Immune-suppressing molecules such as PD-L1 can be co-opted by cancer cells to suppress the natural immune response to cancer. Upregulation of PD-L1 and inhibition of antitumor T-cell activation is observed in several tumor types. MEDI4736 is a human IgG1 antibody which binds specifically to PD-L1, preventing binding to PD-1 and CD80.
An ongoing phase 1 multicenter, open-label study is evaluating safety, pharmacokinetics ( PK ), and antitumor activity of MEDI4736 given IV every 2 ( q2w ) or 3 weeks ( q3w ) in a 3+3 dose escalation with a 28-day ( q2w ) or 42-day ( q3w ) dose-limiting toxicity ( DLT ) window, followed by expansion in 8 solid tumors.
Response was assessed by immune-related response criteria in escalation.
As of Jan 17, 2014, 26 patients ( pts ) ( 13 non-small-cell lung carcinoma [ NSCLC ], 8 melanoma, 5 other ) in dose escalation ( median age 59 yrs; 35-77 ), all performance status ( PS ) 0-1, with a median of 4 prior treatments, received a median of 5 ( 1-25 ) q2w and 4.5 ( 1-7 ) q3w doses of MEDI4736 across 6 cohorts ( 0.1 – 10 mg/kg q2w; 15 mg/kg q3w ).
MEDI4736 showed dose-dependent pharmacokinetics. Evidence of anti-drug antibodies ( ADA ) impacted pharmacokinetics exposure in only 1 patient. No dose-limiting toxicities ( DLTs ) or maximum tolerated dose were identified for q2w or q3w dosing.
Treatment-related adverse effects occurred in 34% of patients, all grade 1-2; none led to discontinuation of study drug. The most frequent treatment-related adverse reactions were diarrhea, fatigue, rash, and vomiting ( 12% each ).
No pneumonitis, colitis, or hyperglycemia occurred.
Of 26 patients, 4 partial responses ( PRs ) ( 3 NSCLC, 1 melanoma ) and 5 additional patients with tumor shrinkage not meeting partial response were observed.
Disease control rate ( PR + SD greater than or equal to 12 weeks ) was 46%.
Tumor shrinkage, as early as 6 weeks, was seen at all dose levels, and benefit was durable; 11 patients remain on study as of the data cutoff ( 2+ to 14.9+ months ).
Expansion cohorts opened September 2013 using a 10 mg/kg q2w dose; 151 patients have been dosed, with the opportunity to enroll more than 600 patients.
Preliminary clinical activity has been observed with acceptable safety across a range of tumors including squamous cell carcinoma of the head and neck [ SCCHN ], pancreatic cancer, gastric cancer, non-small-cell lung carcinoma, and melanoma.
In conclusion, MEDI4736 has demonstrated an acceptable safety profile and durable clinical activity in this dose-escalation study.
Expansion in multiple cancers and development of MEDI4736 as monotherapy and in combination is ongoing. ( Xagena )
Lutzky J et al, J Clin Oncol 2014; 32:5s ( suppl; abstr 3001 )