Matthew Fowler

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 (JNJ-68284528; cilta-cel)  at the recommended phase 2 dose elicited early, deep, and durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data from the phase 1b/2 CARTITUDE-1 study (NCT03548207) published in 

Patients dosed with cilta-cel at the recommended phase 2 dose of 0.75×10

 CAR-positive viable T cells per kg had an overall response rate (ORR) of 97% (95% CI, 91.2%-99.4%), with 67% of patients achieving a stringent complete response (CR) at a median follow-up of 12.4 months (interquartile range [IQR], 10.6-15.2). The median time to first response was 1.0 months (IQR 0.9-1.0).

“This analysis of the phase 1b/2 CARTITUDE-1 study establishes a positive risk–benefit profile for a single low-dose infusion of cilta-cel, yielding early, deep, and durable responses in heavily pretreated patients with multiple myeloma,” the investigators wrote. “Cilta-cel is under further investigation in other populations of patients with multiple myeloma in earlier line settings.”

Trial eligibility required patients to be aged 18 years or older with multiple myeloma as characterized by the International Myeloma Working Group (IMWG) diagnostic criteria. Patients also needed measurable disease at screening and an ECOG performance status of 0 or 1. Additionally, 3 or more prior lines of therapy and documented disease progression at 12 months or less following last line of therapy were required for enrollment.

FDA Extends Cilta-Cel BLA PDUFA Date for R/R Multiple Myeloma

The primary end points of the phase 1b portion of the study were safety and confirming the recommended phase 2 dose. ORR was the primary end point of the phase 2 portion. Phase 1b and 2 of this study occurred sequentially.

Lymphodepletion was undertaken with 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine intravenously daily for 3 days. Five to 7 days after lymphodepletion, cilta-cel was given at the recommended dose of 0.75 × 106 CAR-positive viable T cells per kg.

A total of 113 patients enrolled on the study and underwent apheresis from July 16, 2018 to October 7, 2019, 97 of whom received the cilta-cel infusion. The median patient age was 61 years (IQR, 56.0-68.0) and 59% of patients were male. Seventy-five percent of patients received bridging therapy between apheresis and cilta-cel infusion.

Additional findings from the trial demonstrated a median time to best response of 2.6 months and a median time to complete response or better of 1.9 months. A total of 62% patients who achieved a CR or better responsed within 3.0 months of undergoing infusion. The median duration of response was not reached in this analysis (95% CI, 15.9–not estimable [NE]).

The median progression-free survival (PFS) was not met (95% CI, 16.8-NE) and the overall 12-month PFS rate was 77% (95% CI, 66.0%-84.3%). The 12-month PFS rates for patients achieving a CR or better and for those achieving a very good partial response (PR) or PR were 85% (95% CI, 72.0%-91.8%) and 62% (95% CI, 42.1%-76.9%), respectively. Additionally, the overall survival (OS) rate at 12 months was 89% (95% CI, 80.2%-93.5%).

Adverse effects (AEs) were reported in all 97 patients who underwent cilta-cel infusion. Common grade 3/4 hematological AEs included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Fifty-eight percent of patients experienced infections, 20% of which were grade 3/4 with common infections including pneumonia (8%) and sepsis (4%).

“Cilta-cel might be a viable treatment option for patients with relapsed or refractory multiple myeloma, with the highest overall response rate achieved to date in this heavily pretreated population who received a previous proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, including those who are triple-class refractory or penta-drug refractory,” the investigators wrote.

Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. 

. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

Articles

The recommended phase 2 dose of cilta-cel elicited deep and durable responses, along with a tolerable safety profile.

Cilta-Cel is Well-Tolerated with Durable Efficacy in R/R Multiple Myeloma

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revealed that although the rate of late mortality among patients who received allogeneic blood or 

(BMT) has decreased over the last 40 years, the reduction was specific to patients who underwent transplantation at a younger age or those who received a bone marrow transplant.

Altogether, patients that received BMT were at an 8.8-fold higher risk for all-cause mortality (95% CI, 8.4-9.3) than the general population. Relative mortality was highest in the 2- to 5-year period following BMT (standardized mortality ratio [SMR], 34.3; 95% CI, 31.7-36.9). 

