Anita Schaffer

The off-the-shelf chimeric antigen receptor (CAR) T-cell therapy ALLO-715, which targets B-cell maturation antigen (BCMA), demonstrated responses as treatment of patients with heavily pretreated relapsed/refractory multiple myeloma in a first-in-human clinical trial, according to the early findings presented at the 2020 American Society of Hematology (ASH) Annual Meeting.

The therapy generated responses in 6 of 10 patients (60%), including a very good partial-plus response (VGPR+) in 4 patients (40%), who were treated with ALLO-715 at a dose of 320 x 10

 CAR cells plus a lymphodepleting regimen that included ALLO-647, an anti-CD52 monoclonal antibody, during the ongoing phase 1 UNIVERSAL study (NCT04093596).

The findings mark the first results for an allogeneic CAR therapy directed at BCMA, said lead study author Sham Mailankody, MBBS, a medical oncologist and investigator in the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York. BCMA, which is highly expressed on plasma and multiple myeloma cells, has sparked intensive research interest.

“These results demonstrate the feasibility and safety of an off-the-shelf CAR T cell therapy for multiple myeloma. In this first report of an allogeneic BCMA CAR T-cell therapy, we show that nearly 90% of patients were treated within 5 days of enrollment and without needing any bridging therapy,” Mailankody said.

Allogeneic CAR therapy offers the potential for scalable manufacturing for on-demand treatment with shorter waiting times, which would overcome some of the logistical challenges posed by autologous CAR therapy, Mailankody said. The T cells needed for ALLO-715 are harvested from healthy donors and genetically engineered to express CARs aimed at specific cancer targets, according to Allogene Therapeutics, the company developing the therapy.

ALLO-715 includes a human-derived single-chain variable fragment anti-BCMA cell with a 4-1BB costimulatory domain. Mailankody said the “2 key attributes” of the construct are a knockout of CD52, which allows for selective lymphodepletion with ALLO-647 to prevent graft rejection without affecting the CAR T cells, and a knockout of the TRAC gene, which also minimizes the risk of graft-versus-host disease (GVHD).

The UNIVERSAL study, which is being conducted at 11 cancer centers in the United States, is recruiting patients with multiple myeloma who have received 3 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent, and are refractory to their last treatment. Participants must have an ECOG performance status score of 0 or 1.

The dose escalation portion of the study is testing ALLO-715 as a single infusion across 4 doses: 40, 160, 320, or 480 x 10

 CARs. Lymphodepletion regimens consist of fludarabine (F; 30 mg/m2/day) plus cyclophosphamide (C; 300 mg/m2/day) given on 3 days with ALLO-647 (A; 13-30 mg x 3 days; FCA) or cyclophosphamide plus ALLO-647 (CA).

Among the 35 patients enrolled at the time of the presentation, 4 became ineligible because of organ failure due to rapidly progressing disease. Of 31 patients in the safety population, the median age was 65 years (range, 46-76). Nearly half of the patients (48%) have high-risk cytogenetics and 23% had extramedullary disease. The efficacy population at data cutoff on October 30, 2020, comprised 26 patients across the 4 dosing levels, with a median follow-up of 3.2 months.

The overall response rate (ORR) varied across dosing cohorts and lymphodepleting regimens. No responses were observed among 3 patients each who received CARs at 40 x 10

 with CA, both with low-dose ALLO-647. The ORRs were 50% in 4 patients who received CARs at 160 x 10

 with low–ALLO-647 FCA; 33% in 3 at 480 x 10

 with low–ALLO-647 FCA; and 67% in 3 at 320 x 10

The most robust responses were seen among those who received ALLO-647 at 320 x10

. For this cohort, the ORR was 60% among 10 patients, including 3 of 6 who received CARs with low–ALLO-647 FCA and 3 of 4 who had the therapy with high–ALLO-647 FCA. Overall, 6 patients had a VGPR+, defined as stringent complete response, complete response, or VGPR. These included 1 at 160, 4 at 320, and 1 at 480 10 x 10

CARs. Of the VGPR+ patients, 5 were negative for measurable residual disease. Additionally, 6 of 9 patients treated at the 320 or 480 x 10

Mailankody highlighted the experience of 1 participant, a 71-year-old man whose myeloma had progressed after undergoing 9 prior lines of therapy including autologous stem cell transplant and an experimental BCMA-targeted therapy. The patient received a conditioning regimen of FCA with low-dose ALLO-647 and ALLO-715 at 320 x 10

. He reached a VGPR on day 14 that deepened to a stringent complete response by day 28 that remains in effect at 6 months, while experiencing grade 1 cytokine release syndrome (CRS).

“The patient is clinically doing very well and is back at work,” Mailankody said.

