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R DLBCL treated with Axicabtagene Clioleucel (19-28z CAR T)
Annals of Oncology 30 (Supplement 6): vi82–vi89, 2019 doi:10.1093/annonc/mdz339
ORAL SESSION : ORAL ABSTRACTS SESSION Prediction of toxicity in R/R DLBCL treated with Axicabtagene Clioleucel (19-28z CAR T)
Hiroshi Kotani1, Rawan Faramand2, Sae Bom Lee1, Bin Yu1, Dylan Morrissey3, Frederick L. Locke2,4, Michael D. Jain2, Julio C. Chavez2, Xuefeng Wang2, Asmita Mishra2, Christina A. Bachmeier2, Renier J. Brentjens5, Sarah Yoo5, Jae H. Park5, Marco L. Davila1,3,4 1 Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 2 Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, 3Morsani College of Medicine, University of South Florida, 4Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 5Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center [Background]: A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). [Methods]: Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokines analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. [Results]: 41 patients were identified. Median age was 64 years old (76% male). Nonsevere (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that was nt evident from standard biomarkers. [Conclusions]: We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically.
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Phase 1 study of RM-1929 photoimmunotherapy in Japanese patients with recurrent head and neck squamous cell carcinoma
Makoto Tahara1, Susumu Okano1, Tomohiro Enokida1, Yuri Ueda1, Takao Fujisawa1, Merrill Biel2 1 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 2Rakuten Medical Inc INTRODUCTION: Photoimmunotherapy (PIT) is a novel cancer-targeted platform technology that utilizes monoclonal antibodies conjugated to a dye that can be activated with 690 nm nonthermal red light. PIT using RM-1929, consisting of the EGFRdirected monoclonal antibody cetuximab conjugated to a dye (IRDye 700DX), demonstrated promising clinical activity with overall response rate of 44.8%, median PFS of 5.7 months and median OS of 9.5 months in patients with recurrent head and neck squamous cell carcinoma (rHNSCC) in a phase 2a study with 30 patients (Gillenwater, ASCO 2018). METHODS: The objectives of this phase 1 single-center, open-label, study were to evaluate the safety and objective response with RM-1929 PIT in Japanese patients with rHNSCC, who in the opinion of their physician, could not be satisfactorily treated with surgery, radiation, or platinum-based chemotherapy. Patients received a single fixed dose of RM-1929 (640 mg/m2) followed by tumor illumination with nonthermal red light, 24 hours after RM-1929 administration. Primary endpoint was safety of a single treatment of RM-1929 PIT. RESULTS: Three female patients were enrolled in the study and received RM-1929 PIT. Median age was 68 (53-74). All patients failed more than 3 lines of prior therapy. Tumor sites included gums, temporal and cervical lymph nodes. All patients experienced edema and pain at the light application site. A Grade 3 application site pain treatment-emergent adverse event occurred in one patient. There were no serious adverse events, treatment discontinuation, or treatment-related deaths. Objective response based on modified RECIST 1.1 by central leader was observed in 2 patients.
CONCLUSION: RM-1929 PIT was well tolerated in 3 Japanese patients with rHNSCC. Preliminary efficacy data showed promising activity, and further investigation of this novel therapeutic strategy is warranted in an ongoing phase 3 clinical trial (NCT02422979).
