Notes

5 June 2023 — Updated results from the TROPION-Lung02 Phase Ib trial showed that, with additional enrolment and follow-up from the initial presentation, datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no new safety signals in both previously untreated or pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs).

Results will be presented on 6 June in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (#9004).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

More than one million people are diagnosed with advanced stage NSCLC each year.^1,2 While 1st-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without AGAs, like EGFR or ALK, most patients eventually experience disease progression.^3-5 TROP2 is a protein expressed in more than 90% of NSCLC tumours; there are currently no TROP2-directed ADCs approved for the treatment of lung cancer.^6-8

Across previously untreated and pretreated patients, an objective response rate (ORR) of 38% was observed (95% confidence interval [CI], 26-51) in patients receiving doublet datopotamab deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA), an anti-PD-1 therapy. In patients receiving triplet datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy, an ORR of 49% was observed (95% CI, 37-61). Disease control rates (DCR) of 84% and 87% were observed in the doublet and triplet cohorts, respectively. Median duration of response (DoR) was not reached across cohorts. Although immature, median progression-free survival (PFS) was 8.3 months (95% CI, 6.8-11.8) in the doublet cohort and 7.8 months (95% CI, 5.6-11.1) in the triplet cohort. Response rates were highest in previously untreated patients with ORRs of 50% (95% CI, 32-68) and 57% (95% CI, 42-70) observed in the doublet and triplet cohorts, respectively, with a consistent DCR of 91% observed across cohorts.

Yasushi Goto, MD, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, and investigator in the trial, said: “Nearly all patients with advanced non-small cell lung cancer experience disease progression following initial therapy, underscoring the need for novel therapeutic approaches across treatment lines. The updated results from TROPION-Lung02 signal the potential for datopotamab deruxtecan combinations to improve outcomes for patients with non-small cell lung cancer and are a promising development in the pursuit of a new standard treatment option beyond immunotherapy.”

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “With more patients and nearly a year of additional follow-up, the updated TROPION-Lung02 results show that datopotamab deruxtecan continues to elicit promising and durable responses in a diverse subset of patients with non-small cell lung cancer. These early data give us confidence in the ongoing Phase III development programme evaluating datopotamab deruxtecan combinations as potential first-line treatment options for patients with advanced lung cancer across tumour histologies and PD-L1 expression levels.”

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo said: “We continue to be encouraged by the findings from TROPION-Lung02, the first trial to evaluate the combination of a TROP2-directed antibody-drug conjugate and an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced non-small cell lung cancer. These data, alongside previous results for datopotamab deruxtecan combined with an immune checkpoint inhibitor, reinforce the potential of these combinations to improve outcomes for patients with different advanced cancers.”

The safety profiles of datopotamab deruxtecan-based combinations were consistent with previous data with no new safety signals observed. Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 31% of patients receiving doublet therapy and 58% of patients receiving triplet therapy. The most frequent adverse events of any Grade in the doublet and triplet cohorts, respectively, were stomatitis (56% and 35%), nausea (41% and 47%), anaemia (21% and 48%) and fatigue (31% and 37%). Across treatment cohorts, there were 27 interstitial lung disease (ILD) or pneumonitis events adjudicated as drug-related by an independent committee. The percentage of ILD events was similar across cohorts. The majority of ILD events were low grade with 23 Grade 1 or Grade 2 and four Grade 3 events. No Grade 4 or Grade 5 ILD events or Grade 5 TRAEs were observed.

In the doublet cohort of TROPION-Lung02, 58% of patients were previously untreated and 42% were previously treated with platinum chemotherapy (38%) or immunotherapy (19%). In the triplet cohort, 75% of patients were previously untreated and 25% were previously treated with platinum chemotherapy (24%) or immunotherapy (25%). Eighty percent of patients in the doublet cohort and 73% of patients in the triplet cohort had PD-L1 tumour proportion scores of less than 50%, including 36% and 40% of patients who had PD-L1 tumour proportion scores of less than 1% in the doublet and triplet cohorts, respectively. As of the April 7, 2023 data cut-off, 36% and 46% of patients remained on the doublet and triplet therapy, respectively.

