Opinion ID: 6322310
Heading Depth: 2
Heading Rank: 2

Heading: Industry Understanding of PD-L1 Expression

Text: A few months after the Opdivo trial was announced, Bristol-Myers’s competitor, Merck & Co. (“Merck”), announced a clinical study to test “Keytruda,” Merck’s PD-1 checkpoint inhibitor, as a treatment for NSCLC. In February 2016, Merck disclosed that, for the purpose of its trial, it defined “strong” expression as PD-L1 expression greater than 50%. On June 16, 2016, shortly before Bristol-Myers announced the failure of the Opdivo trial, Merck announced that Keytruda worked better than chemotherapy in patients with PDL1 expression levels greater than 50%. 10 There was little consensus among industry participants and researchers as to the expression levels constituting “strong” PD-L1 expression and PD-L1 “positivity,” which is the baseline level of expression at which a trial would consider a patient’s PD-L1 expression as relevant to results. With respect to PDL1 positivity, the July 2015 Journal of Thoracic Oncology surveyed the threshold used for “positive” expression in various studies, noting that many used 5%, while some used 1% or 10%. The publication showed that in several studies, Merck considered any expression up to 49% “weak.” Similarly, a May 26, 2016 medical publication stated that “[t]he best cut-off percentage of scored cells to determine PD-L1 positivity . . . remains an unresolved question” but “the threshold most often chosen is >5% expression.” JA-735 (Compl. ¶ 54). Several Opdivo studies conducted by Bristol-Myers prior to the relevant Opdivo trial defined positivity as greater than 5%, while others used 1%. Sources also do not agree on the percentage that amounts to “strong” expression. On March 16, 2015, the journal PLOS One defined “strong expression” as at least 50%. On March 3, 2016, Translational Oncology defined “weak positive” as “1% to 49%” and “strong positive” as 50% or more. 11 Beginning with a press release on April 6, 2014, Merck consistently defined “strong” PD-L1 expression as at least 50%, and--as noted above--disclosed in February 2016 that it was using that same threshold in its trial. Throughout the Opdivo trial, investment analysts tried to predict or discern its threshold for “strong” expression. Two months after Merck disclosed that its trial used a 50% threshold, an analyst asked if the trial used the same definition of strong expression. Bristol-Myers refused to disclose its definition of “strong” expression, but allowed that the “actual level of what strongly expressing PD-1 is [is] lower than 50%.” JA-759 (Compl. ¶ 112). On March 7, 2016, SVB Leerink issued a report concluding that Bristol-Myers’s “primary analysis population” “likely represents 30-40%” of lung cancer patients, a figure that indicated a patient population with PD-L1 expression of at least 25%. In June 2016, BMO Capital Markets stated with respect to the Opdivo trial that “we believe [‘strong’] means at least 10%” expression. Goldman Sachs and Alliance Bernstein each predicted that the Opdivo trial used a 5% cut-off for “strong” expression. JA-1282, 1296, 1303, 1315. 12