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Post-marketing survey of safety and efficacy of nivolumab for recurrent or metastatic head and neck cancer in Japan
Naomi Kiyota1, Makoto Tahara2, Ken-Ichi Nibu3, Tomohiro Hoshino4, Osamu Iida4, Ryuichi Hayashi5 1 Kobe University Hospital Cancer Center, 2Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 3Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, 4Pharmacovigilance Division, Ono Pharmaceutical Co., Ltd, 5Department of Head and Neck Surgery, National Cancer Center Hospital East Background: A drug use-results survey (hereinafter referred to as "this survey") was conducted to assess the safety and efficacy profiles of nivolumab in patients with recurrent or metastatic head and neck cancer in the post-marketing phase. Methods: The observation period for this survey was 6 months from the first day of nivolumab administration. Safety was assessed based on the incidence and severity of adverse drug reactions (hereinafter referred to as "ADRs"). ADRs of special interest were also specified and assessed, focusing on immune-related ADRs. Efficacy was rated using a 5-point scale (very effective, effective, stable, progressive, and not applicable) at the physician’s discretion. Results: Between March 2017 and June 2017, 604 patients were registered. Of these, 253 patients were analyzed for safety and 220 patients were analyzed for efficacy at the time of preparation of this abstract*. ADRs occurred in 68 (26.9%) patients, of which 30 (11.9%) were reported as Grade 3 or higher and 9 (3.6%) were reported as ADRrelated deaths. The most common ADRs of special interest (all grades and Grade 3 or higher) were thyroid dysfunction (7.1% and 0%, respectively), liver dysfunction (5.5% and 2.4%, respectively), interstitial lung disease (2.4% and 0.8%, respectively), and colitis/severe diarrhea (2.0% and 0.4%, respectively). In terms of efficacy, the treatment was rated as very effective in 4.6%, effective in 22.7%, stable in 20.9%, and progressive in 51.8% of patients. Conclusions: Most of the ADRs that occurred with treatment with nivolumab in the real-world setting were manageable. The incidences of ADRs with nivolumab in this survey did not exceed those reported in the international phase III study, and no additional safety concerns were identified in patients with recurrent or metastatic head and neck cancer. *This abstract presents the results of an interim analysis, and the updated latest results will be reported at the meeting.
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Japanese Subgroup Analysis of KEYNOTE-048: Ph3 Study of 1L Pembrolizumab for R/M Head and Neck Squamous Cell Carcinoma
Shunji Takahashi Cancer Institute Hospital, Japanese Foundation for Cancer Research Background: The global ph 3 KEYNOTE-048 studied pembrolizumab (P) or Pþchemotherapy (C) vs EXTREME (E) as 1L treatment (tx) for recurrent/metastatic (R/M) HNSCC (NCT02358031). Methods: Patients (pts) with R/M HNSCC and no prior systemic tx (for R/M) were randomized to P, PþC, or E arms (Rischin et al. JCO. 2019;37:15_suppl, 6000). Primary end points: PFS by blinded review and OS. Data cutoff for this ad hoc interim analysis of Japanese (JPN) pts: June 13, 2018. Results: 67/882 were JPN (23 [P], 25 [PþC], 19 [E]). Median (med) follow-up (FU) (P vs E): 19.4 vs 13.6 mo. OS was longer (P vs E) in CPS20 (n ¼ 22; HR, 0.22; 95% CI, 0.06-0.77), CPS1 (n ¼ 37; HR, 0.67; 95% CI, 0.31-1.48), and total population (pop) (n ¼ 42; HR, 0.52; 95% CI, 0.25-1.11). PFS was longer (P vs E) in CPS20 (HR, 0.57; 95% CI, 0.22-1.43) and similar between arms in CPS1 (HR, 1.04; 95% CI, 0.53-2.04) and total pop (HR, 1.19; 95% CI, 0.64-2.23). ORR (P vs E): 29% vs 13% in CPS20, 19% vs 25% in CPS1, and 17% vs 37% in total pop and med DOR was 8.4 vs 2.6 mo, 8.4 vs 5.5 mo, and 8.4 vs 4.1 mo, respectively. Gr 3-5 tx-related AE (TRAE) rates (P vs E): 22% vs 90%. Med FU (PþC vs E): 12.6 vs 13.3 mo. OS was longer (PþC vs E) in CPS20 (n ¼ 17; HR, 0.57; 95% CI, 0.17-1.90) and similar between arms in CPS1 (n ¼ 33; HR, 1.13; 95% CI, 0.50-2.53) and total pop (n ¼ 41; HR, 1.03; 95% CI, 0.502.13). PFS was longer (PþC vs E) in CPS20 (HR, 0.34; 95% CI, 0.09-1.19), CPS1
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
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ORAL SESSION : ORAL ABSTRACTS SESSION Prediction of toxicity in R/R DLBCL treated with Axicabtagene Clioleucel (19-28z CAR T)
Hiroshi Kotani1, Rawan Faramand2, Sae Bom Lee1, Bin Yu1, Dylan Morrissey3, Frederick L. Locke2,4, Michael D. Jain2, Julio C. Chavez2, Xuefeng Wang2, Asmita Mishra2, Christina A. Bachmeier2, Renier J. Brentjens5, Sarah Yoo5, Jae H. Park5, Marco L. Davila1,3,4 1 Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 2 Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, 3Morsani College of Medicine, University of South Florida, 4Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 5Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center [Background]: A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). [Methods]: Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokines analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. [Results]: 41 patients were identified. Median age was 64 years old (76% male). Nonsevere (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that was nt evident from standard biomarkers. [Conclusions]: We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically.
