Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

Talukder, Rafee; Makrakis, Dimitrios; Lin, Genevieve Ihsiu; Diamantopoulos, Leonidas; Dawsey, Scott J.; Gupta, Shilpa; Carril-Ajuria, Lucía; Castellano, Daniel; Kouchkovsky, Ivan de; Jindal, Tanya; Koshkin, Vadim S.; Park, Joseph J.; Alva, Ajjai; Bilen, Mehmet Asım; Stewart, Tyler F.; McKay, Rana R.; Tripathi, Nishita; Agarwal, Neeraj; Vather-Wu, Naomi; Zakharia, Yousef; Morales-Bárrera, Rafael; Devitt, Michael; Cortellini, Alessio; Maria, Fulgenzi Claudia Angela; Pinato, David J.; Nelson, Ariel Ann; Hoimes, Christopher J.; Gupta, Kavita; Gartrell, Benjamin A.; Sankin, Alex; Tripathi, Abhishek; Zakopoulou, Roubini; Bamias, Aristotelis; Murgić, Jure; Fröbe, Ana; Rodríguez‐Vida, Alejo; Drakaki, Alexandra; Liu, Sandy; Lu, Eric; Kumar, Vivek; Lorenzo, Giuseppe Di; Joshi, Monika; Isaacsson-Velho, Pedro; Buznego, Lucía Alonso; Durán, Ignacio; Moses, Marcus W.; Barata, Pedro C.; Sonpavde, Guru; Wright, Jonathan L.; Yu, Evan Y.; Montgomery, Robert B.; Hsieh, Andrew C.; Grivas, Petros; Khaki, Ali Raza

doi:10.1016/j.clgc.2022.08.006

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Early progression on previous platinum-based chemotherapy and a shorter time between the initial time of platinum-based chemotherapy and subsequent therapy were considered to be associated with poor outcomes in mUC. 28 In the current combined analyses, no differences in the ORRs (53.3% v 42.9% v 52.2%) and the mPFS (5.4 months v 6.2 months v 6.2 months) were observed when comparing patients with different median times from initiation of the previous chemotherapy to first DV treatment (<3 months v 3-6 months v >6 months). Hence, the influence of clinical response to previous chemotherapy on the subsequent DV treatment needs to be further explored in a future study on DV treatment.…”

Section: Discussioncontrasting

confidence: 53%

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials

Sheng,

Wang,

et al. 2024

JCO

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PURPOSE To evaluate the efficacy and safety of disitamab vedotin (DV, RC48-ADC), a novel humanized anti–human epidermal growth factor receptor 2 (HER2) antibody conjugated with monomethyl auristatin E, in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC) refractory to standard or regular therapies. PATIENTS AND METHODS The data analyzed and reported are from two phase II, open-label, multicenter, single-arm studies (RC48-C005 and RC48-C009) in patients with HER2-positive (immunohistochemistry 3+ or 2+) locally advanced or metastatic UC who have progressed on at least one previous line of systemic chemotherapy. Patients received DV treatment (2 mg/kg IV infusion, once every 2 weeks). The primary end point was objective response rate (ORR) assessed by a blinded independent review committee (BIRC). Progression-free survival (PFS), overall survival (OS), and safety were also assessed. RESULTS One hundred and seven patients were enrolled in total. The overall confirmed ORR by BIRC was 50.5% (95% CI, 40.6 to 60.3). Consistent results were observed in prespecified subgroups including patients with liver metastasis and patients previously treated with anti–PD-1/L1 therapies. By the cutoff date of May 10, 2022, the median duration of response was 7.3 months (95% CI, 5.7 to 10.8). The median PFS and OS were 5.9 months (95% CI, 4.3 to 7.2) and 14.2 months (95% CI, 9.7 to 18.8), respectively. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (68.2%), leukopenia (50.5%), AST increased (42.1%), and neutropenia (42.1%). Fifty-eight (54.2%) patients experienced grade ≥3 TRAEs, including peripheral sensory neuropathy (18.7%) and neutropenia (12.1%). CONCLUSION DV demonstrated a promising efficacy with a manageable safety profile in patients with HER2-positive locally advanced or metastatic UC who had progressed on at least one line of systemic chemotherapy.

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Section: Discussioncontrasting

confidence: 53%

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials

Sheng,

Wang,

et al. 2024

JCO

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“…A duration of <3 months from the start of platinum-based chemotherapy to the beginning of second-line CPI therapy has been shown to be a negative prognostic factor associated with poorer outcomes after second-line CPI therapy. 28 Therefore, this patient population should be prioritized for clinical trials. Moreover, the site of metastasis can be relevant to the therapeutic decision making in platinum-refractory mUC and the possible differences among clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3

Grivas,

Pouessel,

Park

et al. 2024

JCO

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PURPOSE Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2–directed antibody-drug conjugate with US Food and Drug Administration–accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973 ) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.

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“…Intermediate endpoints, including ORR, DCR, PFS, modified PFS, and milestone survival, have been proposed as surrogate endpoints for immunotherapy in clinical trials. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 However, these studies were specific to one tumour type, one country/region, or with limited high-qualities trials, and the results were often ambiguous or conflicted due to the biological complexity of cancer. Here, though a comprehensive analysis with phase 3 randomised control trials (RCTs), our primary objective was to assess the study-level of ORR, DCR, PFS, and 1-year OS as surrogate endpoint for outcomes in cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Intermediate endpoints as surrogates for outcomes in cancer immunotherapy: a systematic review and meta-analysis of phase 3 trials

Zhang,

Pan,

et al. 2023

eClinicalMedicine

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Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

Cited by 7 publications

References 29 publications

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3

Intermediate endpoints as surrogates for outcomes in cancer immunotherapy: a systematic review and meta-analysis of phase 3 trials

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