Trastuzumab deruxtecan demonstrated antitumor activity in previously treated patients with HER2-expressing biliary tract cancer, with the strongest responses observed among patients whose tumors were confirmed as HER2 immunohistochemistry 3+. Activity was more limited in the pancreatic cancer cohort, which included few patients with centrally confirmed HER2 IHC 3+ disease.
The findings come from an exploratory subgroup analysis of Part 1 of the phase 2 DESTINY-PanTumor02 trial. The article, titled “Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Biliary Tract or Pancreatic Tumors: A Subgroup Analysis of DESTINY-PanTumor02,” appeared in the August 2026 issue of ESMO Open.
Authors: Do-Youn Oh, Iwona Ługowska, Daniil Stroyakovskiy, Kyoung Ha Jung, Olivier Dumas, Konstantin Penkov, Atichart Dechaphunkul, Ana Oaknin, Se Hoon Kim, Naureen Starling, Bhumsuk Chewaskulyong, Chayanon Charonpongsuntorn, David Doroshow, Shih-Ying Hsiao, Yu-Pei Hung, Li Jung, Natalia Kuptsova-Clarkson, Francesca Michelini, Swati Puvvada, and Funda Meric-Bernstam.
Evaluating T-DXd Across Two Difficult-to-Treat Cancers
Biliary tract and pancreatic cancers are associated with poor outcomes, particularly once the disease becomes metastatic. HER2 IHC 3+ expression is uncommon but represents a potentially actionable biomarker, reported in approximately 1%–19% of biliary tract cancers and 1%–7% of pancreatic cancers.
Trastuzumab deruxtecan, also known as T-DXd, is a HER2-directed antibody-drug conjugate composed of a HER2-targeting monoclonal antibody, a cleavable linker, and a topoisomerase I inhibitor payload.
DESTINY-PanTumor02 is a two-part, open-label, multicenter phase 2 study evaluating T-DXd in patients with HER2-expressing locally advanced, unresectable, or metastatic solid tumors that had progressed after previous systemic treatment or for which no satisfactory alternative treatment was available. The current analysis focused specifically on the biliary tract cancer and pancreatic cancer cohorts from Part 1 of the study.
Study Design and Patient Population
Patients received intravenous T-DXd at a dose of 5.4 mg/kg once every three weeks. Tumor assessments were conducted according to RECIST 1.1 at screening and every six weeks, with a permitted variation of ±1 week.
The primary endpoint was investigator-assessed confirmed objective response rate. Secondary endpoints included duration of response, disease control rate, progression-free survival, overall survival, and safety. An independent central review was also conducted. Exploratory analyses evaluated outcomes according to HER2 expression and amplification, circulating tumor DNA findings, KRAS alterations, PD-L1 status, and previous treatments.
Overall, 41 patients with biliary tract cancer and 25 patients with pancreatic cancer were enrolled across 32 centers in 13 countries between October 2020 and July 2022. The pancreatic cancer cohort was closed to further recruitment under a prespecified futility rule after no objective responses were observed among the first 15 patients. By that time, 25 patients had already been enrolled.
At the June 8, 2023, data cutoff, median follow-up was 6.01 months in the biliary tract cancer cohort and 4.99 months in the pancreatic cancer cohort. Patients in both groups had received a median of two previous treatment regimens.
HER2 Status Differed Between Local and Central Testing
Enrollment could be based on either local or central HER2 testing. In the biliary tract cancer cohort, enrollment testing classified 22 patients as IHC 3+ and 19 as IHC 2+. However, central testing confirmed IHC 3+ disease in 16 patients and IHC 2+ disease in 14.
The difference was more pronounced in pancreatic cancer. Enrollment testing classified five patients as IHC 3+ and 20 as IHC 2+, whereas central testing identified only two patients with IHC 3+ tumors and 19 with IHC 2+ tumors.
This discordance between local and central results was an important limitation of the analysis and highlighted the challenges associated with HER2 testing in biliary tract and pancreatic cancers.
Responses Concentrated in HER2 IHC 3+ Biliary Tract Cancer
In the overall biliary tract cancer cohort, the investigator-assessed objective response rate was 22.0%, with nine responses among 41 patients. Independent central review reported an objective response rate of 26.8%, corresponding to 11 responses. The strongest activity was observed among patients with centrally confirmed HER2 IHC 3+ biliary tract cancer. In this subgroup, nine of 16 patients responded, resulting in an investigator-assessed objective response rate of 56.3%.
All investigator-assessed responses in the biliary tract cancer cohort occurred among patients with centrally confirmed IHC 3+ tumors. No investigator-assessed objective responses were observed in the centrally confirmed IHC 2+, IHC 1+, or IHC 0 groups. Among patients classified as IHC 3+ by the test used for enrollment, the objective response rate was 40.9%.
Additional exploratory findings suggested higher response rates among patients with evidence of HER2 amplification. The investigator-assessed response rate was 42.1% among patients with HER2 amplification detected by tissue in situ hybridization, compared with no responses among patients without tissue amplification. Response rates were 42.9% and 11.5% among patients with and without plasma HER2 amplification, respectively. These exploratory biomarker subgroup analyses did not account for HER2 IHC status.
