Early-phase trials demonstrate the potential for TROP-2–directed antibody-drug conjugates to enhance the response to immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC) without actionable genomic alterations, several investigators reported at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer (WCLC). TROP-2 is a protein broadly expressed in a large majority of NSCLC tumors. Two TROP-2–directed antibody-drug conjugates are being investigated in lung cancer.
In preliminary findings from the phase Ib TROPION-Lung04 trial in previously untreated patients, the addition of durvalumab to datopotamab deruxtecan (Dato-DXd) led to an objective response rate of 77% when combined with carboplatin and 50% when the doublet was given alone; disease control rates were 92% and 93%, respectively, according to Saiama N. Waqar, MBBS, MSCI, of Washington University School of Medicine, St Louis.1 “Interim efficacy analyses have demonstrated promising objective response rates, for both doublet and triplet combinations, both in the first-line setting and the overall population, and across all PD-L1 expression levels. No new safety signals were observed,” she said.
“The addition of durvalumab to datopotamab deruxtecan led to an objective response rate of 77% when combined with chemotherapy and 50% when the doublet was given alone.”— Saiama N. Waqar, MBBS, MSCI
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In the international phase II EVOKE-02 trial, sacituzumab govitecan-hziy plus pembrolizumab led to responses in 56% of patients, with 6-month disease control observed in 82% as a first-line treatment. Responses were observed across a range of PD-L1 expression, according to Byoung Chul Cho, MD, of Yonsei Cancer Center in Seoul.2
As background to TROPION-Lung04, Dr. Waqar noted the early efficacy shown with Dato-DXd in phase I trials in patients with metastatic NSCLC: as monotherapy in heavily pretreated patients in TROPION-PanTumor01 (objective response rate = 26%)3 and when combined with pembrolizumab, with or without platinum-based chemotherapy (objective response rate = 57% and 50%, respectively), in the first-line setting in TROPION-Lung02.4 Recently, in the phase III TROPION-Lung01trial,5 monotherapy with Dato-DXd at 6 mg/kg significantly improved progression-free survival vs docetaxel in previously treated advanced disease (unpublished), she noted. “Building upon these findings, we are now looking to determine the role of adding durvalumab in the first-line setting,” Dr. Waqar said.
The current study, TROPION-Lung04, is an ongoing global, open-label, dose-escalation/confirmation and dose-expansion phase Ib trial evaluating the efficacy and safety of Dato-DXd (4 mg/kg or 6 mg/kg) in combination with different immunotherapy agents with or without carboplatin in patients with advanced or metastatic NSCLC lacking actionable genomic alterations. In cohorts 2 and 4, Dato-DXd (6 mg/kg) and durvalumab (1,120 mg) were administered every 3 weeks without chemotherapy (cohort 2 with doublet) or with the addition of up to four cycles of carboplatin at AUC 5 every 3 weeks (cohort 4 with triplet). The majority of patients were previously untreated; some had received one line of systemic therapy. The primary endpoints are safety and tolerability. Key secondary endpoints are objective response rate and disease control rate by investigator assessment per Response Evaluation Criteria in Solid Tumors, version 1.1.
Byoung Chul Cho, MD
The focus of the interim analysis of TROPION-Lung04, presented at the 2023 WCLC, was cohort 2, which evaluated the doublet, and cohort 4, which evaluated the triplet. In the doublet cohort of 19 patients, 14 (73.7%) were previously untreated; in the triplet cohort, 13 of 14 patients (92.9%) were previously untreated. Both the doublet and triplet cohorts included patients with PD-L1 expression levels ranging from less than 1% to 50% or greater. In each cohort, 21% of patients had a history of brain metastases.
At data cutoff, the median study duration was 6 months for cohort 2 (range = 0.7–12.5 months) and 6.2 months for cohort 4 (range = 1.5–11 months). Treatment was ongoing in 31.6% and 50.0% of patients in the doublet and triplet cohorts, respectively.
Response Rates and Safety
In 14 previously untreated patients in cohort 2, Dato-DXd plus durvalumab demonstrated an objective response rate of 50.0% and a disease control rate of 92.9%. The response rate was numerically higher, 76.9%, in the 13 previously untreated patients in cohort 4 receiving the triplet regimen of Dato-DXd plus durvalumab and carboplatin, and the disease control rate was 92.3%. Responses were observed across all PD-L1 expression levels, Dr. Waqar reported.
In both previously treated and untreated patients, the safety profiles of Dato-DXd and durvalumab with and without carboplatin were consistent with other clinical trials and with the known safety profile of each agent. Grade ≥ 3 treatment-emergent adverse events deemed related to study treatment were reported in 31.6% of the doublet group and 57.1% of the triplet group. In patients receiving triplet therapy, the most common grade ≥ 3 were anemia (36%) and thrombocytopenia (21%). No grade ≥ 3 toxicities occurred in more than 15% of patients receiving doublet therapy. Across treatment cohorts, there were four interstitial lung disease events adjudicated as drug-related, including one grade 1 event, two grade 2 events, and one grade 4 event. No grade 5 interstitial lung disease events were observed.