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Phase 1 study of RM-1929 photoimmunotherapy in Japanese patients with recurrent head and neck squamous cell carcinoma
Makoto Tahara1, Susumu Okano1, Tomohiro Enokida1, Yuri Ueda1, Takao Fujisawa1, Merrill Biel2 1 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 2Rakuten Medical Inc INTRODUCTION: Photoimmunotherapy (PIT) is a novel cancer-targeted platform technology that utilizes monoclonal antibodies conjugated to a dye that can be activated with 690 nm nonthermal red light. PIT using RM-1929, consisting of the EGFRdirected monoclonal antibody cetuximab conjugated to a dye (IRDye 700DX), demonstrated promising clinical activity with overall response rate of 44.8%, median PFS of 5.7 months and median OS of 9.5 months in patients with recurrent head and neck squamous cell carcinoma (rHNSCC) in a phase 2a study with 30 patients (Gillenwater, ASCO 2018). METHODS: The objectives of this phase 1 single-center, open-label, study were to evaluate the safety and objective response with RM-1929 PIT in Japanese patients with rHNSCC, who in the opinion of their physician, could not be satisfactorily treated with surgery, radiation, or platinum-based chemotherapy. Patients received a single fixed dose of RM-1929 (640 mg/m2) followed by tumor illumination with nonthermal red light, 24 hours after RM-1929 administration. Primary endpoint was safety of a single treatment of RM-1929 PIT. RESULTS: Three female patients were enrolled in the study and received RM-1929 PIT. Median age was 68 (53-74). All patients failed more than 3 lines of prior therapy. Tumor sites included gums, temporal and cervical lymph nodes. All patients experienced edema and pain at the light application site. A Grade 3 application site pain treatment-emergent adverse event occurred in one patient. There were no serious adverse events, treatment discontinuation, or treatment-related deaths. Objective response based on modified RECIST 1.1 by central leader was observed in 2 patients.
CONCLUSION: RM-1929 PIT was well tolerated in 3 Japanese patients with rHNSCC. Preliminary efficacy data showed promising activity, and further investigation of this novel therapeutic strategy is warranted in an ongoing phase 3 clinical trial (NCT02422979).
