On June 2, 2024 Leading international medical research company, MEDSIR, reported the results of the recent PRIMED clinical trial during the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, MedSIR, JUN 2, 2024, View Source [SID1234643945]). Carried out under the company’s collaborative model, this Investigator-Initiated Trial (IIT) demonstrated the effectiveness of preventative administration of drugs to treat the common side effects of neutropenia and diarrhea that can occur while taking sacituzumab govitecan, an antibody-drug conjugate targeting Trop-2 that has extended overall survival for patients with pretreated triple negative and HR-positive/HER2-negative advanced breast cancer in two previous Phase 3 studies, ASCENT and TROPiCS-02. In the PRIMED study, adding primary prophylactic granulocyte colony-stimulating growth factors (G-CSF) and loperamide during the first two sacituzumab govitecan treatment cycles led to clinically meaningful reductions in neutropenia and diarrhea, lowering the need for dose reductions, treatment interruptions, and permanent discontinuations.

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"This is an exciting finding that highlights the high potential of prophylactic strategies that can mitigate side effects to help keep patients on promising treatments, which was made possible by our collaborative research model," shared Dr. Antonio Llombart-Cussac, Senior Scientific Leader of MEDSIR. "By using a partnership model that combines the benefits of company-sponsored research with all the advantages of IITs, we are turning brilliant ideas into full clinical trials that will safely and efficiently advance cancer solutions. It is our hope that, by working together, we will continue to generate new opportunities for patients worldwide."

Among PRIMED study participants, the incidence of any grade of neutropenia (in the first two cycles) was 28%, compared to 63% and 70% in ASCENT and TROPiCS-02 (in the full study), respectively. The incidence of any grade diarrhea (in the first two cycles) was 34%, compared to 59% and 57% in ASCENT and TROPiCS-02 (in the full study), respectively. The other side effects PRIMED study participants experienced were consistent to the known safety profile of sacituzumab govitecan, with the exception of constipation, which occurred in 46% of patients during the first two cycles compared to 17% in ASCENT and 19% in TROPiC-02 (in the full study). However, most cases of constipation were mild, and no patients experienced adverse events that led to permanent treatment discontinuation.

The study, which is still ongoing to evaluate efficacy and collect longer-term safety data, enrolled 50 patients between February 2023 and September 2023 across 10 sites across Spain, providing them with G-CSF and loperamide during the first two sacituzumab govitecan treatment cycles (physician’s decision to continue after two cycles). These two drugs are commonly used to treat neutropenia and diarrhea, respectively, but are usually administered only after these side effects occur. In PRIMED, researchers wanted to test whether early administration of these drugs, before patients experienced any neutropenia or diarrhea, could reduce the incidence of these side effects and determine how this affected the need for dose reductions, treatment interruptions, and permanent discontinuations.

Showcasing Numerous Promising Collaborative Trials at ASCO (Free ASCO Whitepaper)

PRIMED was not the only trial MEDSIR presented during the ASCO (Free ASCO Whitepaper) Annual Meeting. It shared the results of several other recent and ongoing studies as well.

Recently published in The Lancet, MEDSIR’s PHERGain phase II trial (NCT03161353) demonstrated how a third of patients with HER2-positive early breast cancer could be safely treated without using chemotherapy. At the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, MEDSIR presented a subanalysis of this study comparing PET scan and magnetic resonance imaging (MRI) results; both tests that participants undergo to observe the evolution of their cancer. The comparative study shows tumor assessments can be analyzed with both PET scan and MRI. Although PET scan is the recommended imaging technique for early treatment response, this exploratory study suggests that MRI could alternatively guide the treatment when PET scan are not available.

MEDSIR’s PATHFINDER study evaluated the safety, tolerability, and preliminary efficacy of ipatasertib in combination with non-taxane chemotherapy in patients with advanced triple negative breast cancer who had previously experienced tumor progression after treatment with taxane chemotherapy. Study results revealed that combining ipatasertib with capecitabine and eribulin has an acceptable safety profile in these patients, but that adding ipatasertib alongside carboplatin plus gemcitabine proved to be intolerable. Additionally, the combination of ipatasertib and eribulin demonstrated encouraging efficacy, warranting further investigation.

