Positive results from the ongoing DESTINY-PanTumor02 phase 2 trial (ClinicalTrials.gov Identifier: NCT04482309) * confirms that trastuzumab deruxtecan ([fam-trastuzumab deruxtecan-nxki in the U.S. only] Enhertu®; Daiichi Sankyo and AstraZeneca) continues to demonstrate clinically meaningful and durable responses, leading to a clinically meaningful survival benefit in previously treated patients across multiple human epidermal growth factor receptor 2 (HER2) expressing advanced solid tumors.

These results, which include the first progression-free survival (PFS) and overall survival (OS) findings reported from the trial, were presented as a late-breaking mini-oral session (LBA34) at the annual meeting of the European Society for Medical Oncology (#ESMO23) being held October 20 – 24, 2023 in Madrid, Spain, and simultaneously published in the Journal of Clinical Oncology.

HER2 in Sold Tumors
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.[1][2]

As a well-recognized mediator of the cancerogenic process, the dysregulated of HER2 is observed in a wide range of solid tumors, including, but not limited, via protein overexpression and/or gene amplification, making HER2 an attractive target for tailored treatment. [3]

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In some cancers, HER2 expression is amplified or the cells have activating mutations. [1][4]

HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.[5]

While HER2 directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2 expressing solid tumor types. [2][6][7]

HER2 is an emerging biomarker in solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers. [8]

Routine testing
However, in contrast to testing HER2 status in breast cancer, testing is not routinely performed in these additional tumor types and as a result, available literature is limited. However, HER2 overexpression (IHC 3+) has been observed at rates from 1% to 28% in these solid tumors. [8][9]

And while testing for HER2 is more common in breast cancer to to determine whether the HER2 protein is overexpressed ** in cancer cells, routine testing is only recommended for patients with invasive breast cancer. Guidelines for HER2 testing (in Breast Cancer) published by the College of American Pathologists, recommend using immunohistochemistry assay (IHC) and fluorescence in situ hybridization (FISH) tests to detect HER2 status in breast cancer cells. Earlier this year, these guidelines were updated to include trastuzumab deruxtecan for the treatment of metastatic breast cancer patients with HER2 protein over-expression/amplification.[10]

Unmet medical need
There is an unmet need for effective therapies for certain HER2 expressing solid tumors, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2 directed therapies for these cancers. [2][11]

A targeted drug
Trastuzumab deruxtecan is a HER2 directed Antibody-drug Conjugates or ADC. The drug is designed using Daiichi Sankyo’s proprietary DXd ADC technology, trastuzumab deruxtecan, which is developed and commercialized by Daiichi Sankyo and AstraZeneca, consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.Analysis
In the primary analysis, trastuzumab deruxtecan continued to show a confirmed objective response rate (ORR) of 37.1% (95% confidence interval [CI]: 31.3-43.2), as assessed by investigator, in the overall population of previously treated patients (n=267) with HER2 expressing advanced solid tumors, including either biliary tract, bladder, cervical, endometrial, ovarian, pancreatic or other tumors. A median duration of response (DOR) of 11.3 months (95% CI: 9.6-17.8) was seen with a median PFS of 6.9 months (95% CI: 5.6-8.0) and median OS of 13.4 months (95% CI: 11.9-15.5). Median follow-up was 12.75 months as of the data cut-off of June 8, 2023.

The highest response rates continued to be seen in the exploratory analysis of patients with tumor HER2 expression of immunohistochemistry (IHC) 3+ (n=75) as confirmed by central testing, where trastuzumab deruxtecan demonstrated a confirmed ORR of 61.3% (95% CI: 49.4-72.4). A median DOR of 22.1 months (95% CI: 9.6-NR) was achieved in this population of patients with HER2 IHC 3+ expression, with trastuzumab deruxtecan demonstrating a median PFS of 11.9 months (95% CI: 8.2-13.0) and a median OS of 21.1 months (95% CI: 15.3-29.6).

These clinically meaningful outcomes affirm the interim DESTINY-PanTumor02 results presented earlier this year at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

“These primary analysis results confirm the efficacy shown at an interim analysis of the DESTINY-PanTumor02 trial, with responses leading to clinically meaningful survival outcomes across a broad range of HER2 expressing solid tumors,” noted Funda Meric-Bernstam, MD, Chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and Principal Investigator for the trial.

“Based on these results, trastuzumab deruxtecan has the potential to change the course of disease for certain patients with HER2 expressing advanced cancers who have limited treatment options and currently no approved HER2 directed therapies.”

