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Learn about the key points of the 2024 CSCO NSCLC and SCLC guidelines for DXd-ADC drugs in this article.
The 2024 Chinese Society of Clinical Oncology (CSCO) Guidelines Conference was held on April 26-27, and the latest version of the CSCO guidelines for lung cancer was officially released at this conference. In the field of non-small cell lung cancer (NSCLC), trastuzumab (T-DXd), as the first approved ADC drug in the field of lung cancer, has brought a new revolution to the field of diagnosis and treatment of HER2-mutant NSCLC. These developments have led to the updating of the CSCO Guidelines for the Diagnosis and Treatment of NSCLC (2024). At the same time, in the field of small cell lung cancer (SCLC), the therapeutic potential of I-DXd (DS-7300), a novel ADC drug targeting B7-H3, has been validated, and relevant evidence-based evidence has also become the highlight of the update of the CSCO SCLC Diagnosis and Treatment Guidelines (2024). The key points of DXd-ADC drug updates in the guidelines and their related bases are summarized as follows for the benefit of readers.
Update highlights: T-DXd monotherapy for the post-line treatment of HER2-mutant advanced NSCLC, and the recommended level has been raised to grade II
The clinical efficacy of T-DXd in HER2-mutated advanced NSCLC has been fully validated in the previous phase II DESTINY-Lung02 study, and subgroup data from Asian populations (Japan, South Korea, and Taiwan) have shown consistent benefit. Phase II DESTINY-Lung05 is a Chinese bridging study of DESTINY-Lung02 designed 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
According to the results presented at the 2024 AACR Congress [1], a total of 72 patients with HER2-mutant NSCLC were included in the study, of whom 58.3% had received ≥ 2nd line therapy, 93.1% had received prior cytotoxic chemotherapy, 90.3% had received platinum-containing chemotherapy, and 68.1% had received prior immunotherapy and anti-angiogenic drugs. Although the previous treatment of the enrolled patients is very complex, it undoubtedly poses considerable challenges and difficulties for subsequent treatment. However, the performance of T-DXd was still surprising, with an ICR-confirmed ORR (cORR) of 58.3%, and 1 patient achieved a complete response (CR) and 41 patients achieved a partial response (PR) with a CR of 91.7% and 93.1% ;D mPFS, respectively, and a 12-month PFS rate of 55.1% as assessed by ICR, respectively.
Figure 2. Percent change from baseline in target lesion size
图3. DESTINY-Lung05研究的中位PFS
In addition, in terms of safety, the incidence of grade 3 adverse reactions ≥ INV was 51.4%, most of which were hematologic toxicities, and only 2 patients (2.8%) discontinued the drug due to drug-related adverse events. The overall safety profile was good, the adverse reaction spectrum was consistent with that of the global population, and no new safety signals appeared.
In conclusion, the DESTINY-Lung05 study fully validated the therapeutic benefit of T-DXd in Chinese patients with HER2-mutated advanced NSCLC, and the overall results were consistent with those of the DESTINY-Lung02 study. Together, these support the clinical application of T-DXd in HER2-mutant advanced NSCLC in China. The 2024 CSCO NSCLC guidelines raise the recommended level of T-DXd from Level III to Level II in the 2023 version, which fully affirms the therapeutic value of T-DXd. It is believed that based on the strong evidence of the Chinese population data studied by DESTINY-Lung05, the approval of T-DXd in China is just around the corner.
The 2024 CSCO NSCLC guidelines state that HER2 amplification/mutation can be performed in tumor tissues by single gene detection or next-generation sequencing (NGS), and if tissue specimens are not available, ctDNA testing can be considered (Level II recommendation; category 2B). It is expected that with the improvement of drug access in China, HER2 testing will become more standardized and routine, so as to help more patients with HER2-mutant NSCLC benefit from the treatment of T-DXd.
更新要点：Dato-DXd III期临床研究TROPION-Lung01数据首次写入CSCO NSCLC指南
The TROPION-Lung01 study is the first Phase III clinical trial of an ADC drug to achieve positive results in lung cancer, and the total population data of the study was previously presented at the 2023 ESMO and ESMO Asia conferences, demonstrating the good efficacy and safety of Dato-DXd compared with docetaxel in patients with advanced NSCLC who have received at least one prior therapy with or without targetable driver genomic alterations (AGA). According to data from the non-squamous NSCLC subgroup (N=468) presented at the 2024 ELCC Congress [2], the proportion of patients with AGA in both the Dato-DXd and docetaxel groups was 21 percent, and the proportion of patients in the two groups who had received ≥ two lines of therapy was 46 percent and 44 percent, respectively.
In the non-squamous NSCLC subgroup, Dato-DXd was associated with a greater median PFS benefit of 5.5 months versus docetaxel at 5.5 and 3.6 months, respectively, with a 37% lower risk of disease progression or death (HR = 0.63; 95% CI 0.51-0.79). OS in the dual primary endpoint is not mature, but there is a trend toward better benefit from Dato-DXd (13.4 versus 11.4 months, HR = 0.79; 95% CI 0.60-1.02), and further follow-up is ongoing. In terms of tumor response, the Dato-DXd arm achieved an ORR of 31%, which was better than the 13% of the docetaxel arm, with four patients achieving complete response (CR) in the Dato-DXd arm, while no CR was observed in the docetaxel arm.
