Gina Mauro

Primary findings from the phase 3 SPOTLIGHT trial (NCT03504397) showed that the combination of zolbetuximab plus mFOLFOX6 in the first-line significantly improved progression-free and overall survival (OS) vs placebo/mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma.

Results presented during the 2023 Gastrointestinal Cancers Symposium showed that the median progression-free survival (PFS) by independent review committee was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28) with placebo/mFOLFOX6, leading to a 25% reduction in the risk of disease progression or death (HR, 0.751; 95% CI, 0.589-0.942; 

“Zolbetuximab plus mFOLFOX6 is a new potential standard-of-care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma,” said Kohei Shitara, MD, the lead study author of the trial and a medical oncologist at National Cancer Center Hospital East in Japan, in a presentation during the meeting.

Standard treatment for patients with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, but there is still an unmet need in terms of targeted therapies for this population.

 Currently, the median OS is approximately 1 year.

CLDN18.2 is a tight junction protein that is expressed in normal gastric mucosa cells and is retained in advanced gastric/GEJ tumor cells. As CLDN18.2 may become exposed on the surface of gastric/GEJ cells, Shitara noted that it makes a promising target.

Zolbetuximab, which is a first-in-class CLDN18.2-targeting chimeric IgG1 monoclonal antibody that induces antibody-dependent cellular cytotoxicity/complement dependent cytotoxicity, resulted in a prolongation of survival in patients with higher expression of CLDN18.2 in the phase 2b FAST trial (NCT01630083).

 Here, the median PFS was 9.0 months with zolbetuximab and epirubicin, oxaliplatin, and capecitabine (EOX) vs 5.7 months with EOX alone; the median OS was 16.5 months and 8.9 months, respectively.

The international, double-blind, placebo-controlled SPOTLIGHT trial enrolled patients with previously untreated locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma and CLDN18.2 positivity. To be eligible for enrollment, patients must have had moderate-to-strong CLDN18 staining in at least 75% of tumor cells, have HER2-negative disease, and an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to receive the combination of zolbetuximab and mFOLFOX6 (n = 283) or placebo and mFOLFOX6 (n = 282).

Zolbetuximab was given intravenously (IV), at 800 mg/m2 on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles, every 3 weeks and mFOLFOX6 was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, zolbetuximab was given at the same dosing schedule in combination with 5-fluorouracil (5-FU) and folinic acid IV every 2 weeks. Those in the placebo arm were given placebo at the every-3-week schedule and chemotherapy was administered at the same dosing schedule.

Patients were stratified by region (Asian vs non-Asian), number of organs with metastases (0-2 vs ≥3), and prior gastrectomy (yes vs no).

The primary end point was PFS. Key secondary endpoints were OS, time to confirmed deterioration in global health status/quality of life, physical functioning, and OG25-Pain. Additional outcome measures included objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes (PROs).

As part of the study design, OS was only tested if the PFS benefit with zolbetuximab was found to be significant. Shitara noted that the interim OS analysis was planned at the primary PFS analysis, with a cutoff date of September 9, 2022, for both analyses. In the interim OS analysis, the 1-sided 

 value threshold for significance was .0135.

Regarding baseline characteristics, the median age was 61.0 years (range, 20-86), 62.2% of patients were male, and 31.4% of patients were from Asia. Most patients had 0 to 2 organs with metastases (77.6%), and 29.4% of patients had prior gastrectomy. The primary disease site was stomach in 76.0% of patients and was GEJ in 24.1%.

The Lauren classification of disease was diffuse (35.6%), intestinal (24.3%), or mixed/others (39.8%). More than half of patients had an ECOG performance status of 1 (56.7%). A total 13.2% of patients had tumors with a PD-L1 combined positive score of at least 5, which was part of an ad-hoc analysis.

Forty-eight percent of patients in the zolbetuximab arm received subsequent anticancer therapies vs 53% in the placebo arm.

