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Insights in the Mode of Action of a T Cell Bispecific Antibody in Tumour Bearing Mice
abstracts
Annals of Oncology 166P
Insights in the mode of action of a T cell bispecific antibody in tumour bearing mice
Background: CD3 bispecific antibodies are a very potent means to re-activate the immune system against tumour cells targeting cancer-associated antigens and CD3 on T cells and acting as direct immune activators. The aim of this study was to investigate the early changes occurring in the tumour and peripheral blood in tumour bearing mice treated with a T cell Bispecific (TCB) antibody designed to elicit T cell activation upon simultaneously binding to T cells and to a tumour-specific target. Methods: C57Bl/6 mice bearing a B16 metastatic lung murine melanoma were treated with a single dose iv of a TCB targeting murine CD3 and an antigen highly expressed in the B16 tumour. At 2h, 4h, 7h, 24h, 48h after treatment blood was collected for hematology, serum chemistry, cytokines, flow cytometry and pharmacokinetic analysis and the tumour-bearing lung was collected and analyzed for cytokines, flow cytometry and histopathology. Results: Treatment with the targeted TCB induced, starting from two hours post single dose administration, a transient marked drop in lymphocytes, an increase in neutrophils and monocytes and an increase in acute phase proteins (haptoglobin, SAA1, a1AGP and SAP) in the peripheral blood, correlating with the histopathological changes at the tumour site. Histopathology, immunohistochemistry and flow cytometry of the tumour showed that acute inflammation was already present at two to four hours after treatment in the form of neutrophilic infiltrate, while CD3þ T lymphocytes started to accumulate in the tumour 24h after treatment. These changes were accompanied by an increase of some cytokines in the tumour (e.g. IL-6, MCP1, IL-1b) and in the peripheral blood. Conclusion: Changes observed in tumour bearing mice upon treatment with a tumour-targeted TCB suggest an early engagement of tumour resident T cells resulting in cytokine release locally and systemically within 2h after treatment, with homing and extravasation of inflammatory cells into the tumour progressively increasing 24h to 48h after treatment. This course of events is believed to be translatable to patients treated with TCBs. Legal entity responsible for the study: Roche Glycart AG. Funding: Roche Glycart AG. Disclosure: A.M. Giusti: Full / Part-time employment: Roche Glycart AG. J. Sam: Full / Part-time employment: Roche Glycart AG. M. Karagianni: Full / Part-time employment: Roche Glycart AG. A. Schneider: Full / Part-time employment: Roche Glycart AG.
167P
Efficacy of cetuximab based chemotherapy after immunotherapy treatments (IT) in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts)
A. Hernando-Calvo1, O. Mirallas1, D. Marmolejo1, E. Felip1, E. Garralda2, G. Villacampa Javierre3, B. Feliu2, S. Martınez2, R. Gutierrez2, R. Dienstmann4, I. Bra~ na1 1 2 Medical Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain, Medical Oncology Dept., Vall dHebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 3Statistics Department, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 4Oncology Data Science, Vall d’Hebron University Hospital, Barcelona, Spain Background: A combination therapy based on chemotherapy (CT) and Anti-PD1 is the new standard FDA-approved first-line treatment for (R/M) HNSCC PD-L1 negative pts. The addition of pembrolizumab to cetuximab has been proved feasible in a recent Phase II trial for anti-PD-1/PD-L1 and cetuximab naı¨ve HNSCC pts. The efficacy of cetuximab-based CT regimens in the post-IT setting, has not been assessed. Methods: We analyzed 27 R/M HNSCC pts treated at the Vall dHebron Hospital from 2015-2019 with CT post-IT, including cetuximab-based CT (CTþcetu post-IT) and non-cetuximab CT regimens (CT post-IT). Clinicopathological features and treatment modalities were correlated with outcomes. Overall survival (OS) was calculated from the first cycle of CT post-IT until death or last follow-up with Kaplan-Meier method. Results: Out of 27 pts, median