Past 5 years, rates decreased, although there was still a significantly elevated rate at 30 or more years following BMT (SMR, 5.4; 95% CI, 4.0-7.1). Investigators reported that the reduction in late mortality was most notable among those who were 18 years old or younger and underwent transplantation (1990-2004: HR, 0.62; 95% CI, 0.40-0.96; 2005-2014: HR, 0.30; 95% CI, 0.16-0.54; 

 <.001). Additionally, those who received a bone marrow transplant also had better outcomes in terms of late mortality risk (1990-2004: HR, 0.70; 95% CI, 0.54-0.90; 2005-2014: HR, 0.45; 95% CI, 0.29-0.69; P < .001).

“To our knowledge, this is the first large, multi-institutional study with mature follow-up, inclusion of both adults and children, and use of rigorous methods to evaluate vital status in patients who undergo BMT,” the investigators wrote. “The data showed an improvement in outcomes over 4 decades of allogeneic transplantation among individuals who underwent transplantation at a younger age and those who received bone marrow.”

Future Research With Stem Cell Therapies in Hematologic Malignancies

The main outcomes of this cohort study were all-cause, recurrence-related, and nonrecurrence-related mortality and projected reduction in life expectancy. Research was conducted across 3 sites, including City of Hope, University of Minnesota, and University of Alabama at Birmingham.

The patient population included 4741 patients who underwent allogeneic BMT between 1974 and 2014 and survived for at least 2 years. The median age for patients at BMT was 33 years (range, 0-75 years) and the majority of patients were male (57.7%). Additionally, most patients were non-Hispanic White (68.2%), and 2204 individuals (46.5%) received a transplant between 2005 and 2014. The median follow-up after BMT was 12 years (range, 2.0-44.0 years). The most common indication was in patients with acute myeloid leukemia (AML; 26.3%).

From 2 to 35 years following BMT, mortality rates exceeded the expected population rates, with specifically greater differences in expected rates between patients with the shortest (2 years post-BMT; 39.4 deaths per 1000 person-years) and longest follow-up (35 years post-BMT; 31.0 deaths per 1000 person-years).

Among those who survived 2 or more years after receiving BMT, patients experienced a decrease in life expectancy by 20.8% or 8.7 years of life lost. These years of life lost were greatest among younger patients (age 10 years; 31% reduction or 21.5 years) and less among older patients (age 70 years; 8.4% reduction or 1 year).

Investigators reported a reduction in life expectancy of more than 25% among several patient groups, including those older than 45 years at BMT, patients who underwent transplant for acute lymphocytic leukemia, those who underwent transplant between the years of 1974 and 1989, patients who underwent transplant with high-risk disease, and those with chronic graft-versus-host disease (GVHD).

Some risk factors associated with 10-year, all-cause late mortality included older age (>45 years) at BMT (HR, 2.37; 95% CI, 1.87-3.01), male sex (HR, 1.24; 95% CI, 1.09-1.42), high-risk disease (HR, 1.44; 95% CI, 1.24-1.67), use of peripheral blood stem cells as the source (HR, 1.30; 95% CI, 1.07-1.58), and chronic GVHD history (HR, 2.11; 95% CI, 1.80- 2.49).

A decrease in the HR of 10-year all-cause mortality across all eras, including 1974 to 1989 and 1990 to 2004 (HR, 0.67; 95% CI, 0.53-0.85), as well as 1990 to 2004 (HR, 0.52; 95% CI, 0.39-0.69) after adjusting for demographic and clinical factors (

Cause of death data were available for 83.4% of the population who died, with factors such as recurrence-related mortality (RRM; 40.3%), nonrecurrence-related morbidity (NRM; 57.4%), and external causes (2.3%) included. Investigators reported a 30-year cumulative incidence rate for RRM of 12.2% (95% CI, 11.0%-13.4%).

