ASH Highlights for Monday, December 7, 2020

By Lynne Lederman, PhD

Apollo: Phase 3 Randomized Study of Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) (Abstract 412)

Meletios A. Dimopoulos, MD, National and Kapodistrian University of Athens, Athens, Greece, presented the primary analysis of Apollo (NCT03180736), the first randomized, open-label, phase 3 trial of subcutaneous (SC) daratumumab in combination with oral pomalidomide and low-dose dexamethasone (D-Pd) versus pomalidomide plus dexamethasone (Pd) for relapsed, refractory (RR) multiple myeloma treated with ≥1 prior lines of therapy, including lenalidomide and a proteasome inhibitor (PI).

D-Pd significantly reduced the risk of progression or death by 37% in patients (n=151) versus Pd alone (n=153). At a median follow-up of 16.9 months, the study met its primary endpoint of improved progression-free survival (PFS; HR 0.63; 95% CI, 0.47-0.85; P=.0018. The median PFS for D-Pd versus Pd arm was 12.4 versus 6.9 months, respectively; and was 9.9 versus 6.5 months for those with lenalidomide-refractory disease. The PFS benefit of D-Pd was consistent across subgroups.

The overall response rate (ORR) was 69% with D-Pd versus 46% for Pd (P<.0001). ≥complete response (CR) was 25% vs 4%; ≥very good partial response (VGPR) was 51% versus 20%, and minimal residual disease (MRD)-negativity was 9% versus 2% (P=.01), all favoring D-Pd.

The duration of administration of SC daratumumab was 5 minutes (range 1-22), greatly increasing the convenience and decreasing treatment burden for patients.

No new safety concerns were observed. Infusion-related reactions (IRR) occurred in 5% of patients in the D-Pd arm and were grade 1 or 2; 2% had local injection-site reactions (all grade 1). The rate of treatment-emergent adverse events leading to death was 7% in each arm; secondary malignancies occurred in 2% of each arm.

CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel but Can be Overcome through Novel CAR Engineering (Abstract 556)

Treatment with CD19 CAR-T cells like axicabtagene ciloleucel (axi-cel) results in durable CR in 40-50% of patients with RR large B cell lymphomas (LBCL). Those whose LBCL progresses with treatment have a median overall survival (OS) of only 180 days. Robbie G. Majzner, MD, Stanford University School of Medicine, Palo Alto, CA, discussed efforts to identify resistance mechanisms in the hope of curing more patients.

CD58 mutations, either baseline or emerging at relapse, in circulating tumor DNA are associated with poor outcome after axi-cel treatment. One mutation, K60E, ablates the role of CD58 in co-stimulating T cells through CD2.

Axi-cel- and tis-cel-like CAR-T lose their ability to kill CD58 knockout tumor cells, and cytokine production is reduced. CAR-T treatment of mice inoculated with wild-type CD58 leukemia results in long-term disease control, whereas CAR-T treatment of mice inoculated with CD58 knockout Nalm6 leukemia mimics the patient experience of initial disease control, but only as partial response, followed by fatal return of leukemia.

CD2 on T cells is the ligand and co-stimulatory molecule for CD58. Majzner’s group found that CD2 ligation by CD58 drives the signaling by CAR-T, cell-cell adhesion, and cytoskeletal rearrangements needed for tumor cell killing.

To overcome the effects of CD58 mutations, second- and third-generation CARs integrating CD2 co-stimulatory domains within the CAR molecule, i.e., in cis, were generated. These induced tumor cell killing and cytokine production in vitro. In vivo, however, control of tumor cells occurred initially, only to be followed by overgrowth of CD58 knockout cells and death.

Because CD2 is normally provided to T cell receptors in trans, a novel approach was to co-transduce the conventional CD22 CAR with another CAR with different specificity, CD19, along with an intracellular domain to provide CD2 signaling in trans. The co-transduced CARs control CD58 knockout tumor cells and prolong survival. The ability to restore CAR efficacy may be important in other tumors with CD58 mutations.

Dr. Majzner said they are choosing a candidate construct, possibly one that can also overcome antigen escape, that they hope to have in the clinic within 18 months.

Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL) (Abstract 700)

Caron Jacobson, MD, Dana Faber Cancer Institute, Boston, MA, presented follow-up data from the single-arm phase 2 ZUMA-5 trial (NCT03105336) of axi-cel in RR iNHL, including follicular lymphoma (FL; n=124) and marginal zone lymphoma (MZL; n=22), after ≥2 lines of systemic therapy.

Median follow-up for efficacy was 17.5 months with 104 patients evaluable; median follow-up for safety was 15.1 months with 146 patients evaluable. ORR was 92% and CR was 76%. For FL, ORR and CR were 94% and 80%, respectively. For MZL, ORR and CR were 85% and 60%, respectively. Median duration of response (DOR), PFS, and OS have not been reached. Responses are durable and ongoing in 78% of patients with CR.

The safety profile was manageable, with lower rates of grade ≥3 neurologic events observed in FL (15%) versus MZL (41%). Median time to peak CAR-T cell levels after infusion was 9 days (range 8-371). By 12 months 78% of 67 patients with evaluable samples had low levels of detectable CAR gene-marked cells.

Dr. Jacobson said at a press briefing that in this analysis, “You can see the difference in the DOR curves and the PFS curves with the additional patients reaching longer follow-up. It’s adding to the hope that this is going to be a therapy that elicits durable response” for this patient population.

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