Trodelvy Plus Keytruda Shows Antitumor Activity in NSCLC

Patients with metastatic non-small cell lung cancer (NSCLC) experienced early antitumor activity when treated with the combination of Trodelvy (sacituzumab govitecan-hziy) and Keytruda (pembrolizumab) in a first-line setting, recent trial results have showed.

The objective response rate (ORR, measuring patients whose disease responded to treatment) was 56% and the confirmed partial response (PR, decrease in tumor size or extent of cancer) rate was 49% among 61 treated patients in two cohorts of the EVOKE-02 trial, data from which were presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.

In cohort A, which included 29 patients with a tumor proportion score (TPS) of at least 50%, the ORR was 69%. 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% and the confirmed PR rate was 38%.

“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 (Trodelvy) in combination with (Keytruda) in first-line metastatic NSCLC patients,” Dr. Byoung Chul Cho said in a news release. Cho is a professor in the division of medical oncology at Yonsei Cancer Center, Yonsei University College of Medicine in South 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 (Trodelvy) 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) Trodelvy can improve outcomes in the first-line setting with the PD-1 inhibitor Keytruda 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.

Enrollment criteria included confirmed diagnosis of stage 4 NSCLC, measurable disease per RECIST 1.1 criteria, no known actionable genomic variants, an Eastern Cooperative Oncology Group (ECOG) performance status — assessing how a disease affects a patient’s daily living abilities — 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.

Patients in cohorts A and B received Trodelvy at 10 mg/kg intravenously on days 1 and 8 in combination with Keytruda 200 mg intravenously on day 1 of 21-day cycles. Trodelvy is administered until disease progression or unacceptable toxicity and Keytruda 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, patients whose disease shrunk, disappeared or is stable from treatment), duration of response (DOR), progression-free survival (the time a patient lives without the disease worsening), overall survival and safety.

At baseline, the median age of the 30 patients in cohort A was 67 years, 80% were male, most patients were White (73%), had an ECOG performance status of 1 (80%) and had nonsquamous histology (60%). Stage 4 disease was confirmed in 80% of patients, and five patients had stage 1, 2 or 3 disease.

Among the 33 patients in cohort B, the median age was 68, 79% were male, most patients were White (82%), had an ECOG performance status of 1 (76%), and had nonsquamous histology (61%). Stage 1, 2 or 3 disease was reported among 5 patients, with 85% having stage 4 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 with Trodelvy and 3.6 months with Keytruda. The median number of cycles was six 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 Trodelvy was 4.1 months and was 3.8 months for Keytruda. The median number of cycles was six for both agents. Patients are continuing to Trodelvy 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 Trodelvy was attributed to progressive disease (PD).

At a data cutoff of June 16, 2023, the median follow-up for cohort A was 5 months and was 5.8 months for cohort B. Additional efficacy findings showed that among all patients the DCR with the combination was 82%. The median DOR was not reached and the estimated DOR rate at 6 months was 87%. PD was observed in 8% of patients and stable disease (SD) was reported in 26%.

In cohort A, the DCR was 86% with the median DOR not reached and a six-month DOR rate of 88%. PD was reported among 10% of patients and SD among 17% of patients. In cohort B, the DCR was 78% with the median DOR not reached and a six-month DOR rate of 88%. PD and SD were reported at rates of 6% and 34%, respectively.

In terms of safety, any-grade treatment emergent side effects were reported in all 63 patients in the safety cohort, with 90% related to study treatment. Grade 3 or higher side effects were reported in 70% of patients and 38% were related to study treatment. Serious side effects occurred at a rate of 54% with 14% attributed to study treatment. Discontinuation of Trodelvy due to side effects was reported among 14% of patients and 13% of patients discontinued Keytruda due to side effects. Dose reductions were reported for 18% of patients who received Trodelvy. Four deaths were reported due to side effects 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 side effects included diarrhea (51%), anemia (low red blood cells, 42%), asthenia (weakness, 38%), alopecia (loss of hair, 37%), nausea (30%), constipation (24%), appetite decrease (22%), respiratory tract infection (20%), fatigue (19%), mucosal inflammation (18%), dyspnea (difficulty breathing, 17%) and neutropenia (low numbers of neutrophils, a type of white blood cells, 9%).

Grade 3 or higher side effects included neutropenia (18%), anemia (6%), respiratory tract infection (5%), dyspnea (5%), diarrhea (3%) and fatigue (2%).

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

“These preliminary results warrant further investigation of (Trodelvy) and (Keytruda) 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, which is evaluating Trodelvy and Keytruda vs Keytruda monotherapy as a first-line treatment for patients with metastatic NSCLC with PD-L1 TPS of at least 50%.

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