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Sacituzumab govitecan response rates 'promising' in metastatic urothelial cancer
SAN FRANCISCO – Sacituzumab govitecan showed activity in patients with relapsed or refractory metastatic urothelial carcinoma, including those treated with immune checkpoint inhibitors and those with visceral metastases, according to results of a phase 1/phase 2 study presented at Genitourinary Cancers Symposium.
Sacituzumab govitecan (IMMU-132, Immunomedics) is a novel antibody-drug conjugate consisting of a monoclonal antibody that targets Trop-2, an epithelial cell surface antigen.
“The target, Trop-2, is overexpressed in various solid tumors,” Scott T. Tagawa, MD, medical director of the genitourinary oncology program at Weill Cornell Medicine and NewYork-Presbyterian, said in an interview with HemOnc Today. “In the initial phase 1 basket study, we looked at sacituzumab govitecan in various solid tumors, and looked at safety and the best dose. There happened to be patients with metastatic urothelial carcinoma in this study, and our initial observation was that those patients did very well.
We ended up pooling that data from six patients and publishing it,” he added. “That led to the phase 2 study, which looked at longer-term data in patients with metastatic urothelial carcinoma who have received a standard phase 2 dose.”
In the phase 1/phase 2 basket study, Tagawa and colleagues evaluated 45 patients (median age, 67 years; range, 49-90; n = 41 men) with advanced solid tumors who had received a median two (range, 1-6) previous lines of treatment, including platinum-based chemotherapy (95%) and immune checkpoint inhibitors (38%). Thirty-three patients had visceral metastases involving the liver (n = 15), lung (n = 27) and other organs (n = 5).
Patients received IV sacituzumab govitecan at the 10 mg/kg dose level on days 1 and 8 of 21-day cycles.
The researchers acquired CT/MRI scans at 8-week intervals to evaluate response.
Safety, objective response rate by RECIST version 1.1 criteria, clinical benefit rate — including complete response, partial response or stable disease for at least 6 months — Kaplan-Meier estimated duration of response, PFS and OS served as study endpoints.
Results showed an ORR of 31%, with two complete responses and 12 partial responses. Patients with visceral involvement attained an ORR of 27%. Checkpoint inhibitor-treated patients (n = 17) had an ORR of 23%.
“We’d expect a standard chemotherapy to have a response rate of around 10%, so when we see 30%, that’s promising,” Tagawa said. “Response rates are a cutoff, but the majority had stability or tumor shrinkage.”
The median duration of response was 12.6 months, with two patients continuing to respond beyond 2 years, and the clinical benefit rate was 47%.
Researchers reported median PFS of 7.3 months and median OS of 18.9 months. The adverse event profile was consistent with previous reports.
seen in at least 5% of patients included neutropenia/neutrophil count decrease (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%) and febrile neutropenia (7%).
A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of sacituzumab govitecan in advanced urothelial carcinoma.
good efficacy,” Tagawa told HemOnc Today. “At the same time, patients received a number of cycles, and some went on for multiple years. It was generally well-tolerated.” – by Jennifer Byrne
Reference:
Tagawa ST, et al. Abstract 242541. Presented at: Genitourinary Cancers Symposium; Feb 14-16, 2019; San Francisco.
Disclosures: Tagawa reports consultant/advisory roles with AbbVie, Astellas Pharma, Bayer, Dendreon, Endocyte, Genentech, Immunomedics, Janssen, Karyopharm Therapeutics, Medivation, Sanofi and Tolmar; research funding to his institution from AbbVie, Amgen, Astellas Pharma, AstraZeneca, AVEO, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Dendreon, Eli Lilly, Endocyte, Exelixis, Genentech, Immunomedics, Inovio Pharmaceuticals, Janssen, Karyopharm Therapeutics, Medivation, Merck, Millennium, Newlink Genetics, Novartis, Progenics, Rexahn Pharmaceuticals, Sanofi and Stem CenRx; and travel accommodations or expenses from Immunomedics and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.
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Antibody drug conjugates are a novel type of systemic therapy being evaluated in locally advanced (unresectable) and metastatic urothelial cancer. Enfortumab vedotin (ASG-22ME, Seattle Genetics) —targeting nectin-4 — has shown an impressive overall response rate of about 40% in a phase 1 trial in patients with prior lines of therapy. It was tolerable overall with notable but manageable adverse events, eg, fatigue, alopecia, anorexia, neuropathy, rash, etc.
Based on early data, enfortumab vedotin has received breakthrough designation by the FDA, but it is not yet approved. Detailed results of the ongoing phase 2 trial in patients previously treated with chemotherapy and/or immune checkpoint inhibitors are anticipated very soon, and a recent press release mentioned that the phase 2 trial met its primary endpoint of ORR. There is also an ongoing phase 3 trial comparing this agent to salvage chemotherapy, while a phase 1b trial is evaluating its combination with chemotherapy or immune checkpoint inhibitors.
The other antibody drug conjugate, sacituzumab govitecan, which targets Trop-2, also showed very promising results in this phase 1/phase 2 trial with meaningful ORRs and median PFS, which require validation in the ongoing larger phase 2 trial in patients with prior chemotherapy and/or immune checkpoint inhibitor therapy. The toxicity profile is also manageable and slightly different than that of enfortumab vedotin, including neutropenia, nausea, diarrhea, etc. Considering the differences in the antibody target protein as well as the conjugated toxin, there is expectation that the two agents may have efficacy even when used sequentially in the same patient; however, data are needed to address that question. Biomarker exploration is also interesting in the above studies. There are additional antibody drug conjugates being tested in separate trials in this challenging disease.
Overall, there is significant excitement with antibody drug conjugates in advanced urothelial cancer, both as single agents and in combinations. In the future, those agents may also be tested in earlier stages.