Genmab has acknowledged that its development partner for Darzalex® (daratumumab), Johnson & Johnson’s Janssen Biotech, will halt two clinical trials assessing combinations of the drug with two other cancer treatments—with one combination linked to more deaths in patients with previously treated advanced or metastatic non-small cell lung cancer (NSCLC).

That combination—Darzalex plus Genentech’s anti-programmed death-ligand 1 (anti-PD-L1) antibody Tecentriq® (atezolizumab)—has been the subject of CALLISTO/LUC2001 (NCT03023423), a Phase Ib/II study.

The study will be discontinued at the recommendation of the study’s Data Monitoring Committee (DMC) based on a recent planned review, Genmab said. The DMC found an unspecified “numerical increase in mortality-related events” in the combination arm compared with Darzalex alone, as well as no observed benefit within the combination treatment arm compared with Tecentriq alone, according to Genmab.

“Janssen has informed health authorities about these events and has contacted its partner companies conducting daratumumab and anti-PD-(L)1 combination studies to discuss ceasing enrollment and dosing of the combination while the data is being further investigated,” Genmab said in a statement over the weekend.

LUC2001 was a randomized, multicenter study that included 98 patients with previously treated advanced or metastatic NSCLC. Patients were to be randomized to receive daratumumab at 16 mg/kg weekly for three cycles and on day 1 of every 21-day cycle thereafter. Tecentriq was to be administered at 1200 mg on day 2 of cycle 1 and on day 1 of every 21-day cycle thereafter. Patients were to continue receiving treatment until disease progression or unacceptable toxicity.

Patients in the Tecentriq monotherapy arm with confirmed disease progression will be eligible to crossover to the daratumumab plus Tecentriq arm, if they meet the crossover eligibility criteria. The primary endpoint of the study was percentage of patients with overall response rate, defined as percentage of patients with partial or complete response as defined by Response Evaluation Criteria in Solid Tumors (RECIST).

Tecentriq is marketed by Genentech, a member of the Roche Group, for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy or have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy. Tecentriq is also indicated for metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy.

Separately today, Genentech said Tecentriq plus chemotherapy met its co-primary endpoints of overall survival and progression-free survival in the Phase III IMpower130 study. Patients receiving the combination of Tecentriq and carboplatin and Abraxane® (albumin-bound paclitaxel; nab-paclitaxel) lived “significantly longer” compared to chemotherapy alone in the first-line treatment of advanced NSCLC, the company said.

Genentech offered no details, saying data would be presented at an unspecified upcoming oncology congress—but did say that the Tecentriq/chemo combination also reduced the risk of progression-free survival compared with chemotherapy alone.

MMY2036 Study Also Halted

Also being discontinued, Genmab said, is the Phase I MMY2036 study assessing Darzalex plus Janssen’s anti-programmed cell death protein 1 (anti-PD-1) antibody JNJ-63723283 in patients with multiple myeloma.

MMY2036 (NCT03357952) was a randomized, multicenter, multiphase study estimated to include up to 386 patients with relapsed or refractory multiple myeloma. Approximately six subjects were enrolled in the Part 1 safety run-in cohort, followed by 80 subjects randomly assigned in a 1:1 ratio to the two treatment arms in Part 2. After approximately four months of follow-up for those subjects, investigators were to decide whether to initiate Part 3, where an additional 300 subjects were to be randomly assigned 1:1 to the treatment arms.

Daratumumab was dosed at 16 mg/kg weekly for eight weeks, then once every other week for 16 weeks, then once every four weeks. JNJ-63723283 was dosed at 240 mg IV fixed dose during week 1 on cycle 1 (28 days) day 2, cycle 1 day 15, then every 2 weeks thereafter.

The primary endpoints of MMY2036 for Part 1 were number of participants with adverse events including dose-limiting toxicities during cycle 1. For Part 2, the primary endpoint was overall response rate as per International Myeloma Working Group (IMWG) criteria, while the Part 3 primary endpoint was progression-free survival.

“While we are disappointed that the studies will be discontinued, Genmab fully supports Janssen's decision, as patient safety is paramount in drug development. We look forward to gaining a better understanding of the data upon further analysis,” stated Genmab CEO Jan van de Winkel, Ph.D.

Investors responded to the clinical setbacks with a stock selloff that lowered Genmab’s closing share price yesterday by 20% to DKK 953.20 ($148.21), from Friday’s close of DKK 1192.50 ($185.42). Shares traded at DKK 957.20 ($148.84) as of 9:28 am ET.

Darzalex is indicated alone in patients who have received at least three prior treatments for multiple myeloma, including a proteasome inhibitor and an immunomodulatory agent, or did not respond to a proteasome inhibitor and an immunomodulatory agent.

Darzalex is also indicated in combinations with:

  • Lenalidomide and dexamethasone or bortezomib and dexamethasone, in patients who have received at least one prior treatment for multiple myeloma
  • Pomalidomide and dexamethasone in patients who have received at least two prior treatments for multiple myeloma, including lenalidomide and a proteasome inhibitor.
  • Bortezomib, melphalan, and prednisone, in patients with newly diagnosed multiple myeloma who cannot receive autologous stem cell transplant.
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