TUXEDO-3, one of MEDSIR’s ongoing clinical trials in Austria and Spain, is the first study evaluating the efficacy and safety of patritumab deruxtecan as an anti-cancer therapy for patients with pretreated metastatic breast cancer and advanced non-small cell lung cancer with brain metastases, and metastatic solid tumors with leptomeningeal disease. If positive, this study could streamline the introduction of HER3-DXd as a new treatment for these patients who currently have very limited therapeutic options.

ABOUT UMMET CANCER NEEDS

Unmet cancer needs refer to gaps in resources, support, and treatment options that exist for cancer patients. Addressing unmet cancer needs is crucial to improving quality of life and outcomes for cancer patients. Through the collaborative work of healthcare providers, policymakers, and patient advocacy groups unmet cancer needs can be identified to help provide patients with comprehensive and quality care.

On June 2, 2024 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the presentation of biomarker findings from a Phase II randomized clinical trial of alisertib alone vs. alisertib + fulvestrant for the treatment of patients with endocrine and CDK4/6 inhibitor (CDK 4/6i) resistant, human epidermal growth factor receptor 2-negative (HER2-negative), hormone receptor-positive metastatic breast cancer (TBCRC 041; Clinicaltrials.gov identifier NCT02860000) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting currently being held in Chicago (Press release, Puma Biotechnology, JUN 2, 2024, View Source [SID1234643965]). The Phase II trial was conducted through the Translational Breast Cancer Research Consortium (TBCRC). Results were published by Tufia Haddad et al. (JAMA Oncology, March 2023) and reported promising clinical activity in both arms (overall response rate 19.6% vs. 20.0% and median progression-free survival 5.6 months vs. 5.4 months for alisertib vs. alisertib + fulvestrant, respectively) and a tolerable safety profile.

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The poster (Abstract #1037, Poster Bd #15), entitled, "Molecular profiling of serial liquid biopsy specimens utilizing cell free DNA (cfDNA) and circulating tumor cells (CTCs) in TBCRC 041: A phase II study of alisertib in endocrine resistant metastatic breast cancer (MBC)," was presented at the Breast Cancer – Metastatic Poster Session by Karthik Giridhar, MD, Mayo Clinic, on June 2 at 9:00 a.m. CDT.

Somatic mutations from cell-free DNA derived from pre-treatment plasma were identified in ESR1 (n=45; 56.38%), PIK3CA (n=39; 48.8%), PTEN (n=13; 16.3%), and AKT1 (n=9; 11.3%). Patients with PIK3CA mutation experienced decreased progression-free survival (PFS) (HR 1.8; 95%CI: 1.1 -2.9, p=0.0225) while ESR1 mutation did not impact PFS (p=0.594).

Circulating tumors cells (CTCs) and methylated tumor fraction percentage (mTF) were evaluated in pre-treatment and at the end of cycle 1 (EOC1). Lower CTCs in pre-treatment samples were associated with longer PFS (7.4 months for CTC count <5 vs. 4.5 months for CTC count ≥5, HR=1.8; 95%CI: 1.1-3.0; p=0.018). In EOC1 plasma, lower mTF was associated with longer PFS (11.5 months for mTF ≤1% vs. 3.2 months for mTF>1%, HR 3.0; 95% CI: 1.6-5.2, p<0.001). Additional biomarker analyses are underway.

"Aurora Kinase A has potential importance in the setting of endocrine- and CDK4/6i-resistance," stated Tufia Haddad, MD, Professor of Oncology and Co-Leader of Platform and Digital Innovation, Mayo Clinic Comprehensive Cancer Center. "Further understanding of which patients may derive the greatest benefit to alisertib in the evolving landscape of endocrine- and CDK4/6i-resistant metastatic breast cancer may help us to focus on biomarker-defined populations that can be studied in future clinical trials of alisertib."

Dr. Giridhar, a co-investigator of the trial, said, "We are pleased to have had the opportunity to evaluate liquid biopsy biomarkers for TBCRC 041. Ongoing biomarker analysis from this and future trials of alisertib in endocrine- and CDK4/6i-resistant breast cancer may help clarify which patients could benefit most from alisertib."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are committed to the development of alisertib in biomarker-focused populations. Results from this biomarker analysis contribute to our understanding of which patients may derive greatest benefit from treatment with alisertib and may support our forthcoming clinical studies of alisertib-based therapy in endocrine- and CDK4/6i-resistant metastatic breast cancer."

