Erken evre Mesane kanserinde Erdafitinib(TAR-210 adlı molekül etkili ve ameliyat ihtiyacını önemli oranda azaltabilir

Erken evre Mesane kanserinde Erdafitinib adlı molekül etkili ve ameliyat ihtiyacını önemli oranda azaltabilir

Erken evre mesane kanserinde FGFR mutasyonu sık görülür.  Evre IV mesane kanserinde bu mutasyonun görülme oranı yaklaşık %20-30 oranındayken, erken evre mesane kanserinde %60-80 oranında görülmektedir.

Daha önceki çalışmalar FGFR3 mutasyonu olan evre IV mesane kanserinde Erdafitinib adlı molekülün etkili olduğu saptanmıştı

Yeni yapılan çalışmalar, erken Ta ve T1, BCG tedavisi sonrası nüks gelişen, papiller histoloji ve FGFR3 mutasyonu olan hastalarda bu molekülün etkinliği denendi

Yapılan çalışmada bu grup hastalarda oral verilen Erdafitinib adlı molekül, intravesikal(mesane içi) verilen mitomycin ve gemsitabin kemoterapisine göre nüks oranını yaklaşık %70 oranında azalttığı saptandı.

Oral alınan bu moleküle bağlı daha önce bilinen yan etkiler görüldü.

Yan etkileri azaltmak için Erdafitinib adlı molekülün mesane içine verildiği ve mesane mukozasından tümör dokularına etki ettiği özel bir sistem olan TAR-210 ile ilacın sistemik yan etkilerinin belirgin azaldığı ve etkisinin yüksek olduğu saptandı.

TAR-210 çalışmasına, BCG tedavisi sonrası nüks gelişen, papiller histolojiye sahip pTa ve PT1 ve FGFR3 mutasyonu olan hastalarda bu molekülün etkinliği inravesikal özel sistemle verilerek denendi

Bu küçük hasta grupta ki sonuçlara göre tam yanıtın %87 düzeyinde olduğu, ilaca bağlı sistemik yan etkilerin nerdeyse hiç görülmediği ve sadece üriner sistem ilişkili yan etki gözlendiği saptandı.

Bu yeni yöntemle daha önce inravesikal tedavilere yanıt vermeyen hastalara mesane içi özel sistemle hedefe yönelik tedavilerin verilmesi ile idrar torbası ameliyat ile alınmadan uzun dönem yaşama şansı doğuracak gibi gözüküyor.

Çalışmanın daha büyük hasta grubunda yapılması ve benzer sonuçların çıkması durumunda, erken evre mesane kanseri için önemli bir tedavi seçeneği olacağı görülüyor.

Kaynak

ESMO 2023

Background

Treatment (tx) options are limited for pts with HR NMIBC who have recurrence after BCG tx and are ineligible for/refuse radical cystectomy (RC). Erda, an oral selective pan-FGFR tyrosine kinase inhibitor, demonstrated an overall survival benefit over chemo in the phase 3 THOR study in pts with locally advanced/metastatic urothelial carcinoma with FGFRalt. We report the first randomized data in pts with recurrent, BCG-treated HR NMIBC with FGFRalt from Cohort 1 of THOR-2 (NCT04172675).

Methods

Adult pts with recurrent, BCG-treated, papillary-only HR NMIBC (high-grade Ta/T1) and select FGFRaltrefusing/ineligible for RC were randomized 2:1 to 6 mg oral erda or investigator’s choice of intravesical chemo (mitomycin C or gemcitabine). Primary end point: recurrence-free survival (RFS). Secondary end points: RFS rate at 6 and 12 mo and safety.