age was 62y, all ECOG 1, treated with CTþcetu postIT 20 pts (74%) or CT post-IT 7 pts (26%). P16 immunohistochemistry was present in 3 pts (17%). Median prior lines was 1 (range 1 - 4) and median follow-up was 6 months (m). Median OS was 8 m (CI95% 5 - 23) and median progression free survival (PFS) 5 m (CI95% 3 - 7). No significant differences were found in OS according to cetuximab addition (P ¼ 0.252 log-rank test). In the CT post-IT cohort, 2 pts (29%) had a partial response (PR) and 5 (71%) had progressive disease. Clinical benefit rate (CBR, defined as complete þ partial þ stable disease) was 29%. Among pts treated with CTþcetu post-IT, 2 pts (11%) achieved a complete response (CR), 10 (52%) achieved a PR and 2 (11%) stable disease (CBR¼ 74%). A significantly higher CBR was observed for cetuximab based CT regimens following IT (P ¼ 0.036 chi-square test). Among CR pts in the CTþcetu post-IT cohort, all were cetuximab naı¨ve. Interestingly, both pts achieving a CR had PD as best response on previous IT. Conclusion: In our cohort, the addition of cetuximab to CT post-IT was associated with promising CBR. These results suggest that CTþcetu post-IT regimens may have a role in (R/M) HNSCC pts. Future prospective trials are needed to assess the
Volume 30 | Supplement 11 | December 2019
168P
Analysis of endpoints used for FDA approvals of checkpoint inhibitors
L.A. Mendoza EU Hem/Oncology Unit, IQVIA RDS Czech Republic s.r.o., Prague, Czech Republic Background: The first approval of a checkpoint inhibitor was granted in 2011. Methods: We retrospectively examined all approvals of checkpoint inhibitors (CPIs) granted until January 2019 by FDA. Data regarding the type of approval, cancer type, treatment indication, and endpoints were extracted from the FDA website and from publications. Results: Fifteen therapeutic indications, including agnostic approvals, among seven CPIs have been approved for solid and hematologic malignancies. Of a total of 41 FDA approvals, nine (21.95%) were approved for the first-line of therapy and 32 (78.05%) for subsequent lines. Fourteen (34.15%) approvals, six (14.63%) in the first-line and eight (19.51%) in the subsequent lines, were granted approval based on overall survival (OS). Twenty-seven (65.85%) approvals (regular and accelerated) were granted based on surrogate endpoints: two (4.88%) using the response rate (RR), 20 (48.78%) using RR and the duration of rsponse (DOR); two (4.88%) using RR, progression-free survival (PFS) and DOR; two (4.88%) using relapse-free survival (RFS), and one (2.44%) using PFS alone. Table shows the distribution of these approvals in the first or subsequent lines.
Table: 168P
Lines treatment
RR (%) and DOR (%)
PFS, and RFS (%) PFS (%) OS (%) DOR (%)
First-line 0 (0) 1 (2.44) 2 (4.88) Subsequent 2 (4.88) 19 (46.34) 0 (0) lines Total 2 (4.88) 20 (48.78) 2(4.88)
0 (0) 0 (0) 6 (14.63) 2 (4.88) 1 (2.44) 8 (19.51)
(%)
9 (21.95) 32 (78.05)
2 (4.88) 1 (2.44) 14 (34.15) 41 (100)
Of the total of 41 FDA approvals, 23 (56.10%) were accelerated and 18 (43.90%) regular. Three (7.32%) and 20 (48.78%) were accelerated approvals for the first and subsequent lines, respectively. Six (14.63%) and 12 (29.27%) were regular approvals in the first and subsequent lines, respectively. Conclusion: RR and DOR were the most frequently approved surrogate endpoints, most often for use in later lines of therapy. The majority of CPI approvals need to confirm the real impact on the patients’ survival, since approximately one third of these approvals were based on the OS. Accelerated approvals based on surrogate endpoints were also preferentially granted for later lines of therapy, where such decisions may have a modest impact on the patients’ survival. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
169P
Impact of open-label design on patient-reported outcomes (PROs) data in randomized clinical trials of immuno-oncology (IO) agents in patients with advanced or metastatic cancer: A 10-year systematic literature review (SLR)
