Results from a phase I study investigating fam-trastuzumab deruxtecan-nxki (formerly known as DS-8201a; Enhertu®; Daiichi Sankyo and AstraZeneca) showed signs of clinical activity of the targeted agent in multiple non-breast/non-gastric cancer types. The study results were published in the May 2020 issue of Cancer Discovery, a journal of the American Association for Cancer Research (AACR).[1][2]
The study was, in part, funded by Daiichi Sankyo.
Trastuzumab deruxtecan is approved in the United States and Japan for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer that cannot be removed by surgery or that has metastasized to other parts of your body and have received two or more prior anti-HER2 breast cancer treatments.
HER2 is a gene that can promote cancer progression when mutated or expressed at high levels. High expression levels of HER2 have been observed in many different cancer types, including breast, gastric, lung, and colorectal cancers. Several HER2-targeted therapies are approved for the treatment of HER2-overexpressing breast cancer, and one such therapy is approved for gastric cancer.
“HER2-targeted therapies have proven successful for patients with breast and gastric cancers. However, there are no approved HER2-targeted therapies available for patients with other HER2-overexpressing or HER2-mutated malignancies,” said Bob Li, MD, medical oncologist at Memorial Sloan Kettering Cancer Center who was the senior author of the study.
“Conventional therapies for these other HER2-overexpressing cancers tend to have limited efficacy and considerable side effects. Additional treatment options are urgently needed for these patients,” Li added.
Selectively directed
“Therapies that target HER2 can be selectively directed to HER2-overexpressing or HER2-mutated cancer cells, which could improve efficacy and help reduce toxicities caused by off-target effects on normal cells,” explained Junji Tsurutani, M.D., Ph.D., a medical oncologist at the Advanced Cancer Translational Research Institute at Showa University in Tokyo and lead author of the study.
“Advances in diagnostic testing have improved clinicians’ ability to determine a tumor’s HER2 status, and have thus expanded the population of patients who might benefit from HER2-targeted therapies, Tsurutani further explained.
In this phase I study, Tsurutani, Li, and colleagues tested the safety and clinical activity of the HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan in patients with several different advanced HER2-overexpressing or HER2-mutated solid tumors.
Antibody-drug conjugate
Trastuzumab deruxtecan incorporating an anti-HER2 antibody (trastuzumab), an enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd).
The antibody selectively binds to HER2-expressing cancer cells, and DXd is then released into the target cell, where its inhibitory effect on DNA replication leads to cell death. DXd can also enter and kill neighboring cancer cells due to its ability to pass through cell membranes. Results published within the last year demonstrated promising antitumor activity of trastuzumab deruxtecan in HER2-overexpressing breast and gastric cancers.
In December 2019, trastuzumab deruxtecan was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior treatments with HER2-targeted therapy in the metastatic setting.
Study design
The study included 60 patients with HER2-overexpressing non-breast/non-gastric solid tumors and/or HER2-mutated solid tumors. From a total of 60 patients, 20 patients were diagnosed with colorectal cancer, 18 patients had non-small cell lung cancer (NSCLC), and 22 patients were classified as having “other” cancer types.
These “other” types of cancer included salivary gland tumors (eight patients), esophageal cancer (two patients), endometrial cancer (two patients), biliary tract cancer (two patients), Paget’s disease (two patients), pancreatic cancer (one patient), uterine cervix carcinoma (one patient), extraskeletal myxoid chondrosarcoma (one patient), and small intestine adenocarcinoma (one patient). Additionally, two cases of HER2-mutated breast cancer were included in this category.
Study results
All participating patients were evaluated for response. The investigators observed an overall objective response rate (ORR) of 28.3% with a median progression-free survival (mPFS) of 7.2 months. The median overall survival (mOS) was 23.4 months.
The objective response rate was greatest for NSCLC, with 55.6% of patients having a confirmed objective response (10 partial responses). In HER2-mutant NSCLC, the objective response rate was 72.7% (8 partial responses).
The objective response rates for colorectal cancer and “other” cancer types were 5% (one partial response) and 27.3% (five partial responses and one complete response), respectively.
