Antibody-drug conjugates (ADCs) targeting TROP-2 in lung cancer

Figures & data

Figure 1. TROP-2 pathway (a) and mechanism of action of ADCs anti-TROP-2 (b). the TROP-2 pathway is involved in the promotion of angiogenesis, cell growth, and metastatization throughout calcium and beta-catenin signaling and through the re-localization of RACK1 (a). The mechanism of action of the three ADCs evaluated in clinical trials is reported in Figure (b), along with the so-called ‘bystanders effect’ (c).

Table 1. Available data regarding efficacy and safety of anti-TROP-2 ADCs in lung cancer.

Trial and reference	Phase, Design and Drug	Population	N.	Line of therapy	Clinical activity	TRAEs ≥ G3 (type, %)
King et al. [53]	Phase 1 dose-finding trial, PF-06664178	Advanced or metastatic solid tumors [19% NSCLC]	31	Pre-treated [84%, ≥ 3 lines]	Overall population: SD in 37.9%	Significant DLTs in skin and mucosa in the varying dose ranges tested
Starodub at al [54]. *	Phase I, dose escalation trial, Sacituzumab Govitecan	Advanced or metastatic solid tumors [1 pt NSCLC 2 pts SCLC]	25	Pre-treated [>50%, ≥ 3 lines]	1 patient SCLC: PR 1 patient SCLC: PD 1 patient NSCLC: SD	Tox of any grades: - Fatigue (72%) - Nausea (68%) - Diarrhea (52%) - Neutropenia (56%, 9 pts G3–4)
Heist et al. [55]*	Phase I single-arm expansion trial, Sacituzumab Govitecan	Advanced or metastatic NSCLC	54	Pre-treated [50%, ≥ 3 lines]	ORR: 19% mDOR: 6.0 mo (95% CI, 4.8–8.3) PFS ITT: 5.2 mo (95% CI, 3.2–7.1) OS ITT: 9.5 mo (95% CI, 5.9–16.7)	- Neutropenia (28%) - Diarrhea (7%) - Nausea (7%) - Fatigue (6%) - Febrile neutropenia (4%)
Gray et al. [56]*	Phase II, single-arm expansion trial, Sacituzumab Govitecan	Advanced or metastatic SCLC	53	Pre-treated [32%, ≥ 3 lines]	ORR: 14% mDOR: 5.7 mo (95% CI, 3.6–19.9) PFS ITT: 3.7 mo (95% CI, 2.1–4.3) OS ITT: 7.5 mo (95% CI, 6.2–8.8)	- Neutropenia (34%) - Fatigue (13%) - Diarrhea (9%) - Anemia (6%)
Bardia et al. [57]*	Phase I/II, single-arm dose escalation trial, Sacituzumab govitecan	Advanced or metastatic solid tumors [10.9% NSCLC 12.5% SCLC]	495	Pre-treated	NSCLC cohort: ORR: 16.7% mDOR: 6.0 mo (95% CI, 2.5–21.0) PFS ITT: 4.4 mo (95% CI, 2.5–5.4) OS ITT: 7.3 mo (95% CI, 5.6–14.6) SCLC cohort: ORR: 17.7% mDOR: 5.7 mo (95% CI, 3.6–19.9) PFS ITT: 3.7 mo (95% CI, 2.1–4.8) OS ITT: 7.1 mo (95% CI, 6.2–8.1)	- Neutropenia (42%) - Anemia (10%) - Diarrhea (8%) - Fatigue (6%) - Febrile neutropenia (5%)
Garon et al. [58]§	Phase 1 dose-escalation/expansion trial, Dato-DXd	Advanced or metastatic NSCLC	180	Pre-treated	ORR: 24% (4 mg/kg) 26% (6 mg/kg) 24% (8 mg/kg)	- Nausea (1%) - Stomatitis (2%) - Neutropenia (1%) - ILD of any grade (11%)
Garon et al. [59]§	Phase 1 dose-escalation/expansion trial, Dato-DXd	Advanced or metastatic NSCLC with actionable genomic alterations	34	Pre-treated [82%, ≥ 3 lines]	ORR: 35% mDOR 9.5 mo (95% CI, 3.3-NE)	29% (overall) Most frequent TRAEs: nausea, stomatitis, fatigue, amylase increased
Levy et al. [60]	Phase 1b, Dato-DXd plus Pembrolizumab ± platinum-based chemotherapy	Advanced or metastatic NSCLC without actionable genomic alterations	88	Untreated and Pre-treated	Overall population: ORR 37% (double therapy) ORR 41% (triple therapy) Untreated population: ORR 62% (double therapy) ORR 50% (triple therapy)	40% (double therapy) 60% (triple therapy) Most frequent TRAEs: stomatitis, nausea, decreased appetite, fatigue, anemia, ILD (4/88)

TRAEs, treatment-related adverse events; N, number; NSCLC, non-small cell lung cancer; SD, stable disease; NA, not available; pt, patient; SCLC, small cell lung cancer; ORR, objective response rate; mDOR, median duration of response; mo, months; PFS, progression-free survival; ITT, intention-to-treat population; OS, overall survival; ILD, interstitial lung disease.

* Analyses derived from IMMU-132-01 trial (NCT01631552).

§ Analyses derived from TROPION-PanTumor01 (NCT03401385).

Table 2. Ongoing trials involving anti-TROP-2 ADCs in lung cancer (clinical trials.Gov accessed on January 18, 2023).

