Trastuzumab Deruxtecan Elicits Promising Antitumor Activity in HER2+ mCRC

Kanwal P.S. Raghav, MBBS, MD

Findings from the phase 2 DESTINY-CRC02 study (NCT04744831) showed that the 5.4-mg/kg dose of fam-trastuzumab deruxtecan-nxki (Enhertu) elicited numerically higher activity in patients with HER2-positive, metastatic colorectal cancer (mCRC) compared with the 6.4-mg/kg dose, according to findings presented at the 2023 ASCO Annual Meeting. These results support the lower dose as the optimal, single-agent regimen for this patient population.

The confirmed objective response rate (cORR) among all patients treated with 5.4 mg/kg of trastuzumab deruxtecan (n = 82) was 37.8% (95% CI, 27.3%-49.2%) compared with 27.5% (95% CI, 14.6%-43.9%) for those who received 6.4 mg/kg (n = 40). No complete responses were reported at either dose level. The median durations of response (DOR) were comparable at 5.5 months (95% CI, 4.2-8.1) and 5.5 months (95% CI, 3.7–not estimable [NE]) at the 5.4 mg/kg and 6.4 mg/kg dose levels, respectively. Of note, this study was not powered to statistically compare the 2 arms.

The disease control rate (DCR) was 86.6% (95% CI, 77.3%-93.1%) in the 5.4-mg/kg cohort and 85.0% (95% CI, 70.2%-94.3%) in the 6.4-mg/kg cohort. Stable disease (SD) and progressive disease (PD) were reported among 48.8% and 9.8% of patients, respectively, in the 5.4-mg/kg overall cohort, and in 57.5% and 10.0% of patients in the 6.4-mg/kg cohort, respectively.

“These promising results support the use of trastuzumab deruxtecan at a dose of 5.4 mg/kg given intravenously every 3 weeks as the optimal dose as a single agent in this patient population of HER2-positive mCRC, [for disease that is either] RAS wild-type or RAS-mutant, due to its positive benefit-risk profile,” Kanwal P.S. Raghav, MBBS, MD, said in a presentation of the data. Raghav is an associate professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine, and medical director of the Division of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center, Houston.

The median progression-free survival (PFS) was 5.8 months (95% CI, 4.6-7.0) in the 5.4-mg/kg cohort, and the median OS was 13.4 months (95% CI, 12.5-16.8). In the 6.4-mg/kg cohort, the median PFS was 5.5 months (95% CI, 4.2-7.0), and the median OS was NE (95% CI, 9.9-NE).

HER2 positivity was confirmed centrally via immunohistochemistry (IHC) and defined as IHC 3+ or IHC 2+/in situ hybridization (ISH) positive. “These tumors are seen in [approximately] 2% to 3% of all cases of unselected mCRC and are enriched in the RAS/BRAF wild-type population,” Raghav said. “They have been associated with resistance to anti-EGFR drugs. Our research shows that HER2-targeted therapies, specifically dual anti-HER2 inhibition, is a promising strategy in patients with HER2-positive, RAS wild-type CRC. However, resistance develops, [and] responses are not complete. And this is an area of unmet need.”

Patients with RAS wild-type or mutant mCRC were eligible. Further, prior treatment with anti-HER2 therapy was permitted.

The study was conducted in 2 stages. In stage 1, patients were randomly assigned 1:1 to trastuzumab deruxtecan at either 5.4 mg/kg (n = 40) or 6.4 mg/kg (n = 40) every 3 weeks. In stage 2, 42 patients were enrolled to receive the 5.4-mg/kg dose. The primary end point was cORR by blinded independent central review. Secondary end points included DOR, PFS, OS, and safety.

