Powles, Thomas

Abstract Background: PD-L1 blockade with durvalumab (D) is approved as second-line therapy in platinum-refractory metastatic urothelial cancer (mUC). Adding CTLA-4 blockade with tremelimumab (T) may improve responses, particularly in pts with low PD-L1 expression. Here we report safety and efficacy in the mUC cohort of the dose-expansion phase of a phase I, multicenter, open-label study of D+T in pts with advanced solid tumors (NCT02261220). Methods: Pts with platinum-refractory mUC received D 20 mg/kg + T 1 mg/kg Q4W for 4 months, followed by D 10 mg/kg Q2W for a total of 12 months of treatment. The primary objectives were safety in the mUC cohort and antitumor activity in the subgroup with tumor cell and immune cell PD-L1 expression <25% (assessed by SP263 IHC assay). Secondary objectives included antitumor activity per RECIST v1.1 in other subgroups. Results: As of Oct 20 2017, 168 pts received treatment and had ≥24 weeks' follow-up. Median age was 65.5 yr (range, 35-85), 78.0% were male, 81.0% had visceral metastases (32.1% liver metastases) and 32.1% had received >1 prior line of chemotherapy. Median duration of follow-up was 11.6 mo. Treatment-related AEs occurred in 75.6% of pts and were Grade 3-4 in 28.6%. One pt died due to a treatment-related AE (pulmonary hemorrhage). Treatment-related AEs led to discontinuation of therapy in 11.9% of pts. Confirmed objective response rate (ORR) was 35/168 (20.8%) including 4 CRs. Responses occurred early (median 1.8 mo) and are durable (median DOR not reached, range 1.9-24.9 mo). At 6 months, the PFS rate was 25.4% and the OS rate was 60.9%. Median PFS was 1.9 mo and median OS was 9.5 mo. Clinical activity was seen regardless of PD-L1 status, but patients with either tumor or immune cell expression ≥25% had numerically higher response rates (29.4% vs 15.1%) and 6-month OS rates than those with <25% expression (Table). Conclusions: D+T had a manageable safety profile and encouraging antitumor activity and survival rate in previously treated mUC regardless of PD-L1 status. Response and survivalPD-L1 ≥25% (n=68)PD-L1 <25% (n=86)PD-L1 unknown (n=14)Total (N=168)Confirmed ORR (CR+PR)(95% CI), %29.4 (19.0-41.7)15.1 (8.3-24.5)14.3 (1.8-42.8)20.8 (15.0-27.8)Ongoing ORR, %60.092.310074.3Disease control rate (CR+PR+SD≥24 weeks) (95% CI), %32.4 (21.5-44.8)24.4 (15.8-34.9)42.9 (17.7-71.1)29.2 (22.4-36.7)Median PFS, months (95% CI)3.5 (1.9-3.7)1.8 (1.8-1.9)4.9 (1.8-NE)1.9 (1.8-3.4)PFS 6-month rate, %26.122.638.525.4Median OS, months (95% CI)*18.9 (8.1-NE)8.0 (4.8-10.0)16.4 (7.3-16.4)9.5 (8.1-18.9)OS 6-month rate, %66.451.991.760.9NE, not estimable *Should be interpreted with caution due to limited follow-up at data cutoff Citation Format: Arjun V. Balar, Amit Mahipal, Enrique Grande, Victor M. Villalobos, Sebastien Salas, Taek Won Kang, Se Hyun Kim, Thomas Powles, Frank Tsai, Aung Naing, Albiruni Razak, Yohann Loriot, Ji Youl Lee, Sang Joon Shin, Rafael Morales-Barrera, Natasha Angra, Feng Xiao, Shaad Abdullah, Michiel S. Van der Heijden. Durvalumab + tremelimumab in patients with metastatic urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT112.

