Two-year follow-up of bintrafusp alfa, a bifunctional fusion protein … · 2018. 7. 23. · for...

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Abstract No. 9558. Presented at the ASCO20 Virtual Meeting, May 29–31, 2020 Two-year follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, for second-line (2L) treatment of non-small cell lung cancer (NSCLC) B. C. Cho 1 , T. M. Kim 2 , D. Vicente 3 , E. Felip 4 , D. H. Lee 5 , K. H. Lee 6 , C.-C. Lin 7 , M. J. Flor 8 , M. Di Nicola 9 , R. M. Alvarez 10 , I. Dussault 11 , C. Helwig 12 , L. S. Ojalvo 11 , J. L. Gulley 13 , L. Paz-Ares 14 1 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 2 Seoul National University Hospital, Seoul, Republic of Korea; 3 Hospital Universitario Virgen Macarena, Seville, Spain; 4 Hospital Universitari de la Vall d’Hebron, Barcelona, Spain; 5 Asan Medical Center, University of Ulsan College of Medicine Seoul, Seoul, Republic of Korea; 6 Chungbuk National University Hospital, Chungcheongbuk-Do, Republic of Korea; 7 National Taiwan University Hospital, Taipei, Taiwan; 8 Hospital Universitario Virgen del Rocío, Sevilla, Spain; 9 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 10 Gregorio Marañon Hospital, Madrid, Spain; 11 EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany; 12 Merck KGaA, Darmstadt, Germany; 13 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 15 Hospital Universitario 12 de Octubre, Madrid, Spain Poster No. 324 INTRODUCTION NSCLC Lung cancer is the most common cause of cancer death worldwide 1 NSCLC accounts for 84% of all cases of lung cancer 2 At diagnosis, approximately 75% of patients with NSCLC have advanced or metastatic disease 3 TGF-β activity may play an important role in NSCLC; the plasma level of TGF-β is increased in patients with NSCLC compared with in healthy volunteers 4 TGF-β activity has been documented to be implicated in promoting tumor progression, angiogenesis, fibrosis, and epithelial-mesenchymal transition (EMT), which may lead to anti–PD-(L)1 resistance in NSCLC 5-8 Overall response rates (ORRs) with PD-(L)1 inhibitors in patients with metastatic NSCLC in the 2L or later setting range from 12% to 20%, depending on PD-L1 status 9,10 Median progression-free survival (PFS) ranges from 2.3 to 4.0 months (PD-L1 unselected), 11,12 and the median overall survival (OS) ranges from 9.2 to 13.8 months (PD-L1 unselected), 13,14 highlighting the need for improved treatment options Bintrafusp alfa Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor to function as a TGF-β “trap” fused to a human IgG1 antibody blocking PD-L1 (Figure 1) The bifunctional nature of bintrafusp alfa allows for more localized inhibition of 2 nonredundant immunosuppressive pathways (TGF-β and PD-L1) within the tumor microenvironment 15 Results from a global phase 1 study (NCT02517398) found an ORR of 25.0% per independent review committee (IRC) assessment and a manageable safety profile in patients with advanced NSCLC who received bintrafusp alfa 1200 mg in the 2L setting, with a median follow-up of 51.9 weeks 16 Median OS was not reached in the 1200-mg cohort 16 PFS in the 1200-mg cohort, as adjudicated by an IRC, was 9.5 months for PD-L1–positive patients and 15.2 months for PD-L1–high patients 16 (Table 1) Here we present an update on the efficacy and safety follow-up in a cohort of patients with advanced NSCLC receiving bintrafusp alfa Figure 1. Proposed