Summary of Results

Overall Population

Doublet (n=64)

Triplet (n=72)

Study Duration (range)

14.8 months (1-30.2)

12.9 months (2.6-23.4)

Efficacy Measure

Doublet (n=61)

Triplet (n=71)

ORR, %ⁱ (confirmed and pending) (95% CI)

38% (n=23) (26-51)

49% (n=35) (37-61)

CR, % (confirmed)

0% (n=0)

1% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

34% (n=21)

48% (n=34)

PR, % (pending confirmation)

3% (n=2)

0% (n=0)

SD, %

49% (n=30)

38% (n=27)

Median DoR (months) (95% CI)

NR (8.8-NR)

NR (5.8-NR)

Median PFS (months) (95% CI)

8.3 months (6.8-11.8)

7.8 months (5.6-11.1)

DCR, % ⁱⁱ

84% (n=51)

87% (n=62)

1st-Line Therapy

Efficacy Measure

Doublet (n=34)

Triplet (n=53)

ORR, %ⁱ (confirmed and pending) (95% CI)

50% (n=17) (32-68)

57% (n=30) (42-70)

CR, % (confirmed)

0% (n=0)

2% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

44% (n=15)

55% (n=29)

PR, % (pending confirmation)

6% (n=2)

0% (n=0)

SD, %

47% (n=16)

34% (n=18)

Median DoR (months) (95% CI)

NR (5.5-NR)

NR (5.7-NR)

DCR, %ⁱⁱ

91% (n=31)

91% (n=48)

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NR, not reached; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease iORR is CR + PR iiDCR is best overall response of confirmed CR + confirmed PR + SD

AstraZeneca and Daiichi Sankyo have three Phase III trials evaluating datopotamab deruxtecan as a potential 1st-line treatment option for patients with advanced or metastatic NSCLC without AGAs compared to the respective standard of care for the patient population of each study:

· TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression less than 50%.

· TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater.

· AVANZAR is evaluating datopotamab deruxtecan plus Imfinzi (durvalumab) and platinum chemotherapy in patients regardless of PD-L1 expression or tumour histology.

Non-small cell lung cancer
More than one million people are diagnosed with advanced stage NSCLC each year. ^1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.^3-5

Most patients with NSCLC have tumours that do not express a known AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).^9-11 The current 1st-line standard of care for these patients is treatment with immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40-60% of tumours will not respond to this initial treatment and while these therapies may improve survival for patients whose tumours do respond, most will experience disease progression.^5,7

TROP2, a transmembrane glycoprotein, is expressed in more than 90% of NSCLC tumours.⁶ There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.^7,8

TROPION-Lung02
TROPION-Lung02 is an ongoing global, open-label, six-cohort Phase Ib trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination with pembrolizumab (200 mg) with or without four cycles of platinum chemotherapy (carboplatin or cisplatin) in both previously untreated and pretreated patients with advanced or metastatic NSCLC without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known AGAs).

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, DoR, PFS as assessed by investigator, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

TROPION-Lung02 is one of three clinical trials, alongside TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab.

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 the three lead 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, via tetrapeptide-based cleavable linkers.

A comprehensive development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including NSCLC, triple-negative breast cancer and hormone-receptor positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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4. Walsh RJ, et al. Resistance to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Biomarkers and Therapeutic Strategies. Ther Adv Med Oncol. 2020;12:1758835920937902.

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7. Rodríguez-Abreau D, et al. Pemetrexed Plus Platinum with or without Pembrolizumab in Patients with Previously Untreated Metastatic Nonsquamous NSCLC: Protocol-Specified Final Analysis from KEYNOTE-189. Ann Onc. 2021 Jul;32(7): 881-895.

8. American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html. Accessed June 2023.

9. Chen R, et al. Emerging Therapeutic Agents for Advanced Non-Small Cell Lung Cancer. J Hematol Oncol. 2020;13(1):58.

10. Majeed U, et al. Targeted therapy in advanced non-small cell lung cancer: current advances and future trends. J Hematol Oncol. 2021; 14(1): 108.

11. Adib E, et al. Variation in Targetable Genomic Alterations in Non-Small Cell Lung Cancer by Genetic Ancestry, Sex, Smoking History, And Histology. Genome Med. 2022; 14(1): 39.

Source: AstraZeneca

Posted: June 2023

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