Additional data showed that the 12- and 24-month PFS rates were 49% and 24%, respectively, in the zolbetuximab arm and 35% and 15%, respectively, in the placebo arm. The PFS benefit with zolbetuximab/mFOLFOX6 was observed across most prespecified subgroups, except for those whose primary site of disease was GEJ (HR, 1.015; 95% CI, 0.649-1.586) and with mixed/other classification (HR, 0.929; 95% CI, 0.601-1.434).

The median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab/mFOLFOX6 and 15.54 months (95% CI, 13.47-16.53) with placebo/mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; 

At 12, 24, and 36 months, the OS rates in the zolbetuximab and placebo arms, respectively, were 68% vs 60%, 39% vs 28%, and 21% vs 9%, respectively. Similar to the PFS analysis, the OS benefit was seen in most patient subgroups, except for those with GEJ as the primary site of disease (HR, 1.072; 95% CI, 0.690-1.666) and others with mixed/other classification (HR, 0.992; 95% CI, 0.638-1.543).

The ORR with zolbetuximab was 60.7% (95% CI, 53.72%-67.30%) and 62.1% (95% CI, 55.17%-68.66%). The best overall response was a complete response in 5.7% and 3.3% of zolbetuximab- and placebo-treated patients, respectively; a partial response in 55.0% and 58.8% of patients, stable disease in 21.3% and 24.6% of patients, and progressive disease in 6.6% of patients on both arms. The median DOR was 8.51 months (95% CI, 6.80-10.25) on the zolbetuximab arm and 8.11 months (95% CI, 6.47-11.37) on the placebo arm.

Shitara noted that the formal PROs analysis is pending, but an initial descriptive analysis did not indicate differences between treatment arms.

Regarding safety, the incidence of treatment-emergent adverse effects (TEAEs) was similar between arms, at 99.6% in both treatment groups. Grade 3 or higher TEAEs were reported in 86.7% and 77.7% of those on the zolbetuximab and placebo arms, respectively; serious TEAEs occurred in 44.8% and 43.5%. Treatment-related adverse effects that led to treatment discontinuation of zolbetuximab or placebo occurred in 13.6% and 2.2% of patients, respectively. Moreover, 1.8% and 1.4% of TRAEs, respectively, led to death.

The most common TEAEs associated with zolbetuximab/mFOLFOX6 were nausea (all-grade, 81.0%; grade ≥3, 16.1%), vomiting (all-grade, 64.5%; grade ≥3, 16.1%), and decreased appetite (all-grade, 47.0%; grade ≥3, 5.7%). Shitara added that the first occurrence of nausea and vomiting took place in the first or second treatment cycles.

1. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. 

. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

2. Van Cutsem, Sagaert X, Topal B, et al. Gastric cancer. 

. 2016;388(10060):2654-2664. doi:10.1016/S0140-6736(16)30354-3

3. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. 

. 2021;32:609-619. doi:10.1016/j.annonc.2021.02.005

Articles

The combination of zolbetuximab and mFOLFOX6 prolonged survival in patients with CLDN18.2+ advanced gastric gastroesophageal junction  adenocarcinoma, according to the phase 3 data from the SPOTLIGHT trial.

Zolbetuximab and mFOLFOX6  Survival in CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma 

The humanized IGG1 monoclonal antibody sotigalimab, in combination with pembrolizumab (Keytruda), demonstrated antitumor activity and was well tolerated in the frontline setting of patients with metastatic melanoma, according to updated phase 1/2 findings presented during the Society for Immunotherapy for Cancer’s (SITC) 37th Annual Meeting.

As of October 28, 2022, the overall response rate (ORR) by RECIST 1.1 criteria among 32 patients on the study (NCT02706353) was 47%, which consisted of a 16% complete response rate and a 31% partial response rate; the stable disease rate was 22% and 31% of patients had progressive disease. The disease control rate was 69%.