Among 31 patients in the safety population, most adverse effects were of grade 1 or 2 severity. These included CRS in 14 patients (45%) and infusion-related reactions to ALLO-647 in 7 patients (23%). The use of drugs to manage CRS also was low, at 19% for tocilizumab and 10% for steroids.

All-grade infections were reported in 13 patients (42%), including grade 3 events in 4 (13%). One patient (3%) died from a presumed fungal pneumonia related to progressive disease and the CA conditioning regimen but unrelated to ALLO-715. There were no instances of neurotoxicity or GVHD.

“Notably, the fact that we did not see any GVHD is encouraging for an off-the-shelf allogeneic product,” Mailankody said.

In response to a question from a conference attendee, Mailankody said it is too soon to compare efficacy levels seen with this allogeneic CAR therapy with those observed with investigational autologous CARs, which have been under study for several years.

Moving forward, investigators are continuing to evaluate dosing levels for ALLO-715. UNIVERSAL is enrolling patients to the 480 x 10

 cohort, Mailankody said, adding that the appropriate dose likely would land between 320 and 480 x 10

Mailankody S, Matous JV, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020; Virtual. Abstract 129. Accessed December 5, 2020. https://ash.confex.com/ash/2020/webprogram/Paper140641.html

Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. 

. 2019;9:1821. doi:10.3389/fimmu.2018.01821

AlloCAR T Therapy. Allogene Therapeutics. Accessed December 5, 2020. https://www.allogene.com/allocar-t-therapy

Articles

The off-the-shelf  CAR T-cell therapy ALLO-715, which targets BCMA, demonstrated responses as treatment of patients with heavily pretreated relapsed/refractory multiple myeloma in a first-in-human clinical trial.

First-In-Human Trial Shows Responses With Off-the-Shelf CAR T-Cell Therapy in Myeloma

While the treatment landscape for chronic lymphocytic leukemia (CLL) has expanded with an explosion of new therapeutic options, physicians are plagued with questions about sequencing therapies for those who progress following therapy in the first-line setting, and little data exists to guide optimal therapy selection, according to Anthony Mato, MD.

Since 2013, the FDA has approved 6 new drugs and combinations, resulting in 720 unique sequences of novel therapies, Mato said during a presentation at the 

 CFS® virtual conference.1 “It’s really been an exciting time,” said Mato, director of the CLL Program/Leukemia Service at Memorial Sloan Kettering Cancer in New York, New York. “However, as we have more and more choices available to patients, new challenges are emerging on how to best sequence these therapies and how to manage patients who fail all of these molecules.”

After patients progress on frontline therapy, choices in the second line depend on which upfront therapy they received, reasons for discontinuation, and the levels of evidence available to evaluate options, Mato said. “There’s no comparative frontline data available for novel agent versus novel agent.”

The choices fall into 3 categories: Bruton tyrosine kinase (BTK) inhibitors, the BCL-2 inhibitor venetoclax (Venclexta), or a PI3K inhibitor such as idelalisib (Zydelig), Mato said.

In a real-world study, Mato and colleagues compared sequencing outcomes for 683 patients treated in either the BTK inhibitor ibrutinib (Imbruvica), idelalisib, or venetoclax. In terms of kinase inhibitor (KI) selection, the results showed that those treated with ibrutinib achieved a longer progression-free survival (PFS) than those who had idelalisib in the frontline setting (HR, 2.8; CI, 1.3-6.3; 

 = .01) and in the relapsed/refractory (R/R) setting (HR, 2.8; CI, 1.9-4.1; 

 < .001). Patients who progressed after KI therapy had better outcomes with another KI or with venetoclax than they did with chemoimmunotherapy. The data also suggest that venetoclax may be more effective than idelalisib after ibrutinib failure.

Therapy choices in the R/R setting were explored in the phase 3 ASCEND trial (NCT02970318), which randomized patients between the BTK inhibitor acalabrutinib (Calquence) and either idelalisib plus rituximab (Rituxan; IdR) or bendamustine plus rituximab (BR), which Mato said is not commonly prescribed in the United States. The findings show that median PFS was not reached for acalabrutinib compared with 15.8 months with IdR (HR, 0.29; 95% CI, 0.18-0.46; 

“The take-home from this study was that they found the exact same thing that our real-word study had found 2 years earlier,” Mato said. “BTK was better not only from the perspective of PFS but was also better from the perspective of tolerability and discontinuation rates.”

For patients who received chemotherapy or chemoimmunotherapy in the frontline setting, there are no randomized data to guide R/R therapy choices and no trials are planned, Mato said. The results of an analysis of patients who received either ibrutinib or venetoclax with or without a CD20-targeting agent as the first-line novel therapy after relapse showed a significant PFS advantage favoring venetoclax (HR, 0.29; 95% Cl, 0.10-0.92; 

“In all circumstances when clinical acceptable, the data support using a BTK inhibitor or venetoclax before a PI3K inhibitor,” Mato said. He added that there are no definitive data to support this conclusion but findings from real-world analyses are “intriguing.”

