Three-year follow-up of bintrafusp alfa, a bifunctional fusion … · 2020. 3. 31. · Abstract No....

Abstract No. 1443. Presented at the ESMO Virtual Congress 2020, September 19-21, 2020 Three-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) L. Paz-Ares 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 , C. Helwig 11 , L. S. Ojalvo 12 , J. L. Gulley 13 , B. C. Cho 14 1 Hospital Universitario 12 de Octubre, Madrid, Spain; 2 Seoul National University Hospital, Seoul, Republic of Korea; 3 Hospital Universitario Virgen Macarena, Seville, Spain; 4 Vall d’Hebron University Hospital and Institute of Oncology, UVic-UCC, IOB-Quiron, 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, Seville, Spain; 9 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 10 Gregorio Marañon Hospital, Madrid, Spain; 11 Merck KGaA, Darmstadt, Germany; 12 EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany; 13 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 14 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea Poster No. 1272P BACKGROUND NSCLC • Lung cancer is the leading cause of cancer-related deaths worldwide, and the most common type of lung cancer is NSCLC 1,2 • TGF-β plasma levels are increased in patients with NSCLC compared with levels in healthy volunteers 3 • Activation of the TGF-β pathway promotes epithelial-mesenchymal transition (EMT), which is associated with tumor progression, fibrosis, and drug resistance 4-6 • Objective response rates (ORRs) of 12% to 20% have been reported with PD-(L)1 inhibitors in patients with metastatic NSCLC in the 2L or later setting, depending on PD-L1 expression 7-9 – In patients with PD-L1–unselected tumors, the median progression-free survival (PFS) ranged from 2.3 to 3.5 months, and the median overall survival (OS) ranged from 9.2 to 13.8 months, demonstrating the need for improved treatment options 9-11 Bintrafusp alfa • Bintrafusp alfa 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 might allow for colocalized, simultaneous inhibition of two nonredundant immunosuppressive pathways, TGF-β and PD-L1, within the tumor microenvironment 12 • Previous results from a global phase 1 study (NCT02517398) reported clinical efficacy and a manageable safety profile in patients with advanced NSCLC who received bintrafusp alfa 1200 mg in the 2L setting 13,14 – Here, we present efficacy and safety data for 3 years of follow-up in this 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 block 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. METHODS • NCT02517398 is a phase 1, open-label trial of bintrafusp alfa 13 • 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 mg or the recommended phase 2 dose of 1200 mg (n=40 each) every 2 weeks (Q2W) until disease progression, unacceptable toxicity, or trial withdrawal – Patients who achieved stable disease (SD), complete response (CR), or partial response (PR) with subsequent disease progression may reinitiate treatment for up to 12 months • The primary objective of this expansion cohort study was to assess best overall response (BOR) per RECIST 1.1, as described previously 13 – Key secondary objectives were safety and pharmacokinetics – 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 (PD-L1 IHC 73-10 pharmDx; Dako, Carpinteria, CA, USA); expression levels were categorized as PD-L1 negative (<1%), positive (≥1%), low (1% to <80%), or high (≥80%) – Previous studies comparing the 73-10 and 22C3 antibody clones suggest that the 73-10 assay had greater sensitivity than the 22C3 assay and that these assays had comparable staining at a cutoff of 80% and 50% expression, respectively 15,16 • Database cutoff date: March 31, 2020 RESULTS Baseline patient and disease