Datopotamab Deruxtecan Showed Median Overall Survival of 14.6 Months in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer in TROPION-Lung01 Phase 3 Trial
The TROPION-Lung01 phase 3 trial evaluating datopotamab deruxtecan (Dato-DXd) in advanced nonsquamous non-small cell lung cancer (NSCLC) showed promising results. In the nonsquamous NSCLC subgroup, Dato-DXd demonstrated a 2.3-month improvement in overall survival (OS) compared to docetaxel (14.6 vs 12.3 months; HR=0.84). The safety profile was consistent with previous analyses, with lower rates of dose reduction and discontinuation compared to docetaxel. Additionally, the NeoCOAST-2 trial showed promising response rates for Dato-DXd in combination with durvalumab and chemotherapy in early-stage resectable NSCLC, with a pathological complete response rate of 34.1%.
Lo studio di fase 3 TROPION-Lung01 che valuta datopotamab deruxtecan (Dato-DXd) nel contesto di cancro polmonare non a piccole cellule (NSCLC) non squamoso avanzato ha mostrato risultati promettenti. Nel sottogruppo NSCLC non squamoso, Dato-DXd ha dimostrato un miglioramento di 2,3 mesi nella sopravvivenza globale (OS) rispetto al docetaxel (14,6 contro 12,3 mesi; HR=0,84). Il profilo di sicurezza è stato coerente con le analisi precedenti, con tassi più bassi di riduzione della dose e interruzione rispetto al docetaxel. Inoltre, lo studio NeoCOAST-2 ha mostrato tassi di risposta promettenti per Dato-DXd in combinazione con durvalumab e la chemioterapia in NSCLC resecabile in stadio precoce, con un tasso di risposta patologica completa del 34,1%.
El ensayo de fase 3 TROPION-Lung01 que evalúa datopotamab deruxtecan (Dato-DXd) en cáncer de pulmón no microcítico (NSCLC) no escamoso avanzado mostró resultados prometedores. En el subgrupo de NSCLC no escamoso, Dato-DXd demostró una mejora de 2,3 meses en la supervivencia global (OS) en comparación con docetaxel (14,6 frente a 12,3 meses; HR=0,84). El perfil de seguridad fue consistente con análisis previos, con tasas más bajas de reducción de dosis y descontinuación en comparación con docetaxel. Además, el ensayo NeoCOAST-2 mostró tasas de respuesta prometedoras para Dato-DXd en combinación con durvalumab y quimioterapia en NSCLC resecable en etapa temprana, con un tasa de respuesta patológica completa del 34,1%.
TROPION-Lung01 3상 시험에서 다토포탐 뎰룩스테칸 (Dato-DXd)을 진행된 비편평 비소세포 폐암 (NSCLC)에 평가한 결과와 관련하여 유망한 결과가 나타났습니다. 비편평 NSCLC 하위 그룹에서 Dato-DXd는 도세탁셀에 비해 전체 생존율 (OS)을 2.3개월 개선한 것으로 나타났습니다 (14.6대 12.3개월; HR=0.84). 안전성 프로파일은 이전 분석과 일관되었으며, 도세탁셀에 비해 용량 감소 및 중단율이 낮았습니다. 또한, NeoCOAST-2 시험에서는 초기 절제 가능한 NSCLC에서 durvalumab 및 화학 요법과 병합한 Dato-DXd의 유망한 반응률을 보였으며, 병리학적 완전 반응률은 34.1%에 달했습니다.
L'essai de phase 3 TROPION-Lung01 évaluant datopotamab deruxtecan (Dato-DXd) dans le cancer du poumon non à petites cellules (NSCLC) non squameux avancé a montré des résultats prometteurs. Dans le sous-groupe NSCLC non squameux, Dato-DXd a démontré une amélioration de 2,3 mois de la survie globale (OS) par rapport au docétaxel (14,6 contre 12,3 mois ; HR=0,84). Le profil de sécurité était cohérent avec les analyses précédentes, avec des taux de réduction de dose et d'interruption plus faibles par rapport au docétaxel. De plus, l'essai NeoCOAST-2 a montré des taux de réponse prometteurs pour Dato-DXd en combinaison avec durvalumab et la chimiothérapie dans le cadre de NSCLC résécable à un stade précoce, avec un taux de réponse pathologique complète de 34,1%.
