Phase 1 Study Combining Anti-PD-L1 (MEDI4736) With BRAF (Dabrafenib) and/or MEK (Trametinib) Inhibitors in Advanced Melanoma

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Abigail Carroll
5 years ago
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Lutzky J, Lawrence D, Robert C, Miller W, Linette G, Ascierto PA, Kuzel TM,

1 Phase 1 Study Combining Anti-PD-L1 (MEDI4736) With BRAF (Dabrafenib) and/or MEK (Trametinib) Inhibitors in Advanced Melanoma Abstract #3003 Ribas A, Butler M, Lutzky J, Lawrence D, Robert C, Miller W, Linette G, Ascierto PA, Kuzel TM, Algazi A, Postow M, Nathan P, Curti B, Robbins PB, Li X, Blake-Haskins JA, Gordon M

2 Potential Improvement Through Combinations of Immunotherapy and Targeted Therapy Current treatment options for BRAF V600 -mutated melanoma include: BRAF alone or BRAF/MEK inhibitors rapid clinically significant responses usually with limited durability Immunotherapy less frequent objective responses but clinically significant durability Immunotherapy Targeted Therapy Combination? Percent Alive Percent Alive + = Percent Alive Years Years Years Hypothesis: Combining anti-pd-l1 with BRAF and MEK inhibitors may result in higher frequency of long-lasting responses in patients with advanced BRAF V600 -mutated melanoma

BRAF/MEK Inhibition Modulates the Immune

expression 1 Antitumor activity of combined

antigen expression 3 1. Frederick DT, et al.

Clin Cancer Res. 2011;18(5):1386-1394. 3.

3 BRAF/MEK Inhibition Modulates the Immune Microenvironment CD8+ TILs 1,2 Melanoma antigen expression 1 Antitumor activity of combined BRAFi+MEKi plus anti-pd-1 3 MHC and melanoma antigen expression 3 1. Frederick DT, et al. Clin Cancer Res. 2013;19(5): Wilmott JS, et al. Clin Cancer Res. 2011;18(5): Hu-Lieskovan S, et al. Sci Transl Med. 2015;7(279):279ra41.

4 Cohort A Cohort B Cohort C Study Design and Population BRAF mutation positive BRAF wildtype BRAF wildtype 12-month treatment period MEDI or 10 mg/kg Q2W Dabrafenib 180 mg BID Until PD* Trametinib 2 mg QD 12-month treatment period MEDI or 10 mg/kg Q2W Trametinib 2 mg QD Until PD* 12-month treatment period MEDI mg/kg Q2W 6-week Trametinib 2 mg QD Follow-up Follow-up Follow-up *MEDI4736 can be reintroduced upon PD for up to 12 months Key inclusion criteria Stage IIIC/IV melanoma BRAF mutation status - Cohort A confirmed BRAF V600E/K mutation positive - Cohort B and C confirmed BRAF V600E/K mutation negative ECOG PS 0-1 Adequate organ and marrow function Prior immunotherapy permitted - anti-ctla-4 - anti-pd-l1/anti-pd-l1 Measurable disease required Key exclusion criteria Active or prior autoimmune disease Prior BRAF or MEK inhibitor therapy Prior severe or persistent irae BID, twice daily; ECOG PS, Eastern Cooperative Group Performance Status; irae, immune-related adverse event; PD, progressive disease; Q2W, every 2 weeks; QD, once daily; SD, stable disease

5 Patient Baseline Demographics Characteristic D + T + M T + M T M (sequential) Cohort A (n=26) Cohort B (n=20) Cohort C (n=19) Mean age, years (range) 47.2 (23-71) 62.2 (31-85) 58.7 (34-84) Sex Male (%) 14 (54) 13 (65) 10 (53) ECOG status 0 (%) 19 (73) 13 (65) - 1 (%) 5 (19) 7 (35) - NA (%) 2 (8) 0 (0) 19 (100) a Mutational status BRAF WT (%) 0 (0) 20 (100) 19 (100) BRAF V600E (%) 19 (73) 0 (0) 0 (0) BRAF V600E/K (%) 7 (27) 0 (0) 0 (0) NRAS (%) 0 (0) 3 (15) 6 (32) Stage at study entry Stage III (%) 5 (19) 2 (10) 4 (21) Stage IV (%) 21 (81) 18 (90) 15 (79) Median no. prior systemic therapy regimens (range) 0 (0-2) 2 (0-4) 1 (0-4) Patients who received prior systemic therapy, n (%) 10 (38) 12 (60) 14 (74) Patients who received prior immunotherapy in adjuvant or metastatic setting, n Anti-CTLA-4 (%) 6 (23) 11 (55) 8 (42) Anti-PD-1 (%) 0 (0) 6 (30) 5 (26) Cytokine-based therapy (%) 7 (27) 7 (35) 6 (32) Median follow-up duration: Cohort A 7.1 months Cohort B 6.8 months Cohort C 3.7 months Median exposure duration: Cohort A 6.4 months Cohort B 4.1 months Cohort C 2.7 months a Per protocol, ECOG status for Cohort C was not collected prior to first dose of study drug, but all patients were required to be ECOG 0 or 1 per eligibility criteria As-treated population. Data cut-off: May 7, 2015