On June 2, 2024 Bio-Thera Solutions Inc. (688177:SH), a commercial-stage biopharmaceutical company developing a pipeline of innovative therapies and biosimilars, reported that it will present a poster at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting entitled "Phase 1 study of BAT8006, a folate receptor α antibody drug conjugate with strong bystander effect, in subjects with advanced solid tumors," that highlights clinical data for the potential best-in-class efficacy and safety of BAT8006 as a potential treatment for ovarian cancer patients and other patients with tumors that express Folate Receptor-alpha (Press release, BioThera Solutions, JUN 2, 2024, View Source [SID1234643946]). The poster will be available on the company website after the presentation per ASCO (Free ASCO Whitepaper) rules

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As of May 8, 2024, 156 subjects with advanced solid tumor were treated in phase 1 study. In 84 and 93mg/m2 dose optimal/expansion cohorts (including all advanced solid tumor subjects), 3.5% (2/57) and 3.9% (2/51) subjects experienced dose reduction, and 5.3% (3/57) and 13.7% (7/51) subjects experienced study drug interruption, respectively. No study treatment related death, and no ILD/pneumonitis and keratitis, uveitis, decreased vision was reported in this study. The major TRAEs were hematological toxicity. The dosages of 84 and 93 mg/m2 were selected in dose optimal study, the incidences of ≥ Grade 3 thrombocytopenia and neutropenia were 9% vs 28% and 19% vs 37%, respectively.

To the date of data cut-off, 54 subjects with platinum refractory or platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer were treated with BAT8006 doses of 1.8~2.4 mg/kg and 84/93mg/m2 and have received at least one tumor assessment. Among these patients, 38.9% (21/54) of them had undergone＞3 lines prior systemic treatment. Regardless of the FRα expression, the ORR including unconfirmed partial response (PR) is 37.0% (20/54). In subjects with FRα＜50%, FRα ≥50% and FRα ≥75%, the ORR is 33.3% (7/21), 39.4% (13/33) and 46.7% (7/15), respectively. With a median follow up of 6.5 months (1.3, 18.0 months), the median duration of response (mDOR) was 6.3 months (1.8-16.5months). The median progression free survival (mPFS) was 7.47 months (4.27~NA). The overall survival (OS) rate in 6 months and 1 year were 83.0%, 83.0%.

The safety of BAT8006 is favorable with manageable toxicity. No ILD and notable ocular toxicity was reported. The preliminary efficacy of BAT8006 was superior even in all platinum-resistant ovarian cancer patients regardless of the FRα expression. BAT8006 may benefit broad patient population while providing a promising efficacy. Exploration study on endometrial carcinoma, breast cancer and NSCLC is ongoing, the efficacy was demonstrated in these tumor type as well.

BAT8006 is being developed for use as a single agent and in combination with other agents for the treatment of multiple cancers. BAT8006 is currently being evaluated in a Phase 2 clinical study for the treatment of ovarian and other Folate Receptor-alpha overexpressed cancers. Clinical study of BAT8006 in combination with BAT1308, a PD-1 mAb, was recently approved by the NMPA.

Presentation details are as follows:

Poster Session:

Gynecologic Cancer

Session Date and Time:

Monday, June 3rd, 9:00 am – 11:00 am

Location:

Poster Area/Exhibition Hall

Abstract Number:

5550

Poster Board Number:

421

On June 2, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported the latest data from the inaugural global pivotal study WU-KONG1 Part B (WU-KONG1B) of sunvozertinib in relapsed or refractory non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Dizal Pharma, JUN 2, 2024, View Source [SID1234643947]). The study demonstrated statistically significant outcomes on the primary endpoint for sunvozertinib and highlighted its significant clinical value to patients around the globe.

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As a rationally designed, oral, potent EGFR inhibitor targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity, sunvozertinib was previously granted Breakthrough Therapy designations by both the US FDA and the China Center for Drug Evaluation (CDE) in treating NSCLC with EGFR exon20ins. Sunvozertinib has obtained conditional approval in China through a phase II pivotal study (WU-KONG6), making it the world’s first and only oral drug for the treatment of NSCLC patients with EGFR exon20ins.