When it comes to evaluating R/R options for patients who have received a BTK inhibitor or venetoclax in the frontline setting, Mato said considerations should include prior therapies, resistance, and intolerance. Data on sequencing therapies after BTK inhibitors, which are increasingly being administered in the frontline and R/R settings, are available mostly from retrospective studies but also “a growing list of clinical trials.”

In a patients who received ibrutinib as frontline therapy, the overall discontinuation rate in the real-world setting was 24% (94 events in 391 patients), compared with the initial rate of 12.5% (17 events in 135 patients) in patients 65 years or older with treatment-naïve CLL or small lymphocytic leukemia enrolled in the phase 3 RESONATE-2 trial (NCT01722487). In all, 59.5% of patients said they discontinued therapy due to adverse events (AEs).

After a 5-year follow-up, the discontinuation rate from patients treated with first-line ibrutinib in RESONATE-2 rose to 41%, with AEs most commonly cited for stopping therapy, according to data published in the 

 Mato said other studies have shown similar rates of discontinuation due to AEs or progression of disease because of CLL or Richter transformation.

After discontinuation of ibrutinib or idelalisib, Mato said, there is no role for sequencing chemoimmunotherapy and that venetoclax appears more effective than an alternative KI especially in the setting of ibrutinib resistance; however, there may be a role for switching agents in the BTK class in the case of KI intolerance.

For patients who start with venetoclax as their first novel agent, BTK inhibitors produce high overall response rates and durable remissions among patients who have not previously received a BTK-targeting agent, Mato said. He said follow-up data from the phase 3 MURANO trial (NCT02005471) indicate a response rate of nearly 100% for patients who received ibrutinib after venetoclax. The response rate was 55% among a small number of patients (6 of 11) who were retreated with venetoclax following prior therapy with that agent.

Moving forward, Mato said, therapy choices will become even more complex as new strategies are introduced. “In all of these situations, you should be considering a clinical trial as the best option available for patients. In addition, as we have the emergence of cellular therapies, we should think about use of CAR T [chimeric antigen-receptor T-cell therapy] for patients who fail at least 2 novel agent based–therapies and/or the reemergence of allogeneic stem cell transplantation as we have more and more patients who are being treated with all of the available novel classes of patients and who no longer have standard-of-care options.”

Mato AR. Choosing first-line therapy for CLL. Presented at: 

Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. 

 2017;28(5):1050-1056. doi:10.1093/annonc/mdx031

Ghia P, Pluta A, nWach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: European Hematology Association Annual Meeting; June 13-16, 2019; Amsterdam, Netherlands. Abstract LBA2606. Accessed November 4, 2020. https://bit.ly/363micn

Eyre TA, Lamanna N, Roeker LE, et al. Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia. 

. Published online February 20, 2020. doi:10.3324/haematol.2019.241539

Mato AR, Roeker LE, Allan JN, et al. Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. 

 2018;93(11):1394-1401. doi:10.1002/ajh.25261

Burger J. Treatment of chronic lymphocytic leukemia. 

. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). 

. 2019;134(suppl 1):355. doi:10.1182/blood-2019-123930

While the treatment landscape for chronic lymphocytic leukemia has expanded with an explosion of new therapeutic options, physicians are plagued with questions about sequencing therapies for those who progress following therapy in the first-line setting, and little data exists to guide optimal therapy selection, according to Anthony Mato, MD.

Expert Reviews Sequencing Strategies for Explosion of New CLL Treatment Options

Increasing clinical relevance of less common gene signatures and alterations is leading to a benefit from broad-panel next-generation sequencing (NGS) testing for patients with metastatic nonsmall cell lung cancer (NSCLC), according to an expert at Memorial Sloan Kettering (MSK) Cancer Center.

Michael F. Berger, PhD, described the NGS landscape through the lens of his experience as the associate director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology during a presentation at the 13th Annual New York Lung Cancers Symposium hosted by Physicians&rsquo; Education Resource

, LLC. The center developed the MSK-IMPACT (integrated mutation profiling of actionable cancer targets) comprehensive panel for sequencing 468 cancer-associated genes.

The assay also evaluates tumor mutational burden (TMB) and mismatch repair deficiency (dMMR) or microsatellite instability (MSI).

&ldquo;What might have been done in the context of an individual tumor type for a small core set of genes or mutations has now expanded to all different cancer-associated genes, knowing that mutations that may be more commonly observed in one cancer may also be less frequently observed in other cancers but also can provide informed treatment decisions for those patients,&rdquo; said Berger.

mutations, which have been observed in approximately 50% of melanomas and have prompted the development of dual pathwaytargeting agents, including the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). In NSCLC, the same combination gained FDA approval in 2017 for patients with metastatic disease that harbors

V600E mutations, which are found in 1% to 2% of lung adenocaricnomas.

