Key Points:
- Interim results of the phase 2 trial DESTINY-PanTumor-02 show that T-DXd has broad activity across tumor types and a toxicity profile consistent with previous studies.
- T-DXd had the lowest activity in pancreatic cancer, and this cohort was stopped early.
- Responses were especially high among patients who had cervical, endometrial, and ovarian cancers.
The interim results of the phase 2 trial DESTINY-PanTumor-02, a tumor-agnostic
study including a range of HER2-expressing solid tumors, show that trastuzumab deruxtecan (T-DXd) has broad activity across tumor types and a toxicity profile consistent with previous studies (LBA3000).
The antibody-drug conjugate (ADC) T-DXd consists of the humanized monoclonal antibody trastuzumab covalently linked to the TOP1 inhibitor deruxtecan. T-DXd is approved by the U.S. Food and Drug Administration for use in unresectable or metastatic HER2-positive breast cancer, HER2-low breast cancer, HER2-mutant non–small cell lung cancer, and locally advanced or metastatic HER2-positive gastric cancer.1-4
DESTINY-PanTumor-02 is an international, open-label study that involved 267 patients across 7 different cohorts, including 6 tumor-specific cohorts (urothelial bladder, biliary tract, cervical, endometrial, ovarian, and pancreatic cancers) as well as a rare tumor cohort that included a range of tumor types for which T-DXd is currently either not available or not being investigated (including head and neck cancers and intestinal adenocarcinoma). Patients received T-DXd 5.4 mg/kg every 3 weeks. DESTINY-PanTumor-02 excluded patients with breast cancer, gastric cancer, non–small cell lung cancer, and colon cancer in whom HER2 directed therapies are already available.
To be eligible for the trial, patients had to have a HER2 immunohistochemistry (IHC) score of 2+ or 3+. For eligibility, HER2 status was assessed at the local trial site or through testing at a central site if local testing was not available. Patients also had to have received at least 1 prior systemic therapy or have no treatment options.
“This is a really exciting trial because it is the first basket trial looking at trastuzumab deruxtecan across tumor types. In the phase 1 trial,5 multiple tumor types were involved and there was a signal of efficacy, which led to the thought that that trastuzumab deruxtecan could have broader efficacy,” said Funda Meric-Bernstam, MD, of The University of Texas MD Anderson Cancer Center. Dr. Meric-Bernstam presented the findings during the 2023 ASCO Annual Meeting.
DESTINY-PanTumor-02 Interim Results
Among the 267 patients, the objective response rate (ORR) associated with T-DXd treatment was 37.1%.
“It is also notable that there was a long duration of response for responders,” Dr. Meric-Bernstam said.
Nearly half (49.6%) of the patients who had an objective response continued to have a response at 12 months. Another 41.6% of patients had stable disease, many with prolonged disease control.
HER2 status was confirmed by central testing for 200 patients, of whom 125 were HER2 IHC2+ and 75 were IHC3+. The ORR was 27.2% and 61.3% among patients with a confirmed IHC2+ and IHC3+ score, respectively. “The response rate of 27.2% is compelling, but it was strikingly high in the IHC3+ population,” Dr. Meric-Bernstam said.
Responses were observed across all the tumor types in the study. T-DXd had the lowest activity in pancreatic cancer, and this cohort was stopped early. In this cohort, there was 1 response among 25 patients by investigator review and, interestingly, 3 responses by independent central review, with several patients with prolonged disease control, Dr. Meric-Bernstam said. Notably, this cohort had only 2 patients who were IHC3+, she added.
On the other hand, responses were especially high among patients who had cervical, endometrial, and ovarian cancer—50.0%, 57.5%, and 45.0%, respectively—which could be because the deruxtecan payload is particularly active for these tumor types, Dr. Meric-Bernstam said.
Data on overall survival and progression-free survival for DESTINY-PanTumor-02 are still being analyzed.
DESTINY-PanTumor-02: Potential Clinical Implications and Analysis
“The responses in this study are definitely the level of activity that one would expect would really change practice and, in line or in most cases better, than the activity level of the standard options for that tumor type,” Dr. Meric-Bernstam said. “The fact that that we saw activity across a variety of tumor types … highlights that HER2 is a compelling target that we should be looking at regularly.”
“The fact that that we saw activity across a variety of tumor types … highlights that HER2 is a compelling target that we should be looking at regularly.” – Dr. Funda Meric-Bernstam
The rate of drug-related treatment-emergent adverse events (TEAEs) among the 267 patients was 84.3%, and 38.6% of patients had a grade 3 or higher drug-related TEAE, with drug-related TEAEs associated with dose discontinuations, dose interruptions, and dose reductions in 8.2%, 18.4%, and 18.7% of patients, respectively. The most common drug-related TEAEs—nausea, fatigue, and neutropenia—were similar to what previous studies of T-DXd found, and there were no new safety signals, Dr. Meric-Bernstam said.
“An important aspect of this study is that it is the first one to take a tumor-type agnostic approach for treatment with ADC. This approach has been used with immunotherapy for high microsatellite instability tumors and targeted therapies, such as for tumors with BRAF and NTRK fusions,” said Kohei Shitara, MD, of the National Cancer Center Hospital East, in Kashiwa, Japan, who was the Discussant for the abstract.
“Overall, the result is quite impressive,” Dr. Shitara added. “If trastuzumab deruxtecan gets approved as a tumor-type agnostic therapy for HER2-expressing tumors, the quality assurance of the immunohistochemistry test will be very important.”
Dr. Shitara also noted that it will be interesting to see data in the future about the detailed efficacy results in patients with HER2 status that were discordant between central and local IHC testing.
“There is also some debate whether IHC is a suitable test for a tumor-type agnostic approach or whether next-generation sequencing [NGS] is more suitable because it is widely available internationally. I think IHC is more convenient for screening, and NGS, especially using circulating tumor DNA, could be complementary,” Dr. Shitara said.
“HER2 expression is not routinely tested, but I do think that the results of this study will increase the frequency of HER2 IHC testing because the study shows that there is a compelling treatment option, and HER2 expression is frequent enough in these tumor types,” Dr. Meric-Bernstam said.
— Carina Storrs, PhD
ASCO Daily News updated the article to clarify the FDA-approved indication for trastuzumab deruxtecan.
References
- Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621.
- Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
- Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251.
- Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430.
- Tsurutani J, Iwata H, Krop H, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688-701.
This article was published by: ASCO Daily News