Abstract: 7548 Background: Primary central nervous system lymphoma (PCNSL) is known as an uncommon and extremely aggressive type of non-Hodgkin lymphoma of brain tumors. Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the treatment of relapsed or refractory PCNSL (rrPCNSL) based on the results of phase I/II study in Japan (Trial registration: JapicCTI-173646) in 2020. Methods: In this study, 44 Japanese patients with rrPCNSL received TIR QD at doses of 320 mg (n = 20), 480 mg (n = 7), or 480 mg while fasting (480 mg fasted: n = 17). The International PCNSL Collaborative Group criteria were used to assess the primary endpoint, which was the overall response rate (ORR). We previously reported the interim results with 14.9 (range:1.4–27.7) months of median follow-up in 2020 (Mishima et al., the 25th Society for Neuro-Oncology 2020). The final analysis results with a three-year follow-up are reported here (data cutoff: April 27 th , 2022). Results: For the entire population, the ORR was 63.6% with 36.4% of complete response, the median duration of response was 9.2 months, the median progression-free survival was 2.9 months, and the median overall survival was not reached (median follow-up: 37.1 months). The most frequent adverse events (AEs) were skin and subcutaneous tissue disorders and blood and lymphatic system disorders at any grade, including rash (36.4%) and neutropenia (27.3%), leukopenia (25.0%), lymphopenia (18.2%), and thrombocytopenia (11.4%). Grade ≥3 AEs were neutropenia (9.1%), leukopenia (9.1%), lymphopenia (6.8%), and erythema multiforme (6.8%). One patient with 480 mg had grade 5 AEs (Pneumocystis jirovecii pneumonia and Interstitial lung disease), while neither new grade 5 AEs nor new safety profiles were observed since the last data cutoff. As of the current data cutoff, 15 and 6 of 44 patients had been receiving TIR for more than one and three years, respectively, and 5 of the 6 patients continued receiving TIR, including 4 patients who were receiving 480 mg fasted. Conclusions: In conclusion, TIR showed long-lasting effectiveness in a subset of patients with a tolerable safety profile of rrPCNSL. Clinical trial information: JapicCTI-173646. [Table: see text]

Abstract: 2065 Background: The poor prognosis of glioblastoma (GBM; WHO grade IV) results from a high rate of disease recurrence and lack of effective treatment options. Depatuxizumab mafodotin (depatux-m, ABT-414) is comprised of an EGFR-directed antibody, depatuxizumab (depatux, ABT-806), conjugated to the microtubule toxin monomethyl auristatin F (MMAF, mafodotin). Once bounded with tumor cells, depatux-m is internalized and releases the cytotoxin, resulting in cell death. Here, we report safety, pharmacokinetic (PK) and efficacy in an ongoing phase 1/2 study of Japanese patients with/without EGFR-amplified recurrent GBM (rGBM). Methods: M13-714 (INTELLANCE-J, NCT02590263) is a non-randomized, phase 1/2 study in Japanese patients. Phase 1 assessed tolerability and PK where the dose escalation of depatux-m was from 0.5 to 1.25 mg/kg/Q2W at day 1 and 15 during 28-day cycle until progression disease (PD) or intolerable toxicity. Phase 2 assessed efficacy and safety of depatux-m in EGFR-amplified, rGBM and patients received 1.0 mg/kg of depatux-m on day 1 and 15 + 150 mg/m 2 temozolomide (TMZ) on days 1-5 during each 28-day cycle until PD or intolerable toxicity. Results: As of 10 Jan 2019, 38 patients (WHO grade ≥3) were enrolled (9 in phase 1, 29 in phase 2). There was no dose limiting toxicity in phase 1. The recommended phase 2 dose was 1.25 mg/kg where the most common adverse events (AEs) were punctate keratitis in 21 patients (72%); lymphopenia in 14 patients (45%), thrombocytopenia in 13 patients (41%). Grade 3/4 AEs included thrombocytopenia and lymphopenia in 20 patients (69%). Ocular AEs were reported in 27 patients (93%) including punctate keratitis (72%). PK results (31 patients) in both phases were similar to those of non-Japanese result. Progression Free Survival (PFS) of 27 patients in phase 2 for 12 and 6 months were 8% and 27.5% respectively. The median PFS was 4 months. The overall survival (OS) for 24, 12 and 6 months were 28%, 62.5% and 93% respectively. The median OS was 15.5 months. Conclusions: Preliminary safety, PK and efficacy in Japanese patients with/without EGFR-amplified, rGBM suggests depatux-m was tolerated and showed encouraging anti-GBM effects. Clinical trial information: NCT02590263.

