Japanese Pts Research Articles

MO1-1 6y update of 1L nivolumab + ipilimumab (N+I) in metastatic (m) NSCLC, including in Japanese pts, from CheckMate 227

MO1-1 6y update of 1L nivolumab + ipilimumab (N+I) in metastatic (m) NSCLC, including in Japanese pts, from CheckMate 227

J-TAIL-2: A prospective, observational study of atezolizumab (atezo) combined with carboplatin and etoposide (CE) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) in Japan.

8092 Background: Atezo + CE is approved for the first-line treatment of ES-SCLC based on IMpower133 (IMp133; NCT02763579). Due to the limited data available in Japanese pts, J-TAIL-2 (NCT04501497) is evaluating the efficacy and safety of atezo + CE in Japanese pts in the clinical setting. Methods: Pts from Japan had ES-SCLC, were aged ≥20 y and were scheduled to start atezo + CE in clinical practice. The primary endpoint was 12-mo OS rate. Secondary endpoints included OS, PFS and safety. Efficacy and safety were evaluated in these subgroups: IMp133-unlike (e.g., ECOG PS 2-4, CNS metastases, history/complication of autoimmune or interstitial lung disease, previous treatment for ES-SCLC) vs IMp133-like (met IMp133 eligibility criteria), age <70 vs ≥70 y and geriatric score (G8) < median vs ≥ median. G8 was assessed in pts aged ≥70 y at baseline, with lower vs higher scores indicating poorer health status. Results: From Aug 21, 2020, to data cutoff (Feb 3, 2023), 403 pts were enrolled from 150 sites. Baseline characteristics are shown in the Table. In the efficacy analysis population (n=399), the 12-mo OS rate was 63.7% (95% CI: 58.6, 68.3), median OS (mOS) was 16.5 mo and mPFS was 5.1 mo. In the IMp133-unlike vs -like groups, mOS was 15.5 vs 19.1 mo (HR, 1.32; 95% CI: 0.98, 1.77) and mPFS was 4.8 vs 5.4 mo (HR, 1.14; 95% CI: 0.90, 1.45). In pts aged <70 vs ≥70 y, mOS was 17.9 vs 16.4 mo (HR, 1.18; 95% CI: 0.90, 1.55) and PFS was 5.1 vs 5.1 mo (HR, 1.07; 95% CI: 0.86, 1.33). The median G8 score was 12; in pts with a G8 score < median vs ≥ median, mOS was 11.1 vs 18.4 mo (HR, 1.95; 95% CI: 1.38, 2.77) and mPFS was 4.8 vs 5.2 mo (HR, 1.25; 95% CI: 0.94, 1.67). In the safety analysis population (n=400), treatment-related AEs occurred in 36.0% of pts, Grade (Gr) ≥3 AEs in 66.3% and Gr 5 AEs in 2.8%. Safety outcomes were similar for the IMp133-unlike vs -like and age <70 vs ≥70 y groups. In pts with a G8 score < median vs ≥ median, Gr ≥3 AEs occurred in 70.8% vs 63.5% of pts and Gr 5 AEs occurred in 5.2% vs 0.8% of pts. Conclusions: The efficacy and safety of atezo + CE in Japanese pts treated in clinical practice were consistent with those seen in IMp133. Subgroup analyses support the use of atezo + CE in pts who would have been ineligible for IMp133, although clinical outcomes favored the IMp133-like group. Efficacy and safety were similar for pts aged <70 vs ≥70 y but were worse for those with lower vs higher G8 scores, suggesting that this assessment may be a useful tool for therapeutic strategies. These data support the use of atezo + CE in Japanese pts with ES-SCLC, including in subgroups excluded from IMp133. Clinical trial information: NCT04501497 . [Table: see text]

J-TAIL-2: A prospective observational study of atezolizumab (atezo) combination therapy in patients (pts) with non-small cell lung cancer (NSCLC) in Japan.

8573 Background: The IMpower130 (West et al. Lancet Oncol 2018), IMpower132 (Nishio et al. JTO 2021) and IMpower150 (1) trials led to the approval of first-line atezo combination therapies for NSCLC. As data remain limited in Japanese pts, J-TAIL-2 (NCT04501497) is evaluating the efficacy and safety of 3 atezo combination therapies for NSCLC in the clinical setting in Japan. Methods: Japanese pts had unresectable advanced or recurrent NSCLC, were ≥20 y old, and were scheduled to start atezo combination therapy in clinical practice. Pts received atezo + carboplatin and nab-paclitaxel (atezo + CnP), atezo + carboplatin or cisplatin + pemetrexed (atezo + PP) or atezo + bevacizumab + carboplatin + paclitaxel (atezo + bev + CP). The primary endpoint was 12-mo OS rate. Secondary endpoints included OS and safety. Efficacy and safety were analyzed in the IMpower-unlike (did not meet the main eligibility criteria of each IMpower study) and IMpower-like subgroups. Geriatric assessment (G8) was done in pts ≥70 y old at baseline; a score < median vs ≥ median indicated poorer health status. Results: From Aug 21, 2020, to data cut off (Feb 3, 2023), 814 pts were enrolled at 150 sites (atezo + CnP, n=217; atezo + PP, n=211; atezo + bev + CP, n=386). Baseline characteristics in the efficacy analysis population (n=791) are shown (Table). The IMpower-unlike group included pts with ECOG PS ≥2, brain metastases or interstitial lung disease. Twelve-mo OS rates (95% CI) were 62.9% (55.8, 69.2), 72.1% (65.2, 77.9) and 68.3% (63.2, 72.9), and median OS was 19.7, 23.5 and 17.3 mo with atezo + CnP, atezo + PP and atezo + bev + CP, respectively. OS HRs (95% CI) in the IMpower-unlike vs -like subgroups were 1.36 (0.91, 2.05), 1.08 (0.70, 1.68) and 1.49 (1.09, 2.06), respectively. The median G8 score for all evaluable pts was 13; in pts with a G8 score < median vs ≥ median, OS HRs (95% CI) were 2.10 (1.22, 3.61), 3.53 (1.95, 6.37) and 2.04 (1.22, 3.40) with atezo + CnP, atezo + PP and atezo + bev + CP, respectively. In the safety analysis population (n=800), Grade ≥3 AEs occurred in 60.4% of pts and Grade 5 AEs in 1.3%. Conclusions: In Japanese pts, the efficacy and safety of each atezo combination therapy were comparable to those seen in the relevant IMpower studies and largely consistent in pts who would have been ineligible for the trials. Pts aged ≥70 y with a G8 score < median vs ≥ median had poorer efficacy and safety outcomes. 1. Socinski et al. NEJM 2018. Clinical trial information: NCT04501497 . [Table: see text]

P760 Post-marketing surveillance of tofacitinib in patients with ulcerative colitis in Japan: A final report of effectiveness and safety data

Abstract Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present the final analysis of a 60-week post-marketing surveillance (PMS) study of tofacitinib in patients (pts) with UC in Japan. Methods A final analysis of safety and effectiveness data from a PMS study was conducted (final data as of 30 September 2022). All pts with UC in Japan receiving tofacitinib were registered. All adverse drug reactions (ADRs) during tofacitinib treatment were recorded. Data were excluded for 13 pts from 2 hospitals that did not obtain pt consent and were therefore not permitted for publication. In the risk-management plan, several ADRs were identified as clinically important events or as potential risks, for which all treatment-period data were used to calculate cumulative incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure). Effectiveness was assessed by partial Mayo score as observed. Results In total, 2043 pts receiving tofacitinib were enrolled in the PMS study, of whom 1982 and 1969 were included in the final safety and effectiveness analyses, respectively. In total (safety analysis set), 60.5% of pts were male and mean age was 42.5 years, with 2706.4 PY of exposure. ADRs and serious ADRs were observed in 462 (23.3%) and 46 (2.3%) pts, respectively; one death occurred due to an intestinal abscess (not related to study drug per investigator’s assessment). Herpes zoster (HZ; non-serious/serious) was the most commonly reported infection (89 pts [4.5%]). The IRs of malignancy, cardiovascular events and venous thromboembolic events were all <0.5 per 100 PY of exposure (Table). At Week 60, 735 of 870 ongoing pts (84.5%) were in remission (Figure). Overall, 1038/1982 pts (52.4%) discontinued treatment, most commonly due to inadequate clinical response (508/1038 pts [48.9%]). Conclusion In this final analysis, the overall safety profile during the treatment period from PMS reports of tofacitinib in pts with UC in Japan was generally comparable with tofacitinib safety data previously reported in PMS reports from Japan and worldwide,1 and in the tofacitinib UC clinical programme.2 However, rates of HZ were higher in this final analysis than in the tofacitinib UC clinical programme.2 Tofacitinib was effective in Japanese pts with UC in a clinical practice setting. The majority of pts with evaluable partial Mayo scores achieved remission during the 60-week observation period, consistent with previously reported data from the tofacitinib UC clinical programme.2

HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer (mCRC) refractory to anti-EGFR antibodies.

113 Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .

10152-PEDT-5 JAPANESE SUBGROUP ANALYSIS OF A PHASE II TRIAL OF DABRAFENIB PLUS TRAMETINIB (D+T) IN BRAF V600-MUTANT PEDIATRIC LOW-GRADE GLIOMA (PLGG) AND RELAPSED/REFRACTORY (R/R) BRAF V600-MUTANT PEDIATRIC HIGH-GRADE GLIOMA (PHGG)

Abstract BACKGROUND pLGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. pHGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. The result of a phase II global clinical trial (NCT02684058) of D+T vs carboplatin + vincristine (C+V) in first-line BRAF V600-mutant pLGG and single arm D+T in relapsed/refractory (r/r) BRAF V600-mutant pHGG has already been described. Briefly, the primary endpoint was the independently assessed overall response rate, ORR (CR+PR) using RANO criteria. The ORR was 47% (95% CI, 35%-59%) with D+T vs 11% (95% CI, 3%-25%) with C+V (P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]) in pLGG and 56.1% (95% CI, 39.7%-71.5%) in pHGG. Safety was consistent with the established profile of D+T in other indications. We report results for the Japanese subgroup. RESULTS A total of 6 Japanese pts were included in pLGG (D+T; n=4, C+V; n=2). And a total of 11 Japanese pts with diverse WHO Grade III/IV gliomas were included in r/r pHGG. The best overall response assessed by independent reviewer were as followed; D+T; SD 75% (n=3), PD 25% (n=1), C+V; CR 50% (n=1), PD 50% (n=1) in pLGG and CR 9.1% (n=1), PR 27.3% (n=3), SD 9.1% (n=1), PD 36.4% (n=4) in r/r pHGG. Treatment-related grade ≧3 adverse events were D+T; 25% (n=1) and C+V; 100% (n=2) in pLGG and 27.3% (n=3) in r/r pHGG. DISCUSSION AND CONCLUSIONS Treatment with D+T showed encouraging efficacy in Japanese pLGG and r/r pHGG. Profile of AEs was similar or consistent which is reported in other adult cohorts. Thus, these results suggest that D+T may represent a critical treatment advance for pLGG and r/r pHGG Japanese pts with BRAF V600-mutant.

Cross-sectional study of patients' (pts) and physicians' needs and the financial toxicity of systemic treatment for metastatic renal cell carcinoma (mRCC) in Japan.

702 Background: There is an increasing awareness of the importance of pt-centricity in cancer treatments. To achieve pt-centricity in mRCC treatment, it is important to clarify the differences of preferences between pts and physicians in terms of efficacy, safety, quality of life, and healthcare economics. However, these data are currently lacking for Japanese pts with RCC. This study aims to identify any differences in preferences for drug treatments between pts with mRCC and physicians in Japan, as well as assess the financial toxicity of mRCC and its influencing factors among pts. Methods: This cross-sectional observational study collected data via a web survey of pts with mRCC and physicians. The primary endpoint was to identify the differences in drug-treatment preferences between pts and physicians. The secondary endpoints included identification of the side effects that were most distressing to the pts and those that were most difficult to communicate to the physicians, and the reasons for this. We also evaluated the financial toxicity using the “COST” tool as an exploratory endpoint. Fisher's exact test was used in the evaluation of differences between pts and physicians. Background factors for financial toxicity were evaluated using univariate and multivariate regression analyses. Pearson’s correlation was used to assess the correlation between COST score and FACT-G score. Results: 83 Pts and 165 physicians were included in the analysis. For pts, “eliminating all evidence of disease” ( P < 0.001) was the most important drug-treatment outcome, while for physicians, it was “longer survival” ( P < 0.001). The item of most concern about drug treatment was “disturbing daily activities due to the side effect” for both pts and physicians; while pts were more concerned than physicians about “financial burden” ( P < 0.01) and “lack of the knowledge for the treatment” ( P < 0.001). Diarrhea, fatigue, and vomiting were the most distressing side effects for pts; 51% of pts had difficulty in telling their physicians about side effects such as fatigue, anxiety, and depression. The median COST score was 19 (range, 3–36) and multivariate analysis showed that age and private insurance were independent factors in financial toxicity. In addition, the COST score was positively correlated with the FACT-G total score ( r = 0.40, P < 0.001). Conclusions: There is a gap between pts with mRCC and physicians in their preferences and concerns about drug treatment. Japanese pts with mRCC suffer from side effects, some of which are not shared with physicians, and experience adverse financial impacts even under the universal health insurance coverage system available in Japan. This study highlights the importance of communicating well with pts in clinical practice to achieve pt-centricity in systemic treatment for mRCC.

Real-World Treatment Patterns, Outcomes and Disease Burden of Japanese Patients with High-Risk Myelodysplastic Syndrome: A Claims Database Study

Introduction Inherent complex pathophysiology of myelodysplastic syndrome (MDS) along with its higher occurrences in elderly population often limits available treatment options. In Japan, azacitidine (AZA) is the only first-line (1L) treatment, which is not cytarabine-based, available for patients (pts) with high-risk MDS (HR-MDS) ineligible for hematopoietic stem cell transplantation (HSCT). Prior autoimmune diseases have been associated with susceptibility of MDS. However, durability of AZA treatment and data on MDS-specific comorbidities, especially immune-driven events are currently lacking in Japanese pts. This study aimed to answer clinical questions on AZA real-world treatment outcomes in Japan, the epidemiology of autoimmune diseases in this specific pt cohort, as well as treatment cost. Methods This was a retrospective, longitudinal study utilizing hospital-based administrative claims for MDS patients in the Medical Data Vision (MDV) database in Japan. Data on pt demographics, clinical characteristics, treatments, procedures and hospitalization records were collected. Adult pts with first a confirmed MDS diagnosis either as an inpatient or twice in outpatient setting during the identification period (1October 2008 - 30 September 2017), who had a bone marrow biopsy in ±3 months from index date and at least 1 MDS-related treatment post-index date, were included in this real-world study. Pts with confirmed acute myeloid leukemia (AML) diagnosis or who had any history of HSCT, graft-versus-host-disease or transplant-related disorder/complications were excluded. As IPSS/R scoring is unavailable in MDV, pts were classified as HR-MDS if they had either AZA treatment or HSCT within 6 months post-index date, or pancytopenia diagnosis within 6 months post-index date and initiated AZA within 12 months. Results Of 6204 pts who met the eligibility criteria (main cohort), 2138 pts were assigned as HR-MDS. The median age of pts in the main cohort was 74.0 years (range: 18.0 - 100.0 years, ≥60 years old: 87.8%) vs 73.0 years (range: 20.0 - 95.0 years; ≥60 years old: 88.6%) in the HR-MDS cohort. Mean Charlson Comorbidity Index was 1.7 (± 1.66) and 1.6 (± 1.47) for the main cohort and HR-MDS cohort respectively. The proportion of transfusion-dependent pts in the main cohort was 9.4% vs 7.1% of patients in the HR-MDS cohort. Among 2138 pts with HR-MDS, 251 pts reported having concomitant autoimmune disease with rheumatoid arthritis (32.3%), glomerulonephritis (26.7%) and seronegative arthritis (23.1%) being the most common. More pts in the main cohort (53.2%) compared to pts with HR-MDS (38.9%) received anti-anemic drugs, G-CSF and iron chelators as supportive therapy at 1L. Compared to 39.5% pts in main cohort, 88.3% pts with HR-MDS received antineoplastic agents at 1L therapy. In HR-MDS cohort, 2078 pts received AZA in different cycles (1-3 cycles: 40.5%, 4-6 cycles: 21.1%, 7-9 cycles: 11.5%, >9 cycles: 26.9%) but only 121 pts received intensive chemotherapy (1 cycle: 90.1%, 2 cycles: 9.1%, >2 cycles: 0.8%). Median duration of MDS-specific treatment for patients with HR-MDS was 9.8 months. Significantly higher median OS (P<0.001) was achieved in pts with HR-MDS who received more cycles of AZA (Fig. 1: 1-3 cycles: 14.6 months, 4-6 cycles: 21.4 months, 7-9 cycles: 22.8 months, >9 cycles 40.8 months). After controlling for death as a competing risk, the cumulative incidence function (CIF) of HSCT and AML transformation was not affected by the number of cycles of AZA received. Although more cycles of AZA treatment increased the total treatment cost, median cost per pt per month was inversely affected with the lowest cost for pts receiving >9 cycles (Fig. 2). Conclusion Our findings based on the real-world data analysis in Japanese pts follow the similar trend of elderly pts with HR-MDS mostly receiving AZA as 1L treatment. Despite higher median OS being associated with higher number of AZA cycles, only ~27% pts with HR-MDS received >9 cycles of AZA. Autoimmune disease was reported by 11.7% of pts with HR-MDS. Although treatment cost increased with number of cycles of AZA received, median cost per pt per month was lowest in patients receiving >9 cycles. The cost per pt per month for other MDS-related treatment as well as costs for blood transfusions and infection related treatments were lower as increasing cycles of AZA were given which contributed to lower cost per pt per month. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

390P Entrectinib in Japanese patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC and NTRK-fp solid tumours

Entrectinib is a ROS1/TRK tyrosine kinase inhibitor (TKI) with CNS activity. In an integrated analysis of three phase I/II trials (ALKA-372-001 EudraCT 2012-000148-88; STARTRK-1 NCT02097810; STARTRK-2 NCT02568267), entrectinib showed overall response rates (ORRs) of 67% in pts with ROS1-fp NSCLC and 61% in pts with NTRK-fp solid tumours (data cutoff: 2 Aug 2021). We present primary data for the subset of Japanese pts from STARTRK-2.

85P Safety and efficacy of atezolizumab (Atezo) + bevacizumab (Bev) in Japanese patients (pts) with unresectable hepatocellular carcinoma (uHCC): A prospective, multicenter, observational study (ELIXIR) - A preliminary analysis

Atezo + Bev has been approved as first-line treatment in pts with uHCC based on a global phase 3 study (IMbrave 150). However, there is a lack of real-world data worldwide. Thus, we conducted the ELIXIR study to evaluate the safety and efficacy of Atezo + Bev prospectively in 500 real-world Japanese pts. Here, we report the first pre-planned safety assessment in 105 initially registered pts out of 500 pts.

Abstract A25: Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial

Abstract Introduction: CHRONOS-3 randomized patients (pts) with relapsed iNHL to the PI3K inhibitor copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs. P+R (hazard ratio[HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al., EHA 2022) and in the subset of pts with FL (see Capra et al. AACR Lymphoma 2022 abstract). We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with a particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A comprehensive popPK model for copanlisib was developed using plasma concentrations from 712 pts across 9 copanlisib clinical Phase 1-3 studies. Demographic, laboratory, and comedication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS, overall response rate [ORR], complete response [CR]) and key treatment-emergent safety events using multivariate cox proportional hazards (CPH) and logistic regression analyses, after accounting for predefined potentially prognostic demographic, laboratory, and/or disease related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination from the central compartment following intravenous infusion. Copanlisib PK was dose proportional and time independent with no accumulation. Covariates statistically selected as influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration, female sex, Japanese pts, mild or worse hepatic impairment, and a CHRONOS-3 study effect, however all identified covariates, aside from rifampin/itraconazole, had no clinically relevant effect (≤ 35%) on copanlisib AUC. In CHRONOS-3, CPH analyses demonstrated a statistically significant positive ER relationship for PFS where greater copanlisib exposure was associated with prolonged PFS. Relative to P+R, the HR for C+R at the 5th and 95th percentile of copanlisib time-varying exposure was 0.875 and 0.217, respectively. Thus, lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for ORR and investigated adverse events. Based on the modelling, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. The ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusions: PopPK and ER analyses support copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle dose selection in the relapsed iNHL population. Citation Format: Jonathan Moss, Dirk Garmann, Rupert Austin, Florian Hiemeyer, Patricia DeLora, Matthew J Matasar, Pier Luigi Zinzani, Vita Beckert, Lidia Mongay Soler, Barrett H Childs, Peter N Morcos. Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A25.

O13-4 Efficacy and intracranial activity of tepotinib in Japanese patients with MET exon 14 skipping (METex14) NSCLC (VISION)

Tepotinib is a highly selective MET inhibitor, approved in Japan for advanced METex14 skipping NSCLC, which occurs in 3-4% of NSCLC patients (pts). Brain metastases (BMs) are reported in 20-40% of pts, presenting a high unmet need with a poor prognosis. Tepotinib crosses the blood-brain barrier and has demonstrated intracranial activity in preclinical MET-driven lung cancer. In the phase II VISION study (NCT02864992), pts in Cohorts A+C with METex14 skipping NSCLC, detected by liquid or tissue biopsy, received 500 mg QD oral tepotinib. The primary endpoint was ORR per RECIST v1.1 by independent review committee (IRC). An ad hoc retrospective analysis of brain lesions was conducted by IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. By data cut-off (Feb 1, 2021), 275 pts with ≥3 months' follow-up from Cohorts A+C were evaluable for efficacy (49.1% male, median age 73 years [range: 41-94], 49.8% treatment-naÏve). ORR across treatment lines was 49.1% (95% CI: 43.0, 55.2), with mDOR of 13.8 months (95% CI: 9.9, 19.4), mPFS of 10.8 months (95% CI: 8.5, 12.4), and mOS of 19.7 months (95% CI: 15.6, 22.1). Per RECIST v1.1, 34 pts had BM at baseline; systemic ORR was 58.8% (95% CI: 40.7, 75.4). Of 38 pts from Japan, 68.4% were male, median age was 73 years [range: 62-87], and 47.3% were treatment-naÏve. ORR across treatment lines was 60.5% (95% CI: 43.4, 76.0), with mDOR of 18.5 months (95% CI: 8.3, ne), mPFS of 19.9 months (95% CI: 8.3, ne), and mOS of 20.4 months (95% CI: 16.3, ne). In Cohort A (data cut-off; Jul 1, 2020), 15 pts were evaluable by RANO-BM (12 received prior radiotherapy). Intracranial disease control was achieved in 5 of 7 pts with target lesions (all PRs), and 7 of 8 pts with non-target lesions. Tepotinib demonstrated robust systemic activity in pts with METex14 skipping NSCLC including in Japanese pts, and showed intracranial activity in pts with BM.

P29-1 LIGHT-NING: An observational study of nivolumab plus ipilimumab with or without chemotherapy for 1st line NSCLC in Japan

Based on the efficacy and safety data in patients (pts) with previously-untreated advanced NSCLC in the CheckMate 9LA and CheckMate 227 trials, first-line nivolumab (NIVO) plus ipilimumab (IPI) with or without 2 cycles of chemotherapy was approved in Japan on November 27, 2020, as the first combination therapy with an anti-CTLA-4 agent for NSCLC. Since detailed information regarding efficacy and safety with the combinations is limited in Japanese pts with NSCLC, we conducted this study to assess effectiveness and safety of NIVO plus IPI with or without chemotherapy in real-world clinical practice.

MO38-2 Safety and pharmacokinetics (PK) of tusamitamab ravtansine (tusa) in Japanese patients (pts) with advanced solid tumors

Tusa is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing tumors. The maximum tolerated dose (MTD) of tusa was defined as 100 mg/m2 every 2 weeks in the global study. This phase 1 dose escalation study (NCT03324113) aimed to evaluate safety of tusa in Japanese pts.

MO38-1 Phase I study of BI 836880 alone or combined with ezabenlimab in Japanese patients (pts) with advanced solid tumors

Inhibition of VEGF/Ang2 and PD-1 can enhance the tumor microenvironment to support T-cell mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2; ezabenlimab (BI 754091) is an anti-PD-1 antibody. This study determined the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of BI 836880 alone or combined with ezabenlimab in Japanese pts with solid tumors.

S292: SUSTAINED RESPONSE OFF TREATMENT IN ELTROMBOPAG-TREATED PATIENTS WITH ITP WHO ARE REFRACTORY OR RELAPSED AFTER FIRST-LINE STEROIDS: PRIMARY ANALYSIS OF THE PHASE II TAPER TRIAL

Background: Corticosteroids (CSs) are the standard 1st-line treatment for primary immune thrombocytopenia (ITP); however, long-term CS use is associated with high relapse rates and considerable toxicity. Treatments that achieve a sustained response and reduce the need for long-term CS use are needed. Eltrombopag (EPAG) is a thrombopoietin receptor agonist (TPO-RA) indicated in Europe for the treatment of patients (pts) aged ≥1 year with primary ITP lasting ≥6 months who are refractory to other treatments (eg, CSs). Evidence suggests that a proportion of pts treated with TPO-RAs achieve sustained responses that are maintained after TPO-RA tapering and discontinuation; however, much of the evidence is retrospective with only a few prospective studies investigating sustained response off treatment (SRoT). Aims: TAPER (NCT03524612), a Phase II, open-label, prospective, single-arm study, aims to determine whether EPAG can induce SRoT in pts with ITP after 1st-line CS failure. Methods: Adult (≥18 years) pts with ITP who did not respond to or had relapsed after initial CS therapy, with platelet counts <30×109/L and assessed as needing treatment, were included. Patients received a 50 mg/day starting dose of EPAG (25 mg/day for East/Southeast Asian pts; 12.5 mg/day for Japanese pts in Japan), which could be increased up to 75 mg/day (50 mg/day in Japan) if needed. The primary endpoint was the number (%) of pts with SRoT by Month 12; SRoT was defined as achieving a complete response (CR, ie, platelet count ≥100×109/L), then maintaining a stable platelet count (no counts <70×109/L) for 2 months, followed by successful EPAG tapering and discontinuation with platelet counts ≥30×109/L and no bleeding events or rescue therapy. Patients with SRoT at Month 12 were followed for a further year. Secondary outcomes included SRoT duration and platelet count changes from baseline. Data to Month 12 are presented. Results: N=105 pts were enrolled. The median (interquartile range [IQR]) age was 46 (30-65) years; 61% were female. In the 1st 12 months, median (IQR) duration of exposure to EPAG was 5.6 (2.3-11.9) months and median (IQR) EPAG dose was 57.1 (37.5-69.0) mg/day. Overall, 89 pts (85%) achieved CR at least once and 65 pts (62%) maintained a platelet count ≥70×109/L for 2 months after CR. EPAG tapering and discontinuation was achieved in 44 pts (42%). The primary endpoint was met, with 32 pts (30.5% [95% confidence interval, 21.9-40.2]; P<0.001 [H1: P>15%; alpha: 0.05]) achieving SRoT until Month 12 (Fig. 1); SRoT was maintained from last dose to Month 12 for a median (IQR) of 33.3 (25.7-45.3) weeks. The median (IQR) absolute increase in platelet counts from baseline at Month 12 was 77.0×109/L (35.0-145.0). All-grade adverse events (AEs) occurred in 92/105 (88%) pts (grade ≥3 AEs: 33/105 [31%]). Treatment-related AEs occurred in 37 (35%) pts (8 [7.6%] grade ≥3). The most common all-grade AEs were headache (21% of pts with ≥1 event [grade ≥3: 1% of all pts]), thrombocytopenia (17% [10.5%]), and petechiae (11% [1%]). There were 4 deaths (none were considered treatment related): 3 were on-treatment (central nervous system hemorrhage [n=1], intracranial hemorrhage [n=1], metastases to peritoneum [n=1]) and 1 death (malignant neoplasm) occurred 238 days after last dose. Image:Summary/Conclusion: Data from the TAPER study indicate that a significant proportion of pts experience sustained response following tapering and discontinuation of EPAG, even after a relatively short duration of exposure. Overall EPAG was well tolerated with no unexpected AEs.

Abstract CT517: Amcenestrant, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/HER2- advanced breast cancer (aBC): combined biomarker analyses from a Phase 1/2 study in postmenopausal women and a Phase 1 study in postmenopausal Japanese women

Abstract Background: Amcenestrant is an optimized oral SERD that has shown safety and clinical benefit in patients (pts) with wild-type (WT) and mutated ESR1 aBC. Here we provide a pooled analysis of biomarkers from two studies in heavily-pretreated, postmenopausal women with ER+/HER2- aBC. Methods: Pooled analysis included study data from AMEERA-1 (NCT03284957), in which pts received single-agent amcenestrant in dose escalation (20-600 mg QD or 300 mg BID) and dose expansion (400 mg QD), and from AMEERA-2 (NCT03816839), in which Japanese pts received single-agent amcenestrant at 400 mg QD or 300 mg BID. Mutational profiling of plasma circulating cell-free DNA was conducted by droplet digital polymerase chain reaction (ddPCR) for 12 pathogenic ESR1 mutations at baseline (BL) and on treatment (OT; Cycle 2, Day 28), and by next-generation sequencing (NGS; 77-gene panel) at BL and end of treatment (EOT). Clinical benefit (CB; complete response + partial response [PR] + stable disease ≥ 24 weeks) was assessed in pooled pts who received amcenestrant≥ 150 mg QD or BID. In tumor tissue, ER, progesterone receptor (PgR), Ki67 and Bcl-2 expression levels over time were assessed by immunohistochemistry; functional ER pathway activity was assessed by gene set variation analysis with RNA-seq data (ER activity score). Results: Among pts with data for ESR1 mutation status at BL (N = 80; ddPCR), 41 pts were WT and 39 pts had at least one ESR1 mutation, with D538G and Y537S the most prevalent. CB was observed in pts with both WT (13 pts) and mutated ESR1 (12 pts) at BL. The most frequent pathogenic mutations detected in pts (N = 79; NGS) at BL were ESR1 (49%), followed by PI3KCA (46%)and TP53 (33%). In response-evaluable pts with ESR1 mutational profiling at BL and OT (N = 40; ddPCR), 17 of 19 pts with ESR1 mutation at BL showed a decrease in ESR1 mutation allele frequency, independently of clinical benefit. Eight pts showed an increase (7/25 no CB and 1/15 CB). Among 17 pts with biopsies, pts with ER or PgR -/low (H-score: 0-3) at BL did not derive benefit from treatment. In the remaining patients with ER high (H-score ≥ 140), no difference between pts with and without CB was observed in ER, Bcl-2 or ER activity score, while pts with CB had a tendency for lower Ki67. ER and PgR decreased upon treatment independently of CB, while ER activity score and Ki67 mostly decreased in pts with CB and mostly increased in pts without CB. Conclusions: In postmenopausal women with ER+/HER2- aBC treated with single-agent amcenestrant, low Ki67 at BL and the pharmacodynamic decrease of Ki67 and ER activation score by amcenestrant trended toward an association with CB, whereas increase in ESR1 mutation allele frequency on treatment trended toward an association with lack of CB. Clinical benefit was observed in both pts with WT and mutated ESR1 at BL. Citation Format: Hiroji Iwata, Aditya Bardia, Simon Lord, Hannah M. Linden, Mario Campone, Kenji Tamura, Kan Yonemori, Toru Mukohara, Cécile Combeau, Nils Ternes, Dimitri Carene, Jeff Ming, Joon Sang Lee, Marina Celanovic, Anne-Laure Bauchet, Monsif Bouaboula, Tomoyuki Tanaka, Yumiko Kawabata, Sarat Chandarlapaty. Amcenestrant, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/HER2- advanced breast cancer (aBC): combined biomarker analyses from a Phase 1/2 study in postmenopausal women and a Phase 1 study in postmenopausal Japanese women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT517.

Brigatinib in Japanese patients (pts) with ALK+ NSCLC: Final results from the phase 2 J-ALTA trial.

9075 Background: In previous J-ALTA (NCT03410108) analyses, brigatinib demonstrated substantial efficacy and manageable safety in pts with TKI-refractory and TKI-naive ALK+ NSCLC. We report the final J-ALTA results. Methods: J-ALTA was a single arm, multicenter, open-label study that included ALK TKI-naive and -refractory NSCLC expansion parts. The main cohort within the refractory part was a group with alectinib-refractory NSCLC. Primary endpoints: IRC-assessed confirmed ORR in the alectinib-refractory cohort; IRC-assessed 12-month PFS in the TKI-naive cohort. Secondary endpoints included confirmed ORR (IRC-assessed in the total refractory cohort; investigator-assessed in all cohorts); DoR, PFS, DCR, and iPFS by IRC; and safety. Final analyses were performed following last pt last contact. Results: A total of 104 pts were enrolled; 72 had TKI-refractory (56% female; median age, 53.0 y) and 32 had TKI-naive (53% female; median age, 60.5 y) NSCLC. As of 28 July, 2021 (last pt last contact), median follow-up was 24.2 mo in the refractory cohort (alectinib-refractory subgroup [n = 47], 23.0 mo) and 22.1 mo in the TKI-naive cohort. Confirmed ORR was 34% (95% CI: 21–49) by IRC with 16 partial responses (PR) in the alectinib-refractory cohort and 32% (21–44; 22 PR) in the total refractory cohort. In the TKI-naive cohort, IRC-assessed 24-mo PFS was 73% (90% CI: 55–85); median PFS was not mature. Additional efficacy analyses are reported in Table. TEAEs were reported in all 104 pts (most common: increased CPK, 79%; hypertension, 48%; diarrhea, 47%). Grade ≥3 TEAEs were reported in 68% and 91% of pts in the TKI-refractory and -naive cohorts, respectively; most commonly (TKI-refractory/naive) elevated CPK, 24%/50%; elevated lipase, 15%/19%; hypertension, 11%/34%. Pneumonitis was mandated to be reported as an SAE regardless of severity and was the only SAE reported in &gt; 5% of pts (refractory, n = 5 [7%; early onset, 1]; naive, n = 4 [13%; early onset, 0]). TEAEs led to dose interruption/reduction/discontinuation in 63%/31%/7% of pts in the TKI-refractory cohort and 94%/69%/0% in the TKI-naive cohort. Conclusions: Final efficacy and safety results in pts with TKI-refractory and -naive NSCLC were consistent with previous J-ALTA analyses. No new safety signals were observed in either cohort. Brigatinib demonstrated a favorable benefit-risk profile and is an important option for Japanese pts with ALK+ NSCLC regardless of TKI treatment history. Clinical trial information: NCT03410108. [Table: see text]