mechanism of action of bintrafusp alfa Fibroblast CAF Fibrosis and impaired drug access EMT (leading to metastasis and resistance to therapy [including checkpoint inhibition]) Tumor angiogenesis Tumor cells PD-L1 Bintrafusp alfa PD-1 T cell Suppression of immune response NK cell TAM Dendritic cell Cytotoxic T cell Tumor cells Mesenchymal-like tumor cell TGF-β trap moiety sequesters TGF-β to inhibit downstream signaling Anti–PD-L1 mAb moiety blocks PD-L1 interactions with PD-1 TGF-β* CAF, cancer-associated fibroblast; NK, natural killer; TAM, tumor-associated macrophage. *Tumor cells are also a major source of TGF-β in the microenvironment. Table 1. IRC-Adjudicated efficacy according to RECIST 1.1* 500 mg n=40 1200 mg n=40 Overall N=80 ORR in PD-L1–evaluable patients, n/N (%) All PD-L1 positive (≥1%) PD-L1 high (≥80%)  7/38 (18.4) 6/31 (19.4) 2/6 (33.3) 10/37 (27.0) 10/27 (37.0) 6/7 (85.7) 17/75 (22.7) 16/58 (27.6) 8/13 (61.5) Median PFS (95% CI), months All PD-L1 positive (≥1%) PD-L1 high (≥80%)  1.4 (1.3-4.2) 1.4 (1.2-4.2) 1.3 (0.2-NR)  4.0 (1.3-9.5) 9.5 (2.6-15.2) 15.2 (1.3-NR)  2.6 (1.3-4.2) 2.7 (1.4-9.6) 15.2 (1.0-NR) NR, not reached. *Data published as of the July 23, 2018 data cutoff and includes 52 weeks of median follow-up. METHODS NCT02517398 is an ongoing, phase 1, open-label trial of bintrafusp alfa 16 Study design has been described previously 16 Patients with advanced NSCLC, unselected for PD-L1 expression, who had disease progression after standard first-line (1L) treatment and received no prior immunotherapy were randomized to receive bintrafusp alfa 500 or 1200 mg (n=40 each) every 2 weeks (Q2W) until disease progression, unacceptable toxicity, or trial withdrawal The primary objective of this expansion-cohort study was to assess best overall response (BOR) per RECIST 1.1, as adjudicated by an IRC, as described previously 16 Key secondary objectives reported in this study were BOR per investigator assessment and safety Exploratory objectives included duration of response (DOR), PFS, and OS Tumor cell PD-L1 expression was measured by immunohistochemistry (IHC) using antibody clone 73-10 (Dako PD-L1 IHC 73-10 pharmDx; Dako, Carpinteria, CA, USA); expression levels were categorized as PD-L1 <1% (negative), ≥1% (positive), 1% to <80% (low), or ≥80% (high) Previous studies comparing the 73-10 and 22C3 antibody clones suggest that the 73-10 assay has greater sensitivity than the 22C3 assay and that these assays have comparable staining at a cutoff of 80% and 50% expression, respectively 17,18 RESULTS Baseline patient and disease characteristics 80 patients were enrolled in this cohort, of which, 21.3% (n=17) received ≥2 prior anticancer regimens All patients had disease progression after standard first-line (1L) treatment and received no prior immunotherapy Overall, most patients (72.5% [n=58]) had PD-L1–positive (≥1%) tumors 56.3% (n=45) had low PD-L1 expression (1% to <80%) 16.3% (n=13) had high PD-L1 expression (≥80%) 21.3% (n=17) of patients had PD-L1–negative tumors (<1%) 6.3% (n=5) of patients did not have a PD-L1 status available At a database cutoff of October 15, 2019, median follow-up was 134 weeks (range, 1-144) The final patient was recruited in May 2017 Median duration of treatment was 12 weeks (range, 2-144); 2 patients remain on treatment Efficacy Median DOR as assessed by investigator was 15.3 months for the 500-mg cohort and 18.0 