The 24th World Conference on Lung Cancer (WCLC) was held from September 9 to 12, 2023, in Singapore, organized by the International Association for the Study of Lung Cancer (IASLC). During the oral presentation session on September 10, the EVOKE-02 study, exploring the first-line treatment of advanced non-small cell lung cancer (NSCLC) with the combination of sacituzumab govitecan (SG) and pembrolizumab, revealed its preliminary results. The study demonstrated an objective response rate (ORR) of 56% and a disease control rate (DCR) of 82% for stage IV NSCLC patients, laying the foundation for a new treatment strategy. “ Oncology Frontier” invited Dr. Stephen V. Liu from Georgetown University Lombardi Comprehensive Cancer Center and Dr. Shun Lu from Shanghai Chest Hospital and Shanghai Jiao Tong University for a virtual dialogue to discuss the significance of the EVOKE-02 study and the future possibilities in NSCLC treatment.
Dr. Shun Lu
Chief Physician, Doctoral Supervisor, Professor
Department of Medical Oncology, Shanghai Chest Hospital
School of Medicine, Shanghai Jiao Tong University
Dr. Stephen V. Liu
Georgetown University
Lombardi Comprehensive Cancer Center
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Oncology Frontier: Professor Liu, greetings. In the treatment of NSCLC, Trop-2 ADC has gradually demonstrated its efficacy and safety. The EVOKE-02 study is a crucial exploration of ADC combined with immunotherapy in first-line NSCLC treatment, with its preliminary results disclosed for the first time at WCLC. Could you discuss the background of this study and why the combination of immunotherapy and SG was chosen?
Dr. Stephen V. Liu: The EVOKE-02 study primarily focuses on the first-line application of the antibody-drug conjugate (ADC) SG in NSCLC. SG is composed of the cytotoxic payload SN38 and the Trop-2 antibody, and monotherapy has shown promising activity. Additionally, SG has demonstrated significant efficacy in breast cancer, urothelial carcinoma, and other areas. Preliminary data for SG in lung cancer have also indicated favorable outcomes. The EVOKE-02 study aims to evaluate SG in a more formal setting, exploring its combination with the PD-L1 inhibitor pembrolizumab or the combination of SG, pembrolizumab, and platinum-based chemotherapy in a frontline setting. This aims to investigate whether such drugs can lead to better therapeutic outcomes and understand their toxicities in a more advanced treatment stage.
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Oncology Frontier: Professor Lu, for the benefit of Chinese clinicians seeking a deeper understanding of this study, could you introduce the study design? What aspects of the study design interest you the most? What insights does this study offer for future clinical research design in Chinese NSCLC patients?
Dr. Shun Lu: The EVOKE-02 study is a global, open-label, multicohort phase II study designed to assess the efficacy and safety of sacituzumab govitecan plus pembrolizumab with or without platinum-based chemotherapy in treatment-naive patients with metastatic NSCLC without actionable genetic alterations. The study comprises four cohorts: Cohort A includes squamous or non-squamous patients with PD-L1 tumor proportion score (TPS) ≥50%, Cohort B includes squamous or non-squamous patients with PD-L1 TPS <50%, Cohort C includes non-squamous patients regardless of PD-L1 TPS, and Cohort D includes squamous patients regardless of PD-L1 TPS. The treatment regimens vary based on the cohort. The primary endpoints include objective response rate (ORR) and dose-limiting toxicities (DLT) during the dose-limiting toxicity assessment phase, while secondary endpoints cover disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.
The WCLC presentation focused on the preliminary results of Cohorts A and B, revealing an ORR of 56% for the overall patient population receiving SG plus pembrolizumab. The 6-month DoR rate was 87%, indicating significant progress in efficacy. This study is the first application of the Trop-2 ADC SG in combination with pembrolizumab for first-line NSCLC treatment. The stratification based on PD-L1 TPS and histological classification during the study design reflects the investigators’ selection of advantageous patient populations, providing valuable insights. Currently, we are conducting the EVOKE-03 study comparing SG plus pembrolizumab versus pembrolizumab monotherapy in first-line NSCLC treatment, focusing on the PD-L1 high-expression population. This phase III clinical study is ongoing, and we hope both EVOKE-02 and EVOKE-03 will contribute positively to advancing first-line treatment efficacy.
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Oncology Frontier: Professor Liu, could you please introduce the results of EVOKE-02 and share your perspectives on these results? How do you view the performance of this regimen in the subgroups with PD-L1 TPS ≥50% and <50%, and what impact does it have on the selection of the optimal patient population for this regimen in the future?