Die Phase-3-Studie TROPION-Lung01, die datopotamab deruxtecan (Dato-DXd) bei fortgeschrittenem nicht-squamösem nicht-kleinzelligem Lungenkrebs (NSCLC) bewertet hat, zeigte vielversprechende Ergebnisse. Im nicht-squamösen NSCLC-Subtyp zeigte Dato-DXd eine Verbesserung der Gesamtüberlebenszeit (OS) um 2,3 Monate im Vergleich zu Docetaxel (14,6 gegenüber 12,3 Monaten; HR=0,84). Das Sicherheitsprofil war konsistent mit früheren Analysen und zeigte niedrigere Raten von Dosisreduktionen und Abbrüchen im Vergleich zu Docetaxel. Darüber hinaus zeigte die NeoCOAST-2-Studie vielversprechende Ansprechraten für Dato-DXd in Kombination mit Durvalumab und Chemotherapie bei frühzeitigem resektablem NSCLC, mit einer pathologischen vollständigen Ansprechrate von 34,1%.
- Datopotamab deruxtecan showed a 2.3-month improvement in overall survival for nonsquamous NSCLC patients (14.6 vs 12.3 months)
- Lower rates of dose reduction (20% vs 30%) and discontinuation (8% vs 12%) due to adverse events compared to docetaxel
- NeoCOAST-2 trial showed 34.1% pathological complete response rate for datopotamab deruxtecan plus durvalumab and carboplatin in early-stage NSCLC
- 65.9% major pathological response rate in NeoCOAST-2 trial for the combination therapy
- Overall survival results did not reach statistical significance in the overall trial population
- Datopotamab deruxtecan did not show OS improvement in patients with squamous NSCLC
- Grade 3 or higher treatment-related adverse events occurred in 26% of patients in the datopotamab deruxtecan arm
Insights
The TROPION-Lung01 phase 3 trial results for datopotamab deruxtecan (Dato-DXd) in advanced nonsquamous NSCLC are promising. The 2.3-month improvement in median overall survival (14.6 vs 12.3 months; HR=0.84) compared to docetaxel is clinically meaningful, especially considering the challenging nature of this patient population.
Key points:
- Dato-DXd showed efficacy regardless of actionable genomic alterations, suggesting broad applicability.
- The safety profile was consistent with previous analyses, with lower rates of dose reduction and discontinuation compared to docetaxel.
- The exploratory TROP2-QCS biomarker analysis could potentially help identify patients most likely to benefit from Dato-DXd.
While the OS improvement didn't reach statistical significance in the overall population, the consistent benefit in nonsquamous NSCLC patients is encouraging. This data, combined with the previously reported PFS improvement, supports Dato-DXd's potential as a new treatment option in this setting.
The TROPION-Lung01 trial demonstrates the potential of datopotamab deruxtecan in advanced NSCLC, particularly for nonsquamous histology. However, it's important to note some limitations:
- The primary endpoint of OS in the overall population was not met (HR=0.94, p=0.530), which may impact regulatory decisions.
- The benefit was primarily driven by the nonsquamous subgroup, with no improvement seen in squamous NSCLC.
- While the safety profile was generally favorable, the
4% rate of grade 3+ ILD warrants careful monitoring in clinical practice.
The NeoCOAST-2 results in early-stage NSCLC are intriguing, with a
The TROPION-Lung01 results present a mixed picture for investors in Daiichi Sankyo and AstraZeneca. Positives include:
- Clinically meaningful OS improvement in nonsquamous NSCLC, a large market segment.
- Favorable safety profile compared to docetaxel.
- Potential TROP2-QCS biomarker for patient selection.
- Promising early-stage data from NeoCOAST-2.
However, challenges remain:
- Failure to meet the primary OS endpoint in the overall population.
- Lack of benefit in squamous NSCLC.
- Competitive landscape with other ADCs and immunotherapies.