图4. TROPION-Lung01研究非鳞状NSCLC亚组中位PFS分析
In addition, the overall safety profile of Dato-DXd was good, with a ≥ grade 3 adverse events (TRAEs) rate of 22 percent, significantly lower than 41 percent in the docetaxel group. In addition, the proportion of dose reductions or discontinuations due to TRAEs was also significantly lower. These haematological toxicities, including neutropenia and febrile neutropenia, also show lower levels.
Although previous targeted and immunotherapy has significantly improved the survival and prognosis of patients with advanced NSCLC, the choice of patients after standard therapy is very limited, and chemotherapy is still the main treatment, with poor overall benefit and a high incidence of adverse reactions. The publication of the research results of TROPION-Lung01 has brought hope to such patients, especially for non-squamous NSCLC, and the efficacy and safety advantages of Dato-DXd are more obvious than traditional chemotherapy drugs. Based on the results of this study, the marketing application of Dato-DXd for the treatment of adult patients with locally advanced or metastatic non-squamous NSCLC who have received prior systemic therapy has been accepted by the US FDA and the EU EMA. The inclusion of this study in the 2024 CSCO NSCLC guidelines is in line with the international frontier, which not only reaffirms the therapeutic benefits of Dato-DXd in advanced treatment-experienced NSCLC, but also suggests an important direction for the development of treatment strategies for advanced NSCLC in China.
Update Highlights: The latest data from the Phase I study of I-DXd have been updated to the CSCO SCLC guidelines
B7-H3 is a transmembrane immunomodulatory protein that is overexpressed in 65% of patients with SCLC and is associated with poor disease prognosis[3]. I-DXd (DS-7300) is a novel ADC drug targeting B7-H3, and its Phase I/II DS7300-A-J101 study enrolled patients with advanced, unresectable or metastatic solid tumors (N≈205), divided into Dose Escalation Phase Part1 (Phase I) and Dose Expansion Phase Part2 (Phase II).
The results of the analysis of the SCLC cohort of I-DXd in Part 1 were reported at the 2023 WCLC Congress [3], and as of January 31, 2023, a total of 22 SCLC patients were treated with I-DXd. The median number of prior lines of systemic therapy was 2 for all patients.
Among the 21 efficacy-evaluable patients, the ORR was 52.4%, CR was observed in 1 patient, and PR was observed in 10 patients. The median duration of response (DOR) was 5.9 months. Median PFS was 5.6 months and median OS was 12.2 months. Tumor shrinkage due to I-DXd treatment was observed in patients with different B7-H3 expression levels, but no correlation between B7-H3 expression levels and efficacy results was observed.
Figure 7. Antitumor activity of I-DXd in SCLC patients in phase I study
Figure 8. In the phase I study, I-DXd targeted median PFS and median OS in patients with SCLC
The safety is controllable and manageable, and the most common (≥10%) TEAEs of any grade include nausea (59.1%), fatigue (50%), anemia (27.3%), vomiting (27.3%), etc.
The prognosis for SCLC is poor, with a five-year survival rate of only 3 percent for patients with advanced SCLC [4]. In addition to conventional chemotherapy and immunotherapy, there are limited effective treatment options. This Phase I/II clinical trial is the first human study of I-DXd and demonstrates the preliminary efficacy and favorable safety profile of I-DXd in patients with advanced treatment-experienced SCLC. This not only builds confidence for the subsequent research and exploration of related target ADC drugs, but also is expected to further enrich the treatment options for SCLC. The study was included in the CSCO SCLC guidelines as early as 2023, and its latest data were updated to the 2024 version of the CSCO SCLC guidelines, further highlighting the therapeutic value of I-DXd in advanced treatment-experienced SCLC, which is undoubtedly an important breakthrough in the treatment concept of SCLC and has important indicative significance for the clinical diagnosis and treatment of SCLC.
ADC drugs have set off a new wave of anti-tumor therapy in the field of lung cancer, and the therapeutic benefit of T-DXd against HER2-mutated advanced treatment-treated NSCLC has been validated in multiple clinical trials, and with the DESTINY-Lung05 research results, T-DXd is expected to be approved in China to further expand its global application. Dato-DXd has demonstrated excellent performance in the Phase III TROPION-Lung01 study, is effective in overcoming resistance to prior targeted or immunotherapy, and may be a ≥ second-line standard of care option for patients with advanced treatment-experienced NSCLC. In light of these recent developments, the 2024 CSCO NSCLC guidelines have been updated accordingly. In addition, I-DXd has shown promising treatment in late-stage treatment-experienced SCLC, and the 2024 CSCO SCLC guidelines also include related studies. Overall, the update of the guidelines closely follows the latest research progress in the field of lung cancer, fully reflects the profound wisdom and extensive knowledge of Chinese scholars in the field of lung cancer, and provides valuable guidance and reference for the clinical diagnosis and treatment of lung cancer in China.
Bibliography:
[1] Cheng Y, Wu L, Fang Y, et al. Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the Phase 2 DESTINY-Lung05 (DL-05) trial. 2024 AACR. CT248.
[2] Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. 2023 ESMO. LBA12.
[3] Johnson M, Awad M, Koyama T, et al. Ifinatamab Deruxtecan (I-DXd; DS-7300) in Patients with Refractory SCLC: A Subgroup Analysis of a Phase 1/2 Study. 2023 WCLC. OA05.05.
[4] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May; 71(3):209-249.
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