months for the 1200-mg cohort (Table 2) Overall, there were 16 patients with responses lasting ≥6 months and 12 patients with responses lasting ≥12 months (Figure 2) In the 1200-mg cohort, there were 8 patients with responses lasting ≥6 months and 6 patients with responses lasting ≥12 months (Figure 2) Responses were ongoing in 3 patients in the 1200-mg cohort The DOR was 6.9, 27.8, and 27.9 months for patients with ongoing response All three ongoing responses were in PD-L1 positive tumors and two of the three were PD-L1-high tumors Overall, median OS was 13.6 months; the OS rate was 40.6% at 18 months and 34.6% at 24 months (Figure 3) In the 1200-mg cohort, median OS was 17.1 months; the OS rate was 49.7% at 18 months and 39.7% at 24 months (Figure 4) For PD-L1-positive tumors, the mOS was 21.7 months and OS rate was 61.1% and 47.0% at 18 and 24 months, respectively For PD-L1-high tumors, the mOS was not reached and OS rate was 83.3% and 83.3% at 18 and 24 months, respectively Table 2. Efficacy outcomes for bintrafusp alfa 500 mg n=40 1200 mg n=40 Overall N=80 ORR (CR+PR), n (%) 8 (20) 11 (27.5) 19 (23.8) DOR, median (95% CI), months ≥6-month response, n (%) ≥12-month response, n (%) 15.3 (8.1-18.9) 8 (100) 6 (75.0) 18.0 (4.2-23.5) 8 (72.7) 6 (63.6) 15.3 (8.1-18.9) 16 (84.2) 12 (67.7) OS, median (95% CI), months All PD-L1 positive (≥1%) PD-L1 high (≥80%) PD-L1 low (1% to <80%) PD-L1 negative (<1%) 10.9 (4.5-16.0) 10.3 (4.2-16.5) 14.5 (1.0-NR) 8.8 (4.2-16.5) 11.9 (0.3-NR) 17.1 (12.0-26.7)  21.7 (12.2-NR) NR (9.6-NR) 19.0 (11.0-NR) 12.2 (2.4-24.7 13.6 (10.9-19.3) 16.0 (10.3-23.0) NR (9.6-NR) 13.2 (8.8-19.3) 12.2 (7.2-25.7) CR, complete response; PR, partial response. Figure 2. Change in sum of target lesions per investigator A. Overall population 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Months -100 -50 0 50 100 150 170 Change in sum of diameters, % Start of treatment re-initiation First occurrence of new lesion Patient off treatment SD, PD, or NE PR CR B. 1200-mg cohort 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Months -100 -50 0 50 100 120 Change in sum of diameters, % First occurrence of new lesion Patient off treatment SD, PD, or NE PR CR NE, not evaluable; PD, progressive disease. Figure 3. OS for overall population At Risk 17 14 13 12 7 6 5 5 5 2 1 0 45 38 38 38 29 29 29 24 24 24 21 18 15 13 10 10 6 0 58 49 49 49 49 40 40 40 35 35 35 30 25 25 22 20 17 17 12 12 12 1 13 11 11 11 9 7 7 7 7 7 6 1 <1% 1 % to <80% All 1% 80% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Months 0 10 20 30 40 50 60 70 80 90 100 9.6-NR 10.3-23.0 8.8-19.3 7.2-25.7 95% CI NR 16.0 13.2 12.2 Median, months 5 33 28 13 No. of events (N=13) (N=58) (N=45) (N=17) 80% 1% 1% to <80% <1% 10.9-19.3 13.6 50 All 80% 1% 1% to <80% <1% All 80 64 54 48 38 31 27 25 22 19 13 1 OS, % Figure 4. OS for 1200-mg cohort At Risk <1% 1 % to <80% All 1% 80% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Months 0 10 20 30 40 50 60 70 80 90 100 OS, % 9.6-NR 12.2-NR 11.0-NR 2.4-24.7 95% CI NR 21.7 19.0 12.2 Median, months 1 12 11 8 No. of events (N=7) (N=27) (N=20) (N=10) 80% 1% 1% to <80% <1% 12.0-26.7 17.1 22 All 10 9 8 8 4 3 2 2 2 0 0 20 19 16 13 12 9 8 6 4 4 1 27 26 23 20 17 14 13 11 9 9 6 7 7 7 7 5 5 5 5 5 5 5 80% 1% 1% to <80% <1% All 40 35 31 28 21 17 15 13 11 9 6 Safety As reported previously, 16 the most common treatment-related adverse events (TRAEs) were pruritus (21.3%), maculopapular rash (18.8%), decreased appetite (12.5%), asthenia (11.3%), and rash (10.0%) Grade 3 TRAEs occurred in 23 patients (28.8%); grade 4 TRAEs occurred in 2 patients (2.5%) Since the prior analysis, 16 there have been no additional grade ≥3 TRAEs observed, including no new treatment-related deaths; in the 500-mg cohort, there was 1 additional treatment-related discontinuation due to pruritis 9 patients (11.3%) experienced skin lesions potentially related to TGF-β blockade; 2 additional grade 1 keratoacanthomas were observed since the prior analysis CONCLUSIONS After 2 years of follow-up, treatment with the recommended phase 2 dose (1200 mg Q2W) of bintrafusp alfa continued to show durable responses and long-term survival in patients with advanced 2L NSCLC, especially in those with high PD-L1 expression Median OS was 21.7 months for PD-L1–positive patients and not reached for PD-L1–high patients The median DOR was 18.0 months; 6 patients had responses ≥12 months The overall safety profile remained consistent with results from the prior analysis, with no new safety signals or deaths and 1 additional treatment-related discontinuation in the 500-mg cohort An ongoing phase 3 study is evaluating bintrafusp alfa versus pembrolizumab as 1L treatment for patients with advanced NSCLC that have high PD-L1 expression (INTR@PID LUNG 037; NCT03631706) REFERENCES 1. Bray F, et al. CA Cancer J Clin. 2018;68:394-424. 2. American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer- facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer- facts-and-figures-2020.pdf. Accessed May 1, 2020. 3. Howlader N, et al. National Cancer Institute. SEER Cancer Statistics Review, 1975-2016. https://seer.cancer.gov/csr/1975_2016/. Accessed April 13, 2020. 4. Akhurst RJ and Hata A. Nat Rev Drug Discov. 2012;11:790-811. 5. Colak S and Ten Dijke P. Trends Cancer. 2017;3:56-71. 6. De Jaegar K, et al. Int J Radiat Oncol Phys. 2004;58:1378-87. 7. Principe DR, et al. J Natl Cancer Inst. 2014;106:djt369. 8. Mariathasan S, et al. Nature. 2018;544-8. 9. Gulley JL, et al. Lancet Oncol. 2017;18:599-610. 10.Garon EB, et al. N Engl J Med. 2015;372:2018-28. 11.Borghaei H, et al. N Engl J Med. 2015;373:1627-39. 12.Herbst RS, et al. Lancet. 2016;387:1540-50. 13.Rittmeyer A, et al. Lancet. 2017;389:255-65. 14.Brahmer J, et al. N Engl J Med. 2015;373:123-35. 15.Strauss J, et al. Clin Cancer Res. 2018;24:1287-95. 16.Paz-Ares L, et al. J Thorac Oncol. 2020. [manuscript accepted for publication] 17.Feng Z, et al. J Clin Oncol. 2017;35(suppl):Abstract e20581. 18.Grote HJ, et al. J Thorac Oncol. 2020 Apr 27. [Epub ahead of print]. ACKNOWLEDGMENTS This study is funded by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and GlaxoSmithKline. The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers and at Merck KGaA and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany. Medical writing support was provided by Megan Hyde, PharmD, of ClinicalThinking, Inc, Hamilton, NJ, USA, which was funded by Merck KGaA and GlaxoSmithKline, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). All relevant disclosures will be published with the abstract on the ASCO meeting library website (https://metinglibrary.asco.org/). Correspondence: Byoung Chul Cho, [email protected] Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster. For questions, please contact [email protected]. GET POSTER PDF To be updated

