The OBR Blog

By Mary Ellen Schneider

This year’s annual meeting of the American Society of Hematology (ASH) featured new research on chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) molecules, along with trends toward treating cancer patients with immunotherapies earlier in the course of their disease.

The meeting, which was held virtually for the first time, also highlighted studies evaluating the extent and impact of racial and ethnic health disparities in hematology and oncology.

Health Disparities Highlighted

“As part of caring for patients and our citizens, ASH chose to have a significant light shine upon disparities in health care, or differences in outcomes between different groups of our patients,” Chancellor Donald, MD, an assistant professor of clinical medicine at Tulane University in New Orleans, told OBR.

Bringing attention to disparities in outcomes and access offers the potential for “immediate improvement in outcomes for those persons without a new diagnostic test, or without a new drug,” Dr. Donald said.

The ASH plenary session put the spotlight on poor treatment outcomes for Black patients younger than 60 years with acute myeloid leukemia (AML). In a study that looked both at Surveillance Epidemiology End Results (SEER) data and molecular features by race, researchers found that younger Black patients had a 27% higher likelihood of death than white patients. They also discovered that Black patients had a lower frequency of prognostically favorable NPM1 mutations (Abstract 6).

Another study that focused on health disparities identified a greater risk for cancer-associated thrombosis among Black patients, compared with their white counterparts. These disparities were especially prominent when the researchers looked only at pulmonary embolism (Abstract 203).

What is driving the disparities in cancer-associated thrombosis? The researchers acknowledged possible contributions from underlying biological traits. But they also pointed to the contribution of systemic racism, access to care, and the severity of underlying comorbidities.

“Since current risk prediction models for cancer-associated thrombosis do not include race and ethnicity as parameters, future studies should examine if incorporating these factors can improve predictive value,” said Alisa S. Wolberg, of the University of North Carolina at Chapel Hill and one of the ASH scientific program co-chairs. Dr. Wolberg highlighted the study as part her “Best of ASH” presentation.

Other health disparities research presented at this year’s ASH included a study exploring the impact of living in a socioeconomically disadvantaged neighborhood for Black and Hispanic people with AML. Researchers found that this “structural violence” led to worse survival for minority patients in the study (Abstract 217).

Latest Data in CAR T-Cell Therapy, BiTEs  

The ASH annual meeting also included a variety of studies on CAR T-cell therapy, from clinical trials to real-world data.

“What strikes me now is that in the CD19 CAR T-cell space, you’re getting much more robust real-world data,” Catherine Bollard, MD, director of the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, D.C., and a professor of pediatrics and immunology at George Washington University, told OBR.

Among the noteworthy research, Dr. Bollard pointed to a real-world study that investigated the tumor-specific factors driving inherent or acquired resistance to CAR T cells in large B-cell lymphoma (Abstract 556). The study, led by researchers at Stanford University, identified CD58 status as an important biomarker for durable response to CAR T cells in large B-cell lymphoma.

This type of real-world data will be even more important as CAR T-cell therapy moves earlier in the treatment of disease, Dr. Bollard said.

“As we continue to expand the reach of new targeted therapies, it is imperative that we deeply study our patients to determine the mechanisms that underscore success, and perhaps even more importantly, failure,” said Leslie S. Kean, MD, PhD, of Boston Children’s Hospital and Dana-Farber Cancer Institute and one of the ASH scientific program co-chairs. She highlighted Abstract 556 as part of her “Best of ASH” presentation.

Dr. Kean also highlighted findings from the primary analysis of the phase 2, Zuma-5 trial, which evaluated axicabtagene ciloleucel (axi-cel) in patients with follicular and marginal zone lymphoma (Abstract 700), noting that one of themes of the ASH meeting was an expansion of cellular therapies beyond their initial indications.

“The maturation of the field is evidenced by multiple commercial CARs now being investigated in these more indolent lymphoma patients,” Dr. Kean said.

Dr. Kean also pointed to an early study looking at the combination of the CAR T product lisocabtagene maraleucel (liso-cel) with the BTK inhibitor ibrutinib for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In the phase 1 TRANSCEND CLL 004 study, researchers found promising efficacy and a manageable safety profile with the combination (Abstract 544).

Other immunotherapy studies presented at ASH were focused on the use of these treatments earlier in the course of therapy.