Moreover, several factors were associated with RRM including male sex (HR, 1.28; 95% CI, 1.05-1.57); older age at BMT (HR, 1.99; 95% CI, 1.40-2.81); key primary diagnoses such as acute lymphoblastic leukemia (ALL; HR, 3.95; 95% CI, 1.66-9.37) and AML (HR, 3.22; 95% CI, 1.37-7.53); high-risk disease (HR, 1.52; 95% CI, 1.21- 1.90); and chronic GVHD (HR, 2.28; 95% CI, 1.76-2.96). Additionally, NRM had a cumulative incidence rate of 22.3% (95% CI, 20.4%-24.3%), with associated factors including older age at BMT (HR, 2.54; 95% CI, 1.77-3.66), ALL diagnosis (HR, 2.24; 95% CI, 1.10-4.56), high-risk disease (HR, 1.37; 95% CI, 1.09-1.72), and chronic GVHD (HR, 2.20; 95% CI, 1.72-2.83) as associated factors.

“There is a need to address the causes of late mortality among the older BMT recipients as well as those who receive [peripheral blood stem cells] to improve outcomes,” the investigators concluded.

Bhatia S, Dai C, Landier W, et al. Trends in late mortality and life expectancy after allogeneic blood or marrow transplantation over 4 decades: a blood or marrow transplant survivor study report. 

. Published online September 9, 2021. doi:10.1001/jamaoncol.2021.3676

A reduction in late mortality among patients who received allogeneic blood or marrow transplantation in the last 40 years was limited to those who received treatment at a younger age.


Late Mortality Has Decreased in Younger Patients Undergoing Allogeneic Blood or Marrow Transplantation

Better outcomes were observed with ciltacabtagene autoleucel (cilta-cel) for patients with relapsed/refractory multiple myeloma when compared with conventional therapies in propensity score–matched analyses of the CARTITUDE-1 (NCT03548207) and MAMMOTH trials, according to data presented at the 2021 European Hematologic Association (EHA) Congress.

CARTITUDE-1 explored ciltacabtagene autoleucel whereas the treatments for patients in MAMMOTH included pomalidomide (34% of patients), anti-CD38 monoclonal antibody (24%), carfilzomib (19%), and cytotoxic chemotherapy (35%) as next therapy. After 1:1 propensity score matching, the study included 95 patients in the intent-to-treat population (ITT) and 69 patients in the modified ITT (mITT) population from both the CARTITUDE-1 and MAMMOTH trials.

The analysis found that the overall response rate (ORR) was 84% for the CARTITUDE-1 population compared with 28% in the MAMMOTH population (odds ratio [OR], 13.4; 95% CI, 6.6-27.3; 

“Our analysis provides evidence of better outcomes with cilta-cel compared with conventional treatments in patients with relapsed/refractory multiple myeloma who had received a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody using propensity score matching,” Luciano Costa, MD, of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, explained in his presentation of the data.

In MAMMOTH, which served as the comparative control group for CARTITUDE-1, patients who received a non–CAR T-cell subsequent therapy after becoming refractory to a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody while also not having renal failure or meeting the criteria for plasma cell leukemia were in the ITT population. The mITT population included patients who also did not experience death or progression within 47 days from study inclusion to therapy initiation.

For CARTITUDE-1, the ITT population was defined as patients who underwent apheresis, while the mITT population consisted of patients who also received a cilta-cel infusion.

Survival data in the ITT populations were also significant for CAR T-cell therapy, with a 12-month progression-free survival (PFS) rate of 73% (95% CI, 64%-83%) for patients in the CARTITUDE-1 population and 12% (95% CI, 6%-21%) for patients in the MAMMOTH population. The 12-month overall survival (OS) rate followed suit, with rates of 83% (95% CI, 76%-91%) and 39% (95% CI, 30%-51%) in the CARTITUDE-1 and MAMMOTH populations, respectively.

The mITT analyses produced similar results to that of the ITT populations. The ORR for these patients was 96% in CARTITUDE-1 compared with 30% in MAMMOTH (OR, 50.3; 95% CI, 14.2-178.3; 

The 12-month PFS rate was 79% (95% CI, 69%-90%) in the CARTITUDE-1 population compared with 15% (95% CI, 7%-28%) in the MAMMOTH population (

 < .001). More, the 12-month OS rates were 88% (95% CI, 81%-96%) and 35% (95% CI, 24%-51%), respectively (

“In propensity score–matched analyses of ITT and mITT populations, ORR and 12-month PFS and OS rates were significantly higher in CARTITUDE-1 vs MAMMOTH,” wrote the investigators in their poster presentation of the data.