characteristics • 80 patients who progressed after standard 1L treatment and received no prior immunotherapy were enrolled in this cohort • Most patients (72.5% [n=58]) had PD-L1–positive tumors (≥1%) – 56.3% (n=45) had PD-L1–low expression (1% to <80%) – 16.3% (n=13) had PD-L1–high expression (≥80%) • 21.3% (n=17) of patients had PD-L1–negative tumors (<1%) • PD-L1 expression was not evaluable in 6.3% (n=5) of patients • At a database cutoff of March 31, 2020, median Kaplan-Meier estimate of follow-up was 154 weeks (range, 1-173); the final patient was randomized in May 2017 • Median duration of treatment was 12 weeks (range, 2-171); at database cutoff, 2 patients remain on treatment, 1 in each dosing cohort, with durations of treatment of 160 and 171 weeks Efficacy • Median DOR, as assessed by investigator, was 18.0 months for the 1200-mg cohort (Table and Figure 2) • Overall, 16 patients (84.2%) had responses lasting ≥6 months, 12 patients (67.7%) had responses lasting ≥12 months, and 2 patients (11.3%) had responses lasting ≥24 months (Figure 2) • In the 1200-mg cohort, 8 patients (72.7%) had responses lasting ≥6 months, 6 patients (63.6%) had responses lasting ≥12 months, and 2 patients (21.2%) had responses lasting ≥24 months (Figures 2 and 3) – One patient in the 1200-mg cohort, with a PD-L1–high tumor, has an ongoing response lasting 34.4 months • In the overall population, median OS was 13.6 months; the OS rate was 34.6% at 24 months and 23.7% at 36 months (Figure 4) • In the 1200-mg cohort, median OS was 17.1 months; the OS rate was 39.7% at 24 months and 23.2% at 36 months (Figure 5) – For PD-L1–positive tumors, the median OS was 21.7 months, and the OS rate was 47.0% and 33.6% at 24 and 36 months, respectively – For PD-L1–high tumors, the median OS was not reached (NR), and the OS rate was 83.3% and 66.7% at 24 and 36 months, respectively Table. Efficacy outcomes with bintrafusp alfa as assessed by investigator 1200 mg n=40 Overall N=80 ORR (CR+PR), n (%) 11 (27.5) 19 (23.8) Median DOR, months (95% CI) ≥6-month response, n (%) ≥12-month response, n (%) ≥18-month response, n (%) ≥24-month response, n (%) 18.0 (4.2-23.5) 8 (72.7) 6 (63.6) 4 (42.4) 2 (21.2) 15.3 (8.1-18.9) 16 (84.2) 12 (67.7) 6 (33.8) 2 (11.3) Median OS, months (95% CI) All PD-L1 positive (≥1%) PD-L1 high* (≥80%) PD-L1 low (1% to <80%) PD-L1 negative (<1%) 17.1 (12.0-26.7) 21.7 (12.2-NR) NR (9.6-NR) 19.0 (11.0-33.4) 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) *The ≥80% cutoff for the 73-10 assay is comparable to the ≥50% cutoff for the 22C3 assay. 15,16 Figure 2. Duration of responses as assessed by investigator in the overall population 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Months Subsequent anticancer therapy Ongoing response End of treatment Death PD PR CR 1200 mg 1200 mg 1200 mg 500 mg 500 mg 500 mg 1200 mg 500 mg 500 mg 1200 mg 500 mg 1200 mg 1200 mg 500 mg 500 mg 1200 mg 1200 mg 1200 mg 1200 mg PD, progressive disease. Figure 3. Change in sum of target lesions per investigator in the 1200-mg cohort 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months -100 -50 0 50 100 120 Change in sum of target lesion diameters, % First occurrence of new lesion Patient off treatment SD, PD, or NE PR CR * Ongoing response NE, not evaluable. Data from 2 patients (1 in the 1200-mg cohort) were not included due to ongoing data cleaning. Patient in the 1200-mg cohort had BOR of PD, and patient in the 500-mg cohort had a PR and reinitiated treatment after occurrence of a new lesion. *Patient with CR did not receive any subsequent anticancer therapy. Change in sum of target lesions per investigator for the overall population can be accessed via the QR code. Figure 4. OS in the