2022 ASCO GU Individualized + Strong Combination Leads a New Era of Second-Line Treatment for Advanced UC

Immune checkpoint inhibitors are one of the standard regimens for patients with metastatic urothelial carcinoma (mUC) after progression on platinum-based therapy, but long-term disease control efficacy is limited
.

In the oral report and quick abstract of this year's ASCO GU conference, in the field of mUC treatment, there are three studies involving the research plan after the progress of platinum therapy.
Dual-immune combination therapy may become a new option for second-line treatment of mUC patients! Immune + ADC for second-line treatment of mUC, CBR up to 61% Background: Goxatuzumab (SG) is an ADC composed of anti-trophoblastic cell surface antigen-2 (Trop-2) antibody and SN-38 (topological The active metabolite of the isomerase I inhibitor irinotecan) is linked by a linker
.

Phase II TROPHY-U-01 study showed that SG monotherapy demonstrated good antitumor activity and manageable safety in patients with mUC, and the objective of SG in patients after platinum-containing chemotherapy and immune checkpoint inhibitor progression The response rate (ORR) was 27%, and the median overall survival (OS) was 11 months
.

At this conference, the researchers announced the interim analysis results and safety of goxatuzumab + pembrolizumab for the second-line treatment of mUC after platinum-containing chemotherapy without immune checkpoint inhibitor treatment (cohort 3) result
.

Methods: TROPHY-U-01 is a multi-cohort, open-label, global Phase II clinical study
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Eligible patients had measurable lesions, ECOG PS 0-1, and creatinine clearance ≥30 mL/min
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The recommended dose (RP2D) of the Phase 2 study was determined during the safety run-in period (10 patients), and additional patients were included in the simon Phase II to receive the RP2D dose
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Primary endpoint was ORR as assessed by independent blinded center; key secondary endpoints were ORR as assessed by investigator, clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD]), progression-free Lifetime (PFS) and security
.

Results of study design: At data cutoff, 41 patients received at least 1 dose (RP2D dose: 10 mg/kg) of goxatuzumab, median age was 67 years, 83% were male, and 83% of patients had an ECOG PS of 1.
61%, 76% of patients with more than 1 Bellmunt risk factor, and the median number of prior antitumor regimens was 1
.

At a median follow-up of 5.
8 months, 63% of patients experienced tumor shrinkage, and the investigator-assessed ORR was 34% (95% CI, 20.
1–50.
6), of which 1 patient achieved CR, 13 achieved PR, and the CBR was 61 %, and the 6-month PFS rate was 47%
.

The median time to best change from baseline in target lesions was 2.
0 months, the median duration of response (DOR) was not reached, the median OS was not reached, and the median PFS was 5.
5 months
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The most common treatment-emergent adverse events (TEAEs) were diarrhea (76%), nausea (59%), anemia (56%), neutropenia (44%), and fatigue (41%)
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Treatment-related adverse events of grade 3 or higher occurred in 59% of patients
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Grade 3 or higher TEAEs from any cause included diarrhea (24%), anemia (20%), febrile neutropenia (10%), fatigue (7%), and asthenia (5%)
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Two patients discontinued treatment due to treatment-related AEs
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There were no treatment-related deaths
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Conclusions: Goxatuzumab + pembrolizumab showed encouraging ORR and CBR in immunotherapy-naive patients with mUC after progression on platinum-based therapy, and the combined regimen was safe
.

The study data support further exploration of the efficacy of this combination regimen in patients with mUC
.

New hope for mUC with high HER2 expression: ADC+immunotherapy ORR is 36.
7% Background: HER2 overexpression is seen in invasive urothelial carcinoma, suggesting that HER2 may play a role in the progression of invasive urothelial carcinoma
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T-DXd (DS-8201) is an ADC consisting of a HER2 antibody and a topoisomerase I inhibitor payload linked by a cleavable linker
.

Preclinical studies have shown that DS-8201 + PD-1 antibody combination is more effective than DS-8201 or PD-1 monotherapy
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The investigators conducted a Phase Ib, open-label, multicenter clinical study to evaluate the efficacy of DS-8201 plus nivolumab in HER2-expressing advanced/metastatic urothelial carcinoma (UC)
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Methods: Studies were enrolled aged ≥18 years with histologically confirmed high HER2 expression (IHC 2+/3+ confirmed by immunohistochemistry [IHC], cohort 3) or low HER2 expression (IHC 1+, cohort 4) Advanced/metastatic UC; enrolled patients had previously received platinum-based therapy and had disease progression
.