The CARTITUDE-1 trial treated patients with multiple myeloma who received 3 or more prior therapies or were double refractory to an IMiD and proteasome inhibitor, and who received a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody. Eligible patients received a single cilta-cel infusion of 0.75 × 106 CAR-positive viable T cells/kg, which was given 5 to 7 days after starting lymphodepletion.

Eligible patients with multiple myeloma for the MAMMOTH study were previously treated for 4 or more weeks with an anti-CD38 monoclonal antibody regimen.

While the data are useful, the research team notes that study design differences between CARTITUDE-1 and MAMMOTH limit the results. Specifically, CARTITUDE-1 is a prospective clinical study, while MAMMOTH is retrospective and observational in design.

“In the absence of a direct comparator, however, this analysis indicates that cilta-cel outperforms currently available therapies for heavily pretreated patients with multiple myeloma,” concluded the investigators.

Costa LJ, Lin Y, Martin T, et al. Comparison of Ciltacabtagene Autoleucel Versus Conventional Treatment inPatients With Relapsed/Refractory Multiple Myeloma. Presented at: 2021 European Hematologic Association Congress; Virtual. June 9-17, 2021. Abstract EP990.

Treatment with the CAR T-cell therapy ciltacabtagene autoleucel significantly improved outcomes for patients with relapsed or refractory multiple myeloma when compared with conventional therapies.

Cilta-Cel Significantly Improved Response and Survival Over Conventional Therapy for R/R MM

Frontline pembrolizumab (Keytruda) continued to demonstrate clinically meaningful improvements in overall survival (OS), overall response rate (ORR), and time to progression on next-line therapy (PFS-2) compared with platinum-based chemotherapy in patients with locally advanced or metastatic PD-L1–positive non–small cell lung cancer (NSCLC) without sensitizing 

 mutations, according to updated long-term data from the phase 3 KEYNOTE-042 trial that were presented during the 2020 World Conference on Lung Cancer Singapore.

Patients who completed 35 cycles of pembrolizumab treatment saw durable responses, and many patients experienced a continued response after the completion of therapy. A second course pembrolizumab was found to be feasible and was also associated with antitumor activity.

“These findings continue to support first-line pembrolizumab in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing 

 alterations,” explained lead investigator, Byoung Chul Cho, MD, PhD, in a virtual presentation of the data.

Median OS data for patients in the 50% or higher PD-L1 tumor proportion score (TPS) group treated with pembrolizumab was 20.0 months (95% CI, 15.9-24.2) compared with 12.2 months (95% CI, 10.4-14.6) for patients in the chemotherapy group (HR, 0.68; 95% CI, 0.57-0.82). Moreover, the 3-year OS rate was 31.3% (95% CI, 26.1%-36.6%) for the pembrolizumab group and 18.4% (95% C1, 14.2%-23.0%) for the chemotherapy group.

For the 20% or higher PD-L1 TPS group, patients on pembrolizumab experienced a median OS of 18.0 months (95% CI, 15.5-21.5) compared with 13.0 months (95% CI, 11.6-15.3) for patients on chemotherapy (HR, 0.75, 95% CI, 0.64-0.88). The 3-year OS rates were 28.3% (95% CI, 24.1%-32.8%) for the pembrolizumab group and 18.8% (95% CI, 15.1%-22.8%) for the chemotherapy group.

In the 1% or higher PD-L1 TPS cohort, the pembrolizumab group saw a median OS of 16.4 months (95% CI, 14.0-19.6) compared with the chemotherapy group at 12.1 months (95% CI, 11.3-13.3; HR, 0.80; 95% CI, 0.71-0.90). The 3-year OS rates were 25.3% (95% CI, 22.0%-28.7%) and 16.7% (95% CI, 13.8%-19.7%), respectively.