Three ongoing phase III trials are evaluating Dato-DXd–based combinations as potential first-line treatment options for patients with advanced or metastatic NSCLC without actionable genomic alterations. TROPION-Lung07 (ClinicalTrials.gov identifier NCT05555732) is evaluating Dato-DXd plus pembrolizumab with or without platinum-based chemotherapy in patients with nonsquamous NSCLC and PD-L1 expression < 50%; -TROPION-Lung08(NCT05215340) is evaluating Dato-DXd and pembrolizumab vs pembrolizumab in patients with NSCLC and PD-L1 expression ≥ 50%. Patients with any PD-L1 expression or tumor histology are being enrolled in the AVANZAR trial (NCT05687266), which is evaluating -Dato-DXd plus durvalumab and carboplatin compared to histology-specific platinum doublet and pembrolizumab.
EVOKE-02 is an ongoing multicohort phase II study of sacituzumab govitecan plus pembrolizumab, with and without a platinum agent, in previously untreated patients with metastatic NSCLC. This TROP-2–directed antibody-drug conjugate has previously shown activity in heavily pretreated patients.6
At the 2023 WCLC, Dr. Cho reported preliminary results for 30 patients with a PD-L1 tumor proportion score (TPS) ≥ 50% (cohort A) and 33 patients with a PD-L1 TPS < 50% (cohort B). Patients received sacituzumab govitecan at 10 mg/kg on days 1 and 8 plus pembrolizumab at 200 mg on day 1 of each 21-day cycle for up to 35 cycles. The primary endpoints were investigator-assessed objective response rate and dose-limiting toxicities in the safety run-in phase. Median follow-up was 5 to 6 months.
In cohort A, where all patients had a TPS ≥ 50%, the objective response rate was 69%, and the disease control rate at 6 months was 88%. In cohort B, with a TPS < 50%, these rates were 44% and 78%, respectively. Median duration of response was not reached in either cohort; at 6 months, 88% of responders were still responding, Dr. Cho reported.
Among 63 evaluable patients, 90% had a treatment-emergent adverse event related to study treatment; 38% of them were grade ≥ 3 and 18% led to treatment discontinuation. One death from sepsis was considered related to study treatment.
The most common toxicities of any grade were diarrhea (54%), anemia (48%), and asthenia (38%). Most of these toxicities were grade 1 or 2, with the exception of neutropenia, where two-thirds of cases were grade 3. Immune-mediated toxicities were uncommon.
“These preliminary results warrant further investigation of sacituzumab govitecan plus pembrolizumab for the first-line treatment of metastatic NSCLC,” Dr. Cho said. The ongoing, open-label, global, randomized phase III EVOKE-03 study is evaluating this combination, vs pembrolizumab monotherapy, in untreated patients with metastatic NSCLC who have a PD-L1 TPS ≥ 50%.
DISCLOSURE: Dr. Waqar has served on advisory boards for AstraZeneca and Gilead Sciences. Dr. Cho reported no conflicts of interest.
1. Papadopoulos KP, Bruno D, Kitazono S, et al: Datopotamab deruxtecan + durvalumab ± carboplatin in advanced/mNSCLC: Initial results from phase Ib TROPION-Lung04. 2023 World Conference on Lung Cancer. Abstract OA05.06. Presented September 10, 2023.
2. Cho BC, Dols MC, Cabanillas RR, et al: Sacituzumab govitecan + pembrolizumab in 1L metastatic non-small cell lung cancer: Preliminary results of the EVOKE-02 study. 2023 World Conference on Lung Cancer. Abstract OA05.04. Presented September 10, 2023.
3. Shimizu T, Sands J, Yoh K, et al: First-in-human, phase I dose-escalation and dose-expansion study of trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non-small-cell lung cancer: TROPION-PanTumor01. J Clin Oncol. June 16, 2023 (early release online).
4. Goto Y, Su WC, Levy BP, et al: TROPION-Lung02: Datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy in advanced non-small cell lung cancer. 2023 ASCO Annual Meeting. Abstract 9004. Presented June 4, 2023.
5. AstraZeneca: Datopotamab deruxtecan met dual primary endpoint of progression-free survival in patients with advanced non-small cell lung cancer in TROPION-Lung01 phase III trial. Available at https://www.astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxtecan-met-dual-primary-endpoint-of-progression-free-survival-in-patients-with-advanced-non-small-cell-lung-cancer.html. Accessed September 22, 2023.
6. Heist RS, Guarino MJ, Masters G, et al: Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 35:2790-2797, 2017.
Helena Linardou, MD, PhD
Helena Linardou, MD, PhD, Director of the 4th Department of Oncology and the Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, was invited as the discussant of the studies on antibody-drug conjugates at the 2023 World Conference on Lung Cancer....