WU-KONG1B, a multinational pivotal study, is the equivalent study with a similar design of WU-KONG6 to investigate sunvozertinib in relapsed or refractory NSCLC patients with EGFR exon20ins from 10 countries and regions in Asia, Europe, North America, and South America. The primary endpoint and key secondary endpoint were independent review committee (IRC) assessed objective response rate (ORR) and duration of response (DoR) respectively.

As of March 22, 2024, a total of 111 patients were enrolled to receive sunvozertinib treatment at 300mg as the optimal recommended phase 2 dose (RP2D). 107 patients who met the full analysis set (FAS) definition were included in efficacy analysis, of which Asian, White, and Black or African American enrollees were 57.9%, 40.2% and 1.9%, respectively. The key findings of the primary analysis were as follows:

Per IRC assessment, sunvozertinib achieved a best ORR of 53.3%.
The median DoR has not been reached, and the 9-month DoR rate was 57%, indicating durable efficacy of sunvozertinib.
Anti-tumor efficacy was observed regardless of amivantamab treatment. The best ORRs in patients with or without prior amivantamab treatment were 50% and 53.8%, respectively.
Sunvozertinib was well tolerated with a favorable safety profile consistent with previous reports.
"The WU-KONG1B study is significant in that it enrolled more than 40% of non-Asian patients. On a global scale, sunvozertinib demonstrated potent and durable anti-tumor efficacy with a best ORR of 53.3% and a 9-month DoR of 57% in relapsed or refractory NSCLC patients with EGFR exon20ins. The revelation of 3 patients (2.8%) achieving a confirmed complete response (CR) indicated deep tumor shrinkage with sunvozertinib treatment." said Prof. James Chih-Hsin Yang, MD, PhD at National Taiwan University Hospital and National Taiwan University Cancer Center, the leading principal investigator of WU-KONG1B. "Safety findings were similar to what has been previously reported in other sunvozertinib clinical studies. The majority of treatment-related adverse events (TEAEs) were reversible and clinically manageable. We look forward to more data readouts to validate the clinical benefit of sunvozertinib in EGFR Exon20ins NSCLC."

"It’s encouraging to see that the global pivotal study demonstrated statistically significant and clinically meaningful benefits of sunvozertinib as a single agent in NSCLC patients with EGFR exon20ins. Compared to what is available, sunvozertinib offers significant advantages as a single, oral drug: convenient, safe, and superior efficacies." said Xiaolin Zhang, PhD, CEO of Dizal.

He added, "In parallel, we are advancing the development of sunvozertinib in the first-line setting of NSCLC with EGFR exon20ins through a global phase III study (WU-KONG28). The accumulated clinical data for sunvozertinib has attracted lots of attention and facilitated our studies. We want to thank our patients and investigators for their hard work. We are committed to accelerate ongoing clinical studies and make the drug available to patients globally as soon as possible."

WU-KONG28, a phase III, multinational, randomized study, is ongoing to assess sunvozertinib versus platinum-based doublet chemotherapy in the first-line setting with patients from 14 countries and regions in Asia, Europe, North America, and South America.

About sunvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA to treat advanced NSCLC with EGFR exon20ins after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins. The primary endpoint of the study was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M, and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug-related TEAEs (treatment-emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 Part B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).

On June 2, 2024 Astrazeneca reported detailed positive results from the DESTINY-Breast06 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemotherapy in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer and the overall trial population (patients with HR-positive, HER2-low and HER2-ultralow [defined as IHC 0 with membrane staining] expression) following one or more lines of endocrine therapy (Press release, AstraZeneca, JUN 2, 2024, View Source [SID1234643932]).

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These results will be presented today as a late-breaking oral presentation during the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA1000).

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

In the primary analysis of DESTINY-Breast06, results showed Enhertu reduced the risk of disease progression or death by 38% by blinded independent central review (BICR) versus chemotherapy in patients with HER2-low expression (hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.51-0.74; p<0.0001). Median PFS was 13.2 months in the Enhertu arm compared to 8.1 months for chemotherapy.

