Janssen Biotech, the Johnson & Johnson sub­sid­i­ary that mar­kets the myeloma ther­apy Darzalex globally, has decided to halt two clin­i­cal trials testing the drug in com­bi­na­tion with other cancer treat­ments.

One of the Darzalex trials involves patients with pre­vi­ously treated metastatic non-small cell lung cancer, while the other trial involves patients with re­lapsed or refractory multiple myeloma.

Genmab, the Danish com­pany that initially devel­oped Darzalex (dara­tu­mu­mab) before licensing it to Janssen, announced news of the trial can­cel­la­tions this past Saturday.

Genmab reported that, in the lung cancer trial, no benefit was seen to combining Darzalex with another drug, Tecentriq (atezo­lizu­mab), which already is approved in many countries for the treat­ment of lung cancer.

Furthermore, there were more deaths observed during the trial in patients treated with Darzalex and Tecentriq than in patients treated with Tecentriq alone.

Given the addi­tional deaths and the lack of im­proved efficacy, the lung cancer trial’s data monitoring committee rec­om­mended that the study be stopped, which Janssen has agreed to do.

In addi­tion, based in part on what hap­pened in the lung cancer trial, Janssen decided to halt the second trial, which had been testing Darzalex in com­bi­na­tion with JNJ 63723283, a drug still under devel­op­ment, in patients with multiple myeloma.

News of Janssen’s de­ci­sion to halt the two trials had a dramatic effect on the price of Genmab’s stock, which initially dropped more than 25 per­cent, and is still trading down about 20 per­cent from its close last Friday. Genmab’s income is dependent on royalty pay­ments tied to the success of Darzalex, and in­vestors apparently are con­cerned that Darzalex’s future may not be as bright as they have assumed.

The news about the trials, coupled with the stock mar­ket reac­tion, also are likely to spark con­cern among myeloma patients. The devel­op­ments raise the question: Should the recent devel­op­ments change current ex­pec­ta­tions of the safety and efficacy of Darzalex as a treat­ment for multiple myeloma?

At this point, it would seem that the answer to this question is a firm “No.”

After Genmab’s announcement this weekend, The Beacon reached out to a number of myeloma specialists in the United States and Europe to get their reac­tions. The feedback was con­sis­tently similar. All the specialists believe that the efficacy and safety of Darzalex as a treat­ment for multiple myeloma are well documented, and that the latest devel­op­ments are likely the result of the unique way in which Darzalex, and perhaps other myeloma ther­a­pies, inter­act with the particular kind of drugs with which Darzalex was com­bined in the two trials that were halted.

PD-1/PD-L1 Checkpoint Inhibitors

Both Tecentriq and JNJ 63723283, the two drugs to which Darzalex was added in the now-discontinued trials, are “checkpoint inhibitor” cancer ther­a­pies, which block proteins that stop the immune sys­tem from attacking cancer cells.

More specifically, Tecentriq and JNJ 63723283 are in the category of checkpoint inhibitors known as PD-1 and PD-L1 inhibitors, or anti-PD-(L)1 agents. These drugs focus on the role of the “programmed cell death 1” (PD-1) protein in shielding cancer cells from the body’s defense sys­tem.

Prior to Genmab’s announcement this weekend, there already had been questions about the safety of PD-1/PD-L1 inhibitors when used in com­bi­na­tion with myeloma treat­ments. These con­cerns were based primarily on the results of trials testing Keytruda (pem­bro­lizu­mab), a PD-1 inhibitor, in com­bi­na­tion with either Revlimid (lena­lido­mide) or Pomalyst (poma­lido­mide, Imnovid), and dexa­meth­a­sone, in multiple myeloma patients.

Initial results from two Keytruda trials showed that more deaths occurred in the patients who received Keytruda as part of their treat­ment regi­men than in those whose regi­men did not in­clude Keytruda (related FDA announcement and analysis).

These results led the U.S. Food and Drug Admin­istra­tion (FDA) to suspend, partly or fully, clin­i­cal trials testing Keytruda in patients with multiple myeloma. Other trials investigating PD-1 or PD-L1 inhibitors in multiple myeloma patients also were put on hold, and many of those trials now are either closed to further recruitment or terminated com­pleted.

Myeloma Specialist Reaction To The Recent Developments

The pre­vi­ous clin­i­cal trial ex­peri­ence with PD-1 inhibitors, along with the trial results and ex­peri­ence related to Darzalex as a myeloma treat­ment, played an im­por­tant role in how the myeloma specialists contacted by The Beacon reacted to the Darzalex news announced by Genmab this weekend.

