Early Activity With Frontline Sacituzumab Govitecan/Pembro in Metastatic NSCLC

Byoung Chul Cho, MD, PhD

In the phase 2 EVOKE-02 trial (NCT05186974), promising early clinical activity was observed among patients with metastatic non–small cell lung cancer (NSCLC) who received a combination therapy comprising of sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) in the first-line setting, according to data presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.¹

Findings showed that the objective response rate via investigator assessment (ORR) was 56% (95% CI 42%-69%) among 61 treated patients in 2 cohorts of the trial (A and B). The confirmed partial response (PR) rate was 49%. In cohort A, which included 29 patients with a tumor proportion score (TPS) of at least 50%, the ORR was 69% (95% CI, 49%-85%). The confirmed PR rate in this cohort was 62%. In cohort B, which included 32 patients with a TPS of less than 50%, the ORR was 44% (95% CI, 26%-62%) and the confirmed PR rate was 38%.¹

“Patients with metastatic NSCLC continue to need novel treatment options. The data from the EVOKE-02 study gives us confidence in the clinical activity of sacituzumab govitecan in combination with pembrolizumab in first-line metastatic NSCLC patients,” Byoung Chul Cho, MD, PhD, said in a news release.² Cho is a professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine in the Republic of Korea. “The positive response rates and duration of response across patients treated with the combination shows promise compared with historical responses to anti-PD1 monotherapy in this setting. These data support further investigation of sacituzumab govitecan as a potential [immunotherapy]-combination option in first-line metastatic NSCLC.”

The phase 2 EVOKE-2 trial is evaluating whether the addition of the TROP-2–directed antibody-drug conjugate (ADC) sacituzumab govitecan can improve outcomes in the first-line setting with the PD-1 inhibitor pembrolizumab for patients with treatment-naïve metastatic NSCLC. The ongoing trial will ultimately evaluate the combination alone and with chemotherapy (cisplatin and carboplatin). A safety run-period is underway to determine the recommended dose for the chemotherapy cohorts.¹

Enrollment criteria included confirmed diagnosis of stage IV NSCLC, measurable disease per RECIST 1.1 criteria, no known actionable genomic variants, ECOG performance status of 0 or 1, and no prior treatment for metastatic NSCLC. Patients in cohorts A and B could have squamous or nonsquamous disease and were stratified by TPS status, whereas patients in the chemotherapy cohorts will be stratified by histology not TPS.¹

Patients in cohorts A and B received sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 in combination with pembrolizumab 200 mg intravenously on day 1 of 21-day cycles. Sacituzumab govitecan is administered until disease progression or unacceptable toxicity and pembrolizumab is given for up to 35 cycles. The primary end points are ORR, dose-limiting toxicities in the safety run-in phases, with secondary end points including disease control rate (DCR), duration of response (DOR), progression-free survival, overall survival, and safety.

At baseline, the median age of patients in cohort A (n = 30) was 67 years (range, 47-77), 80% were male, most patients were White (73%), had an ECOG performance status of 1 (80%), and had nonsquamous histology (60%). Stage IV disease was confirmed in 80% of patients, and 5 patients had stage I, II, or III disease.¹

In cohort B (n = 33), the median age of patients was 68 (range, 47-80), 79% were male, most patients were White (82%), had an ECOG performance status of 1 (76%), and had nonsquamous histology (61%). Stage I, II, or III disease was reported among 5 patients, with 85% having stage IV disease at baseline. Per PD-L1 immunohistochemistry 22C3 pharmDx assay, PD-L1 TPS was 1% to 49% in 48% of patients and was less than 1% in 52% of patients.

The median duration of treatment in cohort A was 4.1 months (range, 0-11.2+) with sacituzumab govitecan and 3.6 months (range, 0-11.2+) with pembrolizumab. The median number of cycles was 6 (range, 1-17+) for both agents, and 63% of patients are continuing treatment with both agents. The overall discontinuation rate was 37%.