A. Anota1, A. Pozet1, C. Lefevre2, H. Lemasson3, F-E. Cotte4, S. Guerzider5, G. Mouillet6, G. Eberst5, E. Charton1, V. Westeel7 1 Methodology and Quality of Life in Oncology Unit, University Hospital of Besanc¸on, Besancon, France, 2Market Access, Bristol-Myers Squibb, Rueil-Malmaison, France, 3 Heor, Bristol-Myers Squibb, Rueil-Malmaison, France, 4Health Economics and Outcomes Research, Bristol-Myers Squibb, Rueil-Malmaison, France, 5Chest Disease Department, CHU Besanc¸on, Hoˆpital Jean Minjoz, Besanc¸on, France, 6Medical Oncology, Methodology and Quality of Life in Oncology Unit, CHRU Besancon - Hopital Jean Minjoz, Besancon, France, 7Chest Disease Department, Methodology and Quality of Life in Oncology Unit, University Hospital of Besanc¸on, Besancon, France Background: The unblinded nature of open-label clinical trials may bias patient assessments of treatment efficacy and PRO measures. In this context, we conducted a SLR of IO trials across indications, to assess and quantify the potential impact of open-label vs. double-blind designs on treatment effects of PROs.
doi:10.1093/annonc/mdz450 | xi59
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_11/mdz450.003/5675201 by University of Nebraska-Lincoln Libraries user on 10 January 2020
A.M. Giusti1, J. Sam2, M. Karagianni2, A. Schneider3 1 PS Pathology, Roche Innovation Center Zurich, Schlieren, Switzerland, 2Discovery Pharmacology, Roche Innovation Center Zurich, Schlieren, Switzerland, 3PS Toxicology Project Leaders, Roche Innovation Center Zurich, Schlieren, Switzerland
sensitization effect of IT on cetuximab-based CT and the optimal sequence of treatments in (R/M) HNSCC. Legal entity responsible for the study: Vall dHebron Institute of Oncology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology 166P
Insights in the mode of action of a T cell bispecific antibody in tumour bearing mice
Background: CD3 bispecific antibodies are a very potent means to re-activate the immune system against tumour cells targeting cancer-associated antigens and CD3 on T cells and acting as direct immune activators. The aim of this study was to investigate the early changes occurring in the tumour and peripheral blood in tumour bearing mice treated with a T cell Bispecific (TCB) antibody designed to elicit T cell activation upon simultaneously binding to T cells and to a tumour-specific target. Methods: C57Bl/6 mice bearing a B16 metastatic lung murine melanoma were treated with a single dose iv of a TCB targeting murine CD3 and an antigen highly expressed in the B16 tumour. At 2h, 4h, 7h, 24h, 48h after treatment blood was collected for hematology, serum chemistry, cytokines, flow cytometry and pharmacokinetic analysis and the tumour-bearing lung was collected and analyzed for cytokines, flow cytometry and histopathology. Results: Treatment with the targeted TCB induced, starting from two hours post single dose administration, a transient marked drop in lymphocytes, an increase in neutrophils and monocytes and an increase in acute phase proteins (haptoglobin, SAA1, a1AGP and SAP) in the peripheral blood, correlating with the histopathological changes at the tumour site. Histopathology, immunohistochemistry and flow cytometry of the tumour showed that acute inflammation was already present at two to four hours after treatment in the form of neutrophilic infiltrate, while CD3þ T lymphocytes started to accumulate in the tumour 24h after treatment. These changes were accompanied by an increase of some cytokines in the tumour (e.g. IL-6, MCP1, IL-1b) and in the peripheral blood. Conclusion: Changes observed in tumour bearing mice upon treatment with a tumour-targeted TCB suggest an early engagement of tumour resident T cells resulting in cytokine release locally and systemically within 2h after treatment, with homing and extravasation of inflammatory cells into the tumour progressively increasing 24h to 48h after treatment. This course of events is believed to be translatable to patients treated with TCBs. Legal entity responsible for the study: Roche Glycart AG. Funding: Roche Glycart AG. Disclosure: A.M. Giusti: Full / Part-time employment: Roche Glycart AG. J. Sam: Full / Part-time employment: Roche Glycart AG. M. Karagianni: Full / Part-time employment: Roche Glycart AG. A. Schneider: Full / Part-time employment: Roche Glycart AG.
