Although the phase III EVOKE-01 study did not meet protocol-specified statistical significance for the primary endpoint of overall survival (OS), treatment with sacituzummab govitecan resulted in a 16% reduction in risk of death versus docetaxel in the intention-to-treat (ITT) population and was associated with a numerically higher OS rate at all prespecified landmark time points among patients with metastatic non–small cell lung cancer (NSCLC) with progression on/after platinum-based chemotherapy, anti–PD-(L)1, and targeted treatment for actionable genomic alterations.
There were fewer high-grade adverse events and adverse events leading to dose reduction and/or discontinuation with sacituzummab govitecan than docetaxel; more patients remained on sacituzummab govitecan than docetaxel at final analysis. Patients reported longer time to deterioration symptoms with sacituzummab govitecan treatment in NSCLC Symptom Assessment Questionnaire. Primary results from the study are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Luis G. Paz-Ares of the Hospital Universitario 12 de Octubre, Complutense University and Ciberonc in Madrid, Spain, and colleagues on 31 May 2024 in the JCO.
The authors wrote in the study background that treatment for advanced or metastatic NSCLC progressing after platinum-based chemotherapy and/or immunotherapy, regardless of the presence of actionable genomic alterations and PD-L1 status, remains limited to chemotherapy. However, survival outcomes are poor with current standard-of-care docetaxel. Effective therapies for patients with disease progression on both immunotherapy and platinum-based chemotherapy are needed.
Sacituzumab govitecan is a first-in-class, Trop-2–directed antibody-drug conjugate. In a phase I/II basket IMMU-132-01 study, patients with heavily pretreated metastatic NSCLC derived durable clinical benefit from sacituzummab govitecan, with an objective response rate (ORR) of 16.7% and median duration of response (DoR) of 6.0 months. Sacituzummab govitecan was well tolerated with no new safety findings.
EVOKE-01 is a global, randomised, open-label, phase III study of sacituzummab govitecan versus docetaxel in patients with advanced or metastatic NSCLC that progressed on/after platinum-based chemotherapy and anti–PD-(L)1–containing regimen. Patients were randomly assigned 1:1 (stratified by histology, best response to last anti–PD-(L)1–containing regimen, and treatment for actionable genomic alterations received or not) to sacituzummab govitecan (10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (75 mg/m2 intravenous infusion on day 1) in 21-day cycles. Primary endpoint was OS. Key secondary endpoints were investigator-assessed progression-free survival (PFS), ORR, patient-reported symptom assessment, and safety.
In the ITT population comprising 299 patients who were treated with sacituzumab govitecan and 304 patients treated with docetaxel, 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary endpoint was not met. There was a numerical OS improvement for sacituzummab govitecan versus docetaxel with median 11.1 versus 9.8 months (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.68 to 1.04; one-sided p = 0.0534), consistent across squamous and non-squamous histologies.
Median PFS was 4.1 versus 3.9 months (HR 0.92, 95% CI 0.77 to 1.11). An OS benefit was observed for sacituzummab govitecan (n = 192) versus docetaxel (n = 191) in metastatic NSCLC nonresponsive to last anti–PD-(L)1–containing regimen with 3.5-month median OS increase (HR 0.75, 95% CI 0.58 to 0.97) and this was consistent across histologies.
Sacituzummab govitecan was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals. Among patients receiving sacituzummab govitecan and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs); 1.4% and 1.0% had TRAEs leading to death.
The authors concluded that sacituzummab govitecan conferred modest numerical OS benefit over docetaxel in the ITT population. A numerical OS benefit was also observed in the subgroup of patients who were nonresponsive to last anti–PD-(L)1–containing regimen. A phase II study evaluating sacituzummab govitecan with pembrolizumab with/without platinum-based chemotherapy in previously untreated metastatic NSCLC lacking actionable genomic alterations (EVOKE-02) and a phase III study evaluating sacituzummab govitecan plus pembrolizumab versus pembrolizumab monotherapy in first-line PD-L1–high metastatic NSCLC (EVOKE-03) are underway.
In an accompanied editorial article, Dr. Marice Pérol of the Department of Medical Oncology, Léon Bérard Cancer Center in Lyon, France wrote that two points raise questions about numerical survival benefit, as there was neither PFS improvement nor increase in ORR. Overall, the failure of sacituzummab govitecan to improve ORR and PFS and to extend in a clinically meaningful way OS in comparison with docetaxel makes the EVOKE-01 results disappointing.
These results are broadly in line with those of the TROPION-Lung01 study, which compared datopotamab-deruxtecan with docetaxel in patients who had disease progression after chemoimmunotherapy. Differences between the components of each antibody-drug conjugate account for a distinct tolerance profile with haematological and gastrointestinal toxicity as main TRAEs for sacituzumab govitecan and a lower frequency of stomatitis or interstitial lung disease risks than associated with datopotamab-deruxtecan.
Two keys to the future of current anti-Trop-2 drugs moving to the first-line treatment of advanced NSCLC are whether they will be better partners for immunotherapy than conventional chemotherapy in their ability to generate a real synergy via an immunogenic cell death and the control or prophylaxis of their toxicities, which can overlap those of anti–PD(L)-1 and have a significant impact on patients' quality-of-life. Even, if the current anti-Trop-2 agents do not meet all the promises, new targets and future advances in antibody-drug conjugates technology still suggest that they will be a major weapon in the NSCLC therapeutic arsenal according to Dr. Pérol.
The study was supported by Gilead Sciences, Inc.
References
- Paz-Ares LG, Juan-Vidal O, Mountzios GS, et al. Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study. JCO; Published 31 May 2024. DOI: https://doi.org/10.1200/JCO.24.00733
- Pérol M. TROP2-Directed Antibody-Drug Conjugates in Advanced Non–Small Cell Lung Cancer: A Fading Hope? JCO; Published online 10 July 2024. DOI: https://doi.org/10.1200/JCO.24.01043