Dr. Kean pointed to a phase 3 trial in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (ALL) that assessed the BiTE molecule blinatumomab, compared with high-risk consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Blinatumomab monotherapy achieved significantly better event-free survival, causing the trial’s data monitoring committee to recommend early termination of enrollment due to benefit (Abstract 268).

Another study focused on treatment with a BiTE molecule earlier in the course of therapy was a phase 2 study that examined the use of a hyper-CVAD chemotherapy regimen with sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL (Abstract 464). The researchers found that the combination was effective in front-line treatment, with a high complete response rate and high percentage of patients achieving measurable residual disease negativity.

Potential New Treatments in Multiple Myeloma

Dr. Kean also highlighted two clinical studies of antibody-based and CAR T-cell therapies for the treatment of multiple myeloma.

The phase 1b/2 CARTITUDE-1 study looked at ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-directed CAR T-cell therapy, in the treatment of relapsed/refractory multiple myeloma (Abstract 177). Researchers reported an encouraging progression-free survival profile of at least a year. The safety and efficacy data indicate that larger studies of this agent are warranted, Dr. Kean said.

Along with CAR T-cell advances, Dr. Kean pointed to a new antibody-based therapy with potential in relapsed/refractory multiple myeloma. A phase 1, first-in-human study, evaluated talquetamab, a first-in-class bispecific antibody that binds to the G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) and CD3 (Abstract 290). Researchers reported a manageable safety profile for the antibody treatment.

“This study suggests that there continue to be ‘new kids on the block’ for these otherwise difficult-to-treat patients,” Dr. Kean said.

December 07, 2020 - 08:12 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) Posted in Multiple Myeloma comments0 Comments

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.

Loss of LKB1/STK11 Facilitates Leukemic Progression of the Myeloproliferative Neoplasms (Abstract 1)

By Lynne Lederman, PhD

Myeloproliferative neoplasms (MPN) arise in the hematopoietic stem cells, and provide a model for the earliest stages of malignancy. Mutations leading to MPN frequently arise in utero or childhood, yet MPN develop at a median age of 60 years, suggesting a potentially long time to targeting those mutations.

MPN can progress to aggressive acute myeloid leukemia (AML), although little is known about how this occurs. Most patients with MPN have mutations in the JAK/STAT pathway, and about 60% have additional mutations, some conferring poor prognosis. Genetic mechanisms of progression were addressed in the presentation by Christian Marinaccio, MSc, Northwestern University, Chicago, IL, retitled STK11/LKB1 is a tumor suppressor in the leukemic progression of MPN.

To identify the genetic determinants of progression, an unbiased CRISPR screen was performed in the Jak2V617F Cas9+ Vav-CRE+ mouse which develops MPN. Colony replating assays led to identification of the loss of serine/threonine kinase 11 (Stk11) also known as liver kinase B1 (LKB1) as the driver of progression. In doubly transduced, Stk11 homozygous mouse bone marrow cells, Stk11 loss led to marked changes in gene expression in MPLW515L cells. One upregulated gene is a target of hypoxia inducible factor (HIF). HIF1α is stabilized and sufficient for proliferation, enhancing a lethal MPN phenotype in MPLW515L mice, with intense osteosclerosis, bone marrow failure, and pockets of undifferentiated, immature cells.

Loss of Stk11 enhances the engraftment of human MPN cells in NSGS mice. In 7 paired chronic versus blast phase (AML) samples from patients with MPN, Stk11/LKB1 expression was downregulated in 6 of 7 in the blast phase, with marked increase of HIF1α expression, among other gene expression differences.

Stk11 loss leads to a spent phase MPN in mouse models, and an increase of engraftment in patient-derived xenograft models, suggesting that cooperating mutations might decrease Stk11, driving leukemic transformation. Pseudohypoxia in MPN blast phase could provide avenues of treatment by targeting hypoxia inducible proteins.

BCL10 Gain-of-Function Mutations Aberrantly Induce Canonical and Non-Canonical NF-Kb Activation and Resistance to Ibrutinib in ABC-DLBCL (Abstract 3)

The activated B-cell (ABC) subtype one of the most aggressive of the diffuse large B cell lymphomas (DLBCL). DLBCL have been further subtyped by mutation profiles. A novel class, Cluster 1 or BN2 comprises mostly ABC DLBCL with high levels of BCL10 gain-of-function mutations. According to presenter Min Xia, PhD, Weill Cornell Medical College, New York, NY, BCL10 drives DLBCL as part of the CBM complex (CARD11-BCL10-MALT1), driving NF-κB activation downstream of B-cell receptor signaling.

