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P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma
  1. Michele Maio1,
  2. Matteo Carlino2,
  3. Anthony Joshua3,
  4. Elaine McWhirter4,
  5. Antoni Ribas5,
  6. Paolo Ascierto6,
  7. Wilson Miller7,
  8. Marcus Butler3,
  9. Pier Ferrucci8,
  10. Robert Zielinski9,
  11. Michele Del Vecchio10,
  12. Eduard Gasal11,
  13. Razi Ghori12,
  14. Scott Diede12,
  15. Elizabeth Croydon12 and
  16. Omid Hamid13
  1. 1Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
  2. 2Melanoma Institute Australia, The University of Sydney, Westmead and Blacktown Hospitals, Sydney, NSW, Australia
  3. 3Kinghorn Cancer Centre, St. Vincent’s Hospital, Sydney, NSW, Australia
  4. 4Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada
  5. 5David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  6. 6Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, Naples, Italy
  7. 7Lady Davis Institute for Medical Research, Jewish General Hospital, and McGill University, Montreal, QC, Canad
  8. 8Istituto Europeo di Oncologia – IRCCS, Milan, Italy
  9. 9Buffalo Medical Group, Williamsville, NY, USA
  10. 10Fondazione IRCCS Istituto Nazionale, Milan, Italy
  11. 11Novartis, East Hanover, NJ, USA
  12. 12Merck and Co., Inc., Kenilworth, NJ, USA
  13. 13The Angeles Clinic and Research Institute, Los Angeles, CA, USA


Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib.

Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4.

Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%).

Abstract P863 Table 1

DLT, TRAE, and ORR in KEYNOTE-022 parts 4 and 5

Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.

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