Adverse events
The frequency of treatment-emergent adverse events (TEAEs) was similar across the different tumor types. Overall, 62.7% of patients experienced a TEAE that was grade 3 or higher, and 30.5% experienced serious TEAEs. The most common TEAEs were anemia; decreased counts of neutrophils, white blood cells, and platelets; decreased appetite; increased levels of aspartate aminotransferase, which is a biomarker for liver damage; febrile neutropenia; and decreased blood levels of sodium. Five patients had drug-related interstitial lung disease.
Five patients experienced an adverse event with a fatal outcome, of which two were reported to be treatment-related. One of the treatment-related deaths was due to drug-related interstitial lung disease. Forty-nine patients discontinued treatment due to disease progression, adverse events, death, patient withdrawal, or other reasons.
Additional studies
In an unrelated study published by Li and colleagues in Cancer Discovery, trastuzumab deruxtecan led to a partial response in a patient with lung cancer who had relapsed after treatment with another HER2-targeted ADC, ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).
This study, funded in part by the National Cancer Institute, the AACR-Conquer Cancer Foundation of ASCO Young Investigator Award for Translational Cancer Research, the Carol Lowenstein Fund, Genentech, and Puma Biotechnology, also demonstrated that trastuzumab emtansine treatment led to clinical responses in patients with HER2-mutant or amplified lung cancers and that combining trastuzumab emtansine with an irreversible HER kinase inhibitor enhanced cellular uptake of the drug in cell culture.
The investigators also observed that the combination treatment with trastuzumab emtansine and an irreversible HER kinase inhibitor led to a partial response in a patient with breast cancer who had previously relapsed on trastuzumab emtansine. Together, results from this second study suggest that trastuzumab deruxtecan or a combination of trastuzumab emtansine and an HER kinase inhibitor could be explored as potential treatment options for patients with relapse on trastuzumab emtansine.
Safety profile
“The safety profile of trastuzumab deruxtecan is consistent with the previously reported breast and gastric cancer cohorts from this phase I study,” said Li.
“Interstitial lung disease is an important identified adverse event that may be serious – even fatal – and thus requires monitoring and prompt intervention. Further research is required to minimize and manage this risk,” he added.
“Trastuzumab deruxtecan demonstrated promising antitumor activity in a heterogeneous patient population,” observed Tsurutani.
“These results indicate that trastuzumab deruxtecan should be explored in larger studies as a treatment option for patients with HER2-overexpressing or HER2-mutated solid tumors,” concluded.
Li also noted, “We are very excited by the results of this preliminary study. Trastuzumab deruxtecan shows early promise for transforming the standard of care for patients with HER2-overexpressing or HER2-mutated cancers and we look forward to continuing this important research in future clinical trials.”
Commenting on the results of the second study, Li said: “This study shows the power of translational science through bench-to-bedside-and-back discoveries. This team approach has provided mechanistic understanding and helped us to develop ADCs as a potential new class of drugs for patients with lung cancers and other solid tumors.”
Study limitations
The investigators acknowledged that the limitations of the study included the small sample size, both overall and within each tumor type, as well as the limited diversity of HER2 mutations included in the study. Larger clinical trials are ongoing.
Clinical trials
Study of DS-8201a in Subjects With Advanced Solid Malignant Tumors – NCT02564900
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer – NCT03505710
Neratinib HER Mutation Basket Study (SUMMIT) – NCT01953926
Highlights of prescribing information
Niraparib (Zejula®; Tesaro/GSK). [Prescribing Inform]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Inform]
Ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)[Prescribing Information]
Fam-trastuzumab deruxtecan-nxki (DS-8201a; Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]
Reference
[1] Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors [published correction appears in Cancer Discov. 2020 Jul;10(7):1078]. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014 [AACR][Pubmed][Article]
[2] Correction: Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discov. 2020;10(7):1078. doi:10.1158/2159-8290.CD-20-0703
Featured Image: Research and development. Photo courtesy: © 2020 AstraZeneca. used with permission.
