Lisa Astor

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A retrospective review (NCT03827343) has revealed that young patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) that relapsed  or had a suboptimal response after 

 (CAR) T-cell therapy could benefit from reinfusion.

Findings from the review were published in 

. Investigators include corresponding author Nirali N. Shah, MD, MHSc, National Cancer Institute.

“Our study provides important insights into [second CAR T-cell infusion] outcomes, including with antigen targets beyond CD19,”  Shah and colleagues wrote.

Although CAR T-cell therapy has demonstrated efficacy in many indications, unmet needs remain for patients who have residual disease or who relapse after CAR T-cell therapy. A second infusion with the same CAR T-cell product now looks to be a possible option.

Tisa-Cel Shows Durable Efficacy in Pediatric and Young Adult Patients With R/R B-Cell Acute Lymphoblastic Leukemia

Shah and colleagues analyzed data from patients with B-ALL who received a reinfusion in 1 of 3 phase 1 NCI-based clinical trials (NCT01593696, NCT02315612, NCT0344839). These patients originally received either an anti-CD19, anti-CD22, or an anti-CD19/CD22 agent. If the patients had relapse after complete remission (CR) or suboptimal response and CAR expansion, they were offered a second infusion (n = 18).

Investigators were primarily trying to evaluate CR rates of second infusions as well as incidence of adverse events (AEs). Secondary outcomes included characterizing CAR expansion and antigen expression as well as the impact of lymphodepletion intensity.

A total of 136 patients were treated across the 3 studies, but only 18 (13.2%) went on to receive a second infusion with the same CAR product. As of the time of the second infusion, the median age of patients was 19 (range, 8-31). A majority of the patients were male (88.9%), White (66.7%), and of non-Hispanic ethnicity (83.3%). As of the second infusion, 88.9% had active medullary disease, 22.2% had low marrow involvement, 66.7% had high disease burden, and 11.1% had isolated CNS disease.

Patients had received a median of 6 lines of prior therapy (range, 2-13), including prior hematopoietic stem cell transplantation (HSCT) in 77.8%, prior immunotherapy in 44.4%, and prior alternate CAR T-cell therapy in 50%.

Seven patients (38.7%) had a suboptimal response to the fi rst infusion of either partial response or stable disease, including 4 who did not have a CR from first infusion, and 11 patients (61.1%) had an antigen-positive relapse; all 18 patients had CAR expansion. The median time between the fi rst and second infusion was 116.5 days (range, 35-373), and 38.9% received therapy in between.

The second infusion was administered at the same dose for 15 patients (83.3%), at a lower dose in 2 patients (11.1%) and a higher dose in 1 (5.5%).

Seven patients (38.9%) achieved an objective marrow response to the second infusion, with 5 of these patients (71.4%) achieving a minimal residual disease (MRD) negative CR, and 6 (33.3%) had a morphologic CR.

Long-term survival with second CAR infusion was limited. All patients eventually relapsed—including 2 with CNS disease, 3 with medullary relapse, and 1 with both medullary and extramedullary relapse— and none were eligible for HSCT. The median duration of remission was 77 days (range, 54-292).

“Our results suggest that diminished CAR T-cell expansion alongside antigen downregulation and loss impeded robust responses to CART2. Further exploration of the mechanisms underlying CART2 response is needed,” Shah et al wrote.

Cytokine release syndrome (CRS) was observed in 83.3% of patients with fi rst infusion, including severe CRS of grade 3 or higher in 27.8%. Only 22.2% reported CRS with second infusion at a maximum severity of grade 1. Neurologic toxicity was reported with fi rst infusion in 22.2% and with second infusion in 11.1%.

Observed peripheral blood CAR T-cell expansion was higher with the fi rst infusion than the second (median, 24.05 vs 1.69 cells/mL, respectively; 

 = .03). Five patients (27.8%) showed no CAR expansion post second infusion. CAR expansion tended to be higher with the CD22-targeted agent than the other CAR T-cell products.

Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. 

. 2022;10(5):e004483. doi:10.1136/jitc-2021-004483

Articles

Long term survival was limited and all patients with B-cell acute lymphoblastic leukemia eventually relapsed.