Stable disease lasting at least five weeks was the best investigator-assessed response in 61.0% of patients with biliary tract cancer. The investigator-assessed disease control rate was 82.9% at six weeks and 65.9% at 12 weeks.
In the overall biliary tract cancer cohort:
- Median investigator-assessed progression-free survival was 4.6 months.
- Median overall survival was 7.0 months.
- Median investigator-assessed duration of response was 8.6 months.
Among patients with centrally confirmed IHC 3+ biliary tract cancer, median progression-free survival was 7.4 months and median overall survival was 12.4 months.
Limited Activity in Pancreatic Cancer
In the pancreatic cancer cohort, one of 25 patients responded according to investigator assessment, resulting in an objective response rate of 4.0%. Independent central review identified three responses, producing an objective response rate of 12.0%. All three centrally reviewed responses occurred in patients with HER2 IHC 2+ disease by central testing.
Stable disease lasting at least five weeks was the best investigator-assessed response in 68.0% of patients. The investigator-assessed disease control rate was 72.0% at six weeks and 36.0% at 12 weeks. Median investigator-assessed progression-free survival was 3.2 months, while median overall survival was 5.0 months.
The pancreatic cancer findings require particular caution. The cohort was small, recruitment was stopped early under the prespecified futility criterion, and only two patients had centrally confirmed HER2 IHC 3+ tumors. Therefore, the study could not reliably determine the activity of T-DXd specifically in HER2 IHC 3+ pancreatic cancer.
Exploratory Findings According to KRAS Status
Responses were observed only among patients without detectable KRAS alterations in baseline circulating tumor DNA. In the biliary tract cancer cohort, the investigator-assessed response rate was 25.0% among patients without detectable KRAS alterations, compared with no responses among the four patients with detected alterations.
In pancreatic cancer, one of eight patients without detectable KRAS alterations responded, while no responses occurred among the 15 patients with detected alterations.
However, these findings cannot establish KRAS status as a predictive biomarker for T-DXd. The subgroup sizes were small, and the distribution of HER2 IHC 3+ tumors differed between patients with and without KRAS alterations. The presence or absence of KRAS alterations in circulating tumor DNA was also not validated in tumor tissue.
Interstitial Lung Disease Remained an Important Safety Risk
Drug-related adverse events were reported in 80.5% of patients with biliary tract cancer and 60.0% of those with pancreatic cancer. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in seven patients with biliary tract cancer, representing 17.1% of the cohort. These events included five grade 2 cases, one grade 3 case, and one grade 5 case. One patient with pancreatic cancer developed grade 1 drug-related interstitial lung disease or pneumonitis.
The grade 5 case occurred in a patient with centrally confirmed HER2 IHC 3+ biliary tract cancer who had received T-DXd for 2.9 months and achieved a partial response. Although the case was adjudicated as drug-related interstitial lung disease or pneumonitis, the reporting investigator considered the cause of death to be related to the underlying disease.
The overall safety findings were consistent with the established safety profile of T-DXd. Nevertheless, interstitial lung disease or pneumonitis remains an important identified risk, reinforcing the need for proactive monitoring, early detection, and active management during treatment.
Limitations
The subgroup analysis had several important limitations. Both cohorts were small, particularly the centrally confirmed HER2 IHC 3+ pancreatic cancer subgroup. Each tumor cohort also included multiple histology types. Heterogeneity in HER2 status, previous treatment, and genetic alterations further complicated the identification of biomarkers or treatment factors associated with response.
The exploratory analyses may also have been limited by the sensitivity of circulating tumor DNA detection. HER2 IHC and in situ hybridization testing were performed on archival tissue, whereas circulating tumor DNA analyses used baseline blood samples. These exploratory findings should therefore be interpreted cautiously, considering the complexity of the diseases and the potential for confounding factors.
Moderate discordance was observed between local and central HER2 results. Tumor heterogeneity, interpathologist variability, tissue-fixation quality, and HER2-staining quality may have contributed to these differences. There are also no validated HER2 scoring guidelines specifically for biliary tract or pancreatic cancer. The findings emphasize the importance of using validated HER2 tests and providing comprehensive training at local testing sites to accurately identify patients who may benefit from HER2-directed treatment.
What the Findings Mean
The DESTINY-PanTumor02 subgroup analysis demonstrated clinically meaningful and durable activity with T-DXd in previously treated patients with HER2-expressing biliary tract cancer, with the greatest benefit observed among patients with HER2 IHC 3+ tumors.
The pancreatic cancer results were less conclusive. Although responses were observed, interpretation was limited by the small cohort, its early closure under the prespecified futility criterion, and the low number of patients with centrally confirmed HER2 IHC 3+ tumors.
Overall, the findings further support the use of T-DXd in previously treated patients with locally advanced, unresectable, or metastatic HER2-positive IHC 3+ cancers. The pancreatic cancer findings remain hypothesis-generating and provide preliminary insight into the potential role of HER2-directed therapy in advanced pancreatic cancer.
The full article is available in ESMO Open.
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