Abstract: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up. Methods Eligible patients were aged ≥20 years with histologically diagnosed PCNSL and KPS of ≥70. Patients received oral tirabrutinib once daily at 320 mg or 480 mg, or 480 mg under fasted condition. Results Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapse and refractory, respectively. The 320 mg, 480 mg, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI, 47.8–77.6) with complete response, unconfirmed complete response, partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment. Conclusions The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores being maintained.

Abstract: Tirabrutinib, a second-generation inhibitor of Bruton’s tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data. Methods Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS. Results Forty-four patients (mean age, 60 years [range 29–86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4–27.7). The median KPS of the patients at baseline was 80.0 (range, 70–100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3–17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Conclusions Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

Abstract: In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (r/rPCNSL) based on the results of a phase I/II study in Japan. In this study, 44 Japanese patients with r/rPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff in June 2019 (Narita et al. Neuro Oncol. 2020). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (31.8%), neutropenia (22.7%), leukopenia (18.2%), and lymphopenia (15.9%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for overall survival, duration of response, and time to onset of AEs will also be presented. TIR is a promising new treatment for r/rPCNSL.

Abstract: Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Abstract: Primary central nervous system lymphoma (PCNSL) is known as one of the incurable brain tumors. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (rrPCNSL) based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646). In this study, 44 Japanese patients with rrPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff on June 13, 2019 (Nagane et al., the 61st American Society of Hematology Annual Meeting and Exposition in 2019). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 25, 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for OS, duration of response, and time to onset of AEs will also be presented.

Abstract: The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). Methods Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. Results Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. Conclusion These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. Trial registration JapicCTI-173646.