Reinfusion of CAR T Therapy Shows Promise in B-ALL

Investigators shared details of the ongoing phase 1a/b NEBULA trial (NCT05043714) exploring the use of NG-641, a novel adenoviral vector, in combination with nivolumab (Opdivo) in a population of patients with previously treated metastatic or advanced epithelial tumors. The presentation took place at the recent 

2022 American Association for Cancer Research (AACR) Annual Meeting

The open-label, dose-escalating trial is investigating the safety and preliminary efficacy of NG-641, a next-generation blood-stable and transgene-armed T-SIGn adenoviral vector. T-SIGn vectors allow for intravenous administration for selective infection of cancer cells as well as replication at tumor sites. Activated immune cells from the therapy support functional anti-tumor responses.

The agent expresses 4 immunostimulatory transgenes and works by crosslinking T cells to fibroblast activating-protein–positive cancer-associated fibroblasts, which activates the immune system. Additionally, CXCL9 and CXCL10 induce T-cell migration and interferon-α2 enhances T-cell activation and induces the killing of cancer cells by tumor antigen–specific T cells.

Already, NG-641 has shown encouraging preliminary safety and tolerability results in the ongoing phase 1a dose-escalation STAR trial (NCT04053283), which is a first-in-human study for the gene therapy.

When used in combination with nivolumab in the NEBULA study, the regimen is expected to result in complementary mechanisms of action.

Patients with metastatic or advanced epithelial cancers who have received prior anti–PD-1/PD-L1 therapy, have measurable disease, an ECOG performance status, adequate lung reserve, and adequate organ and bone marrow function are eligible to enroll in the trial. The included tumor types are urothelial carcinoma, squamous cell carcinoma of the head and neck, microsatellite instability–high or mismatch repair deficient cancers, non–small cell lung cancer, uterine or endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, triple-negative breast cancer, cutaneous squamous cell carcinoma, hepatocellular carcinoma, and tumor mutational burden–high tumors.

Those with active infections, viral disease, autoimmune disease, acute kidney injury, renal impairment, or interstitial lung disease as well as patients with risk factors for bleeding or clotting events, bowel obstruction, or tumor flare are ineligible to participate in the trial.

A total of 30 patients are expected to be enrolled in the phase 1a portion of the trial, which consists of 5 escalating dose levels in a Bayesian Optimal Interval design. Phase 1b is the dose-expansion stage of the trial, which will consist of tumor-specific cohorts.

Dose level –1 is an intravenous infusion of NG-641 at 6 x 10

 virus particles (vp) given on days 1, 3, and 5; dose level 1 is 1 x 10

 vp of NG-641 on days 1, 3, and 5; dose level 2 is 1 x 10

 vp on days 3 and 5; dose level 3 is 1 x 10

 vp on days 3 and 5; and dose level 4 is 1 x 10

 vp on days 3 and 5. Across all dose levels, nivolumab will be administered at 480 mg on day 15 of the 4-week cycle.

The primary end point of the NEBULA trial is safety and tolerability as well as the recommended dose of the regimen. The secondary end point is preliminary antitumor activity. Additionally, pharmacokinetics, immunogenicity, and pharmacodynamics will be assessed using tumor tissue and blood samples.

Enrollment to the first cohort is currently ongoing in the United States at the UCLA Medical Center and in the United Kingdom at The Clatterbridge Cancer Centre, Oxford University Hospitals.

Lillie T, Parkes E, Ottensmeier C, et al. A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA). Presented at: AACR Annual Meeting 2022; April 8-13, 2022; virtual. Abstract CT214. https://bit.ly/3xoXv1A

Exploring NG-641 Plus Nivolumab for Previously Treated Metastatic or Advanced Epithelial Tumors

Early results from a phase 2 trial (NCT03019640) showed that cord blood–derived natural killer (NK) immunotherapy plus high-dose chemotherapy and autologous stem cell transplant (ASCT) induced early antitumor response in B-cell non-Hodgkin lymphoma (NHL).

The trial investigators evaluated the potential of the novel cellular cord blood–derived NK immunotherapy in patients with B-cell NHL who are undergoing high-dose chemotherapy and ASCT and presented their findings in a poster at the recent 2021 Transplant & Cellular Therapy Meetings. They chose CB units for NK cell expansion on artificial antigen presenting cells and without human leukocyte antigens (HLA) matching to provide increased expansion and make the treatment “off-the-shelf” capable.