Baseline characteristics in the 5.4-mg/kg cohort were well balanced between the 2 stages of enrollment. Overall (n = 82), the median age was 59.1 years (range, 26-84), most patients were men (54.9%), from the Asia-Pacific region (57.3%), has an IHC of 3+ (78.0%), an ECOG performance status of 0 (56.1%), and RAS wild-type disease (82.9%). In terms of IHC and RAS status, most patients were IHC 3+/RAS wild-type (68.3%), with 7.3% being IHC 2+/RAS mutant, 14.6% being IHC 2+/RAS wild-type, and 9.8% having IHC 3+/RAS-mutant disease. Liver metastases were present in 72.0% of patients at baseline, and central nervous system metastases were reported in 3.7% of patients. Primary tumor sites were as follows: left colon (74.4%), rectum (32.9%), right colon (25.6%).

In the 6.4-mg/kg cohort the median age was 62.3 years (range, 35-81), most patients were women (52.5%), from the Asia-Pacific region (60.0%), had IHC 3+ disease (85.0%), an ECOG performance status of 0 (55.0%), and RAS wild-type disease (85.0%). Like the other patients enrolled, most patients had IHC 3+/RAS wild-type disease (70.0%). The remaining patients had IHC2+/RAS wild-type (15.0%) or IHC 3+/RAS-mutant disease (15.0%). Liver metastases were present in 65.0% of patients at baseline, and central nervous system metastases were reported in 2.5% of patients. Primary tumor sites were as follows: left colon (85.0%), rectum (47.5%), right colon (15.0%).

In terms of prior treatment, all patients received prior systemic chemotherapy. The median number of prior lines of therapy in the 5.4-mg/kg cohort was 3 (range, 1-12) and 4 (range, 1-8) in the 6.4-mg/kg cohort. Most patients received prior EGFR inhibitor (69.5% and 77.5%, respectively), and 20.7% and 25.0% of patients received prior anti-HER2 therapy, respectively. Anti-VEGF therapy was received by 90.2% of patients in the 5.4-mg/kg cohort and by 95.0% of patients in the 6.4-mg/kg cohort. Regorafenib (Stivarga) and tipiracil/trifluridine (Lonsurf) was given as prior treatment in 41.5% and 32.5% of patients in the 5.4-mg/kg cohort and 6.4-mg/kg cohort, respectively.

Among the initial 40 patients enrolled to stage 1 of the study at the 5.4-mg/kg dose, at a median follow-up of 10.6 months (range, 2.9-17.1) the cORR was 45.0% (95% CI, 29.3%-61.5%) with a median DOR of 8.1 months (95% CI, 4.2-NE). SD and PD were reported in 20 (50.0%) and 2 patients (5.0%), respectively, and the DCR was 95.0% (95% CI, 83.1%-99.4%). The median total dose was 39.6 mg/kg (range, 10.5-96.8) and the median number of cycles initiated was 8.0 (range, 2-19).

In stage 2, the cORR for the additional 42 enrolled patients was 31.0% (95% CI, 17.6%-47.1%) with a median DOR of 4.6 months (95% CI, 4.1-7.0). SD and PD rates were 47.6% and 14.3%, respectively, with 3 patients (7.1%) not evaluable. The DCR was 78.6% (95% CI, 63.2%-89.7%) at a median follow-up of 7.7 months (range, 0.5-10.3). The median treatment duration was 4.8 months (range, 0.7-10.8), the median total dose was 37.4 mg/kg (range, 5.4-81.3), and the median number of cycles initiated was 7.0 (range, 1-15).

Additional details for the 6.4 mg/kg cohort include a median treatment duration of 4.9 months (range, 0.7-13.8), a median total dose of 40.8 mg/kg (range, 6.4-128.4), and a median number of cycles initiated of 7.0 (range, 1-20).

The mean best percentage change in sum of diameters by blinded independent central review among patients treated with 5.4 mg/kg of trastuzumab deruxtecan was –25.8% (standard deviation [SD], 29.15). The median best percentage change was –23.0 %(min, –100%; max, 43%). In the 6.4-mg/kg cohort, the mean best percentage change in sum of diameters was –22.2% (SD, 29.88) and the median was –23.0% (min, –100%; max, 34%).

