In two early trials, monoclonal antibody-drug conjugates showed activity in metastatic bladder cancer patients that had failed on checkpoint inhibitors, researchers reported.
Among 45 patients who received sacituzumab govitecan (IMMU-132) in the second- or later-line setting, 31.1% responded overall, including four of 17 patients that had previously received anti-PD-1 therapy, according to Scott Tagawa, MD, of Weill Cornell Medicine in New York City.
And in a phase I EV-101 study of over 100 patients treated with enfortumab vedotin, the rate of response was 43% among those who received the recommended phase II dose, and a rate that was consistent for those receiving the agent following immunotherapy, reported Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York City.
Findings from both trials were presented here at the Genitourinary Cancers Symposium.
The treatment landscape in metastatic bladder cancer has changed dramatically following the approval of five immune checkpoint inhibitors from 2016 to 2017, but response rates with these agents range from 15% to 30%.
“Although these agents are extremely effective, they do not benefit the majority of patients,” said discussant Matthew Milowsky, MD, of the University of North Carolina at Chapel Hill.
“In having the success with immune checkpoint inhibitors, we’ve created a new clinical disease state, namely the post–immune checkpoint inhibitor space,” he said.
While Milowsky noted that more development is needed in this setting, there are already “exciting agents and exciting outcomes,” including these two antibody-drug conjugates.
Sacituzumab govitecan is comprised of a Trop-2 targeting monoclonal antibody linked to an active metabolite of irinotecan (Camptosar and Onivyde), a chemotherapy approved for use in the treatment of colorectal cancer. Similarly, enfortumab vedotin delivers monomethyl auristatin E, a microtubule-disrupting antineoplastic agent, to cells that express Nectin-4.
“We know that bladder cancer is sensitive to chemotherapy, and to toxins, so it’s not totally surprising that these work,” Elizabeth Plimack, MD, of Fox Chase Cancer Center in Philadelphia, told MedPage Today. “I think the key has been development of the molecule and the linker, and development of the targets.”
Outside of these antibody-drug conjugates, the FGFR3-inhibitor erdafitinib has shown high rates of response post-immunotherapy in selected patients (59%), and the combination of ramucirumab (Cyramza) plus docetaxel has also shown activity in this setting (responses in 36%).
“Patients come out of checkpoint inhibitors usually in very good shape and more therapy that can benefit them is really needed,” said Plimack, a co-investigator on the EV-101 study.
“We can fill those trials quickly; we have a space where more and more patients are accumulating,” she said. “And these novel agents to some degree address that.”
IMMU-132
Responses with sacituzumab govitecan were also seen in patients with liver metastases (five of 15), and overall there were two complete responses (CRs) in the 45-patient cohort.
Median progression-free survival (PFS) and overall survival (OS) were 7.3 and 16.3 months, respectively. Among responders, the median duration of response was 12.9 months.
The drug was reasonably well tolerated, said Tagawa, with diarrhea (69%), nausea (67%), fatigue (58%), and neutropenia (51%) of any grade being the most common adverse events (AEs). The most common grade 3 AEs included neutropenia (22%), anemia (13%), diarrhea (9%), and fatigue (9%), and febrile neutropenia (7%); grade 4 neutropenia occurred in 14% of patients.
“There was a relatively low rate of discontinuation due to adverse events, none due to neutropenia, and there were no treatment-related deaths,” said Tagawa, who highlighted that just five of 45 patients discontinued because of drug-related AEs.
“We believe that the activity in this modest subset of patients deserves further study,” he said.
The phase II TROPHY-U-01 study will test the agent in patients who have failed on either platinum-based agents or PD-1 inhibitors.
Enfortumab Vedotin
EV-101 was a dose-escalation study, and among the 112 patients treated at the phase II recommend dose (1.25 mg/kg), median PFS and OS were 5.4 and 12.3 months, respectively. Among responders in the overall group (43%), the median duration of response was 7.4 months.
As with IMMU-132, those with liver metastases — a difficult to treat group — also showed responses with the agent (16 of 45 patients). In the anti-PD-1 group, there were three investigator-assessed CRs among 89 evaluable patients and eight CRs of 74 on central review.
This agent was also generally well tolerated, according to the investigators, with peripheral neuropathy (32%), fatigue (46%), alopecia (39%), and nausea (37%) being common AEs of note. Treatment-related AEs leading to discontinuation in 16 patients, with peripheral sensory neuropathy being the most common reason (n=5). There were four deaths across the total 155-patient safety cohort deemed possibly related to the treatment.
Choosing Post-Immunotherapy
Milowsky noted that if these agents become available for use in clinical practice, there will likely be a lack of phase III data accompanying them.
“So how do we make decisions about which of these drugs to use?” he said. “We do it in the way that we do it now, we try to pick the right drug for the right patient or the right patient for the right drug.”
He suggested checking for biomarkers (14% of bladder cancer patients harbor an FGFR3mutation, which could make erdafitinib an option), considering pharmacokinetic data, and also looking at the agents’ differing toxicity profiles — “We do this all the day long when we see patients in the clinic even with conventional chemotherapy,” he said.
Regarding toxicity, he noted that a patient with significant peripheral neuropathy related to prior platinum-based chemotherapy, underlying diabetes, or other reasons, may not be best selected for a drug enfortumab vedotin, which had some degree of neuropathy in the trial. And for sacituzumab govitecan he noted the risk of myelosuppression and febrile neutropenia as AEs to consider when selecting patients.
Tagawa disclosed relevant relationships with Abbvie, Astellas Pharma, Bayer, Dendreon, Endocyte, Genentech, Immunomedics, Janssen, Karyopharm Therapeutics, Medivation, Sanofi, and Tolmar. Co-authors disclosed multiple relevant relationships with industry.
Rosenberg disclosed relevant relationships with Seattle Genetics, AstraZeneca/MedImmune, Agensys, Bayer, Bristol-Myers Squibb, Chugai Pharma, EMD Serono, Illumina, Merck, Lilly, Pharmacyclics, QED Therapeutics, Roche/Genentech, Sanofi, and others. Co-authors disclosed multiple relevant relationships with industry.
Plimack, a co-author on EV-101, disclosed relationships with AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Exelixis, Genentech/Roche, Horizon Pharma, Incyte, Inovio Pharmaceuticals, Janssen, Merck, and Novartis.
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