The study enrolled patients who were aged 15 to 70 with B-cell NHL, excluding primary central nervous system lymphoma, who were candidates for high-dose chemotherapy and ASCT. Patients were required to have adequate end-organ function, an ECOG performance status of 0 or 1, and prior apheresis of ≥2 x 106 CD34+ cells/Kg in order to be eligible.

Those with prior whole brain irradiation, active hepatitis B, evidence of cirrhosis or high-grade liver fibrosis, active infection, HIV infection, or received radiation therapy within the past month were excluded from joining the trial.

Patients were given intravenous (IV) carmustine over 2 hours 12 days prior to transplant, IV etoposide twice daily over 3 hours and IV cytarabine twice daily over 1 hour for days 11 to 8 prior to transplant, IV melphalan over 30 minutes 7 days prior to transplant, oral lenalidomide (Revlimid) once daily for days 7 through 2 prior to transplant. Additionally, patients who are CD20-positive received IV rituximab (Rituxan) over 3 hours for days 13 through 7 prior to transplant.

Then patients received cord blood–derived expanded allogeneic NK cells intravenously over 1 hour on day 5 prior to ASCT. Five days following ASCT, patients started received daily subcutaneous filgrastim.

The primary end point was 30-day treatment-related mortality (TRM) and secondary end points were relapse-free survival (RFS), overall survival, and NK cell persistence.

Study authors, led by Yago L. Nieto, MD, PhD, in the Department of Stem Cell Transplantation, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center in Houston, provided an update on data for 20 of the enrolled patients in the study. Patients were enrolled between December 2017 and July 2020. One patient experienced rapid tumor progression during culture of NK cells and thus was not treated in the study.

The median age of the 19 treated patients was 60 years (range, 33-70) with the majority (73.7%) being male and having diffuse large B-cell lymphoma (DLBCL; 84.2%); the 3 remaining patients had mantle cell lymphoma (n = 2) or follicular lymphoma (n = 1). More than two-thirds (68.4%) of patients had relapsed disease whereas the 2 patients with MCL were being treated in the frontline setting and 4 patients had primary refractory disease. The median number of prior lines of therapy was 2 (range, 1-4).

Response assessed through PET at ASCT was a complete response for 78.9%, partial response for 15.8%, and progressive disease for 5.3%. Nine patients had 1/6 HLA match of cord blood at DR, 6 had 1/6 match at B, 3 had 1/6 match at A, and 1 had 2/6 match at B and DR.

Cord blood–derived NK cells were expanded a median of 1552-fold (range, 317-4767) with the infused NK product comprising a CD3-CD16+CD56+ phenotype for a median of 98.9% (range, 97.6%-99.5%) of the cells. The cord blood–derived NK cells had a median viability of 96.5% (range, 92%-98%). In the peripheral blood, NK cells were detectable for a mean of 2 weeks (range, 2-3).

For weeks 1 through 3, the cord blood–derived NK cells showed a higher percentage of NKG2D and NKp30 activation receptors than the patient’s own NK cells; the study authors noted that this indicated an effector phenotype. Additionally, NK persistence was found not to be impacted by the degree of HLA mismatch.

At a median follow-up of 18 months (range, 4-340), the RFS rate was 68% and the OS rate was 84%. Eleven of the 16 patients (68.8%) with DLBCL are still in remission.

The study authors concluded that expanded and highly purified cord blood–derived NK immunotherapy was safe and promising in combination with high-dose chemotherapy and ASCT in patients with B-cell NHL.

Nato Y, Kaur I, Hosing C, et al. Immunotherapy with ex vivo-expanded cord blood (CB)-derived nk cells combined with high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) for B-cell non-hodgkin’s lymphoma (NHL). Presented at: 2021 Transplant & Cellular Therapy Meetings; February 8-12, 2021; Virtual. LBA15.

Findings presented at the 2021 Transplant & Cellular Therapy Meetings indicate that patients with B-cell non-Hodgkin lymphoma may benefit from a type of natural killer immunotherapy added to chemotherapy and transplant. 

In B-Cell NHL, Off-the-Shelf NK Immunotherapy Shows Promise When Used With Chemotherapy and ASCT

The CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) led to a high response rate and an acceptable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma, according to findings from the CARTITUDE-1 trial (NCT03548207) that were presented during the 2020 ASH Annual Meeting.1

The objective response rate (ORR) was 96.9%, consisting of stringent complete responses (sCRs) in 67.0% of patients, very good partial responses in 25.8%, and partial responses in 4.1%.