Patients received DS-8201 (5.
4 mg/kg) plus nivolumab (360 mg IV) every 3 weeks
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The primary endpoint was ORR as assessed by an independent central review (ICR)
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Secondary endpoints (assessed by ICR) included DOR, PFS, time to response (TTR), OS and safety
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STUDY DESIGN RESULTS: With a data cutoff date of July 22, 2021, 34 patients (cohort 3, n = 30; cohort 4, n = 4) received DS-8201 + nivolumab
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The median age was 70.
9 years, 88.
2% of patients were male, 61.
8% of patients had received one or more treatment regimens related to locally advanced/metastatic disease, and 26.
5% of patients had a history of liver metastases
.

Median treatment durations for DS-8201 and nivolumab were 3.
2 and 4.
1 months, respectively
.

In cohort 3 patients, ORR as assessed by ICR was 36.
7%, of which 13.
3% achieved CR and 23.
3% achieved PR, median DOR was 13.
1 months, median PFS was 6.
9 months, and median TTR was 1.
9 months, and the median OS was 11.
0 months
.

Exploratory analysis of changes in the sum of tumor diameters from baseline showed no statistically significant difference in ORR for different PD-L1 expression levels
.

The most common TEAEs of any grade in the exploratory analysis were nausea (73.
5%), fatigue (52.
9%), and vomiting (44.
1%)
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Drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.
5% of patients, and there were 2, 4, 1, and 1 grade 1, 2, 3, and 5 adverse events, respectively
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Conclusion: DS-8201 + nivolumab showed good antitumor activity in patients with HER2 overexpressing UC
.

Safety data were consistent with previous studies of DS-8201 and nivolumab monotherapy
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Immune single drug sequential double immunization "strong" dose therapy individualized treatment plan: it is expected to become a new choice for platinum non-responders! Background: Nivolumab has been approved for second-line treatment of patients with mUC that has progressed after platinum-based chemotherapy
.

Recent studies have shown that dual immune checkpoint inhibitors, especially at higher doses of ipilimumab (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) (nivo1/ipi3), can improve mUC patient survival
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The TITAN-TCC study evaluated the efficacy of sequential nivolumab + ipilimumab in non-responders after 4 doses of nivo (8 weeks)
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At this conference, the researchers announced the results of TITAN-TCC cohort 2, the results of sequential use of nivo1/ipi3 booster doses in patients with mUC after previous platinum-based chemotherapy (2-line/3-line) progression
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METHODS: Between April 2019 and February 2021, 83 histologically confirmed patients with mUC (TITAN-TCC cohort 2) started induction therapy with nivolumab (240 mg Q2W)
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A fourth dose was given at week 8, and non-responders (i) (including SD/progressive disease [PD]) after tumor assessment received 2-4 doses of nivo1/ipi3; while responders (ii) (complete remission [CR]) /Partial remission [PR]) Continue nivolumab maintenance therapy, but can receive nivo1/ipi3 if PD develops later
.

The primary endpoint was investigator-assessed ORR
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Secondary endpoints included activity, PFS, OS and safety of nivolumab monotherapy at Week 8
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Study Design Results: Median follow-up was 5.
6 months
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Of all patients, 78 (94%) were on second-line therapy
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The median age was 68 years, and 57 patients (69%) were male
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At the first assessment (week 8), the ORR for nivolumab as a single agent was 20%
.

Forty-four and six received nivo1/ipi3 booster doses at week 8 and post-PD, respectively
.

Thirty-three percent (27/83) of patients achieved nivolumab-induced objective responses ± nivo1/ipi3 treatment (significant >20%, P < 0.
01)
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Efficacy Analysis Patients with tumor cells with PD-L1 ≥1% had a numerically higher ORR (46%) compared with PD-L1 negativity (24%)
.

In patients with initial SD after nivolumab induction, the ORR was 31% (4/13) following sequential nivo1/ipi3 therapy
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After sequential nivo1/ipi3 treatment in PD patients, the ORR was 19%
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In the secondary efficacy analysis, median PFS was 1.
9 months and median OS was 7.
6 months
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No new security events occurred
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Conclusions: Compared with previously reported second-line nivolumab therapy, nivolumab induction therapy plus nivo1/ipi3 booster dose therapy significantly improved ORR, PD-L1, and Patients with positive tumors appeared to benefit the most
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This study provides evidence for the potential role of high-dose ipilimumab (3 mg/kg) in patients with mUC
.

Reference: [1] Petros Grivas, Damien Pouessel, Chandler H.
Park, et al.
TROPHY-U-01 Cohort 3: Sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer ( mUC) who progressed after platinum (PLT)-based regimens[J].
J Clin Oncol 40, 2022 (suppl 6; abstr 434).
[2]Matt D.
Galsky, Gianluca Del Conte, Silvia Foti, et al.
Primary analysis from DS8201-A-U105: A phase 1b, 2-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC).
J Clin Oncol 40, 2022 (suppl 6; abstr 438).
[3]Marc-Oliver Grimm, Barbara Grün, Guenter Niegisch, et al.
Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).
J Clin Oncol 40, 2022 (suppl 6; abstr 441).