“In the KEYNOTE-042 study, pembrolizumab significantly improved OS versus platinum-based chemotherapy as first-line treatment for locally advanced/metastatic NSCLC without sensitizing 

 alterations with PD-L1 tumor proportion score greater than 1%,” Chu explained.

Median PFS in the TPS 50% or greater group was also measured, with no numerical differences noted (HR, 0.85; 95% CI, 0.71-1.02). However, at 3 years, the rate of PFS was higher in the pembrolizumab arm at 14.5% (95% CI, 10.5%-19.0%) versus 5.3% (95% CI, 3.0%-8.7%) with chemotherapy.

Similarly, median PFS was numerically similar between the pembrolizumab and chemotherapy arms in the other groups stratified by TPS. In those with a TPS of 20% or greater, the 3-year PFS rate was higher at 13.2% (95% CI, 10.0%-16.9%) in the pembrolizumab group compared with 4.7% (95% CI, 2.7%-7.5%) for patients undergoing chemotherapy. In those with a TPS of 1% or greater, the 3-year PFS rate was recorded at 11.0% (95% CI, 8.6%-13.7%) for the pembrolizumab group and 4.1% (95% CI, 2.6%-6.2%) for the chemotherapy group.

Median PFS2 was recorded at 15.0 months (95% CI, 11.6-19.2) in the pembrolizumab group compared with 10.1 (95% CI, 8.9-11.2) in the chemotherapy group in those with a PD-L1 TPS of 50% or more (HR, 0.62; 95% CI, 0.52-0.74). For PD-L1 TPS of 20% or more, median PFS2 was 12.9 months (95% CI, 10.9-15.5) for pembrolizumab versus 10.2 months (95% CI, 9.0-11.3) for chemotherapy (HR, 0.66; 95% CI, 0.57-0.77). Finally, median PFS2 was 11.3 months (95% CI, 10.1-12.9) for the pembrolizumab cohort compared with 9.3 months (95% CI, 8.6-10.2) in the chemotherapy group for PD-L1 TPS of 1% or greater (HR, 0.73; 95% CI, 0.65-0.82).

The group of eligible patients (N = 1274) were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for up to 35 weeks or platinum-based therapy. The patients randomized to the pembrolizumab group who completed the 35 treatment cycles or had confirmed complete response were eligible to receive a second course of pembrolizumab.

The primary end point of the research was OS in by PD-L1 TPS by groups of 50% or more, 20% or more, and 1% or more. Secondary end points were PFS and ORR in all expression groups and safety in the TPS 1% or greater group.

“In the primary analysis, pembrolizumab significantly improved the primary end point of overall survival in all 3 TPS populations,” said Cho.

Cho BC, Wu YL, Lopes G, et al. KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC. Presented at: 2020 World Conference on Lung Cancer Singapore. January 27-31, 2021. Abstract FP13.04.

January 28, 2021 — Frontline pembrolizumab continued to demonstrate clinically meaningful improvements in overall survival, overall response rate, and time to progression on next-line therapy compared with platinum-based chemotherapy in patients with locally advanced or metastatic PD-L1–positive non–small cell lung cancer without sensitizing EGFR or ALK mutations. 


Frontline Pembrolizumab Maintains Survival Benefit Over Chemo in PD-L1+ NSCLC 

Data from a 3-year follow up found that an inhibitor of apoptosis proteins (IAPs) antagonist with chemo-radiation therapy significantly improved overall survival (OS) for patients with high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) compared to the control group, a Debiopharm press release announced.

The data also confirmed the statistically significant improvements from the 2-year outcomes published in 

 across other end points including the doubling of the progression free survival (PFS) rate along with superior duration of response.

"These 3-year follow-up results could have major implications for high risk head and neck cancer patients, especially those with negative HPV status who appear to be associated with the poorest prognosis,” lead investigator of the study, Jean Bourhis, said in a press release. “As the compound is now advancing into phase 3, we will be able to gather further evidence for this radio-chemo enhancing IAP antagonist that has the potential to become a standard-of-care treatment for radiation oncology."