“We saw how heavily pretreated these patients were, and to see a one-time treatment give these kinds of response rates is quite exceptional,” said Deepu Madduri, MD, in a presentation during the 2020 ASH Annual Meeting. “What’s even more impressive is that 72% of these patients are still maintaining their response at the time of data cut off.”

Cilta-cel is a second-generation CAR T-cell therapy consisting of a CD3ζ signaling domain, a 4-1BB costimulatory domain, and 2 B-cell maturation antigen (BCMA) binding domains.

CARTITUDE-1 is a phase 1b/2 study exploring the safety and efficacy of cilta-cel in patients with progressive multiple myeloma per IMWG criteria who have received at least 3 prior therapies—including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy—or who are double refractory, and have an ECOG performance status of 0 or 1.

Once patients were screened and enrolled in the study, they underwent apheresis and bridging therapy, if necessary, followed by lymphodepleting chemotherapy of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 on days –5 to –3 prior to CAR T-cell infusion. The target dose was 0.75 x 106 viable CAR-positive T cells/kg, but the median dose administered was 0.71 x 106 (range, 0.51-0.95 x 106).

Primary objectives for the phase 1b portion of the study were to characterize the safety of the agent and set the recommended phase 2 dose; and in phase 2, the primary end point was to evaluate efficacy by ORR.

Previously, results of the phase 1b portion of the study were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showing responses in all 29 patients, including a very good partial response or higher rate of 97%.2

The presentation at ASH covered findings for all patients treated with cilta-cel in the phase 1b and 2 portions of the study (N = 97). Of these patients, 86% are still on the trial.

Median turnaround time for cilta-cel manufacturing was 29 days, and no patients discontinued from the study due to manufacturing failure.

At baseline, the median age of all patients was 61 (range, 43-78), 58.8% were male, and 13.4% had extramedullary disease. Almost one-fourth of patients (23.7%) had a high-risk cytogenetic profile, most often including del(17p), and 91.9% had tumor BCMA expression of at least 50%. The median number of prior therapies was 6 (range, 3-18), indicating a heavily pretreated population, with 87.6% being triple-class refractory and 42.3% being penta-refractory. Ninety-nine percent of patients were refractory to their last line of therapy, which was not required for inclusion in this study, noted Madduri. Additionally, 89.7% previously underwent autologous stem cell transplant and 8.2% received allogenic transplant.

Responses were ongoing at cutoff in 72.2% of patients and the median time to first response was 1 month (range, 0.9-8.5). Of 57 patients evaluable for minimal residual disease (MRD), the negativity rate at 10-5 was 93.0%, accounting for 54.6% of the overall population. A total of 33 patients (34.0%) achieved both sCR and MRD negativity. The median time to MRD negativity was also 1 month (range, 0.8-7.7).

“Early, deep, and durable responses are observed in this heavily pretreated population,” said Madduri, who is an assistant professor of medicine, hematology, and medical oncology at Mount Sinai Medical Center in New York.

The median progression-free survival (PFS) was not reached in responders but at 12 months, the PFS rate was 76.6% (95% CI, 66.0%-84.3%). In those who achieved an sCR, the 12-month PFS rate was 84.5% (95% CI, 72.0%-91.8%) and was 68.0% (95% CI, 46.1%-82.5%) in patients who had a very good partial response.

“Patients with relapsed/refractory myeloma have a median overall survival of only 9.2 months in triple-refractory [disease] and only 5.6 months in penta-refractory. In this study, we know that the median PFS is at least a full year and we still haven't even reached a median PFS after a median duration of follow-up of 12.4 months,” Madduri commented.

At 1 year, the overall survival rate was 88.5% (95% CI, 80.2%-93.5%). The median overall survival was also not yet reached.

The most common grade 3/4 adverse events (AEs) were hematologic and observed in 99.0% of all patients, consisting of neutropenia in 94.8%, anemia in 68.0%, leukopenia in 60.8%, and thrombocytopenia in 59.8%. The median time to recovery of these grade 3/4 cytopenias was 2 weeks for neutropenia and 4 weeks for thrombocytopenia. The rate of any-grade infections was 57.7%, and the most common grade 3/4 infections were pneumonia (8.2%) and sepsis (4.1%).