167P
Efficacy of cetuximab based chemotherapy after immunotherapy treatments (IT) in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts)
A. Hernando-Calvo1, O. Mirallas1, D. Marmolejo1, E. Felip1, E. Garralda2, G. Villacampa Javierre3, B. Feliu2, S. Martınez2, R. Gutierrez2, R. Dienstmann4, I. Bra~ na1 1 2 Medical Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain, Medical Oncology Dept., Vall dHebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 3Statistics Department, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 4Oncology Data Science, Vall d’Hebron University Hospital, Barcelona, Spain Background: A combination therapy based on chemotherapy (CT) and Anti-PD1 is the new standard FDA-approved first-line treatment for (R/M) HNSCC PD-L1 negative pts. The addition of pembrolizumab to cetuximab has been proved feasible in a recent Phase II trial for anti-PD-1/PD-L1 and cetuximab naı¨ve HNSCC pts. The efficacy of cetuximab-based CT regimens in the post-IT setting, has not been assessed. Methods: We analyzed 27 R/M HNSCC pts treated at the Vall dHebron Hospital from 2015-2019 with CT post-IT, including cetuximab-based CT (CTþcetu post-IT) and non-cetuximab CT regimens (CT post-IT). Clinicopathological features and treatment modalities were correlated with outcomes. Overall survival (OS) was calculated from the first cycle of CT post-IT until death or last follow-up with Kaplan-Meier method. Results: Out of 27 pts, median age was 62y, all ECOG 1, treated with CTþcetu postIT 20 pts (74%) or CT post-IT 7 pts (26%). P16 immunohistochemistry was present in 3 pts (17%). Median prior lines was 1 (range 1 - 4) and median follow-up was 6 months (m). Median OS was 8 m (CI95% 5 - 23) and median progression free survival (PFS) 5 m (CI95% 3 - 7). No significant differences were found in OS according to cetuximab addition (P ¼ 0.252 log-rank test). In the CT post-IT cohort, 2 pts (29%) had a partial response (PR) and 5 (71%) had progressive disease. Clinical benefit rate (CBR, defined as complete þ partial þ stable disease) was 29%. Among pts treated with CTþcetu post-IT, 2 pts (11%) achieved a complete response (CR), 10 (52%) achieved a PR and 2 (11%) stable disease (CBR¼ 74%). A significantly higher CBR was observed for cetuximab based CT regimens following IT (P ¼ 0.036 chi-square test). Among CR pts in the CTþcetu post-IT cohort, all were cetuximab naı¨ve. Interestingly, both pts achieving a CR had PD as best response on previous IT. Conclusion: In our cohort, the addition of cetuximab to CT post-IT was associated with promising CBR. These results suggest that CTþcetu post-IT regimens may have a role in (R/M) HNSCC pts. Future prospective trials are needed to assess the
Volume 30 | Supplement 11 | December 2019
168P
Analysis of endpoints used for FDA approvals of checkpoint inhibitors
L.A. Mendoza EU Hem/Oncology Unit, IQVIA RDS Czech Republic s.r.o., Prague, Czech Republic Background: The first approval of a checkpoint inhibitor was granted in 2011. Methods: We retrospectively examined all approvals of checkpoint inhibitors (CPIs) granted until January 2019 by FDA. Data regarding the type of approval, cancer type, treatment indication, and endpoints were extracted from the FDA website and from publications. Results: Fifteen therapeutic indications, including agnostic approvals, among seven CPIs have been approved for solid and hematologic malignancies. Of a total of 41 FDA approvals, nine (21.95%) were approved for the first-line of therapy and 32 (78.05%) for subsequent lines. Fourteen (34.15%) approvals, six (14.63%) in the first-line and eight (19.51%) in the subsequent lines, were granted approval based on overall survival (OS). Twenty-seven (65.85%) approvals (regular and accelerated) were granted based on surrogate endpoints: two (4.88%) using the response rate (RR), 20 (48.78%) using RR and the duration of rsponse (DOR); two (4.88%) using RR, progression-free survival (PFS) and DOR; two (4.88%) using relapse-free survival (RFS), and one (2.44%) using PFS alone. Table shows the distribution of these approvals in the first or subsequent lines.