6 Summary of Drug-Related Adverse Events Drug-Related Adverse Event (AE), n (%) a D + T + M T + M T M (sequential) Cohort A (n = 26) Cohort B (n = 20) Cohort C ( n = 19) Any AE 26 (100) 20 (100) 18 (95) Grade 3 AE 12 (46) 9 (45) 9 (47) Serious AE 8 (31) 4 (20) 4 (21) AE leading to discontinuation of any drug b 3 (12) 3 (15) 4 (21) AE leading to death 0 (0) 0 (0) 0 (0) AE related to MEDI (54) 7 (35) 8 (42) AE related to dabrafenic and/or trametinib 22 (85) 19 (95) 15 (79) Dose-limiting toxicities were observed in two patients Reversible grade 3 thrombocytopenia in Cohort A1 (MEDI mg/kg) Reversible grade 3 choroidal effusion in Cohort B Full doses of all agents were tolerable and chosen for expansion MEDI mg/kg Q2W + dabrafenib 150 mg BID +/or trametinib 2 mg QD a Patients counted once per category regardless of number of events. b In Cohort A (n=3): platelet count decreased (n=1), pyrexia (n=1), and pyrexia, myalgia, and arthralgia in 1 patient. In Cohort B (n=3): skin and subcutaneous tissue disorders (n=1), retinal vein occlusion (n=1), and blurred vision and choroidal effusion with ciliary body shutdown in 1 patients. In Cohort C (n=4): elevated LFTs (n=1), creatinine kinase elevation (n=1), skin urticaria (n=1) and lipase increased (n=1). Data cut-off: May 7, 2015

7 Drug-Related AEs Occurring in 25% of Patients AE Preferred Term, n (%) Cohort A (n=26) Cohort B (n=20) Cohort C (n=19) D + T + M T + M T M (Sequential) All Grades Grade 3 All Grades Grade 3 All Grades Grade 3 Diarrhea 10 (39) 1 (4) 10 (50) 0 (0) 6 (32) 1 (5) Fatigue 15 (58) 0 (0) 6 (30) 1 (5) 5 (26) 0 (0) Pyrexia 20 (77) 1 (4) 2 (10) 0 (0) 2 (11) 1 (5) Rash 8 (31) 1 (4) 7 (35) 0 (0) 9 (47) 2 (11) Chills 14 (54) 0 (0) 1 (5) 0 (0) 2 (11) 0 (0) Vomiting 11 (42) 1 (4) 0 (0) 0 (0) 6 (32) 0 (0) Nausea 9 (35) 0 (0) 1 (5) 0 (0) 4 (21) 0 (0) Edema peripheral 5 (19) 0 (0) 3 (15) 0 (0) 6 (32) 0 (0) Dry mouth a 8 (31) 0 (0) 1 (5) 0 (0) 3 (16) 0 (0) Folliculitis a 2 (8) 0 (0) 5 (25) 1 (5) 5 (26) 0 (0) Arthralgia a 11 (42) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Hyperhidrosis a 8 (31) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) a AEs occurring in 25% of patients in 1 cohorts, but not across 25% of the total population As-treated population. Data cut-off: May 7, 2015