BCL10 mutation patterns define 2 broad classes of mutations. Class I consists mostly of CARD missense mutations, and Class II mostly truncating C-terminal mutations. This presentation focused on one in each class, the missense mutation R58Q (CARD domain) and the nonsense truncation mutations E140X. Both of these mutations highly enhanced NF-κB activation, and enhance MALT1 proteolytic activity and IL6 expression.

Dr. Xia’s group looked at the effect of BCL10 Class I and II mutations on CBM complex structure and function. BCL10R58Q stabilizes BCL10 filaments. BCL10E140X rapidly and spontaneously forms polymers at lower concentrations than wild type protein, and is able to interact with MALT1 even though it lacks the MALT1 interaction domain. Both BCL10R58Q and BCL10E140X filaments recruit MALT1.

BCL10 mutations at least partially rescue ABC-DLBCL cells from dependence on CARD11 signaling for the enzymatic activation of MALT1, as a CARD11 knockdown did not impair MALT1 activation, NF-κB signaling, or cell growth in ABC-DLBCL lines expressing both BCL10 mutants. This has clinical implications, because the CBM complex function is normally dependent on BTK activation, which is a target of widely used drugs, including ibrutinib.

The expression of BCL10R58Q and BCL10E140X, but not wild type BCL10, in ABC-DLBCL cell lines prevented ibrutinib from inhibiting MALT1 activity, and rescued ibrutinib impairment of NF-κB activity. Both classes of BCL10 mutations attenuated ibrutinib-induced growth suppression of ABC-DLBCL cells. Therefore, BCL10 mutations are likely to confer resistance to BTK-targeted therapies, suggesting a need for an alterative approach.

ABC-DLBCL cells with BCL10 truncating mutations that are resistant to ibrutinib remain highly sensitive to MALT1 inhibitors, including the MALT1 inhibitor JNJ-67856633, which is in early phase trials in B-cell lymphomas (Abstract 2091).

 

May 31, 2020 - 08:05 pm Posted in ASCO and ASH Posted in ASCO Conference Coverage Posted in Breast Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) Posted in Melanoma (includes BCC) Posted in Multiple Myeloma comments0 Comments

Sunday’s live broadcast of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting featured late-breaking data from a phase 3 trial evaluating early local therapy in metastatic breast cancer and the results of the phase 3 ENDURANCE trial.

Other important studies from the meeting were the ALPHA trial, which is evaluating an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy, and the C-144-01 trial, which is evaluating an autologous tumor infiltrating lymphocyte (TIL) therapy.

Early local therapy offers no survival benefit in patients with de novo metastatic breast cancer and an intact primary tumor, according to the results of a phase 3 trial by the ECOG-ACRIN Research Group (Abstract LBA2).

The trial included 256 patients who received optimal systemic therapy before being randomly assigned to either continue optimal systemic therapy (n=131) or receive optimal systemic therapy with locoregional therapy (n=125).

The 3-year overall survival (OS) rate was not different for the locoregional therapy arm compared with the optimal systemic therapy alone arm (68.4% vs 67.9%; P=0.63) and neither was the risk of death (HR=1.09; 90% CI, 0.80 – 1.49).

Although the locoregional therapy arm had a reduced risk of locoregional recurrences/progression compared with the optimal systemic therapy alone arm (HR=0.37; 95% CI, 0.19 – 0.73), no improvements were seen for health-related quality of life (HRQOL). At one timepoint (18 months), HRQOL was significantly worse for the locoregional therapy arm (P=0.001).

“For de novo stage metastatic breast cancer, existing data supports that locoregional therapy does not improve survival and should not be routinely applied in this population,” said study discussant Julia White, MD, professor of radiation oncology at The Ohio State University.

Carfilzomib and Bortezomib Tie for First

The replacement of carfilzomib for bortezomib in a regimen of bortezomib, lenalidomide, and dexamethasone (VRd) did not improve outcomes for patients with newly diagnosed multiple myeloma, results showed in the second interim analysis of the phase 3 ENDURANCE trial (Abstract LBA3).