The ORR at the recommended phase 2 dose (RP2D) of 10 mg sotigalimab was 50%.

“[The combination] showed oncologic activity, and from our biomarker analysis we demonstrated that the combination of sotigalimab with pembrolizumab can induce broad innate and adaptive immune activation in both local and distant lesions,” lead study author Salah-Eddine Bentebibel, PhD, of the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center (MD Anderson), said in a presentation.

Intratumoral immunotherapy operates on the principal of using the tumor as its own vaccine; local intratumoral injection of immunostimulatory agents is designed to trigger tumor-specific immunity. This leads to distant effects of systemic antitumor immunity against non-injected tumor sites. 

Although checkpoint inhibitors are an important modality for the treatment of patients with metastatic melanoma, physicians need new combinations to improve benefit-risk profiles. Principal investigator Adi Diab, MD, an associate professor in the Department of Melanoma Medical Oncology at MD Anderson, explained that many patients are unresponsive to immune checkpoint inhibitors or develop resistance after initial tumor regression.

“Results from the ongoing phase 2 trial of intratumoral sotigalimab and the PD-1 inhibitor pembrolizumab showed a promising ORR including responses achieved in PD-L1–negative tumors,” he said in a news release.

 “Moreover, this encouraging anti-tumor activity correlated with treatment-induced immunologic changes, such as activated myeloid dendritic cells and macrophages, which support the mechanism of action and differentiated activity of sotigalimab—ultimately leading to inflammatory immune responses in the local injected tumor as well as distant non-injected lesions.”

In the phase 1/2 dose-escalation/dose-expansion study, investigators assessed the safety and tolerability of sotigalimab plus pembrolizumab in the frontline setting of patients with metastatic melanoma. The primary end point was maximum tolerated dose and RP2D; additional outcome measures were ORR by RECIST 1.1 criteria and biomarker assessment in blood and tumor samples.

To be eligible for enrollment, patients had histologically or cytologically confirmed cutaneous or mucosal stage III/IV melanoma that was measurable and unresectable. Patients had to have an ECOG performance status of 0 or 1, adequate organ function, and fresh biopsy and archival tissue. 

The phase 1 dose-escalation portion (n = 14) included checkpoint inhibitor–naïve patients who received intravenous pem-brolizumab at 2 mg/kg plus sotigalimab at 0.1 mg, followed by increasing doses of sotigalimab at 0.5 mg, 1 mg, 3 mg, and 10 mg. Sotigalimab was given every 3 weeks for a total of 4 injections.

The RP2D was sotigalimab was at 10 mg, which was used in the phase 2 portion (n = 18).In the total population of 32 patients, 84% were male, the median age was 64.5 years (range, 32-81), and 44% of patients had an ECOG performance status of 1. Thirty-four percent of patients had BRAF-positive disease, lactate dehydrogenase (LDH) levels at baseline were below the upper limit of normal in half of patients, and 25% of patients had PD-L1–positive disease. Fifty-three percent of patients had stage IV M1a or M1b disease, 22% had stage MI1c disease, and 25% had stage III disease.

Additional findings showed that clinical responses were reported in both PD-L1–negative tumors and patients with elevated LDH. 

Safety data demonstrated that the combination is well tolerated, Bentebibel said, adding that there were no study discontinuations or deaths due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions, and 18% of patients (n = 6) had grade 3 immune-related AEs. No dose-limiting toxicities were reported at any dose level.

Through NanoString gene expression, investigators noted that sotigalimab engaged CD40 activation, macrophage activation, and upregulation of genes associated with antigen-presenting cells. Additionally, preexisting interferon-γ–mediated immune activation in baseline tumor tissue was not correlated with response to the combination.

Bentebibel also pointed out that patients who responded to pembrolizumab plus sotigalimab appeared to have high preexisting CD11c+ myeloid cells and CD11c+DC-LAMP+ DC cells. Furthermore, the combination activates the DC and increases macrophage signature in both local and distant tumors. 

