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Updated Findings on T-DXd in Gastrointestinal Malignancies


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Updates of phase II studies evaluating fam-trastuzumab deruxtecan-nxki (T-DXd) in gastrointestinal cancers were presented at the 2022 ASCO Gastrointestinal Cancers Symposium, continuing to offer support for the antibody-drug conjugate in these malignancies. In HER2-expressing gastric cancer, T-DXd significantly improved overall survival vs chemotherapy in DESTINY-Gastric01.1 In HER2-expressing colorectal cancer, the drug showed promising activity and durability, with longer follow-up in HER2 high-expressors.2

DESTINY-Gastric01

“Trastuzumab deruxtecan demonstrated a clinically meaningful overall survival benefit—approximately a 40% reduced risk of death—and clinically relevant improvement in objective response rate compared with physician’s choice of chemotherapy,” reported Kensei Yamaguchi, MD, of The Cancer Institute Hospital of JFCR, Tokyo. The results, he said, provide further evidence that T-DXd is an effective approach for patients experiencing disease progression after two or more lines of therapy that have included trastuzumab, fluoropyrimidine, and a platinum agent.

DESTINY-Gastric01 enrolled 187 patients with HER2-expressing advanced gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior regimens that included a fluoropyrimidine and a platinum agent. In addition to chemotherapy, all had received trastuzumab, two-thirds had received ramucirumab, and one-fourth had received an immune checkpoint inhibitor. Patients were randomly assigned 2:1 to T-DXd at 6.4 mg/kg every 3 weeks (n = 126) or chemotherapy of physician’s choice (irinotecan or paclitaxel; n = 62).

In the primary analysis, after a median follow-up of 12.3 months, T-DXd conveyed a statistically significant improvement in overall survival and objective response rate over chemotherapy.3 Dr. Yamaguchi presented an updated analysis based on a median follow-up of 18.5 months.

“As in the primary analysis, where there was 54% maturity of the data, in this updated analysis, with 71% maturity, T-DXd showed superior antitumor activity compared with physician’s choice of chemotherapy,” he said.

KEY POINTS

  • Phase II trials of T-DXd in gastrointestinal malignancies confirmed the activity of fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with HER2-expressing disease who were previously treated for advanced gastric and colorectal cancers. 
  • In DESTINY-Gastric01, patients receiving T-DXd had an objective response rate of 51.3% vs 14.3% for those treated with chemotherapy (P < .0001).
  • In DESTINY-CRC01, in the higher HER2-expressing cohort, treatment with T-DXd produced partial responses in 45.3%, median progression-free survival of 6.9 months, and median overall survival of 15.5 months. No benefit was seen in lower HER2-expressing cohorts.

More Outcomes From DESTINY-Gastric01

The objective response rate was 51.3% with T-DXd vs 14.3% with chemotherapy (P < .0001). This included complete responses in 9.2% and 0%, respectively, and confirmed disease control in 85.7% and 62.5%, respectively. Median overall survival was 12.5 months with T-DXd vs 8.9 months with chemotherapy (hazard ratio [HR] = 0.60; 95% CI = 0.42–0.86).

Grade ≥ 3 adverse events occurred in 85.6% of the T-DXd arm vs 56.5% of the chemotherapy arm. The most common side effects were decreased neutrophil count, anemia, and decreased white blood cell count.

Dr. Yamaguchi noted that the 6.4-mg/kg dose evaluated in this study is higher than is used in the treatment of breast cancer, and dose reductions were needed for about half the patients.

Treatment-related adjudicated interstitial lung disease or pneumonitis developed in 16 patients (12.8%), only in the experimental arm. These events were grade 1 or 2 in 13 patients, grade 3 in two patients, and grade 4 in one patient. 

DESTINY-CRC01

The final results of the phase II, multicenter, open-label DESTINY-CRC01 study were presented by Takayuki Yoshino, MD, of the National Cancer Center Hospital East, Kashiwa, Japan, who commented on the latest data: “These promising results support the continued exploration of T-DXd in patients with HER2-positive metastatic colorectal cancer.”

The study enrolled 86 patients with advanced colorectal cancer previously treated with at least two regimens. The study evaluated three cohorts according to the degree of HER2 expression: Cohort A included 53 patients with HER2 expression by immunohistochemistry (IHC) of 3+ or 2+ with fluorescent in situ hybridization (FISH) positivity. Cohort B included 15 who were HER2-positive IHC 2+ and FISH-negative. Cohort C included 18 who were HER2 IHC1+.

The primary analysis was conducted after 27.1 weeks of median follow-up,4 whereas the final analysis represented 62.4 weeks of median follow-up for Cohort A, 27.0 weeks for Cohort B, and 16.9 weeks for Cohort C.

Activity of T-DXd was observed in Cohort A alone, which comprised the strongest HER2 expressors. The objective response rate (all partial responses) was 45.3% for Cohort A, whereas no responses were observed in the other cohorts. The disease control rate was 83.0% for Cohort A, 60.0% for Cohort B, and 22.2% for Cohort C. For Cohort A, the median duration of response was 5.1 months, median progression-free survival was 6.9 months, and median overall survival was 15.5 months.

Adjudicated drug-related interstitial lung disease or pneumonitis developed in eight patients (9.3%), which included three deaths. The condition was grade 2 in four patients, all of whom recovered, and grade 3 in one patient, who later died due to disease progression. All eight patients received corticosteroids, he said.

“Interstitial lung disease and pneumonitis is an important risk and requires careful monitoring and prompt intervention,” Dr. Yoshino acknowledged. 

DISCLOSURE: Dr. Yamaguchi disclosed financial relationships with Bristol Myers Squibb Japan, Daiichi Sankyo, Chugai Pharma, Lilly, Merck, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda. Dr. Yoshino has received honoraria from Bayer Yakuhin, Chugai Pharma, Lilly, Merck, Ono Pharmaceutical, and Taiho Pharmaceutical.

REFERENCES

1. Yamaguchi K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma: Final overall survival results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 242. Presented January 22, 2022.

2. Yoshino T, Di Bartolomeo M, Raghav KPS, et al: Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing metastatic colorectal cancer: Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 119. Presented January 22, 2022.

3. Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020.

4. Siena S, Di Bartolomeo M, Raghav K, et al: Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial. Lancet Oncol 22:779-789, 2021.

 


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