Grade 3/4 non-hematologic toxicities were not common in the study, including hypophosphatemia at 7.2%, fatigue at 5.2%, aspartate aminotransferase increase at 5.2%, and hyponatremia at 4.1%.

Additionally, cytokine release syndrome (CRS), a common CAR T-cell therapy–related AE, was reported in 94.8% of patients at any grade, but only 4.1% were grade 3/4 in severity.

“One distinguishing aspect of this study is the median time to onset of CRS, which is 7 days, with 89% of these patients having CRS at day 4 or later and 74% of these patients having CRS at day 6 or later, opening the possibility of outpatient administration. This may be explained by the fact that the maximum peripheral expansion of cilta-cel occurred generally around a median of 13 days,” Madduri said.

Tocilizumab and corticosteroid support were required in 69.1% and 21.6% of patients, respectively. CRS resolved in 98.9% of all patients within 14 days of onset.

Neurotoxicity, another known complication of CAR T-cell therapies, was reported in 20.6% of patients at any grade and of grade 3 or higher in 10.3%. Specifically, immune effector cell–associated neurotoxicity syndrome (ICANS) cases were reported in 16.5% at any grade and of grade 3 or higher in 2.1%. All ICANS occurred within a median of 8 days (range, 3-12) and resolved within a median of 4 days (range, 1-12).

Other neurotoxicities, which were reported in 12 patients (12.4%), occurred after resolution of CRS or ICANS and included 5 patients with movement and/or neurocognitive changes and 7 with nerve palsy or peripheral motor neuropathy; 6 of these resolved. In the other 6 patients, 1 patient died from complications of the AE, 4 died of other causes, and 1 has ongoing neurotoxicity. The median time to onset for these toxicities was 27 days (range, 11-108) with recovery in a median of 75 days (range, 2-160).

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these CAR T cells. So we did implement some mitigation strategies in our subsequent CARTITUDE development program allowing patients to have more chemotherapy, having more aggressive steroids for ICANS, like early intervention and extensive monitoring,” Madduri said in the question-and-answer portion of the session following her presentation.

A total of 14 patients died during the study within 45 to 694 days of infusion. Five patient deaths were due to progressive disease, 3 were due to AEs that were not related to treatment, and 6 were due to AEs considered to be related to treatment with cilta-cel. These AEs included sepsis and/or septic shock in 2 patients, and CRS or hemophagocytic lymphohistiocytosis, lung abscess, respiratory failure, and neurotoxicity in 1 patient each.

Cilta-cel is continuing to be studied in patients with multiple myeloma in other clinical trials, including in earlier-line settings. Additionally, both the CARTITUDE-2 (NCT04133636) and CARTITUDE-4 (NCT04181827) studies are considering whether cilta-cel can safely be given in an outpatient setting.

In December 2019, cilta-cel was granted an FDA breakthrough therapy designation for the treatment of patients with previously treated multiple myeloma based on earlier results of the CARTITUDE-1 trial.3

1. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen–Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 177.

2. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. 

 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505

3. Janssen Announces BCMA CAR-T Therapy JNJ-4528 Granted U.S. FDA Breakthrough Therapy Designation for the Treatment of Relapsed or Refractory Multiple Myeloma. News release. Janssen. December 6, 2019. Accessed December 5, 2020. 

Treatment with the CAR T-cell therapy ciltacabtagene autoleucel led to a high response rate and an acceptable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma.

Cilta-Cel Induces High Response Rate in Relapsed/Refractory Multiple Myeloma

Treatment with the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) led to a high response rate and an acceptable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma, according to findings from the CARTITUDE-1 trial (NCT03548207) that were presented during the 2020 ASH Annual Meeting.

Once patients were screened and enrolled in the study, they underwent apheresis and bridging therapy, if necessary, followed by lymphodepleting chemotherapy of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 on days –5 to –3 prior to CAR T-cell infusion. The target dose was 0.75 x 106 viable CAR-positive T cells/kg, but the median dose administered was 0.71 x 10

Previously, results of the phase 1b portion of the study were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showing responses in all 29 patients, including a very good partial response or higher rate of 97%.