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Post-marketing survey of safety and efficacy of nivolumab for recurrent or metastatic head and neck cancer in Japan
Naomi Kiyota1, Makoto Tahara2, Ken-Ichi Nibu3, Tomohiro Hoshino4, Osamu Iida4, Ryuichi Hayashi5 1 Kobe University Hospital Cancer Center, 2Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 3Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, 4Pharmacovigilance Division, Ono Pharmaceutical Co., Ltd, 5Department of Head and Neck Surgery, National Cancer Center Hospital East Background: A drug use-results survey (hereinafter referred to as "this survey") was conducted to assess the safety and efficacy profiles of nivolumab in patients with recurrent or metastatic head and neck cancer in the post-marketing phase. Methods: The observation period for this survey was 6 months from the first day of nivolumab administration. Safety was assessed based on the incidence and severity of adverse drug reactions (hereinafter referred to as "ADRs"). ADRs of special interest were also specified and assessed, focusing on immune-related ADRs. Efficacy was rated using a 5-point scale (very effective, effective, stable, progressive, and not applicable) at the physician’s discretion. Results: Between March 2017 and June 2017, 604 patients were registered. Of these, 253 patients were analyzed for safety and 220 patients were analyzed for efficacy at the time of preparation of this abstract*. ADRs occurred in 68 (26.9%) patients, of which 30 (11.9%) were reported as Grade 3 or higher and 9 (3.6%) were reported as ADRrelated deaths. The most common ADRs of special interest (all grades and Grade 3 or higher) were thyroid dysfunction (7.1% and 0%, respectively), liver dysfunction (5.5% and 2.4%, respectively), interstitial lung disease (2.4% and 0.8%, respectively), and colitis/severe diarrhea (2.0% and 0.4%, respectively). In terms of efficacy, the treatment was rated as very effective in 4.6%, effective in 22.7%, stable in 20.9%, and progressive in 51.8% of patients. Conclusions: Most of the ADRs that occurred with treatment with nivolumab in the real-world setting were manageable. The incidences of ADRs with nivolumab in this survey did not exceed those reported in the international phase III study, and no additional safety concerns were identified in patients with recurrent or metastatic head and neck cancer. *This abstract presents the results of an interim analysis, and the updated latest results will be reported at the meeting.
O1 2 3
Japanese Subgroup Analysis of KEYNOTE-048: Ph3 Study of 1L Pembrolizumab for R/M Head and Neck Squamous Cell Carcinoma
Shunji Takahashi Cancer Institute Hospital, Japanese Foundation for Cancer Research Background: The global ph 3 KEYNOTE-048 studied pembrolizumab (P) or Pþchemotherapy (C) vs EXTREME (E) as 1L treatment (tx) for recurrent/metastatic (R/M) HNSCC (NCT02358031). Methods: Patients (pts) with R/M HNSCC and no prior systemic tx (for R/M) were randomized to P, PþC, or E arms (Rischin et al. JCO. 2019;37:15_suppl, 6000). Primary end points: PFS by blinded review and OS. Data cutoff for this ad hoc interim analysis of Japanese (JPN) pts: June 13, 2018. Results: 67/882 were JPN (23 [P], 25 [PþC], 19 [E]). Median (med) follow-up (FU) (P vs E): 19.4 vs 13.6 mo. OS was longer (P vs E) in CPS20 (n ¼ 22; HR, 0.22; 95% CI, 0.06-0.77), CPS1 (n ¼ 37; HR, 0.67; 95% CI, 0.31-1.48), and total population (pop) (n ¼ 42; HR, 0.52; 95% CI, 0.25-1.11). PFS was longer (P vs E) in CPS20 (HR, 0.57; 95% CI, 0.22-1.43) and similar between arms in CPS1 (HR, 1.04; 95% CI, 0.53-2.04) and total pop (HR, 1.19; 95% CI, 0.64-2.23). ORR (P vs E): 29% vs 13% in CPS20, 19% vs 25% in CPS1, and 17% vs 37% in total pop and med DOR was 8.4 vs 2.6 mo, 8.4 vs 5.5 mo, and 8.4 vs 4.1 mo, respectively. Gr 3-5 tx-related AE (TRAE) rates (P vs E): 22% vs 90%. Med FU (PþC vs E): 12.6 vs 13.3 mo. OS was longer (PþC vs E) in CPS20 (n ¼ 17; HR, 0.57; 95% CI, 0.17-1.90) and similar between arms in CPS1 (n ¼ 33; HR, 1.13; 95% CI, 0.50-2.53) and total pop (n ¼ 41; HR, 1.03; 95% CI, 0.502.13). PFS was longer (PþC vs E) in CPS20 (HR, 0.34; 95% CI, 0.09-1.19), CPS1
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz339/5582766 by Durham University user on 25 October 2019
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