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Abstract No. 9558. Presented at the ASCO20 Virtual Meeting, May 29–31, 2020

Two-year follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, for second-line (2L) treatment of non-small cell lung cancer (NSCLC)

B. C. Cho1, T. M. Kim2, D. Vicente3, E. Felip4, D. H. Lee5, K. H. Lee6, C.-C. Lin7, M. J. Flor8, M. Di Nicola9, R. M. Alvarez10, I. Dussault11, C. Helwig12, L. S. Ojalvo11, J. L. Gulley13, L. Paz-Ares14

1Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 2Seoul National University Hospital, Seoul, Republic of Korea; 3Hospital Universitario Virgen Macarena, Seville, Spain; 4Hospital Universitari de la Vall d’Hebron, Barcelona, Spain; 5Asan Medical Center, University of Ulsan College of Medicine Seoul, Seoul, Republic of Korea; 6Chungbuk National University Hospital, Chungcheongbuk-Do, Republic of Korea; 7National Taiwan University Hospital, Taipei, Taiwan; 8Hospital Universitario Virgen del Rocío, Sevilla, Spain; 9Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 10Gregorio Marañon Hospital, Madrid, Spain; 11EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany; 12Merck KGaA, Darmstadt, Germany; 13National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 15Hospital Universitario 12 de Octubre, Madrid, Spain

Poster No. 324

INTRODUCTION

NSCLC• Lung cancer is the most common cause of cancer death worldwide1

• NSCLC accounts for 84% of all cases of lung cancer2

• At diagnosis, approximately 75% of patients with NSCLC have advanced or metastatic disease3

• TGF-β activity may play an important role in NSCLC; the plasma level of TGF-β is increased in patients with NSCLC compared with in healthy volunteers4

• TGF-β activity has been documented to be implicated in promoting tumor progression, angiogenesis, fibrosis, and epithelial-mesenchymal transition (EMT), which may lead to anti–PD-(L)1 resistance in NSCLC5-8

• Overall response rates (ORRs) with PD-(L)1 inhibitors in patients with metastatic NSCLC in the 2L or later setting range from 12% to 20%, depending on PD-L1 status9,10

– Median progression-free survival (PFS) ranges from 2.3 to 4.0 months (PD-L1 unselected),11,12 and the median overall survival (OS) ranges from 9.2 to 13.8 months (PD-L1 unselected),13,14 highlighting the need for improved treatment options

Bintrafusp alfa• Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the

extracellular domain of the TGF-βRII receptor to function as a TGF-β “trap” fused to a human IgG1 antibody blocking PD-L1 (Figure 1)

– The bifunctional nature of bintrafusp alfa allows for more localized inhibition of 2 nonredundant immunosuppressive pathways (TGF-β and PD-L1) within the tumor microenvironment15

– Results from a global phase 1 study (NCT02517398) found an ORR of 25.0% per independent review committee (IRC) assessment and a manageable safety profile in patients with advanced NSCLC who received bintrafusp alfa 1200 mg in the 2L setting, with a median follow-up of 51.9 weeks16

– Median OS was not reached in the 1200-mg cohort16

– PFS in the 1200-mg cohort, as adjudicated by an IRC, was 9.5 months for PD-L1–positive patients and 15.2 months for PD-L1–high patients16 (Table 1)

• Here we present an update on the efficacy and safety follow-up in a cohort of patients with advanced NSCLC receiving bintrafusp alfa

Figure 1. Proposed mechanism of action of bintrafusp alfa

Fibroblast

CAF

Fibrosis and impaireddrug access

EMT (leading to metastasis and resistanceto therapy [including checkpoint inhibition])

Tumor angiogenesis

Tumor cells

PD-L1

Bintrafuspalfa

PD-1

T cell

Suppression of immune response

NK cell

TAMDendritic

cell

CytotoxicT cell

Tumor cellsMesenchymal-like

tumor cell

TGF-β trap moiety sequestersTGF-β to inhibit downstream signaling

Anti–PD-L1 mAb moietyblocks PD-L1 interactions with PD-1

TGF-β*

CAF, cancer-associated fibroblast; NK, natural killer; TAM, tumor-associated macrophage. *Tumor cells are also a major source of TGF-β in the microenvironment.