In cohort B, the median duration of treatment with sacituzumab govitecan was 4.1 months (range, 0-11.9+) and was 3.8 months (range, 0-11.7+) for pembrolizumab. The median number of cycles was 6 (range 1-17+) for both agents. Patients are continuing to sacituzumab govitecan at a rate of 39% and 42% of patients are continuing treatment with pembrolizumab. Overall, 58% of patients have discontinued all study treatment. Investigators noted that discontinuation of sacituzumab govitecan was attributed to progressive disease (PD).

At a data cutoff of June 16, 2023, the median follow-up for cohort A was 5.0 months (range, 1.7-12.0) and was 5.8 months (range, 1.0-12.2) for cohort B. Additional efficacy findings showed that among all patients (n = 61) the DCR with the combination was 82% (95% CI, 70%-91%). The median DOR was not reached (NR; 95% CI, 7.9-NR) and the estimated DOR rate at 6 months was 87% (95% CI, 58%-97%). PD was observed in 8% of patients and stable disease (SD) was reported in 26%.

In cohort A (n = 29), the DCR was 86% (95% CI, 68%-96%) with a median DOR of NR (95% CI, 5.6-NR) and a 6-month DOR rate of 88% (95% CI, 39%-98%). PD was reported among 10% of patients and SD among 17% of patients. In cohort B (n = 32), the DCR was 78% (95% CI, 60%-91%) with a median DOR of NR (95% CI, 3.5-NR) and a 6-month DOR rate of 88% (95% CI, 39%-98%). PD and SD were reported at rates of 6% and 34%, respectively.

In terms of safety, any-grade treatment emergent adverse effects (TEAEs) were reported in all patients in the safety cohort (n = 63), with 90% related to study treatment. Grade 3 or higher TEAEs were reported in 70% of patients and 38% were related to study treatment. Serious TEAEs occurred at a rate of 54% with 14% attributed to study treatment. Discontinuation of sacituzumab govitecan due to TEAEs was reported among 14% of patients and 13% of patients discontinued pembrolizumab due to TEAEs. Dose reductions were reported for 18% of patients who received sacituzumab govitecan. Four deaths were reported due to TEAEs and included malignant lung neoplasm, respiratory tract infection, and sudden death, with sepsis reported as a death related to study treatment.

The most common grade 1/2 TEAEs included diarrhea (51%), anemia (42%), asthenia (38%), alopecia (37%), nausea (30%), constipation (24%), appetite decrease (22%), respiratory tract infection (20%), fatigue (19%), mucosal inflammation (18%), dyspnea (17%), and neutropenia (9%). Grade 3 or higher TEAEs included neutropenia (18%), anemia (6%), respiratory tract infection (5%), dyspnea (5%), diarrhea (3%), fatigue (2%).

Immune-mediated TEAEs of grade 1/2 included pneumonitis (5%), hyperthyroidism (5%), colitis (2%), and hypothyroidism (2%). Grade 3 or higher immune-mediated TEAEs included pneumonitis (3%), colitis (2%), nephritis (2%), and maculopapular rash (2%). Investigators noted these were consistent with the known safety profile of pembrolizumab.

“These preliminary results warrant further investigation of sacituzumab govitecan and pembrolizumab for the first-line treatment of metastatic NSCLC,” investigators wrote in their conclusions.

Next steps include the ongoing, open label, global, randomized, phase 3 EVOKE 03 trial (NCT05609968), which is evaluating sacituzumab govitecan and pembrolizumab vs pembrolizumab monotherapy as a first-line treatment for patients with metastatic NSCLC with PD-L1 TPS of at least 50%.

References

1. Cho B, Dols MC, Cabanillas RR, et al. Sacituzumab govitecan + pembrolizumab in 1l metastatic non small cell lung cancer: preliminary results of the EVOKE 02 study. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA05.04.

2. Gilead’s phase 2 EVOKE-02 study of Trodelvy (sacituzumab govitecan-hziy) in combination With Keytruda (pembrolizumab) demonstrates promising clinical activity in first-line metastatic non-small cell lung cancer. News release. Gilead Sciences Inc. September 10, 2023. Accessed September 10, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/9/gileads-phase-2-evoke02-study-of-trodelvy-sacituzumab-govitecanhziy-in-combination-with-keytruda-pembrolizumab-demonstrates-promising-clinica