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387 A Phase II, multicenter study of the safety and efficacy of LAG525 in combination with spartalizumab in patients with advanced malignancies
  1. Chia-Chi Lin1,
  2. Elena Garralda2,
  3. Patrick Schöffski3,
  4. David Hong4,
  5. Lillian Siu5,
  6. Miguel Martin6,
  7. Michela Maur7,
  8. Rina Hui8,
  9. Ross Soo9,
  10. Joanne Chiu10,
  11. Tian Zhang11,
  12. Brigette Ma12,
  13. Chrisann Kyi13,
  14. Daniel Tan14,
  15. Philippe Cassier15,
  16. John Sarantopoulos16,
  17. Andrew Weickhardt17,
  18. Rich Carvajal18,
  19. Jennifer Spratlin19,
  20. Taito Esaki20,
  21. Fréderic Rolland21,
  22. Wallace Akerley22,
  23. Barbara Deschler-Baier23,
  24. Catherine Sabatos-Peyton24,
  25. Niladri Roy Chowdhury25,
  26. Daniel Gusenleitner24,
  27. Eunice Kwak24,
  28. Vasileios Askoxylakis24 and
  29. Filippo De Braud26
  1. 1National Taiwan University Hospital, Taipei, Taiwan, Province of China
  2. 2Vall d’Hebron, Barcelona, Spain
  3. 3Gasthuisberg University Hospital, Leuven, Belgium
  4. 4University of Texas and MD Anderson Cancer Center, Houston, TX, USA
  5. 5Princess Margaret Cancer Centre, Toronto, Canada
  6. 6Gregorio Marañón Hospital, Madrid, Spain
  7. 7Università degli Studi di Modena e Reggio Emilia, Emilia-Romagna, Italy
  8. 8Westmead Hospital and the University of Sydney, Sydney, Australia
  9. 9National University Cancer Institute, Singapore, Singapore
  10. 10Queen Mary Hospital, Hong Kong, Hong Kong
  11. 11Duke Cancer Institute, Durham, NC, USA
  12. 12The Chinese University of Hong Kong, Hong Kong, Hong Kong
  13. 13Memorial Sloan Kettering Cancer Center, New York, NY, USA
  14. 14National Cancer Centre, Singapore, Singapore
  15. 15Centre Léon Bérard, Lyon, France
  16. 16Institute for Drug Development, San Antonio, TX, USA
  17. 17Austin Health, Victoria, VT, Australia
  18. 18Columbia University Medical Center, New York, NY, USA
  19. 19University of Alberta, Edmonton, Canada
  20. 20National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
  21. 21Institut de Cancérologie de l’Ouest – Centre René Gauducheau, Nantes, France
  22. 22University of Utah, Salt Lake City, UT, USA
  23. 23Universitätsklinikum Würzburg, Würzburg, Germany
  24. 24Novartis Institutes for Biomedical Research, Cambridge, MA, USA
  25. 25Novartis Pharmaceuticals Corporation, East Hannover, NJ, USA
  26. 26Fondazione IRCCS Istituto Nazionale dei Tumori and the University of Milan, Milan, Italy


Background Expression of LAG-3, an inhibitory immunoreceptor, has been linked to reduced T-cell proliferation and cytokine production. LAG525 is a humanized IgG4 anti-LAG-3 antibody which inhibits LAG-3 binding to MHC class II. Spartalizumab is a humanized IgG4 anti-PD-1 mAb which inhibits PD-1 binding with its ligands PD-L1 and PD-L2. Preclinical data have shown promising antitumor activity when blocking LAG-3 and PD-1.

Methods The Phase II part of the first-in-human study (NCT02460224) explored LAG525 + spartalizumab in patients with advanced/metastatic non-small cell lung cancer (NSCLC), cutaneous and non-cutaneous melanoma, renal cell carcinoma (RCC), mesothelioma, or triple-negative breast cancer (TNBC). The dose/schedule of LAG525 and spartalizumab was 400 mg IV Q3W and 300 mg IV Q3W, respectively. Half of patients with TNBC naïve to anti-PD-1/PD-L1 received LAG525 at 600 mg IV Q4W and spartalizumab at 400 mg IV Q4W. The primary endpoint was overall response rate (ORR) using RECIST v1.1.

Results As of June 1, 2020, 235 patients were enrolled in the Phase II part of the study, including patients with NSCLC (n=42), melanoma (n=42), RCC (n=38), mesothelioma (n=57), or TNBC (n=56). In total, 142 patients were naïve to, and 93 patients were pretreated with, PD-1/PD-L1 inhibitors. Overall, 232 patients (99%) discontinued treatment, 76% due to progressive disease.ORR and disease control rate by indication and prior anti-PD-1/PD-L1 treatment are summarized below (table 1). Best overall response was 3 (1.3%) CR, 23 (9.8%) PR, 84 (35.7%) SD, 95 (40.4%) PD, and 30 (12.8%) unknown. For patients naïve to anti-PD-1/PD-L1, median progression free survival (mPFS) in months (90% CI) was 3.9 (1.7–5.6) for NSCLC, 2.2 (1.6–5.6) for melanoma, 4.4 (2.1–11.1) for RCC, 5.5 (3.5–6.4) for mesothelioma, and 1.9 (1.6–2.6) for TNBC. For patients pretreated with anti-PD-1/PD-L1, mPFS in months (90% CI) was 3.5 (1.9–4.9) for NSCLC, 1.9 (1.8–3.7) for melanoma, 3.0 (1.6–3.9) for RCC, 3.4 (1.8–3.8) for mesothelioma, and 1.7 (1.3–3.4) for TNBC. Adverse events of any grade, regardless of cause, were reported in 233 (99%) patients; the most common (occurring in >20%) were nausea (25%), fatigue (23%), and dyspnea (21%).

Abstract 387 Table 1

Overall response rate (ORR: CR + PR) and disease control rate (DCR: CR + PR + SD) per RECIST v1.1 by indication and prior anti-PD-1/PD-L1 treatment

Conclusions LAG525 + spartalizumab exhibited antitumor activity across different indications, including patients with melanoma, RCC, and mesothelioma who had been pretreated with PD-1/-L1 inhibitors, suggesting that this combination may salvage prior PD-1/-L1 resistance. The combination was well tolerated, and no new safety signals were observed. Biomarker analysis is ongoing.

Trial Registration NCT02460224

Ethics Approval This study was approved by an independent ethics committee or institutional review board at each site.

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