Abstract Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 <25% group. The responses have been durable regardless of PD-L1 status, with the median duration of response not yet reached in the PD-L1 ≥25% group and 12.2 months in the PD-L1 <25% group. Responses lasted ≥12 mo in 62.9% of responders (max 25.7+ mo). Overall, median OS was 10.5 months (95% CI, 6.9, 15.7); 19.8 months in the PD-L1 ≥25% group vs 4.8 months in the PD-L1 <25% group (Table). Pts previously treated with platinum based chemotherapy also reported similar durable responses. At least one treatment-related AE was reported in 120 pts (59.7%), including fatigue (39 [19.4%]), decreased appetite and rash (18 [9.0%] each), and diarrhea (16 [8.0%]). Grade 3/4 treatment-related AEs occurred in 19 (9.5%) pts; 6 (3.0%) treatment discontinuations and 2 (1.0%) deaths were attributed to treatment-related AEs. Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 <25%PD-L1 unknownTotalAll UCn=102n=86n=13N=201Confirmed ORR, %27.55.815.417.4(95% CI)(19.1, 37.2)(1.9, 13.0)(1.9, 45.4)(12.4, 23.4)CR, %7.83.57.76.0PR, %19.62.37.711.4Median DoR, monthsNR12.2NRNR(min, max)(2.7, 25.7+)(8.6, 21.7+)(14.5+, 14.6+)(2.7, 25.7+)Median PFS, months (95% CI)1.9 (1.4, 2.7)1.4 (1.3, 1.5)2.8 (1.4, NE)1.5 (1.4, 1.8)6-month PFS rate, %28.68.625.220.412-month PFS rate, %22.37.125.216.2Median OS, months (95% CI)19.8 (9.3, NE)19.8 (9.3, NE)4.8 (3.3, 8.1)NR (4.9, NE)10.5 (6.9, 15.7)6-month OS rate, %67.645.869.258.912-month OS rate, %57.629.561.546.6 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.

LBA4500 Background: Cisplatin-based chemo is a standard 1L treatment (tx) for mUC and the only tx that prolongs OS; however, age or comorbidities render many pts ineligible, and 30-50% receive no tx. Atezo (MPDL3280A) is active and well tolerated in platinum-treated mUC, justifying testing atezo as 1L tx in cisplatin-ineligible pts. Methods: Pts were chemo naive in the metastatic setting and cisplatin ineligible (renal [GFR > 30 but < 60 mL/min]/hearing impairment, ≥ G2 peripheral neuropathy [PN] or ≥ ECOG PS2). Atezo 1200 mg was given IV q3w until PD (RECIST v1.1). Centrally assessed PD-L1 on tumor infiltrating immune cells (IC; SP142 IHC assay) was scored IC2/3, 1 or 0. The primary efficacy endpoint was confirmed ORR assessed per RECIST v1.1 (central independent review facility) using a data cutoff of Sep 14, 2015. Results: 119 efficacy/safety-evaluable pts of any PD-L1 IC had a median age of 73 y: 21% ≥ 80 y. 18% had prior systemic tx (21% [neo]adjuvant); 10% had radiotherapy. 66% had visceral mets. 71% had CrCl < 60 mL/min; 13% had hearing loss ≥ 25 dB; 6% had prior PN ≥ G2; 20% had ECOG PS2. ORR was 19% (95% CI 13-28; 5% CR), and responses occurred in all IC subgroups (Table; includes DCR/PFS/OS) and in pts with poor prognostic factors. 22/23 responses were ongoing with mDOR not reached. Median follow-up was 8.5 mo (range 0.2-14.3); median tx duration was 15 wk. Atezo was generally well tolerated. Tx-related all-G and G3-4 AEs were seen in 64% and 12% of pts, respectively. Related all-G AEs ≥ 10% included fatigue, pruritus, diarrhea. 1 G5 related AE occurred (sepsis). 3% had a G3-4 immune-mediated AE. Conclusions: Atezo has clinically meaningful activity in 1L cisplatin-ineligible mUC pts, and preliminary OS is encouraging. The durable nature of response and favorable AE profile makes this an attractive alternative to chemo. NCT02108652. Clinical trial information: NCT02108652. [Table: see text]