*For medical professionals only
The results of the DESTINY-Lung05 study were released, adding strong evidence-based evidence for the application of T-DXd in HER2-mutant NSCLC in China.
From April 5 to 10, 2024, the American Association for Cancer Research Annual Meeting (AACR) was successfully held in San Diego, USA. As the first approved ADC drug in the field of lung cancer, the conference brought together many cutting-edge research results in the field of lung cancer, and its research progress has attracted much attention. Data from the DESTINY-Lung05 (DL05) study of T-DXd in the Chinese HER2-mutant NSCLC population were presented at the conference, which showed an objective response rate (ORR) of 58.3% and a 12-month PFS rate of 55.1% as assessed by an independent central review (ICR), with a favorable safety profile [1]. This study further validates the benefit of T-DXd in HER2-mutant NSCLC and provides new evidence for its application in the Chinese population. On this occasion, the Medical Oncology Channel invited the principal investigator Professor Cheng Ying to interpret the results of the study in depth to inspire clinical practice.
Research interpretation
■ Background
No treatment has been approved in China for patients with HER2-mutated advanced NSCLC. The DESTINY-Lung 02 (DL02) study confirmed that T-DXd showed good efficacy, benefit, and manageable safety profile in patients with treatment-experienced HER2-mutated advanced NSCLC. However, the DL02 study did not include Chinese patients. At this AACR Congress, the efficacy and safety of T-DXd monotherapy in Chinese patients with HER2 mutation metastatic advanced NSCLC will be reported.
■ Research design
The DESTINY-Lung05 study is an open-label, single-arm Phase II clinical trial to evaluate the efficacy and safety of T-DXd 5.4 mg/kg in Chinese patients with HER2-mutant metastatic NSCLC whose disease has progressed on or after ≥1st line of anti-tumor therapy. The primary endpoint of the study was ORR determined by independent central review (ICR), and the secondary endpoints were investigator-assessed (INV) ORR, ICR and INV-confirmed duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and safety.
Figure 1. DESTINY-Lung05 study design
■ Research results
Patient baseline
A total of 72 patients with HER2-mutant NSCLC were included, with a median age of 47 years, 58.3% of whom had received ≥ 2nd line of therapy, 93.1% of whom had received prior cytotoxic chemotherapy, 90.3% of whom had received platinum-containing chemotherapy, 68.1% of whom had received immunotherapy, and 68.1% of whom had received anti-angiogenic drugs.
Figure 2. Baseline status of patients in the DL05 study
Efficacy results
At data cut-off (September 23, 2023), the median follow-up was 9.8 months, with an ICR-determined ORR of 58.3% (95% CI 46.1-69.8) for both ICR and INV, with one patient achieving a complete response (CR) and 41 patients achieving a partial response (PR), an ICR-confirmed DCR of 91.7% (95% CI 82.7-96.9), and a 12-month PFS rate of 55.1%; The DCR determined by INV was 93.1% (95% CI 84.5-97.7) and the mPFS was 10.8 months.
Figure 3. Change from baseline in target lesion size
Figure 4. PFS analysis of the DL05 study
Security Data
The incidence of grade ≥3 adverse reactions was 51.4%, and the most common ≥grade 3 adverse reactions were neutropenia, thrombocytopenia and leukopenia, among which 7 patients (9.7%) developed drug-related interstitial lung disease/non-infectious pneumonia, and the safety was manageable and controllable.
Figure 5. Safety results of the DL05 study
■ Conclusions of the study
The DL05 study showed that T-DXd has good efficacy and controllable safety profile in Chinese patients with HER2 mutation metastatic NSCLC, and the results are consistent with DL02, which supports the use of T-DXd in the Chinese HER2-mutant advanced NSCLC population and is of great guiding significance for the treatment of Chinese patients.
Expert commentary
There are still difficulties in the post-line treatment of advanced NSCLC, and new treatment options need to be explored urgently
HER2-mutant NSCLC accounts for approximately 2 to 4 percent of total NSCLC [2], and the incidence of HER2 mutations is higher in Asian populations than in European and American populations (1.4 to 6.7 versus 1 to 3 percent) [3], and the incidence of HER2-mutant NSCLC in mainland China is 4.3 percent [4]. HER2 is a key biomarker for cancer therapy, and the current application exploration of anti-HER2 targeted therapy in NSCLC mainly focuses on monoclonal antibodies and small molecule tyrosine kinase inhibitor (TKI) drugs, but for patients with HER2 mutations in advanced treatment-experienced NSCLC, the ORR is less than 30% and the mPFS is less than 6.9 months [5], and the overall survival benefit needs to be further improved. In the past, due to the lack of effective and selective targeted drugs, HER2-mutant NSCLC mainly referred to the treatment mode of patients with negative driver genes, but after the progression of standard therapy, chemotherapy was still the main treatment, and its efficacy and safety were not ideal, and new treatment strategies need to be explored urgently.
T-DXd breaks through the dilemma of diagnosis and treatment of HER2-mutant NSCLC, or sets a new standard for the treatment of HER2-mutant NSCLC in China
In recent years, the advent of new ADC drugs has rewritten the treatment landscape of HER2-mutant NSCLC. The DL01 and DL02 studies demonstrated the excellent performance of T-DXd in treatment-experienced HER2-mutated advanced NSCLC [6,7]. Based on the results of the DL01 and DL02 studies, T-DXd was approved for the ≥ 2nd line treatment of HER2-mutated advanced NSCLC in the United States, the European Union, and Japan. In this DL05 study, the ICR-confirmed ORR was 58.3%, the DCR was 91.7%, and the 12-month PFS rate was 55.1%, with a manageable safety profile[1]. The results of this study once again verified the therapeutic benefit of T-DXd in HER2-mutant NSCLC, and provided a solid basis for its application in the Chinese population.