Table 1. IRC-Adjudicated efficacy according to RECIST 1.1*500 mg n=40

1200 mg n=40

Overall N=80

ORR in PD-L1–evaluable patients, n/N (%) All PD-L1 positive (≥1%) PD-L1 high (≥80%)

 7/38 (18.4)6/31 (19.4)2/6 (33.3)

10/37 (27.0)10/27 (37.0)6/7 (85.7)

17/75 (22.7)16/58 (27.6)8/13 (61.5)

Median PFS (95% CI), months All PD-L1 positive (≥1%) PD-L1 high (≥80%)

 1.4 (1.3-4.2)1.4 (1.2-4.2)1.3 (0.2-NR)

 4.0 (1.3-9.5)9.5 (2.6-15.2)15.2 (1.3-NR)

 2.6 (1.3-4.2)2.7 (1.4-9.6)15.2 (1.0-NR)

NR, not reached.

*Data published as of the July 23, 2018 data cutoff and includes 52 weeks of median follow-up.

METHODS• NCT02517398 is an ongoing, phase 1, open-label trial of bintrafusp alfa16

– Study design has been described previously16 • Patients with advanced NSCLC, unselected for PD-L1 expression, who had

disease progression after standard first-line (1L) treatment and received no prior immunotherapy were randomized to receive bintrafusp alfa 500 or 1200 mg (n=40 each) every 2 weeks (Q2W) until disease progression, unacceptable toxicity, or trial withdrawal

• The primary objective of this expansion-cohort study was to assess best overall response (BOR) per RECIST 1.1, as adjudicated by an IRC, as described previously16

– Key secondary objectives reported in this study were BOR per investigator assessment and safety

– Exploratory objectives included duration of response (DOR), PFS, and OS

• Tumor cell PD-L1 expression was measured by immunohistochemistry (IHC) using antibody clone 73-10 (Dako PD-L1 IHC 73-10 pharmDx; Dako, Carpinteria, CA, USA); expression levels were categorized as PD-L1 <1% (negative), ≥1% (positive), 1% to <80% (low), or ≥80% (high)

– Previous studies comparing the 73-10 and 22C3 antibody clones suggest that the 73-10 assay has greater sensitivity than the 22C3 assay and that these assays have comparable staining at a cutoff of 80% and 50% expression, respectively17,18

RESULTS

Baseline patient and disease characteristics• 80 patients were enrolled in this cohort, of which, 21.3% (n=17) received ≥2 prior

anticancer regimens

– All patients had disease progression after standard first-line (1L) treatment and received no prior immunotherapy

• Overall, most patients (72.5% [n=58]) had PD-L1–positive (≥1%) tumors

– 56.3% (n=45) had low PD-L1 expression (1% to <80%)

– 16.3% (n=13) had high PD-L1 expression (≥80%)

• 21.3% (n=17) of patients had PD-L1–negative tumors (<1%)

• 6.3% (n=5) of patients did not have a PD-L1 status available

• At a database cutoff of October 15, 2019, median follow-up was 134 weeks (range, 1-144)

– The final patient was recruited in May 2017

• Median duration of treatment was 12 weeks (range, 2-144); 2 patients remain on treatment

Efficacy• Median DOR as assessed by investigator was 15.3 months for the 500-mg cohort and

18.0 months for the 1200-mg cohort (Table 2)

• Overall, there were 16 patients with responses lasting ≥6 months and 12 patients with responses lasting ≥12 months (Figure 2)

• In the 1200-mg cohort, there were 8 patients with responses lasting ≥6 months and 6 patients with responses lasting ≥12 months (Figure 2)

