Data for datopotamab deruxtecan (DS-1062) and ENHERTU® signal strong potential of these antibody drug conjugates in advanced lung cancer
New non-small cell lung cancer data for TAGRISSO® and IMFINZI® further demonstrate the impact of treating patients in early stages of the disease
WILMINGTON, Del.–(BUSINESS WIRE)–AstraZeneca will present new data from across the innovative lung cancer portfolio at the IASLC 2020 World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer, 28 to 31 January 2021.
Eleven AstraZeneca medicines and potential new medicines from the pipeline feature in 39 abstracts showcasing the Company’s leadership across different types and stages of lung cancer, including eight oral presentations with two late breakers.
Presentations include:
- Updated data from the TROPION-PanTumor01 Phase I trial of datopotamab deruxtecan (Dato-DXd; DS-1062) with additional patients, supporting its potential to redefine treatment outcomes in advanced non-small cell lung cancer (NSCLC) Datopotamab deruxtecan is a novel trophoblast cell-surface antigen 2 (TROP2)-directedantibody drug conjugate (ADC)
- New data from the DESTINY-Lung01 Phase II trial highlighting the potential of ENHERTU® (trastuzumab deruxtecan) in HER2-expressing metastatic NSCLC, and data in metastatic HER2-mutant (HER2m) NSCLC, two groups of patients for whom no HER2-directed medicine is currently approved
- New analyses from the ADAURA Phase III trial featured in two oral presentations reinforcing the unprecedented benefit of TAGRISSO® (osimertinib) regardless of prior adjuvant chemotherapy or disease stage in the adjuvant treatment of epidermal growth factor receptor-mutated (EGFRm) NSCLC, and showing patients treated with TAGRISSO maintained their quality of life
José Baselga, Executive Vice President, Oncology R&D, said: “AstraZeneca is leading the next wave of precision-medicine innovations in lung cancer that aim to change clinical practice and ultimately alter the course of the disease. Our data at WCLC for datopotamab deruxtecan and ENHERTU (trastuzumab deruxtecan) illustrate the potentially transformative role next-generation antibody drug conjugates may play in advanced non-small cell lung cancer. New results for TAGRISSO and IMFINZI® (durvalumab) continue to validate our strategy to treat patients earlier, as we progress the science of identifying patients most likely to respond to treatment.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “AstraZeneca is committed to advancing early detection and treatment of lung cancer – and the urgency to achieve this goal has only increased during the pandemic, which has significantly impacted cancer care for patients around the world. Our TAGRISSO and IMFINZI data at WCLC show how we are driving progress in early-stage lung cancer, while also pushing the scientific boundaries in resistant and advanced disease to identify new solutions for patients.”
Harnessing the emerging potential of ADCs to treat different types of lung cancer
Updated data from the TROPION-PanTumor01 Phase I trial of the novel ADC datopotamab deruxtecan will be featured in an oral presentation, demonstrating early antitumor activity in patients with advanced/metastatic NSCLC who had progressed on standard treatment. (Read more…) Additionally, two presentations on the data from the DESTINY-Lung01 Phase II trial will show results of ENHERTU patients with NSCLC, including new data from the HER2-expressing cohort and data from the HER2 mutant cohort.
Collaboration in the scientific community is critical to improving outcomes for patients. AstraZeneca is collaborating with Daiichi Sankyo Company, Limited (Daiichi Sankyo) to develop and commercialize ENHERTU and datopotamab deruxtecan globally.
Treating patients with NSCLC in early stages
A late-breaking analysis from the ADAURA Phase III trial will underscore the practice-changing results for adjuvant TAGRISSO in Stage IB-IIIA EGFRm NSCLC and show the disease-free survival results for patients who had been treated with adjuvant chemotherapy prior to TAGRISSO and those who were not by stage of disease. A second exploratory analysis from the Phase III ADAURA trial will highlight the impact of treatment with adjuvant TAGRISSO on quality of life based on patient-reported outcomes. TAGRISSO was recently approved in the adjuvant setting in the US.