Finally, patients who responded to treatment experienced an on-treatment increase in CD8+ T, cytotoxic, and Th1 scores in the tumor, as well as an increase in CD8+ T-cell proliferation. Bentebibel also noted that, through T-cell receptor sequencing in tumor samples, the regimen led to an increase in T-cell infiltration, clonality, and a new clone expansion shared between local and distal lesions.

Data from a phase 2 trial (NCT03123783) presented during the 2021 SITC Annual Meeting showed that the combination of sotigalimab plus nivolumab (Opdivo) elicited durable responses with a reasonable safety profile in patients with melanoma who were refractory to anti–PD-1 therapy.

 The ORR was 15.2% (95% CI, 6.2%-29.3%) among 33 evaluable patients. 

1. Bentebibel S-E. Intratumoral sotigalimab with pembrolizumab activates antigen-presenting cells and induces local and distant anti-tumor responses in first-line metastatic melanoma: results of a phase I/II study. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 782.

2. Apexigen announces new data from a phase 1/2 trial evaluating its CD40 antibody, sotigalimab, in combination with pembrolizumab in patients with first-line metastatic melanoma at the SITC 2022 Annual Meeting. News release. November 11, 2022. Accessed November 16, 2022. https://bit.ly/3EBf2H7

3. Weiss SA, Sznol M, Shaheen M, et al. Phase II of CD40 agonistic antibody sotigalimab (APX005M) in combination with nivolumab in subjects with metastatic melanoma with confi rmed disease progression on anti-PD-1 therapy. 

. 2021;9(suppl 2). doi:10.1136/jitc-2021-SITC2021.389

Findings from a phase 1/2 trial showed that sotigalimab plus pembrolizumab led to antitumor activity and was well tolerated in the frontline setting of patients with metastatic melanoma.

Broad Immune Activity Is Observed With Sotigalimab Combo in Frontline Melanoma

Investigators from phase 2 TACTI-002 trial (NCT03625323) reported deep and durable responses for the immunotherapy combination of pembrolizumab (Keytruda) and eftilagimod alpha (efti; IMP321) in patients with advanced non–small cell lung cancer (NSCLC). Updated findings from the trial were presented during the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting & Pre-Conference Programs in Boston, Massachusetts.

The first-line combination elicited a 40.4% (95% CI, 31.3%-50.0%) overall response rate (ORR) by immune RECIST (iRECIST) criteria in the intention-to-treat (ITT) population. The ORR was comprised of a 0.9% complete response (CR) rate and a 39.5% partial response (PR) rate. Additionally, 32.5% of patients had stable disease (SD), 15.8% of patients had progressive disease (PD), and 11.4% of patients were not evaluable (NE) (FIGURE

). The median duration of response (DOR) was 21.6 months (95% CI, 17.3-30.0).

When assessed by RECIST v1.1 criteria, the ORR in the ITT population was 38.6% (95% CI, 29.6%-48.2%) and included a 0.9% CR rate and a 37.8% PR rate. The SD and PD rates were 32.5% and 17.5%, respectively. A total of 11.4% of patients were NE.

“We did see deep and durable responses across subgroups; there did appear to be a stepwise benefit by PD-L1 score from 0% to [between] 1% to 49% to greater than 50%,” lead study author Wade T. Iams, MD, said in a presentation during the meeting. Iams is an assistant professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center in Nashville, Tennessee. “The combination of eftilagimod alpha and pembrolizumab is safe and tolerable, and there are ongoing studies in latestage development for this combination,” he said.

Efti is a soluble LAG-3 protein that binds to a subset of major histocompatibility complex class II molecules and mediates antigen-presenting cell and CD8 T-cell activation in patients. T cells are recruited by stimulating the dendritic cell network, which has the potential to produce more potent antitumor responses when paired with pembrolizumab vs what has been reported with pembrolizumab alone.