The results found that locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 95% CI, 20–48) of 48 patients in the placebo group (odds ratio [OR], 2.69; 95% CI, 1.13–6.42; 

More, grade 3 or worse adverse events (AEs) were seen in 41 of the 48 patients in the Debio 1143 group and in 41 of the 47 patients in the placebo group.2 Common grade 3 to 4 AEs in the Debio 1143 and placebo groups included dysphagia (50% vs 21%, respectively), mucositis (31% vs 21%), and anemia (35% vs 23%). No deaths were recorded due to adverse events from treatment.

"This is an important step forward for head & neck cancer patients and the research community as this potential front-line therapy could change the way these patients are treated from the start," Angela Zubel, chief development officer for Debiopharm, said in a press release.

The randomized phase 2 study evaluated the efficacy and safety of the IAP antagonist and chemo-radiation therapy combination to treat patients with LA-SCCHN. The data included 96 patients with La-SCCHN, 48 of which were randomly assigned to the Debio 1143 group and 48 patients to the placebo group.

The data shows that the inhibition of IAPs is a novel and promising approach which warrants a phase 3 study expanding the therapeutic options for patients. The researchers also believe this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator.

The compound received breakthrough therapy designation from the FDA in February 2020.

“I am very encouraged by improvement of long-term outcomes observed in our study,” said Zubel. “These results indicate that Debio 1143 in combination with CRT has the potential to prolong patient lives and achieve better control over their disease.”

1. Debiopharm's IAP Antagonist Significantly Improves Overall Survival of High-Risk Head & Neck Cancer Patients [news release]. Lausanne, Switzerland. Published August 13, 2020. 

https://www.prnewswire.com/news-releases/debiopharms-iap-antagonist-significantly-improves-overall-survival-of-high-risk-head--neck-cancer-patients-301111646.html

2. Sun X, Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study. 

. DOI:https://doi.org/10.1016/S1470-2045(20)30327-2.

A phase 2 study found that data from a 3-year follow up showed statistically significant improvements in overall survival for patients with high-risk locally advanced squamous cell carcinoma of the head and neck treated with an IAP antagonists with chemo-radiation therapy.

Follow Up Data for IAP Antagonist Shows Improved OS for Patients with High-Risk Head and Neck Cancer

CancerNetwork talked with Jesus G. Berdeja, MD, of the Sarah Cannon Research Institute regarding the CARTITUDE-1 study that examined CAR-T cell therapy to treat patients with relapsed/refractory multiple myeloma presented at the 2020 ASCO Virtual Scientific Program.

CancerNetwork: Could you provide a brief summary of the CARTITUDE-1 study that you conducted?

Berdeja: I had the pleasure of presenting the CARTITUDE-1 study at this year’s ASCO Meeting. This is a phase 1b/2 study of JNJ-4528 which is a BCMA-directed CAR T(-cell) therapy in relapsed/refractory multiple myeloma patients. JNJ-4528 is a traditional second-generation CAR T(-cell) therapy that has a cd3 zeta signaling domain and 41bb costimulatory domain. What makes it different from the other BCMA CAR-T’s is that it has 2 BCMA-targeting single chain antibodies and this is thought to confer more avidity. Its identical to the CAR construct that was used in the LEGEND 2 study.

The CAR T dose administered for this CAR T was also lower than traditionally done with other BCMA products. The median administered dose was 0.72x106 CAR-positive viable T cells per kilogram which roughly is about 50 to 60 million, if you want to compare. Basically, we presented the results of the phase 1b portion and these were 29 patients that were heavily pretreated with median 5 prior lines of therapy. The patients did well, and we saw no unexpected safety signals. Most patients had cytokine release syndrome (CRS) as expected, but mostly grade 1/2. Very few patients had grade 3 or higher CRS. In the median time of onset of CRS was 7 days, which is a little bit longer than some of the other BCMA products. Neurotoxicity was very infrequent, and generally low-grade as well with only 1 grade 3 event. We did see cytopenias in virtually all the patients but most result by 60 days and there was low incidence of any infectious complications.