The ongoing NeoADAURA Phase III trial testing the benefit of treating patients with resectable EGFRm NSCLC with neoadjuvant TAGRISSO will be highlighted in a poster presentation.
The MERMAID-1 Phase III trial testing IMFINZI in patients with completely resected, Stage II and III NSCLC who show evidence of minimal residual disease (MRD), will also be highlighted in a poster. MERMAID-1 is an early-stage NSCLC Phase III trial evaluating circulating tumor DNA measurements to monitor for MRD and to identify patients at high risk of recurrence after surgery who may benefit from intervention with immunotherapy.
Progressing research in advanced lung cancer
AstraZeneca will also present data from several trials exploring targeted therapies and novel combinations for advanced lung cancer, including:
- Additional data from the CASPIAN Phase III trial of IMFINZI in extensive-stage small cell lung cancer (ES-SCLC) showing exposure response and pharmacokinetics as well as exploratory analyses based on extent of disease
- The biomarker-directed HUDSON Phase II platform trial of IMFINZI in combination with LYNPARZA© (olaparib) and other novel anti-cancer medicines, including danvatirsen (STAT3 antisense oligonucleotide), ceralasertib (ATR inhibitor) and oleclumab (anti-CD73), in patients with NSCLC who progressed on anti-PD(L)1 therapy
- The ODIN BM Phase I trial assessing TAGRISSO brain exposure in patients with EGFRm NSCLC central nervous system (CNS) metastases
- The TATTON Phase Ib trial of TAGRISSO plus savolitinib in patients with EGFRm MET-overexpressed/amplified NSCLC
- A trial-in-progress update on the Phase I trial of TAGRISSO in combination with patritumab deruxtecan (HER3-DXd; U3-1402) in patients with locally advanced or metastatic EGFRm NSCLC
Key AstraZeneca presentations during WCLC 20201
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Lead author |
Abstract title |
Presentation details |
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Immuno-Oncology |
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Reinmuth, N |
First-line durvalumab plus platinum-etoposide in ES-SCLC: exploratory analyses based on extent of disease in CASPIAN
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Abstract #P48.03 Poster: P48 – Small Cell Lung Cancer/NET – Chemo – IO 28 January 2021 |
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Zheng, Y |
Population pharmacokinetics and exposure-response with durvalumab plus platinum-etoposide in ES-SCLC: Results from CASPIAN
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Abstract #P48.21
Poster: P48 – Small Cell Lung Cancer/NET – Chemo – IO |
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Besse, B |
HUDSON: An open-label, multi-drug, biomarker-directed Phase II platform study in patients with NSCLC, who progressed on anti-PD(L)1 therapy
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Abstract #OA07.08 Oral Session: OA07 – Immuno-biology and Novel Immunotherapeutics from Bench to Bed
30 January 2021 |
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Besse, B |
Immuno-modulatory effects of ceralasertib in combination with durvalumab in NSCLC with progression on anti-PD(L)1 treatment (HUDSON)
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Abstract #P16.07 Poster: P16 – Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) |
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Peters, S |
MERMAID-1: A Phase III study of adjuvant durvalumab plus chemotherapy in resected NSCLC patients with MRD+ post-surgery
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Abstract #P03.03
Poster: P03 – Early Stage/Localized Disease – Clinical Trials in Progress |
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Tumor drivers and resistance |
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Wu, Y-L |
Postoperative chemotherapy use and outcomes from ADAURA: osimertinib as adjuvant therapy for resected EGFR mutated NSCLC
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Abstract #OA06.04 Oral Session: OA06 – Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy 29 January 2021 16:55-17:05 SGT |
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Majem, M |
Patient-reported outcomes from ADAURA: osimertinib as adjuvant therapy in patients with resected EGFR mutated (EGFRm) NSCLC
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Abstract #OA06.03 Oral Session: OA06 – Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy 29 January 2021 16:45-16:55 SGT |
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Tsuboi, M |
Neoadjuvant osimertinib with/without chemotherapy vs chemotherapy for EGFR mutated resectable NSCLC: neoADAURA
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Abstract #P03.02
Poster: P03 – Early Stage/Localized Disease – Clinical Trials in Progress |
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Cho, BC |
ORCHARD: A biomarker-directed Phase 2 platform study in pts with advanced EGFRm NSCLC progressing on first-line osimertinib
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Abstract #P76.27
Poster: P76 – Targeted Therapy – Clinically Focused – EGFR |
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Jänne, PA |
Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with locally advanced or metastatic EGFR-mutated NSCLC2 |
Abstract #P01.03
Poster: P01 – Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics |
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Han, J-Y |
Osimertinib+savolitinib in pts with EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON parts B and D final analysis
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Abstract #FP14.03 Featured Poster Session: FP14 – Targeted Therapy – Clinically Focused 28 January 2021 |
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Ekman, S |
A PET and MRI study exploring osimertinib brain exposure and efficacy in EGFRm NSCLC CNS metastases
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Abstract #P76.72 Poster: P76 – Targeted Therapy – Clinically Focused – EGFR 28 January 2021 |
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Antibody drug conjugates |
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Spira, A |
Datopotamab deruxtecan (dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: updated results of TROPION-PanTumor01 Phase 1 study3 |
Abstract #OA03.03 Oral Session: OA03 – Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC 29 January 2021 10:30-10:40 SGT |
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Nakagawa, K |
Trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: interim results of DESTINY-Lung013 |
Abstract #OA04.05 Oral Session: OA04 – New Data from Rare EGFR Alterations 29 January 2021 12:05-12:15 SGT |
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Smit, EF |
Trastuzumab deruxtecan in HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung013 |
Abstract #MA11.03 Mini Oral Session: MA11 – Expanding Targetable Genetic Alterations in NSCLC 31 January 2021 14:15-14:20 SGT |
1 39 abstracts at WCLC 2020 will feature AstraZeneca medicines and pipeline molecules, of which 24 are company-sponsored or supported.
2 Trial collaboration with Daiichi Sankyo which maintains exclusive rights to patritumab deruxtecan.
3 ENHERTU and datapotamab deruxtecan are developed and commercialized in collaboration with Daiichi Sankyo worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights.
U.S. FDA-APPROVED INDICATION for ENHERTU® (trastuzumab deruxtecan)
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU IMPORTANT SAFETY INFORMATION
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WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
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Contraindications
None.
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).
Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).
Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.
Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.
Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.
Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.
Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.
Adverse Reactions
The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).
Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.
The most common adverse reactions (frequency ≥20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).
Use in Specific Populations
- Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
- Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
- Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
- Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
- Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%).
- Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.
Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.
SELECT SAFETY INFORMATION FOR TAGRISSO® (osimertinib)
- There are no contraindications for TAGRISSO
- TAGRISSO is associated with several serious and sometimes fatal adverse reactions, including interstitial lung disease (ILD)/pneumonitis, QTc interval prolongation, cardiomyopathy, keratitis, erythema multiforme and Stevens-Johnson syndrome, cutaneous vasculitis, and embryo-fetal toxicity
- The most common (≥20%) adverse reactions, including lab abnormalities, were leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough
For additional information, please refer to the complete Important Safety Information.
INDICATIONS
- TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
- TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
- TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy
For additional information, please see the complete Prescribing Information, including Patient Information.
SELECT SAFETY INFORMATION FOR IMFINZI® (durvalumab)
Stage III:
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. IMFINZI can cause severe or life-threatening infusion-related reactions. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody.
Advise women not to become pregnant or breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.
In the PACIFIC trial, the most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%).
The most common adverse reactions were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash.
The safety and effectiveness of IMFINZI have not been established in pediatric patients.
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