The excellent performance of T-DXd in HER2-mutated advanced NSCLC is due to the innovative structural design and unique mechanism of action. T-DXd has the unique advantages of highly active topoisomerase I inhibitor loading, stable intracell-specific cleavage tetrapeptide linkers, up to 8 DARs, and potent bystander effects. In terms of mechanism of action, unlike anti-HER2 monoclonal antibodies or HER2 TKIs, T-DXd enters tumor cells with HER2 mutations under HER2-mediated endocytosis, and is subsequently specifically recognized and degraded by lysosomal proteases, releasing highly active drug-loading to kill tumors, and high DAR and bystander effects help enhance the killing effect of T-DXd on tumor cells [8,9]. In addition, HER2 mutations may enhance the internalization of ADC drugs through the formation of HER2 homodimers or heterodimers, thereby effectively improving the anti-tumor activity of ADC drugs [10].
T-DXd continues to accumulate evidence-based evidence to enrich the treatment decisions of HER2-mutant NSCLC
T-DXd is an important breakthrough in the history of HER2-mutant NSCLC treatment, which has successfully opened a new journey of anti-HER2 therapy in the field of lung cancer. T-DXd is also moving to the first line, and the Phase III DESTINY-Lung04 study is underway in China to evaluate the efficacy and safety of T-DXd versus pembrolizumab + chemotherapy in the first-line treatment of patients with locally advanced or advanced NSCLC harboring HER2 mutations. Together with the results of the DL05 study, this study will provide important evidence-based support for the application of T-DXd in China. A phase I clinical trial is designed to evaluate the efficacy and safety of T-DXd+pembrolizumab in the cohort of HER2-overexpressing and HER2-mutant NSCLC patients, and the exploration of the combination regimen will provide new treatment ideas for HER2-overexpressing NSCLC.
In conclusion, T-DXd has created a new situation in the treatment of HER2-mutant NSCLC, and this DL05 study has added new evidence, providing an opportunity for standard treatment for HER2-mutant NSCLC patients in China.
Expert Profile
Prof. Ying Cheng
- First-level professor, doctoral supervisor, postdoctoral workstation supervisor
- He enjoys the special allowance of the State Council and has made outstanding contributions to young and middle-aged experts from the Ministry of Health
- Director of Jilin Provincial Cancer Center
- Director of Jilin Provincial Lung Cancer Diagnosis and Treatment Center
- Vice President of the Chinese Society of Clinical Oncology (CSCO).
- Member of the International Alliance for Lung Cancer (IASLC) Rare Tumors Committee
- Chairman of the CSCO Small Cell Lung Cancer Professional Committee
- Chairman-elect of the CSCO Clinical Research Expert Committee
- He is the chairman-designate of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association
- Vice Chairman of CSCO Non-Small Cell Lung Cancer Professional Committee
- Vice Chairman of CSCO Tumor Big Data Expert Committee
- Vice Chairman of the Lung Cancer Committee of the Oncology Branch of the Chinese Medical Association
- Vice Chairman of the Multidisciplinary Diagnosis and Treatment Committee of Tumors of the Chinese Medical Doctor Association
- Member of the Expert Group on Standardized Diagnosis and Treatment of Common Tumors of the National Health and Family Planning Commission
- Chairman of the Oncologist Branch of Jilin Medical Doctor Association
- Chairman of the Oncology Professional Committee of Jilin Provincial Medical Association
- 2023 "Global Highly Cited Researcher" in the field of clinical medicine
Bibliography:
[1] A phase 1/2a, multicenter, open-label, first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 (a B7-H3-targeting ADC) in patients with advanced/metastatic solid tumors. AACR Abstract CT165/16
[2] Mar N, Vredenburgh JJ, Wasser JS. Targeting HER2 in the treatment of non-small cell lung cancer. Lung Cancer. 2015 Mar; 87(3):220-5.
[3] Ren S, Wang J, Ying J, et al. Consensus for HER2 alterations testing in non-small-cell lung cancer. ESMO Open. 2022; 7(1):100395.
[4] Wen S, Dai L, Wang L, et al. Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer. Oncologist. 2019; 24(11):e1070-e1081.
[5] Cooper AJ, Gainor JF. Human Epidermal Growth Factor Receptor 2-Mutant Non-Small-Cell Lung Cancer: Continued Progress But Challenges Remain. J Clin Oncol. 2022 Mar 1; 40(7):693-697.
[6] Li BT, Smit EF, Yasushi Goto Y, et al. Phase 2 Trial of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non–Small Cell Lung Cancer: Updated Analyses From DESTINY-Lung01. 2022ESMO. 976P.
[7] Janne P, Goto Y, Kubo T, et al. Trastuzumab Deruxtecan in Patients with HER2-Mutant Metastatic Non-Small Cell Lung Cancer: Primary Results of DESTINY-Lung02. 2023 WCLC. MA13.10.
[8] Nakada T, Sugihara K, Jikoh T, et al. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo). 2019; 67(3):173-185.
[9] Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 2016 Oct 15; 22(20):5097-5108.
[10] Pahuja KB, Nguyen TT, Jaiswal BS, et al. Actionable activating oncogenic ERBB2/HER2 transmembrane and juxtamembrane domain mutations. Cancer Cell 2018; 34:792–806.
[11] Shun Lu et al. Safety, tolerability, pharmacokinetics, and efficacy of SHR-A1811, an antibody-drug conjugate, in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC): a multicenter, open-label, phase 1/2 study.2023 AACR, Poster CT204.
* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform