Elranatamab in Japanese patients with relapsed/refractory multiple myeloma: results from MagnetisMM-2 and MagnetisMM-3.

BACKGROUND: Despite advances, most patients with multiple myeloma (MM) experience relapse and repeat multiple treatment lines, highlighting an unmet need for patients with relapsed or refractory MM (RRMM). Bispecific antibodies are a new option, but their efficacy and safety in Japanese patients are unknown. METHODS: This was an analysis of Japanese patients receiving elranatamab monotherapy in MagnetisMM-2 (NCT04798586) and MagnetisMM-3 (NCT04649359). Both studies evaluated a priming dose regimen of elranatamab followed by weekly subcutaneous doses, in patients with disease progression while receiving or who were intolerant to ≥3 prior therapies (≥1 proteasome inhibitor, ≥1 immunomodulatory drug and ≥1 anti-CD38 monoclonal antibody). The primary endpoints were dose limiting toxicities (DLTs) in MagnetisMM-2 and confirmed objective response rate (ORR) in MagnetisMM-3. In both, key secondary endpoints included safety, tolerability, duration of response, time to response, progression-free survival and overall survival. RESULTS: In MagnetisMM-2 (N = 4) and MagnetisMM-3 (n = 12), median ages were 68.5 and 66.5 years, respectively. No DLTs were observed in MagnetisMM-2. ORRs were 50.0% (95% CI, 6.8-93.2) and 58.3% (95% CI, 27.7-84.8) in MagnetisMM-2 and MagnetisMM-3, respectively. All patients experienced treatment-emergent adverse events in MagnetisMM-2 (grade 3/4: 75.0%) and MagnetisMM-3 (grade 3/4: 100%); cytokine release syndrome occurred in 100% (grade 3/4: 25.0%) and 58.3% (no grade 3/4) of patients, respectively. Neither study reported immune effector cell-associated neurotoxicity syndrome. CONCLUSIONS: No new safety signals were observed, and ORRs were similar to that of the overall MagnetisMM-3 trial population, supporting further studies of elranatamab in Japanese patients with RRMM. ClinicalTrials.gov identifier: NCT04798586 (MagnetisMM-2), NCT04649359 (MagnetisMM-3).

Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101.

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.

Patients with metastatic renal cell carcinoma who benefit from axitinib dose titration: analysis from a randomised, double-blind phase II study.

BACKGROUND: A prospective, randomised phase II study demonstrated clinical benefit of axitinib dose titration in a subset of treatment-naïve patients treated with axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with axitinib dose titration. METHODS: Following a 4-week lead-in period during which all patients received axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive axitinib 5 mg bid plus either axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus < 24 months, and compared their baseline characteristics with Fisher's exact test or Cochran-Armitage trend exact test, with a 5% significance level. Potential predictive baseline characteristics associated with effect of axitinib dose titration on OS were investigated using a Cox proportional hazard model. RESULTS: Overall, 112 patients were randomised. Three of 56 patients receiving axitinib titration were censored; of the remaining 53, 33 (62%) achieved OS ≥24 months versus 20 (38%) with OS < 24 months. Patients with OS ≥24 vs. < 24 months, respectively, had significantly fewer metastatic sites (≤2 metastases: 52% vs. 10%; ≥3 metastases: 48% vs. 90%), fewer lymph node (45% vs. 75%) or liver (15% vs. 45%) metastases, higher haemoglobin level (i.e., ≥ lower limit of normal: 67% vs. 25%) at baseline, lower neutrophil (≤ upper limit of normal, 97% vs. 75%) and platelet (≤ upper limit of normal, 82% vs. 50%) levels at baseline and ≥ 1 year between histopathological diagnosis and treatment (64% vs. 15%). The primary reason for treatment discontinuation in both OS groups was disease progression. The frequency of toxicity-related discontinuation was comparable between the 2 groups, indicating that it was not a factor for a shorter OS. The multivariate analysis showed that ≥1 year from histopathological diagnosis to treatment and baseline haemoglobin level equal or greater than lower limit of normal were significant covariates associated with favourable OS in patients receiving axitinib titration. CONCLUSIONS: The current analyses identified potentially predictive factors that could help selecting patients who may benefit from axitinib dose titration. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00835978. Registered prospectively, February 4, 2009.

Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study.

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6 months in treatment-naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and safety in 44 Japanese patients and compared the results with 169 non-Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first-line metastatic RCC were explored in all patients using a Cox proportional hazard model. With median follow-up of 33 months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9 months (95% CI, 28.9-42.7). Estimated 1-year, 2-year and 3-year survival probability (95% CI) was 86.4% (76.2-96.5), 75.0% (62.2-87.8) and 68.2% (54.4-81.9), respectively, in Japanese patients, and was higher than that in non-Japanese patients (75.1% [68.4-81.8], 62.1% [54.5-69.7] and 47.2% [39.3-55.1], respectively). The updated safety analysis did not reveal any new adverse events of concern among Japanese or non-Japanese patients. The multivariate analysis identified that lower baseline Eastern Cooperative Oncology Group performance status, lower baseline tumor burden, and longer time from histopathological diagnosis to treatment were significant positive predictors of OS. The current analysis confirmed the clinical activity of axitinib in treatment-naïve Japanese patients with metastatic RCC, with an acceptable toxicity profile.