Additionally, cytokine release syndrome (CRS), a common CAR T-cell therapy–related AE, was reported in 94.8% of patients at any grade, but only 4.1% were grade 3/4 in severity (

In December 2019, cilta-cel was granted an FDA breakthrough therapy designation for the treatment of patients with previously treated multiple myeloma based on earlier results of the CARTITUDE-1 trial.

2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505

December 5, 2020 - Treatment with the CAR T-cell therapy ciltacabtagene autoleucel led to a high response rate and an acceptable safety profile at the recommended phase 2 dose in patients with relapsed or refractory multiple myeloma.

Cilta-Cel Confers 97% ORR in Relapsed/Refractory Multiple Myeloma

The FDA has granted a fast track designation to the investigational KRAS inhibitor AMG 510 for the treatment of patients with 

 G12C—mutated non–small cell lung cancer (NSCLC) who have received prior treatment.

The decision is based on updated phase I data that were recently presented during the 2019 World Conference on Lung Cancer, which showed that AMG 510 elicited a 100% disease control rate (DCR) at the target dose in evaluable patients with 

“There is a need for targeted treatments for specific driver mutations of cancer that do not have an approved therapy,” Ramaswamy Govindan, MD, principal investigator and professor at the Washington University School of Medicine in St. Louis, stated in a press release and who also presented the updating findings during this year's conference. “These data continue to show encouraging antitumor activity with AMG 510, underscoring the potential to close the treatment gap for patients with previously treated 

AMG 510 is a first-in-class investigational agent that selectively and irreversibly targets the KRAS G12C protein. The phase I dose-escalation/expansion study was conducted in patients with previously treated solid tumors who harbor a 

 G12C mutation. The updated data presented at the 2019 World Conference on Lung Cancer focused on additional follow-up among patients with NSCLC from the data that were originally presented at the 2019 ASCO Annual Meeting.

The findings covered 34 patients with NSCLC treated with AMG 510, including 19 who were treated in the dose-escalation phase with doses starting at 180 mg and 15 who were treated in the expansion phase at the determined phase II dose of 960 mg once daily.

No dose-limiting toxicities were observed among the patients with NSCLC and although 4 patients discontinued treatment, none discontinued due to adverse events. Twenty-seven patients remained on treatment at the time of data cutoff.

Among 23 evaluable patients who had completed the first 6-week CT scan or had early progressive disease, the objective response rate was 48% and the DCR was 96%. Thirteen of these patients received the phase II dose of 960 mg, and of these patients, 7 (54%) achieved a partial response and 6 (46%) achieved stable disease.

“These new data reinforce the earlier positive response rate we shared at ASCO in more non-small cell lung cancer patients receiving AMG 510,” David M. Reese, MD, executive vice president of research and development at Amgen, the developer of AMG 510, stated in the press release. “We remain enthusiastic about the promise of AMG 510 and continue to rapidly advance its development program both as monotherapy and in combination.”

Grade 1/2 treatment-related adverse events (TRAEs) were observed in 26.5% of patients and grade 3 TRAEs included anemia and diarrhea (8.8% each). No grade ≥4 TRAEs were reported.

Additional findings from the phase I study will also be presented at the 2019 ESMO Congress.

Amgen announces new clinical data evaluating novel investigational KRASG12C inhibitor in larger patient group at WCLC 2019 [news release]. Thousand Oaks, CA: Amgen; September 8, 2019. https://bit.ly/2kqnxi4. Accessed September 9, 2019.

Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRASG12C inhibitor, evaluated in NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02.

The FDA has granted a fast track designation to AMG 510 for the treatment of patients with KRAS G12C–mutated metastatic non–small cell lung cancer who received prior therapy.

FDA Grants Fast Track Designation to AMG 510 for KRAS G12C+ NSCLC

The CAR T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) elicited a 71% overall response rate (ORR) as well as a tolerable safety profile in a cohort of patients with relapsed/refractory mantle cell lymphoma (MCL), according to results from the TRANSCEND NHL 001 trial that were presented at the 2019 ASCO Annual Meeting. 

The ORR consisted of a 53% complete response (CR) rate of 53%, and 7 of the 9 CRs were ongoing as of data cutoff.

"In the ongoing TRANSCEND NHL 001 study, treatment of patients with relapsed/refractory mantle cell lymphoma receiving both dose levels of liso-cel was associated with tolerable toxicity, including a low incidence of grade 3 or 4 cytokine release syndrome and neurotoxicity," the study authors, led by Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, wrote in their poster. "Liso-cel showed promising clinical activity in patients with relapsed/refractory mantle cell lymphoma."