PFS results by BICR in the overall trial population were similar and showed Enhertu achieved a 37% reduction in the risk of disease progression or death compared to chemotherapy, with a median PFS of 13.2 months with Enhertu versus 8.1 months for chemotherapy (HR 0.63; 95% CI: 0.53-0.75; p<0.0001).

A prespecified exploratory analysis showed the clinically meaningful improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, Enhertu reduced the risk of disease progression or death by 22% compared to chemotherapy with a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI: 0.50-1.21).

Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and principal investigator for the trial, said: "Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following one or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy. With a median progression-free survival of more than a year, the results from DESTINY-Breast06 show that Enhertu could become a new standard of care for patients with HER2-low- and HER2-ultralow-expressing tumours following endocrine therapy in the metastatic setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer. The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "Enhertu continues to deliver pioneering results for a HER2-directed medicine across many different types of cancer. These latest results from DESTINY-Breast06 demonstrate clinically meaningful results with Enhertu even in tumours with very low levels of HER2 expression, suggesting that it may have an important role in treating a wide range of HER2-expressing metastatic breast cancer."

In patients with HER2-low expression, confirmed objective response rate (ORR) was 56.5% for Enhertu versus 32.2% with chemotherapy. In the overall trial population, confirmed ORR was 57.3% for Enhertu versus 31.2% with chemotherapy and in patients with HER2-ultralow expression the confirmed ORR was 61.8% versus 26.3%, respectively. Complete responses were seen in 13 patients from the Enhertu arm, including nine patients with HER2-low expression. In the HER2-ultralow subgroup, four patients in the Enhertu arm had complete responses. No complete responses were seen in the chemotherapy arm.

Summary of results: DESTINY-Breast06

HER2-low
(IHC 1+ or IHC 2+/ISH-)i

Overall trial population
(HER2-low and HER2-ultralow)

HER2-ultralow (defined as IHC 0 with membrane staining)i

Enhertu

(n=359)

Chemo

(n=354)

Enhertu

(n=436)

Chemo

(n=430)

Enhertu

(n=76)

Chemo

(n=76)

PFSii

Median PFS in months

13.2

8.1

13.2

8.1

13.2

8.3

HR (95% CI)

0.62 (0.51-0.74)

0.63 (0.53-0.75)

0.78 (0.50-1.21)

p-value

p<0.0001

p<0.0001

—

OSiii

HR (95% CI)

0.83 (0.66-1.05)

0.81 (0.65-1.00)

0.75 (0.43-1.29)

p-value

p=0.1181iv

Not testedv

—

12-month OS rate (%)

87.6

81.7

87.0

81.1

84.0

78.7

ORRii,vi

Confirmed ORR (%) (n)vii

56.5

(203)

32.2

(114)

57.3

(250)

31.2

(134)

61.8

(47)

26.3

(20)

CR (%) (n)

2.5 (9)

0

3.0 (13)

0

5.3 (4)

0

PR (%) (n)

54.0 (194)

32.2 (114)

54.4 (237)

31.2 (134)

56.6 (43)

26.3 (20)

SD (%) (n)

34.8 (125)

48.0 (170)

33.9 (148)

49.3 (212)

28.9 (22)

55.3 (42)

Median DOR in months

14.1

8.6

14.3

8.6

14.3

14.1

PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DOR, duration of response

i HER2-low status determined per IRT data, and HER2-ultralow status determined per central laboratory data

ii As assessed by BICR

iii Less than 40% maturity for interim OS analysis

iv P-value of <0.0046 required for statistical significance

v No test of significance was performed in line with the multiple testing procedure

vi ORR is (CR + PR); ORR based on RECIST v1.1

vii Response required confirmation after 4 weeks

Patients in the trial received a median of two prior lines of endocrine therapy in each treatment arm. In the overall trial population, 14.9% of patients (n=65) in the Enhertu arm and 19.2% of patients (n=82) in the chemotherapy arm had received one prior line of endocrine therapy. No patients in the trial had received prior chemotherapy treatment in the metastatic setting. Median duration of follow-up was 18.2 months. As of the data cut-off of 18 March 2024, a total of 119 patients (14%) remained on treatment, 89 patients receiving Enhertu and 30 receiving chemotherapy.