The commercial potential will depend on regulatory decisions and market positioning. The biomarker strategy and early-stage combination data could be key differentiators. Investors should monitor upcoming regulatory decisions and further trial results, particularly in earlier treatment settings and combinations. While not a clear home run, Dato-DXd still shows promise in the evolving NSCLC treatment landscape.
- TROPION-Lung01, evaluating Daiichi Sankyo and AstraZeneca’s datopotamab deruxtecan versus chemotherapy, previously met the dual primary endpoint of progression-free survival in the overall trial population
- Presidential Symposium for NeoCOAST-2 demonstrates potential for datopotamab deruxtecan plus durvalumab and chemotherapy in neoadjuvant early-stage non-small cell lung cancer
Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).
In the overall trial population, OS results numerically favored datopotamab deruxtecan compared to docetaxel (median OS 12.9 months versus 11.8 months) but did not reach statistical significance (hazard ratio [HR] =0.94;
“Despite many efforts to surpass docetaxel with novel approaches in previously treated advanced or metastatic non-small cell lung cancer, patients only survive for about one year,” said Jacob Sands, MD, Dana-Farber Cancer Institute, Medical Oncology and investigator in the trial. “For datopotamab deruxtecan to show a statistically significant improvement in progression-free survival along with improved response rate, duration of response and an overall survival improvement numerically consistent with progression-free survival is clinically meaningful for patients with nonsquamous lung cancer.”
The safety profile of datopotamab deruxtecan in TROPION-Lung01 was consistent with the previous analysis including lower rates of dose reduction (
This final analysis of OS builds on the positive progression-free survival (PFS) results presented at the European Society for Medical Oncology (#ESMO23) 2023 Congress, which showed datopotamab deruxtecan demonstrated a statistically significant improvement in PFS in the overall trial population and a clinically meaningful PFS benefit in patients with nonsquamous NSCLC. The OS data have been shared with health authorities currently reviewing applications for this indication.
“For patients with nonsquamous non-small cell lung cancer, disease progression is common, making this patient population difficult to treat,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The data from TROPION-Lung01 demonstrate the potential of datopotamab deruxtecan in this setting and support our comprehensive development program where we also are evaluating this TROP2 directed antibody drug conjugate as part of combination strategies in earlier treatment settings of non-small cell lung cancer.”
“TROPION-Lung01 showed a clinically meaningful trend towards improving the survival of patients with advanced or metastatic nonsquamous non-small cell lung cancer, building on the previously reported progression-free survival data,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “Together with the data we have presented for the potential TROP2-QCS biomarker and from NeoCOAST-2 in early-stage disease, these results underscore our confidence in the important role datopotamab deruxtecan can play across segments and settings of non-small cell lung cancer.”
In TROPION-Lung01, patient enrollment by tumor histology was balanced across treatment arms and consistent with real world incidence with approximately
Summary of TROPION-Lung01 Overall Survival Results
Overall Trial Population |
Datopotamab Deruxtecan
|
Docetaxel
|
Median OS (months) ( |
12.9 months (11.0-13.9) |
11.8 months (10.0-12.8) |
HR ( |
0.94 (0.78-1.14) |
|
p-value |
0.530 |
|
Pre-specified boundary (2-sided) |
0.045 |
|
Nonsquamous Histology |
Datopotamab Deruxtecan
|
Docetaxel
|
Median OS (months) ( |
14.6 months (12.4-16.0) |
12.3 months (10.7-14.0) |
HR ( |
0.84 (0.68-1.05) |
|
OS Probability at 12 months (%) ( |
|
|
OS Probability at 24 months (%) ( |
|
|
Nonsquamous Histology - with Actionable Genomic Alterations |
Datopotamab Deruxtecan
|
Docetaxel
|
Median OS (months) ( |
15.6 months |
9.8 months |
HR ( |
0.65 (0.40-1.08) |
|
Nonsquamous Histology - without Actionable Genomic Alterations |
Datopotamab Deruxtecan
|
Docetaxel
|
Median OS (months) ( |
13.6 months |
12.3 months |
HR ( |
0.89 (0.70-1.13) |
|
Squamous Histology |
Datopotamab Deruxtecan
|
Docetaxel
|
Median OS (months) ( |
7.6 months (5.0-11.0) |
9.4 months (7.2-12.5) |
Hazard Ratio ( |
1.32 (0.91-1.92) |
|
CI, confidence interval; HR, hazard ratio; OS, overall survival |
||
iMedian follow-up was 23.1 months for both the datopotamab deruxtecan and docetaxel arms |
||
Results from an exploratory analysis of TROPION-Lung01 were featured in a WCLC Presidential Symposium (PL02.11) on September 8 which showed TROP2 as measured by AstraZeneca’s proprietary computational pathology platform, quantitative continuous scoring (QCS), was predictive of clinical outcomes in patients with advanced or metastatic NSCLC treated with datopotamab deruxtecan.