The ongoing, open-label TRANSCEND NHL 001 trial (NCT02631044) is a phase I trial exploring the safety and efficacy of the anti-CD19, 4-1BB-containing CAR T-cell therapy in adult patients with relapsed/refractory B-cell non-Hodgkin lymphomas.

In the MCL cohort, patients were eligible to enroll in the trial if they had received ≥1 line of prior therapy, had an ECOG performance status of 0 to 2, and had confirmed cyclin D1 expression or evidence of transformation (11;14). Prior stem cell transplant was allowed and patients were eligible for enrollment even if they had secondary central nervous system (CNS) involvement.

Patients received lymphodepletion of 30 mg/m2 of fludarabine and 300 mg/m

 of cyclophosphamide for 3 days before receiving liso-cel. Twenty-five patients were enrolled and underwent leukapheresis for liso-cel manufacturing. Seventeen patients received the liso-cell product and were evaluable for safety. Liso-cel was given at one of 2 doses: 50 x 10

 CAR-positive T cells (n = 6), or 100 x 10

Of note, 1 additional patient received a nonconforming liso-cel product with reduced CD8-positive CAR-positive T cell viability at the lower dose and was not included in the safety and efficacy analyses.

Across the 2 dose levels, the median age was 66 years (range, 53-80) and three-fourths of the patients were male. The patients had received a median of 4 prior lines of therapy (range, 1-8), which included prior ibrutinib (Imbruvica) in 94% of patients and venetoclax (Venclexta) in 12%.

The majority of patients had a poor risk factor, including blastoid variant in 4 patients, TP53 mutation in 1, and a Ki-67 level >30% in 13 patients. Ten patients received a bridging chemotherapy while waiting for the liso-cel product.

In the patients who received the lower dose of liso-cel, the ORR was 67%, which consisted of 2 CRs (33%). The median time to CR was 3.6 months (range, 1-6.3). At a median follow-up for 18.0 months, the median progression-free survival (PFS) in patients receiving the lower dose was 2.6 months (range, 0.7-18.2+) and the median overall survival (OS) was 10.9 months (range, 1.2-18.2+).

Patients receiving the higher dose of liso-cel demonstrated an ORR of 73%, consisting of a CR rate of 64%. The median time to CR was 0.9 months (range, 0.9-4.9). The median PFS with the higher dose was 5.8 months (range, 0.4-6.0+) and the median OS was not reached (range, 0.4-9.2+) after a median follow-up of 6.2 months.

Overall, the median PFS was 5.8 months (range, 0.4-18.2+) and the median OS was 11.1 months (range, 0.4-18.2+). The median duration of response has not yet been reached (range, 1.0-16.2+), but patients receiving the lower dose maintained their response through day 545, the time of data cutoff.

Of the 5 patients who did not respond to treatment with liso-cel, 1 had secondary CNS involvement but this patient had stable disease as of day 29.

Regarding safety, treatment-emergent adverse events (TEAEs) were observed in all 17 patients, and 13 patients experienced a grade 3/4 TEAE (76%). Serious TEAEs were observed in 10 patients (59%) and a grade 5 TEAE was observed in 1 patient, who had a dose-limiting toxicity of tumor lysis syndrome. This patient refused intubation and later died. One other patient experienced grade 5 diffuse alveolar damage, but the investigators did not consider this to be related to treatment with liso-cel.

The most common grade 3/4 TEAEs included thrombocytopenia in 6 patients at the higher dose and 1 at the lower dose (41% total), anemia in 4 patients at the higher dose and 2 at the lower (35% total), and neutropenia in 4 patients at the higher dose level and 2 at the lower dose level (35% total).

Cytokine release syndrome (CRS) occurred in 7 patients (41%), 6 of which were receiving the higher dose level of the CAR T-cell product, and 1 patient in the higher dose level had grade 3/4 CRS. The median time to onset of CRS was 7 days (range, 2-10) and the median time to resolution was 4 days (range, 2-8).

