Hormon pozitif meme kanseri ve Küçük hücreli dışı akciğer kanserinde yeni bir tedavi seçeneği olarak Datopotamab deruxtecan

Hormon pozitif meme kanseri ve Küçük hücreli dışı akciğer kanserinde yeni bir tedavi seçeneği olarak Datopotamab deruxtecan

Kanser tedavisinde son yıllardaki en önemli gelişmelerden biri, kanser hücrelerinde yoğun bulunan proteinlere karşı geliştirilmiş antikor-sitotoksik tedavi kombinasyonlarıdır.

Antikor-sitotoksik kombinasyonu, kanser hücrelerinin yüzeyindeki hedeflenen proteine bağlanır, sitotoksik kemoterapi kısmı endoliz ile kanser hücresine girer ve hücre içinde aktive olarak kanser hücresinin ölümüne neden olur.

Bu yöntemle normal hücreler korunmuş, kanser hücreleri hedeflenerek yok edilmiş olur. Diğer önemli sonucu, bir tümör hücresini öldüren sitotoksik kemoterapi yan taraftaki kanser hücresine sızarak etkisini devam etmesi ile beklenen etkinlik normal kemoterapiye göre çok artmaktadır.

Datopotamab deruxtecan, meme ve akciğer kanserinde bol sentezlenen TROP2 proteine karşı geliştirilmiş antikor yapısı ve kanser hücrelerinin gelişimi için önemli olan topoizomeraz 1 enzimini inhibe eden sitotoksik kemoterapi kompleksinden oluşur.

Son yapılan çalışmalarda, tedavi seçeneği tükenmiş hormon pozitif meme kanseri hastalarında Datopotamab deruxtecan sık kullanılan kemoterapilere karşı daha etkili olduğu ve hastalıksız süreyi uzattığı gösterilmiştir.

Akciğer yapılan çalışmada, tedavi seçenekleri tükenmiş hastalarda Datopotamab deruxtecan, dosetaksel kemoterapisine göre daha iyi yanıt ve hastalıksız süreyi uzattığı görüldü. Bu etkinliği skuamöz hücreli olmayan grupta daha belirgin olduğu saptanmıştır.

Kaynaklar

ESMO 2023

Background

The TROP2-directed antibody-drug conjugate Dato-DXd demonstrated promising activity in heavily pre-treated patients (pts) with inoperable or metastatic HR+/HER2-BC in the Phase 1 TROPION-PanTumor01 trial (NCT03401385). Here we report primary PFS results from the global, Phase 3 TROPION-Breast01 trial (NCT05104866).

Methods

Adult pts with inoperable or metastatic HR+/HER2-BC, who had experienced progression on endocrine therapy (ET) and for whom ET was unsuitable, and who had received 1-2 prior lines of systemic chemotherapy (CT), were randomised 1:1 to Dato-DXd (6 mg/kg Q3W) or investigator’s choice of CT (ICC; eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. Dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS).

Results

732 pts were randomised (Dato-DXd: 365; ICC: 367). Median age (range) was 56 (29–86)/54 (28–86) yrs in the Dato-DXd/ICC groups. At data cut-off (17 Jul 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Results are shown in the table. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52–0.76]; p<0.0001). OS data were not mature; a trend for improvement favouring Dato-DXd was observed. Pts receiving Dato-DXd had lower rates of grade ≥3 TRAEs and dose reductions vs ICC (Table).

Conclusions

TROPION-Breast01 met the primary endpoint of PFS; the study continues to final OS. Pts receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS compared with ICC, along with a favourable and manageable safety profile. Results support Dato-DXd as a novel treatment option for pts with inoperable or metastatic HR+/HER2-BC who have received 1–2 prior lines of CT.  Table: LBA11

Dato-DXd             ICC

Efficacy  N=365   N=367

PFS

Median PFS (BICR), mo (95% CI)      6.9 (5.7‒7.4)        4.9 (4.2‒5.5)

HR (95% CI)       0.63 (0.52‒0.76); p<0.0001

Median PFS (investigator assessed), mo (95% CI)       6.9 (5.9‒7.1)        4.5 (4.2‒5.5)

HR (95% CI)       0.64 (0.53‒0.76)