Table: 168P
Lines treatment
RR (%) and DOR (%)
PFS, and RFS (%) PFS (%) OS (%) DOR (%)
First-line 0 (0) 1 (2.44) 2 (4.88) Subsequent 2 (4.88) 19 (46.34) 0 (0) lines Total 2 (4.88) 20 (48.78) 2(4.88)
0 (0) 0 (0) 6 (14.63) 2 (4.88) 1 (2.44) 8 (19.51)
(%)
9 (21.95) 32 (78.05)
2 (4.88) 1 (2.44) 14 (34.15) 41 (100)
Of the total of 41 FDA approvals, 23 (56.10%) were accelerated and 18 (43.90%) regular. Three (7.32%) and 20 (48.78%) were accelerated approvals for the first and subsequent lines, respectively. Six (14.63%) and 12 (29.27%) were regular approvals in the first and subsequent lines, respectively. Conclusion: RR and DOR were the most frequently approved surrogate endpoints, most often for use in later lines of therapy. The majority of CPI approvals need to confirm the real impact on the patients’ survival, since approximately one third of these approvals were based on the OS. Accelerated approvals based on surrogate endpoints were also preferentially granted for later lines of therapy, where such decisions may have a modest impact on the patients’ survival. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
169P
Impact of open-label design on patient-reported outcomes (PROs) data in randomized clinical trials of immuno-oncology (IO) agents in patients with advanced or metastatic cancer: A 10-year systematic literature review (SLR)
A. Anota1, A. Pozet1, C. Lefevre2, H. Lemasson3, F-E. Cotte4, S. Guerzider5, G. Mouillet6, G. Eberst5, E. Charton1, V. Westeel7 1 Methodology and Quality of Life in Oncology Unit, University Hospital of Besanc¸on, Besancon, France, 2Market Access, Bristol-Myers Squibb, Rueil-Malmaison, France, 3 Heor, Bristol-Myers Squibb, Rueil-Malmaison, France, 4Health Economics and Outcomes Research, Bristol-Myers Squibb, Rueil-Malmaison, France, 5Chest Disease Department, CHU Besanc¸on, Hoˆpital Jean Minjoz, Besanc¸on, France, 6Medical Oncology, Methodology and Quality of Life in Oncology Unit, CHRU Besancon - Hopital Jean Minjoz, Besancon, France, 7Chest Disease Department, Methodology and Quality of Life in Oncology Unit, University Hospital of Besanc¸on, Besancon, France Background: The unblinded nature of open-label clinical trials may bias patient assessments of treatment efficacy and PRO measures. In this context, we conducted a SLR of IO trials across indications, to assess and quantify the potential impact of open-label vs. double-blind designs on treatment effects of PROs.
doi:10.1093/annonc/mdz450 | xi59
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_11/mdz450.003/5675201 by University of Nebraska-Lincoln Libraries user on 10 January 2020
A.M. Giusti1, J. Sam2, M. Karagianni2, A. Schneider3 1 PS Pathology, Roche Innovation Center Zurich, Schlieren, Switzerland, 2Discovery Pharmacology, Roche Innovation Center Zurich, Schlieren, Switzerland, 3PS Toxicology Project Leaders, Roche Innovation Center Zurich, Schlieren, Switzerland
sensitization effect of IT on cetuximab-based CT and the optimal sequence of treatments in (R/M) HNSCC. Legal entity responsible for the study: Vall dHebron Institute of Oncology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.