Neurotoxicity was observed in 3 patients (18%) receiving the higher dose level of liso-cel, and 2 of these events were grade 3/4. The median time to onset was 9 days (range, 7-25) and the median time to resolution was 3 days (range, 1-3). Three patients received tocilizumab (Actemra) and corticosteroids. The median maximum concentration (C

) at the lower dose level was 9790 copies/µg and was 24,400 copies/µg at the higher dose level. Wang et al noted that the increased cell expansion at the higher dose level might have been associated with the increased CRS and neurotoxicity seen in the patients who received the higher dose, yet they stressed that this observation was based on a small number of patients.

Wang M, Gordon LI, Palomba ML, et al. Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001. 

. 2019;37(suppl; abstr 7516). https://meetinglibrary.asco.org/record/174890/abstract.

The CAR T-cell therapy lisocabtagene maraleucel elicited a 71% overall response rate as well as a tolerable safety profile in a cohort of patients with relapsed/refractory mantle cell lymphoma.

Lisocabtagene Maraleucel Shows Promising Response Rates in Relapsed/Refractory MCL

The FDA has granted an orphan drug designation to the autologous CAR T-cell therapy P-BCMA-101 for the treatment of patients with relapsed/refractory multiple myeloma.

The designation is based on results of a phase I trial (NCT03288493), which demonstrated tolerability and responses with P-BCMA-101 in this patient population.

“FDA orphan designation is an important regulatory milestone in the continued development and commercialization of P-BCMA-101,” Eric Ostertag, MD, PhD, chief executive officer of Poseida, the developer of the CAR T-cell product, said in a press release. “P-BCMA-101 has demonstrated outstanding potency, with strikingly low rates of toxicity in our phase I clinical trial. In fact, the FDA has approved fully outpatient dosing in our phase II trial starting in the second quarter of 2019.”

P-BCMA-101 is comprised of self-renewing, long-lived stem cell memory T cells that are targeted to BCMA, which is known to be expressed on multiple myeloma cells. P-BCMA-101 requires only plasmid DNA and mRNA, which differs from other CAR T-cell therapies that require a viral vector. This method is said to not only lead to a higher percentage of the favorable stem cell memory T phenotype, but is also less expensive.

Orphan drug status is granted to agents and biologics that are intended to treat rare diseases that affect less than 200,000 people in the United States and also allows for increased assistance from the FDA in the accelerated development of the agent.

In the phase I dose-escalation trial, heavily pretreated patients with relapsed/refractory multiple myeloma who had received ≥3 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory drug, were enrolled. The majority of patients received ≥6 prior regimens and had prior exposure to daratumumab (Darzalex; 91%) and/or had undergone an autologous stem cell transplant (83%). Patients were not required to have any level of BCMA at baseline.

All patients underwent apheresis to harvest T cells before P-BCMA-101 could be manufactured and administered intravenously. A conditioning regimen consisting of 3 days of cyclophosphamide at 300 mg/m

 daily was administered prior to administration of P-BCMA-101.

Twenty-three patients received treatment with P-BCMA-101 in 1 of 5 dose cohorts and no dose-limiting toxicities were observed at any dose, according to results presented at the 2018 ASH Annual Meeting.

All 3 patients who received P-BCMA at a mean dose of 857 x 106 achieved a response, with 2 achieving a very good partial response. The third patient achieved a partial response and minimal residual disease negativity. Seven patients received a mean dose of 456 x 106 and the objective response rate (ORR) was 43% in these patients. In the 7 patients who received a mean dose of 152 x 106, the ORR was 71%. A minor response or better was seen in 13 of 19 evaluable patients by IMWG criteria.

Grade 1/2 cytokine release syndrome was suspected in 2 patients but was minimal and transient. Neurotoxicity was observed in 1 case of grade 2 CAR T-cell—related encephalopathy syndrome with grade 3 confusion. Neutropenia, neutrophil, and platelet count decreases were reported more frequently at any grade, as well as anemia and infections.

The phase II trial of P-BCMA-101 is expected to begin in the second quarter of 2019 with a potential biologics license application filing by the end of 2020, according to Poseida.

Poseida Therapeutics Receives US FDA Orphan Drug Designation for P-BCMA-101 for the Treatment of Multiple Myeloma [press release]. San Diego, CA: Poseida Therapeutics Inc. Published May 13, 2019. https://bit.ly/2YjCMHM. Accessed May 13, 2019.

Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-Bcma-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM). 

. 2018;132(suppl 1):1012. doi: 10.1182/blood-2018-99-111419.