PFS rate (BICR), % (95% CI)6 mo 9 mo           53.3 (47.7‒58.5)37.5 (31.9‒43.2)   38.5 (32.8‒44.1)18.7 (13.8‒24.3)

OS*

HR (95% CI)       0.84 (0.62‒1.14)

Response

Confirmed ORR (BICR), % (n)           36.4 (133)            22.9 (84)

Safety    N=360   N=351

TRAEs, %Any grade Grade ≥3          93.620.8 86.344.7

AEs associated with dose reduction/discontinuation, %           23.1/3.1 32.2/2.8

∗23% maturity.AEs, adverse events; mo, months; ORR, objective response rate; TRAEs, AEs possibly related to study treatment.

Clinical trial identification

NCT05104866; release date November 3, 2021.

Background

Dato-DXd is a novel TROP2-directed antibody-drug conjugate under clinical investigation in multiple tumor types. This is the first report of TROPION-Lung01 (NCT04656652), a randomized, global, open-label, phase 3 study of Dato-DXd vs docetaxel (DTX) in pretreated patients (pts) with adv/met NSCLC with or without actionable genomic alterations (AGAs).

Methods

Pts were randomized 1:1 to Dato-DXd 6 mg/kg or DTX 75 mg/m2 Q3W. Dual primary endpoints were progression-free survival (PFS; by blinded independent central review [BICR]) and overall survival (OS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety.

Results

604 pts were included in the full analysis set (FAS); 43.1% had received ≥2 prior lines of systemic therapy. Median age was 64 y (range, 24-88). PFS was significantly improved with Dato-DXd over DTX in the FAS (HR, 0.75; 95% CI, 0.62-0.91; P=.004; median, 4.4 vs 3.7 mo). Confirmed ORRs were 26.4% (Dato-DXd) and 12.8% (DTX), with median DORs of 7.1 and 5.6 mo. Longer median PFS was observed in the prespecified non-squamous histology subgroup (NSQ; 5.6 vs 3.7 mo). Median treatment duration was 4.2 mo (range, 0.7-18.3 mo) for Dato-DXd and 2.8 mo (range, 0.7-18.9 mo) for DTX. The most common treatment-emergent adverse events (TEAEs) seen with Dato-DXd were stomatitis (49.2%, mostly grade [gr] 1/2) and nausea (37%). Adjudicated drug-related interstitial lung disease gr ≥3 occurred in 3.4% of pts with Dato-DXd vs 1.4% with DTX. Fewer drug-related gr ≥3 TEAEs and AEs leading to dose reduction or discontinuation were seen with Dato-DXd vs DTX.  Table: LBA12

Efficacy  Dato-DXdN=299  DTXN=305           HR (95% CI)

Median PFSa (95% CI), mo

FAS      4.4 (4.2-5.6)         3.7 (2.9-4.2)         0.75 (0.62-0.91); P=.004b

NSQ; n=229/232c           5.6 (4.4-7.0)         3.7 (2.9-4.2)         0.63 (0.51-0.78)

Confirmed ORRa(95% CI), %            26.4 (21.5-31.8)  12.8 (9.3-17.1)    –

Median DOR (95% CI), mo 7.1 (5.6-10.9)      5.6 (5.4-8.1)         –

Safety, n (%)         Dato-DXd n=297  d            DTX n=290  d       –

Related TEAEs                                   –

Any grade          257 (86.5)            252 (86.9)

Grade ≥3           73 (24.6)              120 (41.4)

Related TEAEs associated with:

Dose reduction 58 (19.5)              85 (29.3)

Discontinuation 23 (7.7)  34 (11.7)

Deathe               3 (1.0)    2 (0.7)

aBy BICR. bPFS P value boundary = .008. cNo. of pts in the Dato-DXd and DTX arms. dNo. of pts treated. ePer Investigator; adjudicated data will be presented.

Conclusions

PFS was significantly improved with Dato-DXd over DTX in pts with pretreated adv/met NSCLC. NSQ patients appeared to derive the most benefit. Dato-DXd was well tolerated, with a manageable safety profile. The trial is continuing until the final OS analysis. M-J. Ahn and A. Lisberg have equally contributed to the study.

Clinical trial identification

NCT04656652.