HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: biomarker analyses of DESTINY-CRC01

Abstract

DESTINY-CRC01 (NCT03384940) was a multicentre, open-label, phase 2 study that investigated the safety and efficacy of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing metastatic colorectal cancer (CRC). The present exploratory biomarker analysis aims to investigate relationships between biomarkers and clinical outcomes in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH] positive) Cohort A (N = 53) of DESTINY-CRC01. Higher levels of HER2 biomarkers in baseline tissue and liquid biopsies, including HER2 status (IHC/ISH), HER2/CEP17 ratio, HER2 ISH signals, HER2 H-score, plasma HER2 (ERBB2) amplification status, HER2 adjusted plasma copy number, and HER2 extracellular domain correlate with antitumor activity (indicated by objective response rate, progression-free survival, and overall survival) of T-DXd. Baseline circulating tumor DNA (ctDNA) analysis suggests antitumor activity of T-DXd in patients who had baseline activating RAS, PIK3CA, or HER2 mutations detected in ctDNA.

Fig. 1. Biomarker analysis sets.

^aNo somatic mutation detected. C, cycle; ctDNA, circulating tumor DNA; D, day; EOT, end of treatment; HER2ECD, human epidermal growth factor receptor 2 extracellular domain.

Fig. 2. Antitumor activity of T-DXd as best percentage change from baseline in sum of tumor diameters according to ctDNA genomic landscape at baseline.

Waterfall plot shows the best percentage change in the sum of diameters from baseline, amplifications and mutations of CRC-related genes, bTMB status, histological grade, and primary tumor site. Amplification type was reported from Guardant Health. HER2 gain-of-function mutations were selected based on OncoKB; RAS: mutation at codon 12, 13, 59, 61, 117, or 146. PIK3CA mutation was selected according to previous publication; PTEN: loss-of-function mutations were selected based on OncoKB. bTMB of ≥ 20 mut/Mb was considered high based on the Guardant Health report. Of 4 patients with evaluable ctDNA data and no data available for best percentage change in the sum of diameters, 2 had focal HER2 plasma amplification, 2 had aneuploidy HER2 plasma amplification, none had HER2 mutation, 1 had RAS mutation, 2 had PIK3CA mutation, 1 had PTEN mutation/loss, 2 had aneuploidy MET amplification, 3 had bTMB ≥ 20 mut/Mb, and 1 had bTMB < 20 mut/Mb. amp, amplification; bTMB, blood tumor mutational burden; ctDNA, circulating tumor DNA; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; mut, mutation.

Fig. 3. Antitumor activity of T-DXd according to baseline HER2 biomarker status.

Exploratory cutoff values for each HER2 biomarker were defined as the maximum value of the Youden index for ORR. Vertical red dashed line shows the ORR of 45.3% in the overall population for Cohort A. P values are based on two-sided Fisher’s exact test for ORR and those based on two-sided log-rank test for PFS and OS are shown, without adjustment for multiple comparisons. Error bars represent the 95% CI. The exact P values for HER2 H-score for OS, HER2 ISH signal for PFS, HER2 ApCN for PFS, and HER2 ApCN for OS were 0.000175, 0.000394, 0.0000168, and 0.0000991, respectively. Amp, amplification; ApCN, adjusted plasma copy number; HER2, human epidermal growth factor receptor 2; HER2ECD, human epidermal growth factor receptor 2 extracellular domain; IHC, immunohistochemistry; ISH, in situ hybridization; NA, not applicable; ND, not determined; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Fig. 4. Probability of PFS according to baseline HER2 biomarker status.

The probability of PFS is shown according to HER2 IHC status (panel A) HER2 biomarkers based on exploratory cutoff values (panels B, C, D, F, G), and type of HER2 gene amplification (panel E). ^aExploratory cutoff values (panels B, C, D, F, G) were determined using receiver operating characteristics analysis: H-score cutoff = 240; HER2/CEP17 ratio cutoff = 6.30; HER2 ISH signal cutoff = 11.25; HER2 ApCN cutoff = 30.99; serum HER2ECD cutoff = 23.5 ng/mL. ^bAmplification type (panel E) was reported from Guardant Health. Amp, amplification; ApCN, adjusted plasma copy number; HER2, human epidermal growth factor receptor 2; HER2ECD, human epidermal growth factor receptor 2 extracellular domain; IHC, immunohistochemistry; ISH, in situ hybridization; mPFS, median progression-free survival; NA, not applicable; ND, not determined; PFS, progression-free survival.

Fig. 5. Antitumor activity of T-DXd according to mutation in PIK3CA, RAS, and HER2 in ctDNA at baseline and bTMB.

Vertical red dashed line shows the ORR of 45.3% in the overall population for Cohort A. P values are based on two-sided Fisher’s exact test for ORR and those based on two-sided log-rank test for PFS and OS are shown, without adjustment for multiple comparisons. Error bars represent the 95% CI. PIK3CA variants were determined according to published data. NRAS and KRAS variants were determined as mutation at codon 12, 13, 59, 61, 117, or 146. bTMB ≥ 20 mut/Mb was considered high according to the Guardant Health report. bTMB, blood tumor mutational burden; Mut, mutant; NA, not applicable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; WT, wild type.

Fig. 6. Probability of PFS according to mutation in PIK3CA, RAS, and HER2 in ctDNA at baseline.

The probability of PFS is shown according to mutation in PIK3CA (panel A), RAS (panel B), or HER2 (panel C) genes. PIK3CA variants were determined according to published data. NRAS and KRAS variants were determined as mutation at codon 12, 13, 59, 61, 117, or 146. mPFS, median progression-free survival; Mut, mutant; NA, not applicable; PFS, progression-free survival; WT, wild type.

Fig. 7. Plasma HER2 amplification status at baseline and at disease progression.

Analysis included 29 patients in Cohort A who discontinued T-DXd because of disease progression and had detectable ctDNA at C1D1 and at EOT. Responder/non-responder status was determined by blinded independent central review. Amp, amplification; C1D1, cycle 1, day 1; ctDNA, circulating tumor DNA; EOT, end of treatment.

Fig. 8. Acquired plasma ctDNA mutations at disease progression in patients with HER2-positive mCRC treated with T-DXd.

Acquired refers to patients with acquired mutations detected only at disease progression. Lost refers to patients with mutations detected only at cycle 1, day 1. Maintained refers to patients with mutations at cycle 1, day 1, and at disease progression. bTMB, blood tumor mutational burden; CBOR, confirmed best overall response; ctDNA, circulating tumor DNA; HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.