The safety profile observed in DESTINY-PanTumor02 was consistent with previous clinical trials of trastuzumab deruxtecan with no new safety concerns identified. Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 40.8% of patients. The most common grade 3 or higher TEAEs occurring in ≥5% of patients were neutropenia (19.1%), anemia (10.9%), fatigue (7.1%) and thrombocytopenia (5.6%). In DESTINY-PanTumor02, 10.5% of patients (n=28) experienced interstitial lung disease (ILD) or pneumonitis of any grade related to treatment with trastuzumab deruxtecan as determined by an independent adjudication committee.

The majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 2.6%] or grade 2 [n=17; 6.4%]) with one grade 3 (0.4%), zero grade 4 (0%) and three grade 5 (1.1%) events observed.

“Improving survival outcomes for patients is one of the primary goals of cancer treatment and the clinically meaningful progression-free and overall survival results seen in DESTINY-PanTumor02 are encouraging,” noted Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo.

“These results provide additional evidence for trastuzumab deruxtecan to potentially become the first antibody drug conjugate approved in a tumor agnostic setting in patients whose tumors express HER2.”

“These updated data from DESTINY-PanTumor02 continue to illustrate the importance of HER2 as an actionable biomarker across a range of studied solid tumor types,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca.

“Trastuzumab deruxtecan has the potential to offer improved outcomes for specific patients with previously treated HER2 expressing cancers and we hope to bring this important medicine to patients as quickly as possible,” Massacesi added.

In DESTINY-PanTumor02, 40.8% of patients (n=109) had received three or more prior lines of therapy. As of the data cut-off of June 8, 2023, a total of 267 patients had received treatment and of those 75 (28.1%) were IHC 3+ as determined by central testing.


Note: * The DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of trastuzumab deruxtecan (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors.
** Overexpression of HER2 protein is associated with more aggressive breast cancer and a higher risk of recurrence

Clinical trials
DESTINY-PanTumor02 | A Phase 2 Study of T-DXd in Patients With Selected HER2 Expressing Tumors (DPT02 (ClinicalTrials.gov Identifier: NCT04482309)

Highlights of Prescribing Information
Trastuzumab deruxtecan ([fam-trastuzumab deruxtecan-nxki in the U.S. only] Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]

References
[1] ASCO. Breast Cancer. Accessed October 2023. [Abstracts]
[2] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi: 10.1155/2014/852748. Epub 2014 Sep 7. PMID: 25276427; PMCID: PMC4170925..
[3] Martin V, Cappuzzo F, Mazzucchelli L, Frattini M. HER2 in solid tumors: more than 10 years under the microscope; where are we now? Future Oncol. 2014 Jun;10(8):1469-86. doi: 10.2217/fon.14.19. PMID: 25052756.
[4] Omar N, Yan N, Salto-Tellez M. HER2: An emerging biomarker in non-breast and non-gastric cancers Pathogenesis. 2015;2(3):1-9.[Article]
[5] Pillai RN, Behera M, Berry LD, Rossi MR, Kris MG, Johnson BE, Bunn PA, Ramalingam SS, Khuri FR. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017 Nov 1;123(21):4099-4105. doi: 10.1002/cncr.30869. Epub 2017 Jul 25. PMID: 28743157; PMCID: PMC5650517..
[6] National Cancer Institute. Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer. Accessed October 2023.
[7] Siena S, Sartore-Bianchi A, Marsoni S, Hurwitz HI, McCall SJ, Penault-Llorca F, Srock S, Bardelli A, Trusolino L. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018 May 1;29(5):1108-1119. doi: 10.1093/annonc/mdy100. PMID: 29659677; PMCID: PMC5961091..
[8] Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015 Mar;34(1):157-64. doi: 10.1007/s10555-015-9552-6. PMID: 25712293; PMCID: PMC4368842.
[9] Buza N, English DP, Santin AD, Hui P. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Mod Pathol. 2013 Dec;26(12):1605-12. doi: 10.1038/modpathol.2013.113. Epub 2013 Jun 14. PMID: 23765245..
[10] Schnitt SJ, Tarantino P, Collins LC. The American Society of Clinical Oncology-College of American Pathologists Guideline Update for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Arch Pathol Lab Med. 2023 Sep 1;147(9):991-992. doi: 10.5858/arpa.2023-0187-ED. PMID: 37303241. [Guidelines]
[11] Meric-Bernstam F, Farhangfar C, Mendelsohn J, Mills GB. Building a personalized medicine infrastructure at a major cancer center. J Clin Oncol. 2013 May 20;31(15):1849-57. doi: 10.1200/JCO.2012.45.3043. Epub 2013 Apr 15. PMID: 23589548; PMCID: PMC4878103.

Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

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