Dr. Heather Landau of Memorial Sloan Kettering Cancer Center in New York City told The Beacon:

“I think it is well under­stood that Darzalex is beneficial to myeloma patients. What is less well under­stood is how to use anti-PD(L)1 ther­a­pies in myeloma. On the heels of the FDA approval of Darzalex as up­front ther­apy for l multiple myeloma [related Genmab press release], I do not think this [news] will impact use of Darzalex in multiple myeloma in the near term.”

Dr. Maximilian Merz, a myeloma specialist at the University of Heidelberg in Germany, echoed Dr. Landau’s feedback in his comments for The Beacon. He said:

“I do not think that the current use of Darzalex for myeloma will be affected, since the safety issues are more likely attributed to PD-1/PD-L1 blockade as ex­peri­enced in pre­vi­ous multiple myeloma trials.”

Dr. Kenneth Shain of the Moffitt Cancer Center in Tampa believes the latest devel­op­ments emphasize the need for careful testing and research of com­bi­na­tion ther­a­pies in cancer. At the same time, he feels it is im­por­tant to keep in mind the ex­peri­ence thus far with Darzalex in multiple myeloma:

“This news highlights the need for science and med­i­cine to carry out clin­i­cal trials to identify the safety and efficacy of new drug com­bi­na­tions. It will also focus us on continuing to learn how and where interrupting PD-1/PD-L1 can be safely implemented in cancer treat­ment. Results such as these will help us learn more about the drugs as well as cancer / myeloma-immune sys­tem inter­actions.

“This [news] should not change, how­ever, the current use of Darzalex in multiple myeloma patients. Recall that the approvals of Darzalex com­bi­na­tions in multiple myeloma have been based on a number of ran­domized controlled trials. So both safety and efficacy have been dem­onstrated. This being said, we should always have a healthy respect for any thera­peutic we use.”

Dr. Katja Weisel, a myeloma specialist at the University of Tuebingen in Germany, began her feedback for The Beacon by saying that she was not particularly surprised by the recent Darzalex news, noting that a trial investigating the com­bi­na­tion of Darzalex and the PD-L1 inhibitor Imfinzi (durvalumab) also was closed prematurely. She then added:

“Independent of this [recent] news, the role of Darzalex will not be affected, and Darzalex will stay as one of the very im­por­tant drugs for treating myeloma. Its activity was dem­onstrated in several large Phase II and III trials. However, where and if checkpoint inhibition will find a place in myeloma treat­ment remains a fully open question at this time.”

Dr. Weisel also noted a sig­nif­i­cant aspect of the recent news that she feels should not be overlooked:

“This is an im­por­tant message for all patients and physicians involved in clin­i­cal trials, making it clear that, in case of any con­cern or safety event, there is an im­medi­ate reac­tion by the sponsor and/or the responsible author­i­ties, con­firming that patient safety stays the most im­por­tant issue in clin­i­cal trials.”

 Additional Information Related To The Discontinued Trials

The trial of Darzalex in multiple myeloma that was halted was known as MMY2036 . It was organized in three parts. In the first part, at least six patients were to be treated with Darzalex and the inves­ti­ga­tional drug JNJ-63723283. In the second and third parts of the trial, half of the patients were once again to receive the com­bi­na­tion of the two drugs, and the other half would receive Darzalex as a single agent.

A Janssen rep­re­sentative informed The Beacon that the first part of the trial did enroll six patients, and that “There was no safety signal seen in the first part of the MMY2036 study.”

Two patients had been enrolled in the second part of the trial.

All patients who have enrolled in the trial thus far, and have been benefiting from treat­ment, will be given the oppor­tu­ni­ty to con­tinue treat­ment with Darzalex mono­therapy.

There is no in­­for­ma­tion at this time, the Janssen rep­re­sentative told The Beacon, as to how the causes of death differed be­tween the Darzalex-Tecentriq com­bi­na­tion ther­apy arm and the Tecentriq mono­therapy arm of the lung cancer trial.

Finally, there are plans to present results of the trial at a future medical conference, or to publish them, after a full analysis of the data. The timing of when the data will be made public is not yet set.

For more in­­for­ma­tion, see the Genmab press release issued this past weekend, “Genmab Announces That Janssen Will Stop Studies Of Dara­tu­mu­mab In Combination With Anti-PD-(L)1.”