The product works quite well. It had an overall response rate of 100%. Eighty-six percent of the patients had stringent complete remissions and 97% of the patients had at least a VGPR or better at a median follow-up of 11.5 months. There were 16 patients in complete remission that also had MRD assessment and of these 81% were MRD negative at 10-5 and 69% were MRD negative at 10-6. The progression-free survival at 9 months was 86% and based on this JNJ-4528 has received breakthrough therapy designation. The phase 2 portion of this study is fully enrolled, and we can’t wait to show you the results.

CancerNetwork: What is the main takeaway you want professionals to see from this study and the corresponding data?

Berdeja: I think it’s very impressive data in this patient population. I’ll remind us that in relapsed/refractory multiple myeloma the drugs that have been approved for this indication had response rates of about 30% with PFS of about 4 months. So, these types of responses are just unprecedented, and I think it’s in keeping with what we’ve seen with other BCMA products. I would say the depth of response here so quickly is actually quite impressive. I think the other thing that’s make this a little bit different is again like we’ve seen with other BCMA products its relatively well tolerated compared to the earlier cd-19 products, but also the time of onset of CRS here is very different. It’s a little bit delayed, about a week into it which may allow this to be dosed as an outpatient which I think will be a significant difference from our standard.

CancerNetwork: How does this data change the way professionals will go about treating multiple myeloma?

Berdeja: I think this is no doubt one of the lead products to become FDA approved for multiple myeloma. I think this is one of the first products that will be available hopefully to most of us. I think it will change significantly the current treatment paradigm of relapsed/refractory myeloma. Obviously at this point that’s not the case yet but I think it’s coming soon.

CancerNetwork: What are the next steps for phase 2 following the results of the 1b study?

Berdeja: I think what everyone is interested in is we’ve seen these great responses and the question is durability. Unfortunately, with the more advanced products so far, we are not seeing a flattening of the curve like we saw with lymphoma and leukemia. We were a little bit disappointed form that standpoint, but a PFS of close to a year is still quite impressive in this patient population. I think what I’m really hoping to see is that this will translate a little more, and maybe behave more like the LEGEND 2 data that was presented before. If you look at the LEGEND 2 data they presented at ASH, the most recent PFS is about 20 months and that’s obviously quite impressive. Of course, the patient population was not the same, so the question is will it translate to this population. So far, what we’re seeing is the response rates and safety data has all behaved very similarly to what the LEGEND 2 study has shown. Hopefully it will be the same with the long-term data.

CancerNetwork: Is there anything I haven’t asked that you wanted to discuss regarding this research?

Berdeja: The only thing I would mention is that like with everything else in myeloma we think this will probably work better in earlier lines of therapy. There are phase 2 and 3 studies being planned in earlier lines of therapy for myeloma patients. My suspicion is that CAR T will not be the last therapy used in patients in the near future.

Jesus G. Berdeja, MD, of the Sarah Cannon Research Institute discussed the CARTITUDE-1 study that examined CAR-T cell therapy to treat patients with relapsed/refractory multiple myeloma presented at the 2020 ASCO Virtual Scientific Program.

CARTITUDE-1 Study Results Show Promise for Patients with Relapsed/Refractory Multiple Myeloma

The FDA granted breakthrough therapy designation to JNJ-61186372 (JNJ-6372) to treat metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (

) Exon 20 insertion mutations, according to a Janssen press release.

The breakthrough therapy designation for JNJ-6372, an EGFR-mesenchymal epithelial transition factor (MET) bispecific antibody, was approved for those whose disease has progressed on or after platinum-based therapy.

"JNJ-6372 is a novel bispecific antibody that we believe has the potential to benefit patients with Exon 20 mutation insertions who often do not respond to currently available oral EGFR-targeted or immune checkpoint inhibitor therapies," Peter Lebowitz, MD, PhD, global therapeutic area head, Janssen Research & Development, LLC, said in a press release.

Data from the open-label, multicenter phase I trial supported the FDA’s breakthrough designation, in which the researchers examined the safety, pharmacokinetics and preliminary efficacy of JNJ-6372 monotherapy and in combination with lazertinib in adult patients with advanced NSCLC. The study aims to determine the recommended phase II dose.

exon 20 is typically insensitive to EGFR tyrosine kinase inhibitor (TKI) treatments, according to the press release. Enrollment in the phase II cohort is ongoing, with researchers hoping to evaluate JNJ-6372 monotherapy in a number of NSCLC sub-populations.