Results

73 pts (median age: 69 y) were randomized to erda (n=49) and chemo (n=24). Study enrollment was discontinued because of slow accrual. Median follow-up was 13.4 mo for both groups. Median RFS was not reached for erda and was 11.6 mo for chemo, with an estimated hazard ratio of 0.28 (Table). 6- and 12-mo RFS rate was 96% and 77% for erda vs 73% and 41% for chemo, respectively. Grade (Gr) 3-4 tx-related adverse events (TRAEs) occurred in 15 (31%) and 1 (4%) pts with erda and chemo, respectively; 14 (29%) and 0 pts had TRAEs leading to discontinuation of erda and chemo, respectively. Central serous retinopathy occurred in 19 pts (39%) with erda (Gr 1-2, 17 pts) and resolved in 11 pts (58%).Table: LBA102

Value (95% CI)          Erda n=49                   Chemo n=24

Median RFS, moa    NE (17-NE)                 11.6 (6-20)

Hazard ratiob            0.28 (0.13-0.62) nominal p=0.0008c

6-mo RFS, %              96 (84-99)                 73 (50-87)

12-mo RFS, %            77 (60-87)                 41 (19-62)

aCensoring: 1) Recurrence-free + alive or unknown status, censored at last assessment; 2) no post-baseline assessment, censored at randomization; 3) withdrew consent or lost to follow-up prior to RFS event, censored at last assessment; 4) start subsequent anticancer tx prior to RFS event, censored at last assessment before new tx start. bEstimated using stratified Cox proportional hazards regression model. Hazard ratio <1 indicates longer RFS in erda vs chemo. cBased on an unstratified log-rank test.

Conclusions

Erda prolonged RFS compared with chemo in pts with papillary-only HR NMIBC with FGFRalt who had recurrence after BCG tx. Erda toxicity was generally consistent with the known safety profile of oral FGFR inhibitors.

Clinical trial identification

NCT04172675.

Background

Treatment (tx) options are limited in NMIBC that recurs after intravesical chemotherapy or bacillus Calmette-Guérin (BCG). TAR-210 is a novel intravesical drug delivery system designed to provide local, continuous release of erda (selective pan-FGFR tyrosine kinase inhibitor) within the bladder while limiting systemic toxicities. This open-label, multicenter phase 1 study (NCT05316155) evaluates the safety, PK, and efficacy of TAR-210 in pts with NMIBC whose tumors harbor select FGFRalt.

Methods

FGFRalt were identified in tumor tissue or urine cell-free DNA. Cohort 1 (C1) pts had recurrent, BCG-experienced high-risk NMIBC (high-grade Ta/T1; papillary only) and refused or were ineligible for radical cystectomy. Cohort 3 (C3) pts had recurrent, intermediate-risk NMIBC (Ta/T1) with history of only low-grade papillary disease. Before tx, C1 pts must have all visible disease resected; C3 requires the presence of visible tumors. TAR-210 systems with 2 different erda release rates were evaluated. Response is assessed every 3 mo with continued tx for up to 1 year if recurrence-free (RF) (C1) or in complete response (CR) (C3).

Results

As of Aug 29, 2023, 16 pts in C1 and 27 pts in C3 have been treated; 11 and 15 pts, respectively, had ≥1 response assessment. 82% in C1 were RF; 87% in C3 achieved CR (Table). Most common tx-related AEs were grade 1/2 lower urinary tract AEs. There were no dose-limiting toxicities, no deaths, 2 pts discontinued due to AEs of low-grade urinary symptoms, and 1 pt had serious AEs of pyelonephritis and sepsis. PK showed sustained erda concentrations in urine, with very low plasma exposures.  Table: LBA104

Efficacy outcomes and Tx exposure

Cohort 1 (n=11 with response assessment)

RF, n (%)  9 (81.8)

Median RFS (95% CI), mo        NE (2.96-NE)

Cohort 3 (n=15 with response assessment)

CR, n (%) 13 (86.7)

Median duration of CR (95% CI), mo*   NE (NE-NE)

Both cohorts (n=43 all-treated)

Median duration of tx exposure (range), mo          3.7 (0-12)

Total duration of tx, n (%)

≥0-<3 mo 18 (41.9)

≥3-<6 mo 13 (30.2)

≥6-<9 mo 6 (14.0)

≥9-<12 mo                 5 (11.6)

≥12 mo    1 (2.3)

CI, confidence interval; mo, months; NE, non-estimable; RF, recurrence-free; RFS, recurrence-free survival. *All CR in Cohort 3 were ongoing as of data cutoff.

Conclusions

TAR-210 appears safe and well tolerated with predominantly low-grade urinary system AEs and high CR rate and RF survival in pts with NMIBC with FGFRalt. Results justify further study of targeted tx of erda using a novel intravesical delivery system in early-stage bladder cancer.

Clinical trial identification

NCT04083976.