Morphology of the fibular insertion of the posterolateral corner and biceps femoris tendon.

PURPOSE: To clarify the fibular head insertion of the fibular collateral ligament (FCL), popliteofibular ligament (PFL), and biceps femoris tendon and related osseous landmarks on three-dimensional (3-D) images. METHODS: Twenty-one non-paired, formalin-fixed human cadaveric knees were evaluated in this study. The fibular head insertions of the FCL, PFL and biceps femoris tendon were identified and marked. 3-D images were created, and the surface area, location, positional relationships, and morphology of the fibular insertions of the FCL, PFL, and biceps femoris tendon and related osseous structures were analysed. RESULTS: The fibular head had a unique pyramidal shape, and the relationships of the fibular insertion of the FCL, PFL, and biceps femoris tendon were consistent. The fibular head consists of three aspects: lateral aspect, posterior aspect, and proximal tibiofibular facet. The insertions of the FCL, PFL, and biceps femoris tendon were attached to the centre from the distal side of the lateral aspects of the fibular head, posterior aspect of the fibular styloid process, and lateral aspect surrounding the FCL, respectively. The mean surface areas of the FCL and PFL fibular insertions were 100.1 ± 29.5 and 18.5 ± 7.2 mm2, respectively. CONCLUSION: This study showed that the relationships between the characteristic features of the fibular head and insertions of the FCL, PFL, and biceps femoris tendon were consistent. The clinical relevance of this study is that it improves understanding of the anatomy of the insertions of the PLC and biceps femoris tendon.

Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial.

OBJECTIVE: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study. METHODS: Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m(2) once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival. RESULTS: Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival. CONCLUSIONS: Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.

Core Needle Percutaneous Transpedicular Vertebral Body Biopsy: A Study of 128 Cases.

STUDY DESIGN: We report an accurate technique for percutaneous transpedicular core needle biopsy of vertebral body lesions, and evaluate its effectiveness for histologic diagnosis retrospectively. OBJECTIVE: The purpose of this study is to evaluate the effectiveness and accuracy of this method retrospectively. SUMMARY OF BACKGROUND DATA: Better knowledge of vertebral pedicle morphometry has led to the development of transpedicular fixation techniques in spinal surgery. After experience with these techniques, we have been performing percutaneous transpedicular vertebral body core needle biopsies (transpedicular biopsy) for histologic diagnosis since 1993. METHODS: A total of 128 patients who had undergone transpedicular biopsy for T1-L5 vertebral body lesions were evaluated. The biopsies were carried out under local anesthesia, except in children, for whom general anesthesia was used. Biopsy specimens were obtained by passing 8 or 11 G needle biopsy instruments percutaneously through the pedicle into the site of the lesion under C-arm fluoroscopy guidance. Histologic analyses were performed, and the accuracy and effectiveness of this technique were evaluated. RESULTS: The pathologic evaluations were definitive in 120 patients (93.8%) and not diagnostic in 8. The accuracy of the results differed among the diagnostic categories. Diagnostic accuracy was 78.6% for primary neoplasms and 97.0% for metastatic neoplasms. There was a significant difference in the diagnostic criteria and spinal segment. True positive rate was higher in the thoracic spine (92.2%) than that of lumbar spine (76.6%). CONCLUSIONS: Transpedicular biopsy is a useful procedure for evaluation of thoracic and lumbar vertebral body lesions.

Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine-refractory metastatic renal cell carcinoma.

In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty-four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6-49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7-64.2); the median duration of response, 11.1 months (95% CI, 8.2-13.7); and the median progression-free survival was 11.0 months (95% CI, 9.2-12.0), assessed by the independent review committee. Common treatment-related all-grade adverse events were hypertension (88%), hand-foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and dysphonia (53%). In an exploratory analysis, median overall survival was found to be significantly longer in patients who had greater decreases in plasma levels of soluble vascular endothelial growth factor receptor-2 during the first cycle of treatment. In conclusion, the present study showed axitinib to be effective, and toxicities with long-term treatment were generally controllable with axitinib dose modification and/or standard medications in these Japanese patients. Some frequently reported adverse events warrant close monitoring and management. Changes in the plasma levels of soluble vascular endothelial growth factor receptor-2 may be used as a prognostic factor for overall survival in metastatic renal cell carcinoma following axitinib treatment. This study is registered at ClinicalTrial.gov (identifier NCT00569946).

Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial.

INTRODUCTION: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Regulatory elements directing gut expression of the GATA6 gene during mouse early development.

The GATA6 transcription factor, as well as GATA4 and GATA5, is expressed in a variety of mammalian tissues including the precardiac mesoderm and endoderm, and gut-related organs. Genetic studies have also implicated GATA factors as important regulators of gut endoderm development. Previously, we identified the promoter and a cardiac-specific enhancer of mouse GATA6 [Sun-Wada et al. (2000) J. Biochem. 127, 703-709], however, little is known about the regulatory elements that govern GATA6 expression in the primitive gut. Here, we identified a distal enhancer of the GATA6 gene directing expression in the gut by creating transgenic mice. A sequence of approximately 200 bp between -8.0 kb and -7.8 kb contains element(s) that enhance transcription in the gut during embryonic development, when linked to the hsp68 promoter/lacZ fusion gene. Our results also show that GATA6 expression is controlled by multiple regulatory regions including cardiac-specific and gut-specific enhancers.