, capping a decade of collaboration with clinicians, advocates, and patients to transform standards of care, and to deepen the understanding of this disease and its impact on various aspects of patients' lives."

"Non-advanced systemic mastocytosis is a lifelong disease with severe physical, emotional, and social impacts that profoundly reduce patients' quality of life," said Lauren Denton, executive director of The Mast Cell Disease Society, in the press release. "Patients with SM continue to be challenged by efforts to avoid various triggers of everyday life while also managing complex therapies. The PIONEER clinical trial results offer hope to these patients and help pave the way for new innovation in treatment."

"These new data are the culmination of a dedicated long-term collaboration and shared 'patients first' core value between Blueprint Medicines and The Mast Cell Disease Society. We are excited by these results and further energized to work together with these exceptional investigators to transform the lives of patients, offering them a better quality of life and the gift of time," said Valerie Slee, board chair of The Mast Cell Disease Society, in a statement.

Blueprint medicines announces positive top-line results from PIONEER trial of ayvakit® (avapritinib) in patients with non-advanced systemic mastocytosis achieving primary and all key secondary endpoints. News release. Blueprint Medicines; August 17, 2022. Accessed August 18, 2022. https://bit.ly/3dFtind

In the PIONEER study, clinically meaningful benefit was shown with avapritinib in patients with non-advanced systemic mastocytosis across both primary and secondary end points.

PIONEER Study of Avapritinib in Non-Advanced Systemic Mastocytosis Achieves Key End Points

The amcenestrant (SAR 439859) global clinical development program will be discontinued, according to a press release by Sanofi, the parent company. Amcenestrant is an investigational oral selective estrogen receptor degrader (SERD).

The decision to discontinue the program come from the results of the prespecified interim analysis of the AMEERA-5 trial (NCT04478266). This phase 3 trial evaluated amcenestrant in combination with palbociclib (Ibrance) vs letrozole (Femara) combined with palbociclib in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.

The AMEERA-5 study is a randomized, double-blind study that assessed the safety and efficacy of amcenestrant and palbociclib in the first line. A total of 1068 patients were randomized 1:1 to receive oral amcenestrant and palbociclib or oral letrozole and palbociclib. This study’s primary end point was progression-free survival, and secondary end points include overall survival (OS), objective response rate, duration of response, and clinical benefit rate.

An independent data monitoring committee recommended stopping the trial after learning that the amcenestrant and palbociclib combination did not meet the prespecified boundary for continuation compared with the control arm. Investigators observed no new safety signals, and the trial patients will be transitioned to letrozole plus palbociclib treatment or to another standard of care therapy, according to their physician.

Sanofi continues to review the data and will share the results in the future. Other studies of amcenestrant, including AMEERA-6 (NCT05128773) which is evaluating it in early-stage breast cancer, will be discontinued.

The AMEERA-6 trial is a randomized, double-blind study that evaluated amcenestrant vs tamoxifen (Soltamox) in patients with hormone receptor-positive early breast cancer who discontinued adjuvant aromatase inhibitor therapy because of toxicity. Investigators randomized patients to receive oral amcenestrant or oral tamoxifen. The primary end point of the study was invasive breast cancer-free survival, and the secondary end points were invasive disease-free survival, OS, distant recurrence-free survival, locoregional recurrence-free survival, and safety.

“While we are disappointed by this outcome, our research will further the scientific understanding of endocrine therapies in people with breast cancer. Our sincere gratitude goes to the patients, families, and healthcare professionals involved in the amcenestrant clinical development program. Oncology remains a priority area for Sanofi, and we will continue to pursue transformative research to develop new medicines for people living with cancer,” said John Reed, MD, PhD, global head of Research and Development at Sanofi, said.

Sanofi also announced earlier in the year that the phase 2 AMEERA-3 trial (NCT04059484) had not met the primary end point of progression-free survival vs physician’s choice in patients with ER+/HER2- advanced or metastatic breast cancer.

1. Sanofi provides update on amcenestrant clinical development program. Press release. Sanofi; August 17, 2022. Accessed August 17, 2022. https://bit.ly/3ArwdbP

2. Amcenestrant (SAR439859) plus palbociclib as first line therapy for patients with ER (+) HER2(-) advanced breast cancer (AMEERA-5). ClinicalTrials.gov. Updated May 10, 2022. Accessed August 17, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04478266?term=AMEERA-5&draw=2&rank=1

3. Study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer, who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6). ClinicalTrials.gov. Updated August 3, 2022. Accessed August 17, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05128773?term=AMEERA-6&draw=2&rank=1

Sanofi has discontinued the clinical development program for amcenestrant due to unsatisfactory results from the phase 3AMEERA-5 trial.