Abstract: BACKGROUND The first-generation Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL). Tirabrutinib is a second-generation oral BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety, tolerability, efficacy, and pharmacokinetics (PK) of tirabrutinib once daily (QD) as monotherapy in patients with PCNSL to investigate BTK targeting as a novel therapeutic strategy. This multicenter clinical trial was sponsored by Ono Pharmaceutical Co., Ltd. and was conducted in Japan. METHODS Patients with r/r PCNSL, at least 1 parenchymal disease, Karnofsky performance status (KPS) ≥70, and normal end-organ function were treated with tirabrutinib 320 and 480 mg QD in the phase 1 portion to evaluate dose-limiting toxicity (DLT) within 28 days using a 3+3 dose escalation design, and with 480 mg QD in a fasted condition in the phase 2 portion to assess the safety, efficacy, and PK of tirabrutinib. The primary objective of the phase 2 portion was to evaluate overall response rate (ORR) as assessed by an independent review committee (IRC) according to International PCNSL Collaborative Group (IPCG) criteria. RESULTS Forty-four patients were enrolled; 20 received tirabrutinib at 320 mg, 7 at 480 mg, and 17 at 480 mg under fasted conditions as of June 13, 2019. The median patient age and KPS were 60 years (range 29-86) and 80, respectively. The median number of prior therapies was 2 (range 1-14); all patients had received methotrexate; and 28 had isolated parenchymal disease, 14 cerebrospinal fluid (CSF) involvement, and 3 intraocular involvement. No DLTs were observed, and the maximum tolerated dose (MTD) was not reached up to 480 mg. Commonly observed events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%). Commonly observed grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). Two grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease) were observed in a patient 33 days after starting tirabrutinib at 480 mg QD. IRC-assessed ORR was 64% (28/44); 60% (12/20) with 5 complete response (CR)/unconfirmed complete response (CRu) at 320 mg, 100% (7/7) with 4 CR/CRu at 480 mg, and 53% (9/17) with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival (PFS) was 2.9 months (95% confidence interval [CI]: 1.8-11.1); 2.1 months (95% CI: 1.8-NA) at 320 mg, 11.1 months (95% CI: 1.4-NA) at 480 mg, and 5.8 months (95% CI: 1.0-5.8) at 480 mg under fasted conditions. Median overall survival was not reached (95% CI: NA-NA). ORR was similar among patients harboring the oncogenic mutants CARD11, MYD88, CD79B, and wild type (Table 1). Mean values of maximum observed plasma concentration of tirabrutinib after multiple administration on Day 28 at 320 mg, 480 mg, and 480 mg under fasting conditions were 1360, 2270, and 2690 ng/mL, respectively. The area under the plasma concentration time curve over a dosing interval was 6370, 11800, and 11800 ng*h/mL, respectively. The exposure of tirabrutinib increased with increasing dose, regardless of fasting status. Mean trough concentration of tirabrutinib in CSF/plasma at 320 mg and 480 mg on Day 28 was 2.19/16.3 ng/mL and 14.0/89.3 ng/mL, respectively. This indicated that CSF concentration increased with increasing plasma concentration at trough, while the trough concentration ratios between CSF and plasma at each dose were comparable with the free fraction of tirabrutinib in plasma. CONCLUSION Tirabrutinib had a tolerable safety profile and MTD was not reached in patients with PCNSL. IRC-assessed ORR was 64%, despite the presence of CARD11 mutation. Median PFS was longer with the increasing dose. Further investigation is warranted. Disclosures Nagane: Tsumura: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Otsuka: Research Funding; Bristol-Myers-Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Dainippon-Sumitomo: Honoraria; NovoCure: Honoraria; UCB Japan: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; MSD: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ono: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Research Funding; Sanofi: Research Funding. Narita:Ono: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Dainippon-Sumitomo: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Meiji-seika: Honoraria, Research Funding; SBI pharma: Honoraria, Research Funding. Mishima:Ono: Research Funding; Chugai: Research Funding; MSD: Research Funding; Eisai: Research Funding; Teijin Pharma: Research Funding; Medical U and A: Research Funding; AbbVie: Research Funding; Otsuka: Research Funding; Daiichi-Sankyo: Research Funding; Nihon-Medi-Physics: Research Funding. Terui:Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Research Funding. Arakawa:UCB: Honoraria; Otsuka: Honoraria; AbbVie: Honoraria; NovoCure: Honoraria; CSL Behring: Honoraria; Nippon-Kayaku: Honoraria; Pfizer: Research Funding; Takeda: Research Funding; CLS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; TanabeMitsubishi: Research Funding; Zeiss: Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Sanofi: Research Funding; Philips: Research Funding; Siemens: Research Funding; Ono: Research Funding. Yonezawa:Ono: Research Funding. Asai:Ono: Research Funding. Fukuhara:Mundi: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Bayer: Research Funding; Gilead: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen Pharma: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Solasia Pharma: Research Funding. Sugiyama:Ono: Research Funding; Taiho: Research Funding; Daiichi-Sankyo: Research Funding; Bristol-Myers-Squibb: Research Funding; Chugai: Research Funding; Meiji Seika: Research Funding; Yakult: Research Funding. Shinojima:Ono: Research Funding. Kitagawa:Ono: Employment. Aoi:Ono: Employment. Nishikawa:Ono: Honoraria, Research Funding; MSD: Research Funding; AbbVie: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; NovoCure: Honoraria; Daiichi-Sankyo: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Abstract: INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263).