Sacituzumab Govitecan Induces Durable Responses in NSCLC

Rebecca S. Heist, MD

Results from a single-arm, multicenter trial showed that the antibody-drug conjugate sacituzumab govitecan (IMMU-132) was well-tolerated and produced a median duration of response of 6.0 months in previously treated patients with metastatic non—small cell lung cancer (NSCLC).¹

The results, which were published online in the Journal of Clinical Oncology, showed a median progression-free survival of 5.2 months (95% CI, 3.2-7.1) and median overall survival of 9.5 months (95% CI, 5.9-16.7) in the intent-to-treat population. The clinical benefit rate of 43%.

“This study shows that IMMU-132 can be effective in patients who did not respond to or progressed after multiple treatments, including immune checkpoint inhibitors, although these results are early and in a small number of patients,” first author Rebecca S. Heist, MD, assistant professor in Medicine, Massachusetts General Hospital, Harvard Medical School, and colleagues wrote. “We also observed activity in squamous cells, a subtype with a high unmet need.”

Sacituzumab govitecan is a novel antibody-drug conjugate that targets Trop-2, a 46-kD glycoprotein overexpressed in many epithelial cancers. High Trop-2 expression correlates with poor prognosis in many cancers, including NSCLC.

Results from a previous phase I trial, published by Starodub et al in 2015,² showed encouraging therapeutic activity in advanced solid cancers. These results come from a single-arm expansion of the previous trial, evaluating the activity of sacituzumab govitecan in patients with metastatic NSCLC who progressed after at least 1 prior therapy.

Fifty-four patients enrolled in the study from December 2013 to March 2016. Eight patients received a starting dose of 8 mg/kg of sacituzumab govitecan and 46 started at 10 mg/kg. Most patients (83%) had nonsquamous disease.

Thirty-one patients died by the October 14, 2016, data cutoff, 3 were lost to follow-up, and 20 were still alive. Median follow-up was 9.0 months (range, 4.4-25.3), including 6 patients who remained on study.

Investigators administered more than 800 doses of sacituzumab govitecan for a median of 5 cycles per patient and a median treatment duration of 3.3 months.

Patients in the study had undergone a median of 3 prior lines of therapy for metastatic disease (range, 2-7), and all patients had received prior platinum-based therapy. Forty patients (74%) had at least 1 prior platinum-based chemotherapy with a taxane; the remaining 14 patients also received gemcitabine and/or pemetrexed (Alimta).

Eighteen patients (33%) had received a prior checkpoint inhibitor and 17 (32%) had received an EGFR inhibitor.

Forty-seven patients were available for response assessment. Of those, 67% had a reduction of tumor size from baseline and 19% had confirmed partial response. The objective response rate in the intention-to-treat was 17% (9 of 54 patients).

Median time to tumor response was 3.8 months (1.8-11.6) and the median duration of response was 6.0 months (95% CI, 4.8-8.3) for those 9 patients, with 2 of these responses still ongoing (one at ≥7.6 months, the other at ≥19.1 months).

Four other patients have continued therapy, including 1 responder who stayed on-study after physicians discovered and treated a brain lesion with radiation.

Among the 7 response-assessable patients who had squamous cell histology, 43% had >30% reductions of their target lesions, including 1 partial response and 2 with stable disease, 1 for nearly 6 months.

Fourteen of the 18 patients who had a prior immunotherapy with a checkpoint inhibitor were assessable for response. Two had partial response, 7 had stable disease, and 5 had durable disease control that lasted >4 months. Investigators said that these results suggest that even patients who developed refractory or relapsed disease while receiving immunotherapy could benefit from sacituzumab govitecan.

Neutropenia (28%) was the most common grade 3 or higher adverse event (AE), and was the primary cause for dose reductions, which occurred in 23 (43%) patients. Researchers said that after the initial reduction, additional dose reductions were rare.

Other serious AEs that occurred in ≥5% of patients were leukopenia (9%), pneumonia (9%), diarrhea (7%), nausea (7%), and fatigue (6%). Only 2 patients (4%) experienced febrile neutropenia.

One patient with grade 3 pneumonia after 8 cycles and another with grade 3 recurrent pruritus after 2 cycles discontinued the study.

The investigators wrote that immunohistochemistry staining of tumor specimens did not produce enough evidence to determine whether Trop-2 staining is a useful biomarker for predicting response.

References

1. Heis 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 [published online May 26, 2017]. J Clin Oncol. doi: 10.1200/JCO.2016.72.1894.
2. Starodub AN, Ocean AJ, Shah MA, et al. First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res. 2015;21(17):3870-3878. doi: 10.1158/1078-0432.CCR-14-3321.