MSK now seeks to offer NGS testing to patients with meta- static cancer across all solid tumor types, particularly those with NSCLC, Berger said. He added that some patients with earlier-stage cancers may also undergo testing if they are treated through surgical oncology.

In NSCLC, such testing is growing increasingly relevant, notably because of novel therapies being developed for less prevalent gene fusions, Berger said in an interview with

fusions, which have been identified in less than 3% of NSCLC cases. Larotrectinib (Vitrakvi), a selective tyrosine receptor kinase (TRK) inhibitor, and entrectinib (RXDX-101), an oral pan-TRK inhibitor, are among the drugs being developed in this space.

&ldquo;The broad testing allows us to capture not just the common but also the rare mutations, and it also gives us information about more complex mutational signatures that are increasingly important for predicting response to immunotherapy,&rdquo; Berger said.

TMB is being explored as a biomarker in NSCLC. The FDA is currently considering a supplemental biologics license application for the combination of nivolumab (Opdivo) plus low-dose ipilimumab (Yervoy) for the frontline treatment of patients with advanced NSCLC with TMB &ge;10 mutations per megabase.

Although dMMR/MSI is &ldquo;very rare in lung cancer,&rdquo; Berger says patients with this signature may be candidates for pem- brolizumab (Keytruda), a PD-1 inhibitor that is approved for patients with unresectable or metastatic MSI-high or dMMR solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.

In describing the current landscape for NGS testing, Berger said there are 3 main test categories: hotspot panel, with amplicon capture of approximately 10 to 50 genes; cancer gene panel, with hybridization capture of about 100 to 500 genes; and whole exome sequencing, with hybridization capture of approximately 20,000 genes. At one end of the spectrum, hotspot panel testing is a lower-cost option that offers a fast turnaround, while at the other end, whole exome sequencing provides the greatest potential for discovery.

&ldquo;There is a sweet spot in the middle, and this has been our approach,&rdquo; he said, referring to MSK-IMPACT. &ldquo;It is cheaper, more rapid, more economical than the more comprehensive approaches, and in some ways more clinically suited.&rdquo;

At the same time, Berger said the choice of NGS strategy depends on clinical and practical factors. &ldquo;There is really no one right approach. It depends on the disease, the lab, the resources available, the throughput in the laboratory, the turnaround time requirements, and cost consider- ations,&rdquo; he said.

One advantage of the MSK-IMPACT test, he said, is that it analyzes DNA from tumor cells and a matched normal control sample for comparison; in lung cancer, blood is the source used in the normal test.

&ldquo;When we set up this program and developed the test, it was really with the goal of identifying individual muta- tions that might elicit responses to particular targeted therapies,&rdquo; Berger said. &ldquo;But we can move beyond that, and that is enabled largely by the fact that we are sequencing both tumor and matched normal [samples].&rdquo;

Thus far, more than 32,000 tumors have been sequenced with MSK-IMPACT, with approximately 200 additional tumors tested every week, Berger said. In 2017, the FDA approved the test, which is typically available only to patients treated at MSK, as an in vitro diagnostic.

Commercially available NGS tests approved by the FDA include the FoundationOne CDx assay, which tests for 324 genes; the Praxis Extended RAS Panel, which detects 56 mutations in

family genes; and the Oncomine Dx Target Test, which analyzes 23 genes and

fusions. The FoundationOne and Oncomine tests are approved as companion diagnostics for NSCLC drugs that target specific mutations.

Evaluation of automatic class III designation for MSK-IMPACT (integrated mutation pro- filing of actionable cancer targets): decision summary. FDA website. accessdata.fda.gov/ cdrh_docs/reviews/DEN170058.pdf. Accessed December 7, 2018.

Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previ- ously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4.

3. Drilon A, De Braud FG, Siena S, et al. Entrectinib, an oral pan-Trk, ROS1, and ALK inhib- itor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements: up- dated phase I results [AACR abstract CT007]. Cancer Res. 2016;76(suppl 14):CT007. doi: 10.1158/1538-7445.AM2016-CT007.

Increasing clinical relevance of less common gene signatures and alterations is leading to a benefit from broad-panel next-generation sequencing testing for patients with metastatic non&ndash;small cell lung cancer, according to an expert at Memorial Sloan Kettering Cancer Center.

Anita Schaffer | Authors

Articles

First-In-Human Trial Shows Responses With Off-the-Shelf CAR T-Cell Therapy in Myeloma

Expert Reviews Sequencing Strategies for Explosion of New CLL Treatment Options

Broad-Panel NGS Benefits Metastatic NSCLC