– Responses were ongoing in 3 patients in the 1200-mg cohort – The DOR was 6.9, 27.8, and 27.9 months for patients with ongoing response – All three ongoing responses were in PD-L1 positive tumors and two of the three

were PD-L1-high tumors• Overall, median OS was 13.6 months; the OS rate was 40.6% at 18 months and 34.6%

at 24 months (Figure 3)• In the 1200-mg cohort, median OS was 17.1 months; the OS rate was 49.7% at 18

months and 39.7% at 24 months (Figure 4) – For PD-L1-positive tumors, the mOS was 21.7 months and OS rate was 61.1% and

47.0% at 18 and 24 months, respectively – For PD-L1-high tumors, the mOS was not reached and OS rate was 83.3% and

83.3% at 18 and 24 months, respectively

Table 2. Efficacy outcomes for bintrafusp alfa500 mg n=40

1200 mg n=40

Overall N=80

ORR (CR+PR), n (%) 8 (20) 11 (27.5) 19 (23.8)DOR, median (95% CI), months ≥6-month response, n (%) ≥12-month response, n (%)

15.3 (8.1-18.9)8 (100) 6 (75.0)

18.0 (4.2-23.5)8 (72.7)6 (63.6)

15.3 (8.1-18.9)16 (84.2)12 (67.7)

OS, median (95% CI), months All PD-L1 positive (≥1%) PD-L1 high (≥80%) PD-L1 low (1% to <80%) PD-L1 negative (<1%)

10.9 (4.5-16.0)10.3 (4.2-16.5)14.5 (1.0-NR)8.8 (4.2-16.5)11.9 (0.3-NR)

17.1 (12.0-26.7) 21.7 (12.2-NR)

NR (9.6-NR) 19.0 (11.0-NR)12.2 (2.4-24.7

13.6 (10.9-19.3)16.0 (10.3-23.0)

NR (9.6-NR)13.2 (8.8-19.3)12.2 (7.2-25.7)

CR, complete response; PR, partial response.

Figure 2. Change in sum of target lesions per investigatorA. Overall population

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32Months

-100

-50

0

50

100

150170

Cha

nge

in s

um o

f dia

met

ers,

%

Start of treatment re-initiationFirst occurrence of new lesionPatient off treatmentSD, PD, or NEPRCR

B. 1200-mg cohort

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31Months

-100

-50

0

50

100

120

Cha

nge

in s

um o

f dia

met

ers,

%

First occurrence of new lesionPatient off treatmentSD, PD, or NEPRCR

NE, not evaluable; PD, progressive disease.

Figure 3. OS for overall population

At Risk

17 14 13 12 7777 6 5 5 5 2 1 0

45 383838 292929 242424 21 18 15 13 10 10 66 0

58 49494949 404040 353535 30 2525 22 20 17 17 121212 1

13 11 11 11 9 77 7 7 7 7 6 1

<1%1% to <80%

All

≥1%≥80%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Months

0

10

20

30

40

50

60

70

80

90

1009.6-NR10.3-23.08.8-19.37.2-25.795% CI

NR16.013.212.2Median, months5332813No. of events

(N=13)(N=58)(N=45)(N=17)≥80%≥1%1% to <80%<1%

10.9-19.313.650

All

≥80%≥1%1% to <80%<1%All

80 64 54 48 38 31 27 25 22 19 13 1

OS,

%

Figure 4. OS for 1200-mg cohort

At Risk

<1%1% to <80%

All

≥1%≥80%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Months

0

10

20

30

40

50

60

70

80

90

100

OS,

%

9.6-NR12.2-NR11.0-NR2.4-24.795% CINR21.719.012.2Median, months112118No. of events