"This breakthrough therapy designation is a significant milestone in our ongoing efforts to advance JNJ-6372 in clinical development and target genetically-defined lung cancer," said Lebowitz in a press release.

NSCLC makes up about 80%-85% of all lung cancer cases, making it the second most common cancer behind skin cancer. The 

mutation is present in roughly 10%-15% of patients, while the 

exon 20 insertion mutation is found much less frequently, accounting for at least 9% of 

The FDA grants breakthrough designation to investigational medicine in the hopes of expediting the review process. The designation requires preliminary clinical evidence for the drug which hopes to treat a serious or life-threatening condition.

Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for JNJ-6372 for the Treatment of Non-Small Cell Lung Cancer [news release]. Raritan, New Jersey. Published March 10, 2020. 

https://www.prnewswire.com/news-releases/janssen-announces-us-fda-breakthrough-therapy-designation-granted-for--jnj-6372-for-the-treatment-of-non-small-cell-lung-cancer-301020992.html

Janssen Pharmaceutical Companies recently announced the FDA granted breakthrough therapy designation to JNJ-61186372, an EGFR-MET bispecific antibody, for the treatment of metastatic non-small cell lung cancer with EGFR exon 20 mutations.

FDA Grants Breakthrough Therapy Designation to JNJ-6372 for NSCLC

The FDA approved an application for an investigational new drug (IND) for Calibr’s “switchable” CAR T-cell therapy to treat certain cancers, such as non-Hodgkin lymphoma and chronic lymphocytic leukemia, according to a news release.

Calibr, a drug discovery and development division of Scripps Research, announced the approval on February 3. The division will now look to begin clinical trials for CLBR001 + SWI019, the organization’s novel cell therapy candidate.

The therapy, as described by the Scripps Research Institute news release, “leverages a patient's own immune cells to treat cancer.” If successful, the therapy has the potential to eliminate the life-threatening side effects typically seen in cell therapies to date by putting the immune cells under the control of a molecular “switch.”

"CLBR001 + SWI019 is a first-in-class switchable CAR-T cell platform designed to confer the efficacy associated with engineered T cell therapies, while potentially affording greater safety and versatility through the incorporation of a control switch," said Travis Young, PhD, in a news release.

Young, Calibr's vice president of biologics and leader of its CAR T development program, believes this therapy has the potential to be “universally applied to other types of cancer, including solid tumor cancers that have yet to reap the benefits of CAR T therapies.”

The switchable CAR T-cell therapy Calibr invented incorporates the antibody SWI019, which activates the cell and directs it to engage the cancer target. The switch, which proved extremely effective at eliminating tumors and managing cytokine levels in preclinical trials, has the potential to help doctors regulate the potency of therapies and safety of treatment.

"AbbVie continues to be impressed by Calibr's progress on advancing this innovative switchable cell therapy technology," said Mohit Trikha, PhD, in a news release.

Calibr recently partnered with AbbVie in which the biopharmaceutical company holds specific rights to commercialization. Trikha, the vice president and head of oncology early development and Bay Area site head at AbbVie, continued to say, “This milestone is an important step forward for this potential CAR-T therapy and our recently expanded collaboration with Scripps Research, which holds promise to rapidly advance additional treatment options for patients.”

Calibr expects to begin recruitment and enrollment for this phase I clinical trial in the first half of 2020, with Calibr’s chief medical officer Pamela D. Garzone, PhD, leading the clinical development of CLBR001 + SWI019. The trial has the potential to eventually evolve its platform to include solid tumors.

FDA clears investigational new drug application for Calibr's 'switchable' CAR-T therapy [news release]. La Jolla, California. Published February 3, 2020. 

https://www.eurekalert.org/pub_releases/2020-02/sri-fci020320.php

Calibr received approval from the FDA to move forward with an investigational new drug to treat relapsed/refractory B-cell malignancies with a switchable CAR T-cell therapy.