In a subgroup analysis, the greatest benefit of response was seen among those who received 5.4 mg/kg was observed those with IHC 3+ disease (n = 64), with a cORR of 46.9% (95% CI, 34.3%-59.8%). “The biggest difference is in the IHC 3+ population where the response rate is nearly 47% compared with 2+/ISH-positive cases where the response rate is 5.6%,” Raghav said. “But notably, in the RAS wild-type and RAS-mutant populations, the response rate was 39.7% [95% CI, 28.0%-52.3%] and 28.6% [95% CI, 8.4%-58.1%], respectively. Patients with prior anti-HER2 therapy derive the same level of clinical benefit [as those without], and responses also occurred across both sides of the colon.”

In terms of safety, treatment-emergent adverse effects (TEAEs) were reported in all but 1 patient in the 5.4-mg/kg safety cohort (n = 83) and all patients in the 6.4-mg/kg safety cohort (n = 39). Grade 3 or higher TEAEs were reported in 49.4% and 59.0% of patients with drug-related grade 3 or higher TEAEs reported in 41.0% and 48.7%, respectively. Serious TEAEs occurred at rates of 24.1%, including 13.3% that were drug-related, in the 5.4-mg/kg cohort. These rates were 30.8% and 15.4% in the 6.4-mg/kg cohort.

TEAEs associated with discontinuation, dose reduction, and drug interruption were reported in 9.6%, 18.1%, and 47.0% of patients in the 5.4-mg/kg group, respectively, and among 7.7%, 25.6%, and 48.7% of patients in the 6.4-mg/kg group, rspectively. These events were drug related in 7.2%, 18.1%, and 26.5% of patients in the 5.4-mg/kg group and among 5.1%, 23.1%, and 25.6% in the 6.4-mg/kg group.

TEAEs resulted in the death of 4 patients in the 5.4-mg/kg group, one of which was drug related, and in 3 patients in the 6.4-mg/kg group, none of which were drug related.

In the 5.4- and 6.4-mg/kg groups the most common any-grade TEAEs were nausea (57.8% vs 56.4%), fatigue (45.8% vs 46.2%), neutropenia (30.1% vs 46.2%), decreased appetite (30.1% vs 15.4%), anemia (26.5% vs 41.0%), thrombocytopenia (25.3% vs 35.9%), alopecia (24.1% vs 28.2%), constipation (24.1% vs 12.8%), diarrhea (22.9% vs 28.2%), and vomiting (20.5% vs 7.7%).

Grade 3 or higher events occurred in the 5.4- and 6.4-mg/kg groups as follows: nausea (8.4% vs 0%), fatigue (9.6% vs 5.1%), neutropenia (16.9% vs 28.2%), decreased appetite (2.4% vs 0%), anemia (9.6% vs 23.1%), thrombocytopenia (6.0% vs 12.8%), diarrhea (2.4% vs 0%), and vomiting (4.8% vs 0%).

Adjudicated drug-related interstitial lung disease (ILD) was reported at any grade in 8.4% of patients in the 5.4-mg/kg cohort, with most events being grade 2 (7.2%) and 1 instance of grade 1 ILD (1.2%). In the 6.4-mg/kg cohort, 12.8% of patients reported ILD. Grade 1 events occurred in 2 patients (5.1%), grade 2 events were observed in 2 patients (5.1%), and 1 patient died because of ILD and was reported as respiratory failure, which was considered unrelated to the study drug by the investigator.

Editor’s note: Dr Raghav reported receiving institutional research grant/funding from Daiichi Sankyo, Bayer, UCB Biosciences, Hibercell, Merck, Janssen, Eisai, AbbVie, Guardant, Innovent, and Xencor; receiving honoraria from Bayer, Daiichi Sankyo, and Seagen; and serving on an advisory board for Daiichi Sankyo, Eisai/Merck, SAGA Diagnostics, Bayer, Seagen, Pfizer, and AstraZeneca.

Reference

Raghav K, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol. 2023;41(suppl 16):3501. doi:10.1200/JCO.2023.41.16_suppl.3501