T-DXd for Advanced Solid Tumors With Activating HER2 Mutations

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As reported in The Lancet Oncology by Bob T. Li, MD, PhD, MPH, and colleagues, the phase II DESTINY-PanTumor01 trial showed activity of fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with unresectable or metastatic solid tumors that have specific activating HER2 mutations. The antibody-drug conjugate is currently approved for the treatment of HER2-mutant non–small cell lung cancer (NSCLC).

Bob T. Li, MD, PhD, MPH

Bob T. Li, MD, PhD, MPH

Study Details

One hundred and two patients with solid tumors other than NSCLC with specific activating HER2 mutations (ie, S310F, S310Y, G660D, R678Q, D769Y, D769H, V777L, Y772_A775dup/A775_G776insYVMA, L755S, G778_P780dup/P780_Y781insGSP, T862A, and V842I) were enrolled into the trial from sites in Asia, Europe, and North America between December 2020 and January 2023. Patients had received a median of three (interquartile range [IQR] = 2–4) previous treatment regimens.

The most common tumor types in enrolled patients were breast (20%), colorectal (20%), and biliary tract (19%) cancers. Patients had had disease progression following previous treatment (previous HER2-targeted therapy was permitted) or no satisfactory alternative treatment options.

Treatment consisted of 5.4 mg/kg of T-DXd every 3 weeks until disease progression or unacceptable toxicity. The primary outcome measure of the study was confirmed objective response rate on independent central review.


Median follow-up was 8.61 months (IQR = 3.71–12.68 months). Objective responses were observed in 30 patients (29.4%, 95% confidence interval [CI] = 20.8%–39.3%), including complete response in 2 (2%). Median response duration was not reached (95% CI = 6.8 months to not estimable). Stable disease was observed in an additional 41 patients (40%).

Median progression-free survival was 5.4 months (95% CI = 2.7–7.1 months), with 6- and 12-month rates of 41.4% and 30.9%, respectively. Subsequent anticancer therapy was received by 33 patients (32%). Median overall survival (at 57% data maturity) was 10.9 months (95% CI = 8.3–14.9 months) with 6- and 12-month rates of 67.6% and 46.3%, respectively.


  • T-DXd produced objective response in 29.4% of patients.
  • Median response duration was not reached.

Adverse Events

Grade ≥ 3 adverse events occurred in 51% of patients, most commonly anemia (in 16%), decreased neutrophils (in 8%), asthenia (in 5%), and decreased platelets (in 5%). Serious adverse events occurred in 35% of patients and were considered drug-related in 10%. Adverse events led to discontinuation of treatment in 10 patients (10%), due to interstitial lung disease/pneumonitis in 8 (8%) and peritonitis and pneumonia in 1 patient (1%) each. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11 patients (11%) and was grade 1 in 3, grade 2 in 5, and grade 3 in 1; there were 2 fatal cases.

The investigators concluded: “[T-DXd] showed antitumor activity and durable responses in heavily pretreated patients across multiple tumor types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody–drug conjugates and our findings support further investigation of [T-DXd] in the pan-tumor setting.”

Dr. Li, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AstraZeneca and Daiichi Sankyo. For full disclosures of the study authors, visit

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