No significant survival benefit with sacituzumab govitecan over docetaxel in metastatic NSCLC patients who progressed on chemotherapy and an anti-PD-(L)1 containing regimen
Results of the phase III EVOKE-01 study indicate a numerical overall survival (OS) benefit with the antibody-drug conjugate (ADC) sacituzumab govitecan (SG) over docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) who were previously treated with platinum-based chemotherapy and a PD-(L)1 inhibitor. However, this difference did not reach the threshold for statistical significance. SG did come with a more favourable safety profile and was better tolerated than docetaxel.
Background
Docetaxel continues to be the standard of care for mNSCLC patients who progress after platinum-based chemotherapy and an anti-PD-(L)1-containing regimen. SG is a TROP-2 directed ADC that is currently approved for the treatment of patients with metastatic breast cancer who received at least two prior lines of systemic therapy. In the phase I/II IMMU-132-01 study, SG induced a durable clinical benefit in a proportion of patients with heavily pretreated mNSCLC. These findings formed the basis for the phase III EVOKE-01 study in which SG was compared to docetaxel in patients with mNSCLC who progressed on or after platinum-based chemotherapy and an anti-PD-L1 containing regimen.
Study design
In EVOKE-01, a total of 603 patients with mNSCLC with disease progression after platinum-based chemotherapy and anti-PD-(L)1-containing therapy were randomised (1:1) to receive SG (10 mg/kg IV, days 1 and 8) or docetaxel (75 mg/m2 IV, day 1) in 21-day cycles until disease progression or unacceptable toxicity. Patients with an actionable oncogenic driver mutation also had to be pretreated with at least one approved tyrosine kinase inhibitor. Patients with previously treated, stable brain metastases were allowed to enter the study. The primary endpoint of the study was OS, with investigator assessed progression-free survival (PFS), objective response rate (ORR), patient-reported outcomes (PROs), and safety as key secondary objectives.
Results
The median age of patients in the study was 65 years and two thirds had an ECOG performance status (PS) of 1. Overall, 55% of patients had received one prior line of therapy (i.e., concurrent chemo-immunotherapy), while a third received two prior treatment lines. About 12% of patients enrolled in the study had a history of brain metastases. The best response to the last anti-PD-(L)1-containing regimen was a complete or partial response in about 35% of patients. The majority of patients (~93%) in the study did not have an actionable oncogenic driver mutation.
The study failed to show a significant difference in OS between the 2 treatment arms, with a median OS of 11.1 months for SG and 9.8 months for docetaxel (HR[95%CI]: 0.84[0.68-1.04]; p= 0.0534). However, at the 12-month landmark SG came with an OS rate of 46.6%, which was numerically higher than the 36.7 months OS rate seen with docetaxel. Also in terms of PFS (median 4.1 vs. 3.9 months; HR[95%CI]: 0.92[0.77-1.11]) and ORR (13.7% vs. 18.1%) the investigators did not see a significant difference between the two treatment arms. Apart from a signal for a significant OS benefit with SG in patients with stable disease or disease progression as their best response to the last anti-PD-(L)1-containing regimen (HR[95%CI]: 0.75[0.58-0.97]), the results were consistent across all the investigated subgroups.
The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was lower with SG than with docetaxel at 66.6% and 75.7%, respectively. In line with this, SG also came with a lower rate of TEAEs leading to treatment discontinuation than docetaxel (9.8% vs. 16.7%). TEAEs leading to death were reported in 3.4% of patients in the SG arm and in 4.5% in the docetaxel arm. The better tolerability of SG relative to docetaxel was also reflected by a significantly longer time to deterioration in shortness of breath (HR[95%CI]: 0.75[0.61-0.91]) and overall symptoms as assessed by the symptom assessment questionnaire (HR[95%CI]: 0.80[0.66-0.97]).
Conclusions
While SG was shown to induce a numerical OS benefit over docetaxel in mNSCLC patients who previously received platinum-based chemotherapy and an anti-PD-(L)1-containing regimen, this difference did not reach statistical significance. In terms of PFS and ORR similar results were obtained with SG and docetaxel. However, SG did prove to be more tolerable than docetaxel. Despite it being a negative study, EVOKE-01 does show that SG is an active and tolerable treatment option in this setting. In the EVOKE-02 and EVOKE-03 studies, the combination of SG and immunotherapy is currently being evaluated as first line therapy for patients with mNSCLC.
Reference
Paz-Ares L, et al. Sacituzumab govitecan (SG) vs docetaxel (doc) in patients (pts) with metastatic non-small cell lung cancer (mNSCLC) previously treated with platinum (PT)-based chemotherapy (chemo) and PD(L)-1inhibitors (IO): Primary results from the phase 3 EVOKE-01 study. Presented at ASCO 2024, Abstract LBA8500.
