Final results from cohort 1 of the phase 3 TROPHY-U-01 trial reported continued significant activity with sacituzumab govitecan-hziy as treatment of patients with metastatic urothelial carcinoma who progressed on both platinum-based chemotherapy and checkpoint inhibition.
Final results from cohort 1 of the phase 3 TROPHY-U-01 trial reported continued significant activity with sacituzumab govitecan-hziy (Trodelvy) as treatment of patients with metastatic urothelial carcinoma who progressed on both platinum-based chemotherapy and checkpoint inhibition, according to a presentation during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.
Results showed that the antibody-drug conjugate (ADC) elicited an overall response rate (ORR) of 27% (n = 31; 95% CI, 19%-37%), thus meeting the primary end point of the trial; this included a complete response (CR) rate of 5% (n = 6) and a partial response (PR) rate of 22% (n = 25). Moreover, the median duration of response (DOR) was 5.9 months with sacituzumab govitecan (95% CI, 4.70-8.60).
"The final results from TROPHY-U-01 cohort 1 confirmed the interim findings and the results from the prior phase 1 study, and showed that sacituzumab govitecan is generally well tolerated and has significant anticancer activity in heavily pretreated [patients with] metastatic urothelial cancer who have progressed on both platinum-based chemotherapy and checkpoint inhibitors,” Yohann Loriot, MD, PhD, lead author of the study and a medical oncologist at the Institut de Cancèrologie Gustave Roussy, in Villejuif, France, said in a presentation during the congress.
Sacituzumab govitecan is a Trop-2–directed ADC that is unique from other agents in its class because of its high drug-to-antibody ratio, as well as its bystander effect because of its hydrolysable linker hydrolysis, explained Loriot. The agent has demonstrated significant activity across several tumors. Earlier results from the IMMU-132-01 trial (NCT01631552) showed that the ADC resulted in a 31% ORR with a median progression-free survival (PFS) of 7.3 months and a median overall survival (OS) of 16.3 months, with an acceptable safety profile.
In the open-label, global phase 2 TROPHY-U-01 trial (NCT03547973), investigators evaluated sacituzumab govitecan in 3 cohorts: patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and checkpoint inhibition (n = 100; cohort 1); those who were ineligible for platinum-based chemotherapy and progressed following checkpoint inhibition (n = 40; cohort 2); and those who never received checkpoint inhibitors but had progressed on platinum-based therapy (n = up to 61; cohort 3).
The data presented at the 2020 ESMO Congress comprised those of cohort 1, in which patients received 10 mg/kg of the ADC on days 1 and 8, every 21 days and continued treatment until loss of clinical benefit or intolerable toxicity. The primary end point of this analysis was ORR per central review and secondary end points included safety/tolerability, DOR, PFS, and OS.
A Simon 2-stage design was used with an enrollment of 100 patients at a 90% power to reject the null hypothesis of an ORR of 12% or less, explained Loriot. The 100-patient sample size was designed to have sufficient statistical power to confirm that the lower bound of the 95% CI would exclude an ORR of 15% or less, assuming a 24% ORR.
Previous results from an interim analysis of the trial presented during the 2019 ESMO Congress showed that sacituzumab govitecan elicited an ORR of 29% in 35 response-evaluable patients; this was comprised of 2 CRs, 6 PRs, and 2 additional PRs that had been pending confirmation. These data led to the continued enrollment of cohort 1, said Loriot.
The final intent-to-treat analysis was based on blinded independent central assessment of data per RECIST v1.1 criteria and the data cutoff for the final analysis presented at this year’s meeting was May 18, 2020.
The median age of participants was 66 years, with 23% of patients 75 years of age or older and 78% male. Moreover, the majority of patients were white, at 74%. Twenty-eight percent of patients had an ECOG performance status of 0, while 72% had a status of 1. Overall, 62% of patients had visceral metastases; 40% had lung metastases, 28% had liver metastases, and 12% had other.
Notably, the median number of prior anticancer regimens received was 3. “Therefore, this is a heavily pretreated patient population, and sacituzumab govitecan was the fourth line of therapy,” noted Loriot.
At the time of the final analysis, 14% of patients (n = 16/113) continued to receive treatment with sacituzumab govitecan. The majority of patients who discontinued treatment did so because of disease progression (66%; n = 75). Only 7% (n = 8) of patients discontinued the ADC because of toxicity. Three percent of patients (n = 3) discontinued because of withdrawn consent and 3% (n = 3) died. The median time on treatment was 3.7 months, according to Loriot, and the maximum time on treatment is 16 months thus far. Fifty-percent of patients (n = 56) are in follow-up for survival.
The median time to onset of response was 1.6 months. The ORR, median DOR, and median time to response reported were consistent with investigator assessments.
“There was a reduction in target lesion size in three-quarters of patients,” noted Loriot. Moreover, 27 of 31 responders were alive with 8 of these patients still experiencing a response and receiving the treatment at the time of the data cutoff.
Tumor assessments were made every 6 weeks through cycle 12, added Loriot. “Looking at the depth of reduction in tumor size in all patients, you can see that most patients, including many who did not meet the criteria for a CR or PR, had a reduction in tumor size that was sustained for a long period of time.”
The estimated median PFS with sacituzumab govitecan was 5.4 months (95% CI, 3.5-6.9), while the estimated median OS was 10.5 months (95% CI, 8.2-12.3).
With regard to safety, diarrhea was the most commonly experienced treatment-related adverse effect (TRAE), occurring in two-thirds of patients (all grade, 65%); this is consistent with what has been reported in prior studies with the ADC. However, most of these effects were grade 1/2, noted Loriot. Nine percent of patients experienced grade 3 diarrhea and only 1% experienced it as grade 4.
Forty-six percent of patients experienced neutropenia, with 22% having a grade 3 effect and 12% reporting a grade 4 effect. “However, neutropenia was manageable with dose reductions and granulocyte colony-stimulating factor; it was reversible,” said Loriot. “Thirty-percent of patients received GCSF either as primary prophylaxis or in response to neutropenia.”
Six percent of participants (n = 7) discontinued treatment because of TRAEs; 3 patients discontinued because of neutropenia or complications associated with the toxicity. Moreover, 1 treatment-related death was reported, with a patient presenting with sepsis due to febrile neutropenia.
“Sacituzumab govitecan received fast track designation [from the FDA] for this indication and may have the potential to change practice in this setting,” Loriot concluded.
These data have led to the initiation of the phase 3 confirmatory trial TROPiCs-04 (NCT04527991), which will enroll 482 patients with locally advanced and resectable or metastatic urothelial carcinoma who have progressed following platinum-based chemotherapy and checkpoint inhibition.
Participants will be randomized to either sacituzumab govitecan at 10 mg/kg on days 1 and 8 of each 21-day cycle or physician’s choice of chemotherapy consisting of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine at 320 mg/m2. The primary end point of the trial is OS, while key secondary end points include PFS, ORR, DOR, and quality of life.
1. Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based reigmens and checkpoint inhibitors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA24.
2. Tagawa STT, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer (mUC) after failure of platinum-based regimens or immunotherapy. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA55.