Datopotamab deruxtecan plus durvalumab and chemotherapy showed promising response rates in patients with early-stage resectable NSCLC
Results from the NeoCOAST-2 phase 2 platform trial evaluating durvalumab in multiple novel combinations, before and after surgery, in patients with early-stage (stage IIA-IIIB) resectable NSCLC were featured in a WCLC Presidential Symposium (PL02.07). Preliminary results from the trial arm testing neoadjuvant durvalumab plus datopotamab deruxtecan and carboplatin demonstrated a pathological complete response (pCR) rate of
The safety profile of durvalumab plus datopotamab deruxtecan and carboplatin was consistent with the known safety profiles of these agents with grade 3 or higher TRAEs occurring in
About TROPION-Lung01
TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/m2) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.
The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate (ORR), duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety.
TROPION-Lung01 enrolled approximately 600 patients in
About NeoCOAST-2
NeoCOAST-2 is a global, randomized, multicenter, open-label, multi-arm phase 2 platform trial evaluating the efficacy and safety of durvalumab in multiple novel combinations, before and after surgery, in patients with resectable, early-stage (stage IIA-IIIB) NSCLC.
The dual primary endpoints of NeoCOAST-2 are antitumor activity of neoadjuvant treatment assessed by pCR and the safety and tolerability of neoadjuvant and adjuvant treatment. Key secondary endpoints include event-free survival, disease-free survival and ORR as assessed by both RECIST version 1.1 and investigator, OS, tumor resection and mPR as defined by central blinded independent pathologist review.
NeoCOAST-2 will enroll approximately 490 patients in
About Advanced Non-Small Cell Lung Cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.1 NSCLC is the most common type of lung cancer, accounting for about
TROP2 is a protein broadly expressed in the majority of NSCLC tumors.7 There is currently no TROP2 directed ADC approved for the treatment of lung cancer.8,9
About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.
About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in
About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
About Daiichi Sankyo
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.
| _______________________________ |
References |
1 World Health Organization. Global Cancer Observatory: Lung. Accessed September 2024. |
2 Cancer.net. Lung Cancer – Non-Small Cell: Statistics. Accessed September 2024. |
3 National Cancer Institute. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer. Accessed September 2024. |
4 Chen R, et al. J Hematol Oncol. 2020:13(1):58. |
5 Majeed U, et al. J Hematol Oncol. 2021;14(1):108. |
| 6 Pircher A, et al. Anticancer Research. 2020;70(5):287-294. |
7 Mito R, et al. Pathol Int. 2020;70(5):287-294. |
8 Rodríguez-Abreau D, et al. Ann Onc. 2021 Jul;32(7):881-895. |
9 American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Accessed September 2024. |
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Daiichi Sankyo, Inc.
jennifer.brennan@daiichisankyo.com
+1 908 900 3183 (mobile)
Daiichi Sankyo Co., Ltd.
DS-PR@daiichisankyo.co.jp
Investor Relations:
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Source: Daiichi Sankyo
FAQ
What was the median overall survival for datopotamab deruxtecan in nonsquamous NSCLC patients in the TROPION-Lung01 trial?
Did datopotamab deruxtecan (AZN) show improved safety compared to docetaxel in the TROPION-Lung01 trial?
What was the pathological complete response rate for datopotamab deruxtecan combination therapy in the NeoCOAST-2 trial for early-stage NSCLC?
Did datopotamab deruxtecan (AZN) show improved overall survival in squamous NSCLC patients?