ClinicalTrial.gov ID	Phase	Setting	N	Treatment arms	Primary endpoint	Selected secondary endpoints	Status
TROPiCS-03 (NCT03964727)	2	Metastatic solid tumors (NSCLC progressed after platinum-based chemotherapy and anti-PD(L)1)	165	Sacituzumab govitecan	ORR by IA	ORR by BIRC, DOR, CBR, PFS	Recruiting
EVOKE-01 (NCT05089734)	3	Advanced or metastatic NSCLC with progression on or after platinum- chemotherapy and immunotherapy	520	Sacituzumab govitecan vs docetaxel	OS	PFS, ORR, DOR, DCR, TEAEs	Recruiting
EVOKE-02 (NCT05186974)	2	First Line, advanced or metastatic NSCLC without actionable genomic alterations.	164	Sacituzumab govitecan plus pembrolizumab ± platinum-based chemotherapy	ORR by BIRC DLTs	PFS, OS, DOR, DCR, TEAEs	Recruiting
KEYNOTE D46/EVOKE-03 (NCT05609968)	3	First-line, PD L1 TPS≥50% Metastatic NSCLC	614	Sacituzumab govitecan plus pembrolizumab vs pembrolizumab	PFS by BIRC, OS	OR, DOR, Quality of Life	Not yet recruiting
TROPION-PanTumor01 (NCT03401385)	1	Advanced or metastatic solid tumors (Including treatment naïve NSCLC)	770	Datopotamab deruxtecan (dose escalation and dose expansion cohorts)	DLT, AEs, G>/ = 2 mucositis/stomatitis	Cmax, Tmax, AUC	Recruiting
TROPION-PanTumor02 (NCT05460273)	1/2	Advanced or metastatic solid tumors (Including pretreated NSCLC)	118	Datopotamab deruxtecan	ORR by BICR	ORR by IA, DOR, DCR, BoR, TTR, PFS, OS, TEAE and AESI, Immunogenicity of Dato-DXd	Recruiting
ICARUS-LUNG01 (NCT04940325)	2	Advanced and/or unresectable NSCLC, II to IV line	100	Datopotamab deruxtecan	ORR by IA	DOR, PFS, CBR, AEs	Recruiting
TROPION-Lung01 (NCT04656652)	3	Previously treated advanced or metastatic NSCLC with or without actionable genomic alterations	590	Datopotamab deruxtecan vs Docetaxel	PFS by BIRC, OS	PFS by IA, ORR, DOR, DCR, TTR, TTD	Recruiting
TROPION-Lung02 (NCT04526691)	1b	Advanced or metastatic NSCLC, previously treated or are treatment naïve in I line	140	Datopotamab deruxtecan plus Pembrolizumab ± platinum-based chemotherapy	DLT, TEAEs	ORR, DOR, PFS, OS	Recruiting
TROPION-Lung04 (NCT04612751)	1b	Advanced or metastatic NSCLC who are either treatment-naïve or have received 1 prior line without ICI	232	Datopotamab deruxtecan plus immunotherapy (Durvalumab, AZD2936, MEDI5752) ± carboplatin	DLTs; TEAEs and other safety parameters	ORR, DOR, DCR, PFS, TTR, OS	Recruiting
TROPION-Lung05 (NCT04484142)	2	Advanced or metastatic NSCLC with actionable genomic alterations and progressed on or after targeted therapy and platinum-based chemotherapy	137	Datopotamab deruxtecan	ORR by BIRC	DOR, PFS, OS, TEAEs, Pharmacokinetic Parameters	Active, not recruiting
TROPION-Lung07 (NCT05555732)	3	Advanced or metastatic NSCLC treatment naïve	975	Datopotamab deruxtecan plus pembrolizumab vs pembrolizumab plus platinum-based chemotherapy	PFS by BIRC OS	ORR, PFS by IA, ORR, DOR, TTR, DCR, PFS2	Not yet recruiting
TROPION-Lung08 (NCT05215340)	3	Untreated advanced or metastatic NSCLC expressing PD L1 TPS≥50%	740	Datopotamab deruxtecan plus pembrolizumab vs. pembrolizumab	PFS by BIRC OS	ORR, PFS, PFS2, ORR, DOR, TTR, DCR, TTD, TEAE	Recruiting
ORCHARD (NCT03944772)	2	Advanced or metastatic EGFR mutant NSCLC with progression on frontline osimertinib	250 (all platform)	Datopotamab deruxtecan plus osimertinib	ORR	PFS, DOR, OS	Recruiting
A264 (NCT04152499)	1/2	Locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies (Including NSCLC)	430	SKB264	Phase 1: MTD, RDEs Phase 2: ORR	Phase I: DLTs, Safety and tolerability profile, ORR, DOR, PFS, OS. Phase II: Safety and tolerability profile, DOR, PFS, OS, Levels of TROP2 in tumor	Recruiting

N, number – estimated enrollment; NSCLC, non-small cell lung cancer; PFS, progression-free survival; BIRC, blinded independent central review; DCR, disease control rate; PFS2, PFS on the next line of treatment; ORR, objective response rate; DOR, duration of response; IA, investigator-assessed; AE, Adverse event, CBR, clinical benefit ratio; ICI, immune-checkpoint inhibitor; BoR, Best Overall Response; TTR, Time To Response; TEAE, treatment-emergent adverse event; AESI, adverse event of special interest, DLT, Dose Limiting Toxicities; MTD, Maximum Tolerated Dose; RDE, Recommended Doses for Expansion; G, Grade; Cmax, Maximum concentration; Tmax, Time at which Cmax is reached, AUC, Area under the drug concentration-time curve, TTD, Time to Deterioration; CBR, Clinical Benefit Rate.

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