(N=7)(N=27)(N=20)(N=10)≥80%≥1%1% to <80%<1%

12.0-26.717.122

All

10 9 8 8 44 3 2 2 2 0 0

20 19 16 13 12 9 8 6 4 4 11

27 26 23 20 17 14 13 11 9 9 6

7 7 7 7 5 5 5 5 5 5 5

≥80%≥1%1% to <80%<1%All

40 35 31 28 21 17 15 13 11 9 6

Safety• As reported previously,16 the most common treatment-related adverse events (TRAEs)

were pruritus (21.3%), maculopapular rash (18.8%), decreased appetite (12.5%), asthenia (11.3%), and rash (10.0%)

• Grade 3 TRAEs occurred in 23 patients (28.8%); grade 4 TRAEs occurred in 2 patients (2.5%)

• Since the prior analysis,16 there have been no additional grade ≥3 TRAEs observed, including no new treatment-related deaths; in the 500-mg cohort, there was 1 additional treatment-related discontinuation due to pruritis

• 9 patients (11.3%) experienced skin lesions potentially related to TGF-β blockade; 2 additional grade 1 keratoacanthomas were observed since the prior analysis

CONCLUSIONS

• After 2 years of follow-up, treatment with the recommended phase 2 dose (1200 mg Q2W) of bintrafusp alfa continued to show durable responses and long-term survival in patients with advanced 2L NSCLC, especially in those with high PD-L1 expression

– Median OS was 21.7 months for PD-L1–positive patients and not reached for PD-L1–high patients

– The median DOR was 18.0 months; 6 patients had responses ≥12 months

• The overall safety profile remained consistent with results from the prior analysis, with no new safety signals or deaths and 1 additional treatment-related discontinuation in the 500-mg cohort

• An ongoing phase 3 study is evaluating bintrafusp alfa versus pembrolizumab as 1L treatment for patients with advanced NSCLC that have high PD-L1 expression (INTR@PID LUNG 037; NCT03631706)

REFERENCES1. Bray F, et al. CA Cancer J Clin. 2018;68:394-424.2. American Cancer Society. Cancer Facts & Figures 2020.

https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed May 1, 2020.

3. Howlader N, et al. National Cancer Institute. SEER Cancer Statistics Review, 1975-2016. https://seer.cancer.gov/csr/1975_2016/. Accessed April 13, 2020.

4. Akhurst RJ and Hata A. Nat Rev Drug Discov. 2012;11:790-811.5. Colak S and Ten Dijke P. Trends Cancer. 2017;3:56-71.6. De Jaegar K, et al. Int J Radiat Oncol Phys. 2004;58:1378-87. 7. Principe DR, et al. J Natl Cancer Inst. 2014;106:djt369.8. Mariathasan S, et al. Nature. 2018;544-8.

9. Gulley JL, et al. Lancet Oncol. 2017;18:599-610. 10. Garon EB, et al. N Engl J Med. 2015;372:2018-28.11. Borghaei H, et al. N Engl J Med. 2015;373:1627-39. 12. Herbst RS, et al. Lancet. 2016;387:1540-50. 13. Rittmeyer A, et al. Lancet. 2017;389:255-65.14. Brahmer J, et al. N Engl J Med. 2015;373:123-35.15. Strauss J, et al. Clin Cancer Res. 2018;24:1287-95.16. Paz-Ares L, et al. J Thorac Oncol. 2020. [manuscript accepted

for publication]17. Feng Z, et al. J Clin Oncol. 2017;35(suppl):Abstract e20581.18. Grote HJ, et al. J Thorac Oncol. 2020 Apr 27. [Epub ahead of print].

ACKNOWLEDGMENTSThis study is funded by Merck KGaA, Darmstadt, Germany, and is part of an alliance between Merck KGaA and GlaxoSmithKline. The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers and at Merck KGaA and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany.

Medical writing support was provided by Megan Hyde, PharmD, of ClinicalThinking, Inc, Hamilton, NJ, USA, which was funded by Merck KGaA and GlaxoSmithKline, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

All relevant disclosures will be published with the abstract on the ASCO meeting library website (https://metinglibrary.asco.org/). Correspondence: Byoung Chul Cho, [email protected]

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