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Abstract CT124: Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor

Abstract Background: The PARP inhibitor rucaparib is approved in the US for pts with recurrent ovarian or metastatic castration-resistant prostate cancer. This phase 1 study (NCT03499444) evaluated safety, pharmacokinetics (PK), and antitumor activity (per RECIST v1.1) of rucaparib in Japanese pts. Methods: Pts were enrolled in a 3+3 dose-escalation phase to establish the recommended dose (RD) in Japanese pts; dose-limiting toxicities (DLTs) were assessed in the first 21 days. Pts must have had an advanced solid tumor that had progressed on standard treatment. A dose-expansion phase enrolled pts at the RD to further assess safety, PK, and efficacy. Results: The visit cutoff was Oct 20, 2020; 29 pts received rucaparib, including 15 in the dose-escalation phase (400 mg BID, n=3; 500 mg BID, n=6; and 600 mg BID, n=6) and 14 in the dose-expansion phase at the RD of 600 mg BID. Median (range) time on treatment was 5.1 (1.3-16.4) months overall and 5.3 (1.4-16.4) months for 600 mg BID pts (n=20).One DLT was reported (treatment interruption &amp;gt;7 days due to grade 1/2 nausea, vomiting, diarrhea, fatigue; 500 mg BID cohort). Across all doses, the most frequent any-grade treatment-emergent adverse events (TEAEs) were alanine aminotransferase/aspartate aminotransferase increased (82.8%), anemia (82.8%), and nausea (69.0%); the most frequent grade ≥3 TEAE was anemia (51.7%). Among 600 mg BID pts, 25.0% (5/20) had a TEAE leading to treatment interruption or dose reduction, most commonly due to anemia (20.0%; 4/20).Steady-state PK was evaluated for the 400, 500, and 600 mg BID cohorts (Table).Most pts with measurable disease had a best response of stable disease (63.0%; 17/27); the confirmed objective response rate was 18.5% (5/27) overall and 21.1% (4/19) among 600 mg BID pts (Table).Conclusions: Rucaparib 600 mg BID had a manageable safety profile for Japanese pts with advanced solid tumors, with a PK profile similar to that of Western pts. These results support further exploration of rucaparib in Japanese pts. 400 mg BID(n=3)500 mg BID(n=6)600 mg BID(n=20)Overall(N=29)Baseline characteristicsAge, median (range), years67.0 (45.0-68.0)61.5 (44.0-73.0)59.5 (43.0-74.0)61.0 (43.0-74.0)Female, n (%)3 (100)6 (100)16 (80.0)25 (86.2)ECOG PS 0, n (%)a3 (100)4 (66.7)15 (75.0)22 (75.9)Tumor type, n (%)Ovarian2 (66.7)1 (16.7)9 (45.0)12 (41.4)Primary peritoneal1 (33.3)2 (33.3)2 (10.0)5 (17.2)Pancreatic004 (20.0)4 (13.8)Breast02 (33.3)1 (5.0)3 (10.3)Other01 (16.7)4 (20.0)5 (17.2)Steady-state PK dataCmax, mean (CV%), ng/mL1,690 (38.7)3,650 (61.9)b2,800 (37.0)cNCtmax, median (range), h1.48 (1.47-2.45)3.95 (2.47-9.95)b2.50 (0.93-9.83)cNCCmin, mean (CV%), ng/mL1,590 (38.7)2,380 (78.5)2,130 (44.4)NCAUClast, mean (CV%), h × ng/mL14,400 (36.6)30,200 (64.7)b23,800 (39.9)cNCCL/F, mean (CV%), L/h26.1 (45.2)22.1 (68.5)d24.3 (34.6)eNCAUC0-12, mean (CV%), h × ng/mL17,200 (35.8)33,900 (78.9)d28,100 (40.8)eNCEfficacy dataORR, n/N (%) [95% CI]1/3 (33.3) [0.8-90.6]0/5 (0) [0.0-52.2]4/19 (21.1) [6.1-45.6]5/27 (18.5) [6.3-38.1]aAll other pts had ECOG PS 1.bn=5.cn=18.dn=3.en=13.AUC0-12, area under the concentration-time curve up to 12 h; AUClast, area under the concentration-time curve up to last time point (10 h) with a quantifiable concentration; CL/F, apparent total clearance of drug after oral administration; Cmax, maximum concentration; CV, coefficient of variation; ECOG PS, Eastern Cooperative Oncology Group performance status; NC, not calculated; ORR, objective response rate; PK, pharmacokinetics; tmax, time to maximum concentration. Citation Format: Kenji Tamura, Koji Matsumoto, Kan Yonemori, Kosei Hasegawa, Jenn Habeck, Eric Jones, Jim Xiao, Aaron Enke, Keiichi Fujiwara. Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT124.