8 Selected Drug-Related AEs of Interest AE Peferred Term, n (%) Cohort A (n = 26) Cohort B (n =20) Cohort C (n = 19) D + T + M T + M T M (sequential) All Grades Grade 3 All Grades Grade 3 All Grades Grade 3 Pneumonitis 0 (0) 0 (0) 0 (0) 0 (0) 1 (5) 0 (0) Colitis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Hypothyroidism 1 (4) 0 (0) 2 (10) 0 (0) 0 (0) 0 (0) Hyperthyroidism 1 (4) 0 (0) 0 (0) 0 (0) 1 (5) 0 (0) Hepatic events AST increased 5 (19) 2 (8) 1 (5) 0 (0) 2 (11) 0 (0) ALT increased 5 (19) 1 (4) 1 (5) 0 (0) 1 (5) 0 (0) Blood bilirubin increased 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Liver function test abnormal 0 (0) 0 (0) 1 (5) 1 (5) 0 (0) 0 (0) Tubulointerstitial nephritis 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Cardiac events Ejection fraction decreased 1 (4) 1 (4) 1 (5) 1 (5) 0 (0) 0 (0) Hypertension 0 (0) 0 (0) 2 (10) 2 (10) 1 (5) 1 (5) Ocular toxicities Retinal vein occlusion 0 (0) 0 (0) 1 (5) 0 (0) 0 (0) 0 (0) Detachment of retinal pigment epithelium 1 (4) 0 (0) 1 (5) 0 (0) 0 (0) 0 (0) Vision blurred 2 (8) 0 (0) 2 (10) 0 (0) 0 (0) 0 (0) Cutaneous squamous cell carcinoma 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Hyperkeratosis 1 (4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) As-treated population. Data cut-off: May 7, 2015

Immune Activation Post-Treatment Evidence of immune activation is observed post-treatment in all cohorts Frequency of tumor-infiltrating CD8 T cells increases post-treatment

9 Immune Activation Post-Treatment Evidence of immune activation is observed post-treatment in all cohorts Frequency of tumor-infiltrating CD8 T cells increases post-treatment Levels of interferon gamma and other Th1- associated factors in plasma are increased post-treatment More dramatic and consistent changes are observed in Cohort A versus Cohorts B and C

10 Clinical Activity to Date Response evaluable population includes all patients dosed 16 weeks prior to the cut-off date with measurable disease at baseline and 1 f/u scan (or discontinuation due to death or PD prior to 1 st scan) Cohort A (n = 26) Cohort B (n = 19) Cohort C* (n = 15) Clinical activity D + T + M T + M T M (sequential) ORR, n (%) 18 (69) 4 (21) 2 a (13) DCR (CR + PR + SD), n (%) 26 (100) 15 (79) 12 (80) SD 12 weeks, n (%) b 4 (15) 10 (53) 6 (40) Ongoing responders, n/n (%) 16/18 (89%) 4/4 (100%) 1/2 (50%) Range of duration of ongoing response, weeks c 7.7+ to to Median duration of response has not yet been reached for cohorts A and B *Shorter follow up in cohort C, with 5 additional patients ongoing with best response of unconfirmed PR D, dabrafenib; DCR, disease control rate; M, MEDI4736; ORR, overall response rate; T, trametinib a Responses based on the principles of immune-related RECIST; the two patients in Cohort C had unconventional confirmed PRs; b Includes subjects with unconfirmed PR or SD as the best overall response. c Duration of response is calculated for subjects with confirmed responses Data cut-off: May 8, 2015

Tumor Size Change and Time to Response: Cohort A Cohort A (D+T+M) Tumor size change from baseline Cohort A (D+T+M) Time to response and duration of response Figure

11 Tumor Size Change and Time to Response: Cohort A Cohort A (D+T+M) Tumor size change from baseline Cohort A (D+T+M) Time to response and duration of response Figure includes subjects with confirmed response in response evaluation population. D/C treatment=discontinuation of the regimen As-treated population. Data cut-off: May 8, 2015

12 Tumor Size Change and Time to Response: Cohort B and C Cohort B (T+M) Cohort C (T M) As-treated population. Data cut-off: May 8, 2015

13 Conclusions Combination of a checkpoint inhibitor with BRAF + MEK combination therapy was feasible and tolerable No maximum tolerated dose identified, and full doses of all agents were selected for dose expansion Toxicities observed were consistent with the known safety profiles of the combination components No exacerbation of immune-related AEs was apparent Markers of immune activation were observed post-treatment in all cohorts Early clinical activity was observed in all cohorts with the majority of patients having ongoing responses Results too preliminary to detect differences in concurrent vs sequenced dosing of trametinib and MEDI4736 Long follow-up is necessary Patients with a BRAF mutation treated with a combination of BRAF and MEK inhibition exhibited the greatest immune activation as well as the greatest clinical activity

Melanoma. Il parere dell esperto. V. Ferraresi. Divisione di Oncologia Medica 1

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