overall population No. at risk 80 64 54 48 38 31 27 25 22 19 18 16 9 2 All 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months 0 10 20 30 40 50 60 70 80 90 100 OS, % ≥80% ≥1% 1% to <80% <1% All NR (9.6-NR) 16.0 (10.3-23.0) 13.2 (8.8-19.3) 12.2 (7.2-25.7) Median, months (95% CI) 31.9 (19.4-45.1) 25.9 (13.1-40.9) 0 23.7 (13.9-35.0) 36-month OS, % (95% CI) 36.8 (23.8-49.9) 50.8 (21.4-74.2) 59.2 (27.9-80.7) 29.7 (16.3-44.3) 36.2 (13.9-59.2) 34.6 (23.7-45.7) 24-month OS, % (95% CI) 6 36 30 14 No. of events ≥80%* (n=13) ≥1% (n=58) 1% to <80% (n=45) <1% (n=17) 13.6 (10.9-19.3) 54 All (N=80) 17 14 13 12 7 6 5 5 5 2 2 2 0 0 45 38 29 24 21 18 15 13 10 10 9 8 4 0 58 49 40 35 30 25 22 20 17 17 16 14 9 2 13 11 11 11 9 7 7 7 7 7 7 6 5 2 <1% 1% to <80% ≥1% ≥80% *The ≥80% cutoff for the 73-10 assay is comparable to the ≥50% cutoff for the 22C3 assay. 15,16 Figure 5. OS in the 1200-mg cohort No. at risk 40 35 31 28 21 17 15 13 11 9 8 6 3 All Months 0 10 20 30 40 50 60 70 80 90 100 OS, % ≥80% ≥1% 1% to <80% <1% All NR (9.6-NR) 21.7 (12.2-NR) 19.0 (11.0-33.4) 12.2 (2.4-24.7) Median, months (95% CI) 33.6 (13.9-54.7) 0 0 23.2 (9.6-40.3) 36-month OS, % (95% CI) 47.0 (25.7-65.8) 66.7 (19.5-90.4) 83.3 (27.3-97.5) 32.7 (12.1-55.3) 28.1 (4.5-59.6) 39.7 (23.0-56.0) 24-month OS, % (95% CI) 2 14 12 8 No. of events ≥80%* (n=7) ≥1% (n=27) 1% to <80% (n=20) <1% (n=10) 17.1 (12.0-26.7) 24 All (n=40) 10 9 8 8 4 3 2 2 2 0 0 0 0 20 19 16 13 12 9 8 6 4 4 3 2 0 27 26 23 20 17 14 13 11 9 9 8 6 3 7 7 7 7 5 5 5 5 5 5 5 4 3 <1% 1% to <80% ≥1% ≥80% 0 3 6 9 12 15 18 21 24 27 30 33 36 39 *The ≥80% cutoff for the 73-10 assay is comparable to the ≥50% cutoff for the 22C3 assay. 15,16 Safety • After 3 years of follow-up, the most common treatment-related adverse events (TRAEs) were pruritus (22.5%), 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%) • No treatment-related deaths occurred • This safety profile is consistent with previous reports for this cohort, with no new grade ≥3 TRAEs 13,14 CONCLUSIONS • After 3 years of follow-up in patients with advanced 2L NSCLC unselected for PD- L1 expression, durable responses and long-term survival were observed with the recommended phase 2 dose (1200 mg Q2W) of bintrafusp alfa, especially in patients with high PD-L1 expression – Median OS was 21.7 months in patients with PD-L1–positive tumors, with a 36-month OS rate of 33.6% ■ Bintrafusp alfa showed favorable median OS in patients with advanced 2L NSCLC compared with historical data of PD-(L)1 inhibitors; median OS ranged from 8.5 to 15.7 months for PD-L1–positive tumors 17,18* – Median OS was not reached in patients with PD-L1–high tumors, with a 36-month OS rate of 66.7% – The median DOR was 18.0 months; 21.2% of patients had responses lasting ≥24 months • The overall safety profile remained consistent with results from the 2-year follow-up analysis, with no new safety signals or deaths • An ongoing phase 3 study is evaluating bintrafusp alfa vs pembrolizumab as 1L treatment for patients with advanced NSCLC that has high expression of PD-L1 (INTR@PID LUNG 037; NCT03631706) *No direct comparison can be made in the absence of a head-to-head study. REFERENCES 1. Bray F, et al. CA Cancer J Clin. 2018;68:394-424. 2. Planchard D, et al. Ann Oncol. 2018;29:iv192-237. 3. De Jaegar K, et al. Int J Radiat Oncol Phys. 2004;58:1378-87. 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. Eser PO and Janne PA. Pharmacol Ther. 2018;184:112-30. 7. Gulley JL, et al. Lancet Oncol. 2017;18:599-610. 8. Garon EB, et al. N Engl J Med. 2015;372:2018-28. 9. Brahmer J, et al. N Engl J Med. 2015;373:123-35. 10. Rittmeyer A, et al. Lancet. 2017;389:255-65. 11. Borghaei H, et al. N Engl J Med. 2015;373:1627-39. 