The University of Texas MD Anderson Cancer Center, Houston, TX
Kanwal Pratap Singh Raghav , Salvatore Siena , Atsuo Takashima , Takeshi Kato , Marc Van Den Eynde , Maria Di Bartolomeo , Yoshito Komatsu , Hisato Kawakami , Marc Peeters , Thierry Andre , Sara Lonardi , Kensei Yamaguchi , Jeanne Tie , Cristina Gravalos Castro , John H Strickler , Daniel Barrios , Qi Yan , Takahiro Kamio , Kojiro Kobayashi , Takayuki Yoshino
Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831.
5.4 mg/kg T-DXd n = 82 | 6.4 mg/kg T-DXd n = 40 | |
---|---|---|
Median follow-up, mo (range) | 8.9 (0.5-17.1) | 10.3 (0.7-16.4) |
Median DoR by BICR, mo (95% CI) | 5.5 (4.2-8.1) | 5.5 (3.7-non-evaluable) |
Median PFS, mo (95% CI) | 5.8 (4.6-7.0) | 5.5 (4.2-7.0) |
Best overall response by BICR in subgroups, n/N (%) [95% CI] | ||
Prior anti-HER2 therapy | 7/17 (41.2) [18.4-67.1] | 4/10 (40.0) [12.2-73.8] |
HER2 IHC 3+ | 30/64 (46.9) [34.3-59.8] | 10/34 (29.4) [15.1-47.5] |
HER2 IHC 2+/ISH+ | 1/18 (5.6) [0.1-27.3] | 1/6 (16.7) |
RAS wt | 27/68 (39.7) [28.0-52.3] | 11/34 (32.4) [17.4-50.5] |
RASm | 4/14 (28.6)a [8.4-58.1] | 0/6 |
aAll RASm responders were IHC 3+.
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