Patients who received carfilzomib, lenalidomide, and dexamethasone (KRd; n=545) had a similar progression-free survival (PFS; HR=1.04; 95% CI, 0.8 – 1.3; P=0.74) and OS (HR=0.98; 95% CI, 0.71 – 1.36; P=0.92) to those who received VRd (n=542). A higher proportion of particularly good partial responses was seen with KRd compared with VRd (55.5% vs 49.9%).

KRd had a significantly higher rate of cardiac, pulmonary, and renal treatment-related adverse events (16.1% vs 4.8%; P<0.001), while VRd had a significantly higher rate of peripheral neuropathy (53.4% vs 24.4%; P<0.001). No difference in frequency of secondary primary cancers was seen.

Study discussant Jesus Berdeja, MD, director of myeloma research at Sarah Cannon Research Institute, pointed out that KRd costs nearly $16,000 more per cycle than VRd, which totals to a nearly $100,000-difference for 12 cycles.

“In newly diagnosed multiple myeloma without high-risk features, VRd and KRd appear to be equivalent options for frontline treatment,” Dr Berdeja said. “Comorbidities and toxicity profiles should guide the choice between the two regimens in any individual patient.”

ALPHA Trial Debuts Off-the-Shelf CAR T

An off-the-self allogeneic CAR T-cell therapy known as ALLO-501 appeared safe and showed clinical activity in a small group of patients with relapsed or refractory large B-cell or follicular lymphoma, according to data from the single-arm phase 1 ALPHA trial (Abstract 8002).

“Allogeneic CAR T-cell therapy may provide the benefits of autologous CAR T-cell therapy, while also addressing its challenges,” said study presenter Sattva Neelapu, MD, MD Anderson Cancer Center. “It has the potential to treat all eligible patients, the convenience of repeat dosing, and simplifies the logistics of manufacturing.”

Patients received CD19-targeted ALLO-501 at one of three dose levels and, during lymphodepleting chemotherapy, an investigational monoclonal antibody called ALLO-647, which targets CD52. Patients were heavily pretreated (median of 4 prior therapies), and 4 patients previously received autologous CAR T-cell therapy.

About one-third of patients (7 of 22) had cytokine release syndrome, which included only one grade 3 event and no grade 4. Half of patients developed infection, most of which was grade 1 (23%) or 2 (18%). There were no reports of graft-versus-host disease.

At a median follow-up of 3.8 months, 12 of 19 patients (63%) available for efficacy analysis achieved a response, which included 7 complete responses (37%). Nine patients who achieved a response continue to have a response.

Dr. Neelapu said these results suggest that the safety and the short-term efficacy, in terms of the response rates, for this product is “comparable” to autologous CAR-T products that are currently in clinic. “Further follow-up is necessary to determine the durability of those responses.”

C-144-01 Trial Shows Potential of TILs

Autologous TIL therapy lifileucel appeared safe and to have clinical activity in patients with unresectable metastatic melanoma, according to the results of cohort 2 from the phase 2 C-144-01 trial (Abstract 10006).

Lifileucel is an autologous adoptive cell transfer therapy that involves surgically resecting a patient’s tumor and sending it to the manufacturing facility. Tumor infiltrating lymphocytes (TILs) are then obtained from the tumor, expanded, shipped back to clinical sites, and infused into the patient. Patients in cohort 2 (n=66) received lifileucel that was cryopreserved before shipment. Patients also received up to 6 doses of interleukin-2 after infusion to promote expansion of the TILs.

Most patients (97.0%) had grade 3 or 4 treatment-emergent adverse events, with thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%) being the most common. The number of adverse events decreased over time.

Overall, 24 (36.4%) patients achieved a response, which included 2 complete and 22 partial responses. The disease control rate was 80.3%. At a median follow-up of 18.7 months, the median duration of response had not yet been reached (range, 2.2 – 26.9+ months). Responses were seen across subgroups, which include age, PD-L1 status, and BRAF mutation status.

“Notable, observed responses tended to deepen over time,” said study presenter Amod Sarnaik, MD, Moffitt Cancer Center. “These data therefore demonstrate potential efficacy and durability of response in a patient population with severely limited treatment options.”

By Christina Bennett, MS

 

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