No Survival Advantage With Sacituzumab Over Chemo in Previously Treated NSCLC

CHICAGO — Treatment with single-agent sacituzumab govitecan (Trodelvy) offered no survival advantage over docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and a PD-L1 inhibitor, according to the EVOKE-01 study.

In the global open-label phase III trial, median overall survival (OS), the primary endpoint, was 11.1 months in patients randomized to sacituzumab compared with 9.8 months in those randomized to docetaxel (HR 0.84, 95% CI 0.68-1.04, P=0.0534) after a median follow-up of 12.7 months, reported Luis G. Paz-Ares, MD, PhD, of Complutense University and Ciberoncse University in Madrid.

The 12-month OS rates were 46.59% in the sacituzumab arm versus 36.72% in the docetaxel arm, he stated in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

“Importantly, two-thirds of the patients did not achieve a CR [complete response] or a PR [partial response] prior to (anti)-PD-1 or PD-L1-containing regimens,” and were therefore considered to be nonresponders before study entry, Paz-Ares stated. In a prespecified analysis, “sacituzumab govitecan had a 3.5-month median OS improvement over docetaxel among subgroups with nonresponsive disease,” he said. In this group, median OS was 11.8 months in the sacituzumab arm versus 8.3 months in the chemotherapy arm (HR 0.75, 95% CI, 0.58-0.97).

In the subgroup with a CR or PR to prior immunotherapy, median OS was 9.6 months versus 10.6 months in the sacituzumab and docetaxel arms, respectively (HR 1.09, 95% CI 0.76-1.56).

By histologic subtype, there were similar nonsignificant numerical improvements in OS with sacituzumab over docetaxel in both nonsquamous and squamous advanced NSCLC.

Median progression-free survival was also not significantly different between the two arms, at 4.1 months with sacituzumab and 3.9 months with docetaxel (HR 0.92, 95% CI 0.77-1.11).

The overall incidence of grade ≥3 treatment-related adverse events (TEAEs) was lower with sacituzumab compared with docetaxel (66.6% vs 75.7%), and TEAEs led to discontinuation less often (9.8% vs 16.7%, respectively).

“Patients reported improvement in NSCLC-related symptoms, reflective of better tolerability and disease control with sacituzumab govitecan,” said Paz-Ares. The shortness of breath domain on the NSCLC-Symptom Assessment Questionnaire (SAQ), showed a longer median deterioration-free probability with sacituzumab versus docetaxel (2.8 vs 2.1 months, HR 0.75-0.91). A longer median time to deterioration in the NSCLC-SAQ score was also observed in the group randomized to sacituzumab versus docetaxel (3.1 vs 2.7 months, HR, 0.80, 95% CI, 0.66-0.97).

ASCO invited discussant Egbert F. Smit, MD, PhD, of Leiden University Medical Center in the Netherlands, said that although TROP2 is highly expressed in NSCLC, and high TROP2 expression is associated with a poor prognosis, the data from EVOKE-1 demonstrate that targeting it with a TROP2 antibody drug conjugate (ADC) such as sacituzumab is not superior in the second line to standard of care chemotherapy in non-oncogene-driven NSCLC.

The findings from EVOKE-1 are consistent with those from TROPION-Lung01, which compared a different anti-TROP2 ADC to docetaxel in a similar patient population.

A better understanding of sensitivity to and resistance to ADCs is required to move forward, said Smit, noting the downregulation of antigen expression by tumor cells with exposure to ADCs, as well as altered intracellular trafficking pathways or drug breakdown in lysosomes and payload resistance by upregulation of drug efflux pumps.

Sacituzumab govitecan is being evaluated in combination with immunotherapy in the first-line setting in EVOKE-02, noted Paz-Ares.

The results are “disappointing as we need better therapies in the refractory space,” David Spigel, MD, of the Sarah Cannon Research Institute in Nashville, told MedPage Today. “We have seen data with dato-DXd [datopotamab deruxtecan] improve outcomes for patients with adenocarcinoma [not squamous], so to have this [sacituzumab] not hit is disappointing.”

He expressed skepticism that response to prior immunotherapy can be used as a measure to predict benefit from sacituzumab.

Regarding combination with immunotherapy, he said that if the sacituzumab/immunotherapy combination “hit,” the absolute contribution of sacituzumab will be questioned. “Could we do just as well with docetaxel plus immunotherapy?” he said.

EVOKE-1 randomized 603 patients with measurable stage IV NSCLC who showed radiographic progression after a platinum-based and anti-PD-L1-containing regimen to sacituzumab govitecan (10 mg/kg on days 1 and 8 of 21-day cycles) or docetaxel (75 mg/m2 on day 1 of 21-day cycles).

Median patient age was 66 and 64 in the sacituzumab and docetaxel arms, respectively, and about 44% in each arm had received ≥2 prior lines of therapy. Histology was nonsquamous in ≥70% of patients in each treatment arm.

Patients with known actionable genomic alterations (AGAs) had to have received at least one approved tyrosine kinase inhibitor (an EGFR or ALK test was required and testing of other AGAs was recommended). Some 6.4% in the sacituzumab arm and 8.2% in the docetaxel arm received prior therapy for AGAs.

One-third (33.4%) of patients randomized to sacituzumab had exposure to the study drug ≥6 months compared with 17.4% assigned to docetaxel.

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