Immune checkpoint inhibitor-based regimens have been established as the standard-of-care first-line treatment in the setting of metastatic NSCLC. However, novel combination approaches are called for to further improve outcomes. Clinical trials are exploring the efficacy and safety of antibody-drug conjugates directed against trophoblast cell-surface antigen 2 (Trop-2), such as sacituzumab govitecan and datopotamab deruxtecan, together with immune checkpoint inhibitors.
First-line findings for SG plus pembrolizumab
Sacituzumab govitecan (SG) in combination with pembrolizumab is being assessed in the open-label, multicohort phase II EVOKE-02 study in hitherto untreated patients who have been diagnosed with stage IV NSCLC. At WCLC 2023, Cho et al. presented preliminary results for the Cohorts A and B into which the study participants had been allocated according to their PD-L1 expression status . Cohort A had PD-L1 TPS ≥ 50 % (n = 30), while PD-L1 TPS was < 50 % in Cohort B (n = 33). All patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles until disease progression in addition to pembrolizumab 200 mg on day 1 for up to 35 cycles.
After a median follow-up of 5.0 and 5.8 months for Cohorts A and B, respectively, SG plus pembrolizumab showed encouraging antitumor activity across the PD-L1 subgroups. The objective response rates (ORR) were 69 % and 44 % for Cohorts A and B, respectively, with disease control achieved in 86 % and 78 %, respectively (Table). Only 10 % and 6 % of patients, respectively, had progressive disease as best response, which suggests that the addition of SG might contribute to overcoming primary resistance to pembrolizumab. Responses were rapid, deep and durable. The waterfall plot indicated significant tumor shrinkage in the majority of patients regardless of PD-L1 expression. Median duration of response had not been reached yet in either cohort. At 6 months, the duration of response rate was 88 % in both groups.
The safety profile was manageable and consistent with the known safety of each agent. Treatment-emergent AEs (TEAEs) primarily included diarrhea (any grade, 54 %), anemia (48 %), asthenia (38 %), alopecia (37 %), and nausea (32 %), which were predominantly grade 1 or 2. Neutropenia occurred in 27 %, with grade ≥ 3 events noted in 18 %. Immune-mediated TEAEs were consistent with the safety profile of pembrolizumab. Pneumonitis was reported in 8 % (grade ≥ 3, 3 %), hyperthyroidism in 5 % (no grade ≥ 3 events), and colitis in 4 % (grade ≥ 3, 2 %). TEAEs prompting treatment discontinuation and dose reduction emerged in 18 % each. One case of fatal sepsis (2 %) was deemed related to the study treatment.
As the authors emphasized in their summary, these preliminary findings warrant further investigation of SG plus pembrolizumab for the first-line treatment of patients with metastatic NSCLC. The ongoing, open-label, randomized, phase III EVOKE-03 trial is evaluating SG plus pembrolizumab versus pembrolizumab monotherapy in patients with untreated metastatic NSCLC and PD-L1 TPS ≥ 50 % (NCT05609968).
Dato-DXd and durvalumab ± chemotherapy
The multicenter, open-label, dose escalation/confirmation and expansion TROPION-Lung04 study is investigating datopotamab deruxtecan (Dato-DXd) in combination with different immunotherapy agents with or without carboplatin across eleven cohorts of patients with advanced or metastatic NSCLC. Papadopoulos et al. reported an interim analysis for the Cohorts 2 and 4 of this phase Ib trial . In Cohort 2, Dato-DXd 6 mg/kg is being administered together with durvalumab 1,120 mg Q3W (n = 19). Cohort 4 is testing the same regimen in addition to four cycles of carboplatin AUC 5 Q3W (n = 14). Most patients are receiving the Dato-DXd combination in the first-line setting, while smaller proportions in each arm (26.3 % and 7.1 %, respectively) are being treated in the second line and beyond. In both cohorts, 21 % have a history of brain metastases.
Throughout the dose escalation and dose expansion phases, no new safety signals were observed in either cohort. The most frequent any-grade TEAEs were stomatitis, alopecia and nausea. In general, grade ≥ 3 TEAEs were more commonly observed with the triplet than with the doublet combination (57.1 % vs. 31.6 %), which was mainly driven by higher rates of cytopenia and was largely attributed to carboplatin being part of the triplet regimen. Interstitial lung disease (ILD) adjudicated as drug-related occurred in 15.8 % and 7.1 % in Cohorts 2 and 4, respectively. In the triplet-treated group, grade 2 ILD was reported in one patient (7.1 %), while in the group receiving the doublet, one patient each (5.3 %) developed grade 1, 2, and 4 ILD. No grade 5 adjudicated ILD events were reported. Discontinuation of any drug due to TEAEs was necessary in 21 % in both cohorts.
With respect to efficacy, the analysis suggested durable responses with promising ORRs for both strategies. In the first-line setting, ORRs were 50 % and 76.9 % in Cohorts 2 and 4, respectively. Both cohorts obtained disease control in 92 %. The overall population that includes patients treated in the first and later lines showed ORRs of 47.4 % and 71.4 % for Cohorts 2 and 4, respectively. Responses were numerically higher with the triplet than with the doublet approach and were observed across all PD-L1 expression levels. Combinations of Dato-DXd with immune checkpoint inhibitors are being evaluated as first-line treatment options in the phase III AVANZAR (NCT05687266), TROPION-Lung07 (NCT05555732), and TROPION-Lung08 (NCT05215340) trials in patients with advanced or metastatic NSCLC.
- Cho BC et al., Sacituzumab govitecan + pembrolizumab in 1L metastatic non-small cell lung cancer: preliminary results of the EVOKE-02 study. WCLC 2023, abstract OA05.04
- Papadopoulos KP et al., Datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced/metastatic NSCLC: initial results from the phase 1b TROPION-Lung04 study. WCLC 2023, abstract OA05.06
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