Dr. Stephen V. Liu: The WCLC presentation primarily revealed results from Cohorts A and B of the EVOKE-02 study. Cohort A focused on high PD-L1 expression, specifically patients with PD-L1 TPS ≥50%, while Cohort B included patients with low PD-L1 expression or negativity (PD-L1 <50%), with an ORR of 44%. It’s essential to note that these data are not from a randomized trial and lack a direct control group. Historically, the ORR achieved with SG plus pembrolizumab seems higher than the previously reported data for pembrolizumab monotherapy. Additionally, both cohorts showed a prolonged median duration of response (mDOR), suggesting a substantial and sustained response to treatment. The spider plot indicates a rapid and deep response, with a long duration of maintenance. While these results are promising, we eagerly await randomized data to confirm whether this regimen outperforms current monotherapy approaches. Presently, we have preliminary evidence that SG plus pembrolizumab improves response rates, and immunotherapy combined with chemotherapy also enhances response rates. The question now is whether the combination of the three can achieve superior results. If further confirmation shows that ADCs can improve long-term efficacy, extend patient survival, and exhibit a synergistic effect when combined with immunotherapy—calling upon immune cells to improve long-term outcomes—then, in my view, it will be the moment when ADCs truly demonstrate a bright future.
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Oncology Frontier: Professor Lu, the latest results from the EVOKE-02 study provide an opportunity for the application of Trop-2 ADC in NSCLC. Simultaneously, results from the TROPION-Lung04 study, evaluating another Trop-2-targeting ADC, Dato-DXd, in the treatment of NSCLC, have also been disclosed. How do you perceive the future development of different Trop-2 ADC drugs in the NSCLC field? What differences do you see between these two ADCs, and what are your expectations for their futures?
Dr. Shun Lu: The widespread presence of the Trop-2 target in lung cancer cells provides an opportunity for the application and development of Trop-2 ADCs. Both SG and Dato-DXd are ADC drugs targeting Trop-2, each with distinct design concepts and research trajectories. Besides the EVOKE-02 study on SG in phase II, the TROPION-Lung04 study for Dato-DXd in phase Ib has explored its effectiveness in combination with immunotherapy and chemotherapy for advanced NSCLC. TROPION-Lung04 revealed an ORR of 50% for Dato-DXd plus davutuzumab in first-line NSCLC treatment and an ORR of 76.9% for Dato-DXd plus davutuzumab plus carboplatin.
At the clinical research level, the current Dato-DXd study has only disclosed phase Ib results, focusing on safety and tolerability. The study has reported results for two cohorts, with 19 and 13 patients, respectively, and only 27 treatment-naive patients evaluated for efficacy (14 in the dual-drug arm and 13 in the triple-drug arm). The sample size is small and requires further validation. The EVOKE-02 study is a phase II clinical study, with BICR-assessed ORR being the primary endpoint. The reported data indicate a 56% ORR for SG in 61 patients, and the phase III study is progressing steadily, providing a faster overall timeline.
Regarding safety, there are significant differences in the adverse event profiles of the two drugs. In the TROPION-Lung04 study, the dual-drug regimen of Dato-DXd plus immunotherapy plus chemotherapy had a higher incidence of treatment-related adverse events ≥ grade 3 compared to the dual-drug regimen of Dato-DXd plus immunotherapy (31.6% vs. 57.1%). The dual-drug regimen of Dato-DXd plus immunotherapy exhibited common adverse events, including constipation (58%), fatigue (37%), vomiting (31%), and hematological adverse events. It also highlighted specific concerns about oral mucositis and interstitial lung disease (ILD). Although most events were grade 1-2, they significantly impacted patients’ quality of life. The EVOKE-02 study’s current data did not reveal new safety signals, and the known safety profiles for both drugs were consistent. The higher incidence of adverse events during treatment included diarrhea (54%), anemia (48%), and weakness (38%). The main ≥ grade 3 adverse events for SG plus immunotherapy were neutropenia (18%) and anemia (6%), with no observed ILD symptoms. It’s important to note that both studies’ data are based on relatively small sample sizes, requiring further assessment with larger datasets.
In terms of drug design, there are differences in the antibodies, payloads, and linkers targeting Trop-2 between the two ADCs. Dato-DXd uses the humanized IgG1 antibody MAAP-9001a, while SG uses the humanized IgG1 antibody hRS7, both with strong affinity for the Trop-2 target. Regarding payloads, Dato-DXd contains DXd, and SG contains SN38, both being topoisomerase inhibitors, minimizing cross-resistance with commonly used NSCLC chemotherapeutic agents. Both ADCs have cleavable linkers, but they differ in linker types: enzymatic cleavage for Dato-DXd and pH-sensitive acid cleavage for SG. Although both exhibit bystander effects, the mechanisms slightly differ. Additionally, Dato-DXd has a drug-to-antibody ratio (DAR) of 1:4, while SG has a DAR of 1:8. These structural and mechanistic differences may be contributing factors to the varied clinical efficacy and safety between the two.
Overall, Trop-2 ADCs, as a novel antitumor drug mechanism in the NSCLC field, have shown preliminary feasibility and potential for combination with immunotherapy. We look forward to more extensive datasets confirming the synergistic effects of ADCs and immunotherapy at the mechanistic level, reflecting improvements in patient survival in clinical settings, and providing more treatment possibilities for patients.
TAG: WCLC 2023, SG and immunity therapy, EVOKE-02 Study, NSCLC