The safety profile of Enhertu was consistent with previous breast cancer clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events occurring in 5% or more of patients treated with Enhertu were neutropenia (20.7%), leukopenia (6.9%) and anaemia (5.8%). Interstitial lung disease (ILD)/pneumonitis, adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with Enhertu. The majority of ILD events were low Grade (Grade 1 [n=7; 1.6%]; Grade 2 [n=36; 8.3%]). There were three Grade 3 ILD events (0.7%), no Grade 4 events and three Grade 5 events (0.7%).

Additional Enhertu data at ASCO (Free ASCO Whitepaper)

DESTINY-Breast03 updated results
Updated overall survival (OS) results from the DESTINY-Breast03 Phase III trial showed Enhertu continued to demonstrate a clinically meaningful survival improvement over trastuzumab emtansine (T-DM1) after more than three years of follow up in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab.

Results showed median OS was 52.6 months in the Enhertu arm compared to 42.7 months for T-DM1 (HR 0.73; 95% CI: 0.56-0.94).

The safety profile of Enhertu continues to be generally manageable and no cumulative toxicities were observed with longer follow-up. Results will be presented during the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (abstract #1025).

DESTINY-Breast07 results
Interim results from the DESTINY-Breast07 Phase Ib/II trial of Enhertu alone or in combination with other anticancer therapies as a 1st-line treatment for HER2-positive metastatic breast cancer demonstrated promising clinical activity for Enhertu as a monotherapy (n=75) and in combination with pertuzumab (n=50). Results were presented as an oral presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (abstract #1009).

Results showed a confirmed ORR of 76.0% with Enhertu and 84.0% with Enhertu in combination with pertuzumab. The 12-month PFS rate was 80.8% with Enhertu monotherapy and 89.4% with Enhertu and pertuzumab.

The safety of Enhertu as a monotherapy and in combination with pertuzumab was consistent with the known safety profiles of each therapy. ILD/pneumonitis was reported in seven patients (9.3%) in the Enhertu monotherapy arm and seven patients (14.0%) in the combination arm. All ILD events were Grade 3 or lower.

These are the first data presented for Enhertu as a 1st-line treatment in HER2-positive metastatic breast cancer. Analyses from the ongoing DESTINY-Breast09 Phase III trial will provide further insights regarding the efficacy and safety of Enhertu in this HER2-positive patient population.

Notes

Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.1 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or who progress to metastatic disease are expected to live five years after their diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.3 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers.4 Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.5

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.2 Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.5 It is estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.6,7

Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however, after two lines of treatment, further efficacy from endocrine therapy is often limited.8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.8-11

Prior to the approval of Enhertu in HER2-low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2-low expression. There are no targeted therapies specifically approved for patients with HER2-low expression prior to chemotherapy or for patients with HER2-ultralow expression.12

DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), OS in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) randomised at multiple sites in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast03
DESTINY-Breast03 is a global, head-to-head, randomised, open-label, pivotal Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of DESTINY-Breast03 is PFS based on BICR. OS is the key secondary efficacy outcome measure. Other secondary endpoints include ORR, DOR, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Australia and South America. Primary results from DESTINY-Breast03 were published in The New England Journal of Medicine, with updated OS results published in The Lancet. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast07
DESTINY-Breast07 is a global, randomised, open-label Phase Ib/II dose-finding and dose-expansion trial to explore the safety, tolerability and anti-tumour activity of Enhertu alone or in combination with other anticancer agents in patients with HER2-positive metastatic breast cancer.

The study consists of two phases: a dose escalation phase and a dose expansion phase. The dose escalation phase enrolled patients with locally assessed HER2-positive or advanced metastatic breast cancer in 2nd-line or later treatment. The dose expansion phase enrolled patients with previously untreated for HER2-positive advanced or metastatic breast cancer.

The primary endpoints of DESTINY-Breast07 are safety and tolerability. Secondary endpoints include ORR and PFS based on investigator assessment.

DESTINY-Breast07 enrolled 244 patients at multiple sites in Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or in-situ hybridisation [ISH]+) breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4 mg/kg) is approved in more than 35 countries for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

Enhertu (5.4 mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and who have no satisfactory alternative treatment options based on results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.