12. Strauss J, et al. Clin Cancer Res. 2018;24:1287-95. 13. Paz-Ares L, et al. J Thorac Oncol. 2020;15:1210-22. 14. Cho BC, et al. J Clin Oncol. 2020;38(Suppl 15):Abstract 9558. 15. Feng Z, et al. J Clin Oncol. 2017;35(Suppl 15):Abstract e20581. 16. Grote HJ, et al. J Thorac Oncol. 2020;15:1306-16. 17. Leighl NB, et al. Lancet Respir Med. 2019;7:347-57. 18. Fehrenbacher L, et al. J Thorac Oncol. 2018;13:1156-70. 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). Correspondence: Luis Paz-Ares, [email protected] DISCLOSURES LP-A reports honoraria from Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Incyte, Ipsen, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Sysmex, Takeda; received research funding from Astra Zeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; has leadership roles at Altum sequencing; and is an Officer/ on the Board of Directors at Genomica. TMK reports consulting/advisory (without honoraria) roles at AstraZeneca, Novartis, Sanofi, Takeda, Voronoi, and Boryung; and received research funding from AstraZeneca. EF reports consulting/advisory and speaking/ expert testimony roles for Abbvie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Guardant Health, Janssen, Eli Lilly, Medscape, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Novartis, Pfizer, priME Oncology, Roche, Samsung, Springer, Takeda, and Touchtime; and received research funding from EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany, and Fundacion Merck Salud. DHL reports honoraria (self) from Abbvie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chong Kun Dang Pharmaceutical, Green Cross Corp., Janssen, Eli Lilly, Menarini, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Ono Pharmaceutical, Roche, ST Cube, and Takeda; and received travel/ accommodation/expenses from Takeda and Blueprint Medicines. KHL reports honoraria (self) from AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. C-CL reports honoraria (self) from Bristol Myers Squibb, Daiichi Sankyo, Novartis, and Roche; consulting/advisory role for Blueprint Medicines, Daiichi Sankyo, Novartis, and Takeda; and received travel/ accommodation/expenses from BeiGene and Eli Lilly. MJF reports honoraria (self) from Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Eisai, Kyowa Kirin, Angelini, and Grunenthal. RMA reports consulting/advisory roles for Roche, Takeda, and AstraZeneca; speaking/expert testimony roles for Bristol Myers Sqibb, Eli Lilly, Pharmamar, and Novartis; and received travel/ accommodation/ expenses from Pharmamar and Roche, Bristol Myers Squibb, Janssen Oncology, Merrimack, Merck Sharp & Dohme Oncology, Novartis, PharmaMar, Roche/Genentech, and Takeda. CH is an employee of Merck KGaA, Darmstadt, Germany. LSO is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany. JLG reports research funding (institution) from Merck KGaA, Darmstadt, Germany. BCC reports honoraria (self) from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme; had consulting/advisory roles for Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Medpacto, Blueprint Medicines; received research funding (institution) from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, Abbvie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines; had shareholder/stockholder for TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, Kanaph Therapeutic Inc; licensing/royalties for Champions Oncology; and is an Officer/ on the Board of Directors for Daan Biotherapeutics. The remaining authors have nothing to declare. 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Three-year follow-up of bintrafusp alfa, a bifunctional fusion … · 2020. 3. 31. · Abstract No....

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