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CAR T therapies show durable responses, potential benefits from combinations

CAR T therapies show durable responses, potential benefits from combinations

The dawn of regulator-approved chimeric antigen receptor (CAR) T-cell therapies, such as Kymriah (tisagenlecleucel, Novartis AG), have provided doctors with important new options for treating people with several types of aggressive blood cancers. But how long the new therapies can help and whether their costs can be made sustainable remain open questions. New research presented at the American Society of Hematology (ASH) Annual Meeting and Exposition is shedding light on the duration question with what City of Hope’s Joe Alvarnas called “practice-changing” results.

In two of the studies presented at the meeting, longer-term follow-up analyses demonstrated sustained responses to T cells designed to target the CD19 protein, which is frequently expressed on malignant lymphoma cells.

Stephan Grupp, of Children’s Hospital in Philadelphia, presented long-term follow-up on Novartis’ Eliana trial, an international phase II. With two additional years of follow-up data beyond the trial’s initial readout, he found that, among the 79 patients who were followed for three or more months after being infused with Kymriah, 82 percent achieved a complete remission. Furthermore, 66 percent of patients who had a complete response to CAR T were still in remission at 18 months. Also, at 18 months post-infusion, overall survival (OS) was 70 percent, while median OS has not been reached.

Updated results from another Novartis trial of Kymriah, called Juliet, looked at the durable response rates still seen among adults with relapsed or refractory diffuse large B-cell lymphoma. Nineteen months after receiving a single dose of Kymriah, an overall response rate of 54 percent persisted, with 40 percent achieving a complete response and 16 percent achieving a partial response. Median duration of response and median overall survival in responding patients has yet to be reached.

Looking for synergy in combinations

Two other studies investigated combining CAR T-cell therapies with additional treatments. One tried a combination with Imbruvica (ibrutinib, Abbvie Inc./Johnson & Johnson) while the other analyzed the addition of PD-1 checkpoint blockade to determine whether such a combination might enhance the effect of and sustained response to CAR T.

Jordan Gauthier, of the Fred Hutchinson Cancer Research Center in Seattle, reported that for patients with difficult-to-treat chronic lymphocytic leukemia (CLL), continuing to take Imbruvica before, during and after receiving CAR T-cell therapy “may be associated with less severe adverse effects and better responses” vs. outcomes for a similar group who received the same CAR T-cell therapy without Imbruvica. “These results suggest that combining ibrutinib with CAR T-cell therapy may lead to better outcomes by improving efficacy and reducing toxicity,” he said.

Shannon Maude, of the Children’s Hospital of Philadelphia, presented a first-of-its-kind study of whether giving a PD-1 checkpoint inhibitor to heavily pretreated pediatric patients with relapsed B-cell acute lymphocytic leukemia (B-ALL) could augment CD19-directed CAR T therapy.

Maude’s small, single-center study included 14 children, ages 4 to 17, 13 of which had heavily pretreated relapsed B-ALL and one with lymphocytic lymphoma. Patients in the study were given either Keytruda (pembrolizumab, Merck & Co. Inc.) or Opdivo (nivolumab, Bristol-Myers Squibb Co.). Researchers administered checkpoint inhibitors no sooner than 14 days after patients received their CAR T-cell infusion since levels of CAR T cells often decline 14 days following infusion of the cell therapy, and because patients often experience cytokine release syndrome within the same window.

Half of patients in the study maintained either partial or complete disease responses. Among four patients who failed to achieve disease remission with initial CAR T-cell infusion, no complete responses were achieved with the addition of Opdivo, although partial responses were observed.

A sustainable pace?

Despite calling the current period an “extraordinary period of innovation, particularly in the domain of CAR T-cell therapeutics,” Alvarnas, vice president of government affairs and senior medical director for employer strategy at City of Hope, said that “there are some challenges ahead.” He pointed to how T-cell therapeutics will be paid for.

Referring to comments by FDA Commissioner Scott Gottlieb, Alvarnas noted that “unless we’re able to navigate a reimbursement system, it does pose a challenge to the level of innovation and the sustainable pace of innovation around these therapeutics.”

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