Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer

Figures & data

Figure 1 HER2 signaling pathway (Adapted from “HER2 Signaling Pathway”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates).

Figure 2 Structure of Trastuzumab Deruxtecan.

Notes: Reproduced with permission from Egbert F. Smit, Kazuhiko Nakagawa, Misako Nagasaka, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(15_suppl):9504. copyright 2020, Wolters Kluwer Health, Inc.⁵⁶

Figure 3 Trastuzumab Deruxtecan mechanism of action (Adapted from “Antibody–Drug Conjugate Drug Release”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates).

Table 1 Clinical Trials of Trastuzumab Deruxtecan in Non-Small Cell Lung Cancer (NSCLC)

NCT	Title	Phase	Combination Therapy	Status
04644237	A Phase 2, Multicenter, Randomized Study of Trastuzumab Deruxtecan in Subjects with HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY- LUNG02)	II	N/A	Recruiting
03505710	A Phase 2, Multicenter, Open-Label, 2-Cohort Study of Trastuzumab Deruxtecan (DS-8201a), an Anti-HER2 Antibody Drug Conjugate (ADC), for HER2-Over-Expressing or -Mutated, Unresectable and/or Metastatic Non-Small Cell Lung Cancer (NSCLC) (DESTINY- LUNG01)	II	N/A	Active, not recruiting^Citation56
04042701	A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan (DS-8201a), An Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), In Combination with Pembrolizumab, An Anti-PD-1 Antibody, In Subjects with Locally Advanced/Metastatic Breast or Non-Small Cell Lung Cancer (NSCLC)	Ib	Pembrolizumab	Recruiting
04686305	A Phase Ib Multicenter, Open-label Dose-escalation Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Durvalumab in Combination with Cisplatin, Carboplatin or Pemetrexed in First-line Treatment of Patients with Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 Overexpression (HER2+) (DESTINY- Lung03)	Ib	● Durvalumab ● Durvalumab + Cisplatin ● Durvalumab + Carboplatin ● Durvalumab + Pemetrexed	Active, not recruiting
03334617	An Open-Label, Multi-Drug, Biomarker-Directed, Multi-Centre Phase II Umbrella Study in Patients with Non-Small Cell Lung Cancer, Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (HUDSON)	II	Durvalumab	Recruiting

Table 2 Comparison of DESTINY-Lung01 Trial Results Between HER-Mutant and HER2-Overexpressing Cohorts

DESTINY-Lung01
	HER Mutation	HER2 Overexpression
Patients (n)	42	49
Objective response rate	n = 26 (61.9%)	n = 2 (24.5%)
Complete response	n = 1	n = 1
Partial response	n = 25	n = 11
Duration of response	Not reached	6 months
Disease control rate	90.5%	69.1%
Progression-free survival	14 months	5.4 months
Dose interruption	n = 25 (59.5%)	n = 26 (53.1%)
Dose reduction	n = 16 (38.1%)	n = 17 (34.7%)
Dose discontinuation	n = 10 (23.8%)	n = 11 (22.4%)
Treatment emergent adverse events	n = 42 (100%)	n = 49 (100%)
Nausea	n = 32 (76.2%)	n = 29 (59.2%)
Alopecia	n = 20 (47.6%)	-
Anemia	n = 18 (42.9%)	-
Decreased appetite	n = 18 (42.9%)	n = 19 (38.8%)
Decreased neutrophil count	n = 18 (42.9%)	-
Fatigue	-	n = 16 (32.7%)
Grade 3 adverse events	n = 27 (64.3%)	n = 36 (73.5%)
Decreased neutrophil count	n = 11 (26.2%)	n = 10 (20.4%)
Anemia	n = 7 (16.7%)	-
Fatigue	-	n = 5 (10.2%)

Table 3 ILD Incidence Rate and Grading Among DESTINY Trials

	DESTINY-Breast01	DESTINY-Gastric01	DESTINY-Lung01
			HER2 Mutation	HER2 Overexpression
Number of treated patients	184	125	42	49
T-DXd dose	5.4 mg/kg	6.4 mg/kg	6.4 mg/kg	6.4 mg/kg
Number of patients with ILD	25 (13.6%)	12 (10%)	5 (11.5%)	8 (16.3%)
ILD Grading
I	20 (80%)	9 (75%)		2 (25%)
II			5 (100%)	3 (37.5%)
III	1 (4%)	2 (16.7%)
IV		1 (8.3%)
V	4 (16%)			3 (3.75%)

Notes: Pneumonitis grading: Grade 1: asymptomatic; clinical or diagnostic observations only; intervention not indicated; Grade 2: symptomatic; medical intervention indicated; limiting instrumental ADL; Grade 3: severe symptoms; limiting self-care ADL*; oxygen indicated; Grade 4: life-threatening respiratory compromise; urgent intervention indicated (eg, tracheostomy or intubation); Grade 5: death. Shading refers to no ILD reported at the specific grade.

Figure 4 Schema for DESTINY-Lung02. Additional details can be found at: https://clinicaltrials.gov/ct2/show/NCT04644237.

Abbreviations: *ECOG PS, Eastern Cooperative Oncology Group performance status; LV EF, left ventricular ejection fraction; ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan; ORR, objective response rate; RECIST, response evaluation criteria in solid tumors; BICR, blinded independent central review; DCR, disease control rate; DOR, duration of response; PFS, progression-free survival; OS, overall survival.

Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(15_suppl):9504.

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