Jan van de Winkel, PhD
Two separate early-phase clinical trials exploring daratumumab (Darzalex) in combination with either a PD-1 inhibitor for multiple myeloma or a PD-L1 inhibitor for non–small cell lung cancer (NSCLC) were terminated following a planned interim analysis, according to a statement from Genmab, the company codeveloping daratumumab with Janssen.
The first study, known as LUC2001, explored the CD38 inhibitor daratumumab in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) for patients with previously-treated NSCLC. At a routine analysis of the study, an independent data monitoring committee (DMC) noted a lack of clinical efficacy with the combination compared with single-agent atezolizumab. Moreover, the DMC identified a higher rate of mortality in the daratumumab/atezolizumab combination arm.
Based on the magnitude of these mortality findings, Janssen also made the decision to discontinue the MMY-2036 study, which was exploring daratumumab with the investigational PD-1 inhibitor JNJ 63723283 for patients with multiple myeloma.
In addition to these clinical trial closures, Janssen is in communication with global health authorities and has contacted other companies investigating daratumumab in combination with a PD-1/PD-L1 inhibitor to explore future for these trials. Findings from the LUC2001 analysis were not yet made public.
"While we are disappointed that the studies will be discontinued, Genmab fully supports Janssen's decision, as patient safety is paramount in drug development," Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement. "We look forward to gaining a better understanding of the data upon further analysis."
The phase Ib/II LUC2001 trial enrolled 98 patients with previously-treated advanced or metastatic NSCLC. The study began recruiting participants in December 2016, with primary results originally anticipated in February 2019. The expected full enrollment for the study was 132 patients, with the first 6 included in a safety run-in phase (NCT03023423).
The phase I MMY-2036 study began enrolling patients in November 2017, with a target enrollment of 386 patients. This study also contained a safety run-in cohort of 6 patients (NCT03357952). An announcement regarding other studies exploring PD-1/PD-L1 inhibitors plus daratumumab was not available at this time, including the GO29695 study examining atezolizumab and daratumumab for patients with relapsed/refractory multiple myeloma (NCT02431208).
The halt of the trial joins other disappointing news announced in 2017 for checkpoint inhibitors in multiple myeloma. In June 2017, the FDA called the safety of the PD-1 inhibitor pembrolizumab (Keytruda) into question for patients with multiple myeloma, when it placed clinical trials of the agent on hold. Subsequently, in July 2017, the agency asked for the discontinuation of 2 phase III studies exploring pembrolizumab in combination with dexamethasone and an immunomodulatory drug (IMiD; either lenalidomide or pomalidomide) for patients with multiple myeloma.
In a review conducted by the FDA of these 2 studies, there was a 61% increase in the relative risk of death with the addition of pembrolizumab to an IMiD and dexamethasone. At the 8.1-month analysis, there had been 29 deaths in the pembrolizumab arm compared with 21 deaths in the control group. The overall survival hazard ratio between the groups was 1.61 (95% CI, 0.91-2.85). There was also a higher rate of severe, grade 3-5 toxicity with the addition of pembrolizumab compared with the control arm (83% vs 65%, respectively).
Following this announcement, several clinical trials exploring checkpoint inhibitors in multiple myeloma were placed on hold by the FDA. In September 2017, the GO29695 trial was placed on clinical hold to examine the safety of the study. The hold on the trial, which contained arms exploring atezolizumab and daratumumab, was lifted in December 2017, along with clinical holds on other trials exploring PD-1/PD-L1 inhibitors for multiple myeloma.
The status of several other clinical trials exploring daratumumab with a PD-1/PD-L1 inhibitor remains unclear, following the announcement of the LUC2001 and MMY2036 trials. For instance, phase I/II studies are currently exploring the PD-1 inhibitor nivolumab (Opdivo) with daratumumab for patients with breast cancer, pancreatic cancer, virus-associated tumors, and multiple myeloma (NCT03098550, NCT01592370, NCT02488759).
Another phase II study was exploring durvalumab (Imfinzi) and daratumumab for multiple myeloma; however, this trial was terminated shortly following the mandated partial hold in September 2017. This single-arm trial, however, was stopped due to a lack of efficacy, according to its clinicaltrials.gov listing (NCT03000452).
FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA® (pembrolizumab) in Patients with Multiple Myeloma. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed August 31, 2017.