In October 2022, the FDA granted a fasttrack designation to efti for use in combination with pembrolizumab as a frontline treatment for patients with stage IIIB/IV NSCLC with a PD-L1 tumor proportion score (TPS) of at least 1%, based on earlier findings from the TACTI-002 trial.

In the 3-part, international, open-label trial, patients with NSCLC had measurable disease per RECIST v1.1 criteria, had an ECOG performance status of 0 to 1, and submitted available tumor tissue for central PD-L1 testing. Patients were unselected for PD-L1 status. The trial used the combination in the first-line setting where patients were unselected for PD-L1 (part A; n = 114), the second-line setting for patients resistant to PD-1/PD-L1–based therapy (part B; n = 36), and the second-line setting for patients with head and neck squamous cell carcinoma who had received platinum-based therapy (part C; n = 39).

The findings from part A were presented during the SITC 37th Annual Meeting & Pre-Conference Programs. In this part, efti was administered every 2 weeks and pembrolizumab administered every 3 weeks for 8 cycles, followed by both efti and pembrolizumab given every 3 weeks for 9 cycles up to 1 year. Maintenance pembrolizumab was given every 3 weeks for 16 cycles up to 1 year. Patients were followed for progression-free survival (PFS) and overall survival (OS).

The primary end point was ORR by iRECIST criteria, and secondary end points were ORR by RECIST v1.1 criteria, DOR, safety, PFS, OS, and pharmacokinetics/ pharmacodynamics. The data cutoff date for part A was July 1, 2022.

Part A comprised 114 patients from 18 sites across 6 countries between March 2019 and November 2021, and the minimum follow-up was 7 months. The median time since diagnosis was 1.5 months.

Regarding baseline characteristics for part A, the median age was 67 years (range, 44-85), 26.3% of patients were female, and 62.3% of patients had an ECOG performance status of 1. Most patients were current or former smokers (94.7%) and had metastatic disease (99.1%). Squamous histology was reported in 35.1% of patients.

A total of 35.6% and 42.2% of patients had a PD-L1 TPS of less than 1% and between 1% and 49% by central assessment only, respectively. Additionally, 34.3% and 38.9% of patients had a PD-L1 TPS of 1% and between 1% and 49% by central and local assessment, respectively. A total of 22.2% and 26.9% of patients had a PD-L1 TPS of 50% or greater by central and central plus local assessment, respectively. Additional data showed that in the efficacy evaluable population (n = 101), the ORR was 45.5% (95% CI, 35.6%-55.8%) by iRECIST criteria and 43.6% (95% CI, 33.7%- 53.8%) by RECIST v1.1 criteria.

Response rates improved with increasing PD-L1 TPS. For example, in those with a PD-L1 TPS of less than 1% (n = 32), the ORR was 31.3% (95% CI, 16.1%-50.0%), compared with a 44.7% ORR (95% CI, 28.6%-61.7%) in those with a PD-L1 TPS of 1% to 49% (n = 38) and a 55% ORR (95% CI, 31.5%-76.9%) in those with a PD-L1 TPS of 50% or greater (n = 20). In patients whose tumors had a PD-L1 TPS of 1% or greater (n = 58), the ORR was 48.3% (95% CI, 35.0%-61.8%).

The disease control rates (DCRs) in patients whose tumors had a PD-L1 TPS of less 1%, between 1% and 49%, 50% or greater, and 1% or greater were 65.6% (95% CI, 46.8%-81.4%), 78.9% (95% CI, 62.7%-90.5%), 80% (95% CI, 56.3%-94.3%), and 79.3% (95% CI, 66.7%-88.8%), respectively.

Furthermore, response rates were similar in those with squamous (37.5%; 95% CI, 22.7%-54.2%) and nonsquamous (40.3%; 95% CI, 28.9%-52.5%) histology. The DCRs were 82.5% (95% CI, 67.2%-92.7%) and 66.7% (95% CI, 54.6%-77.3%), respectively.

Overall, the median PFS was 6.6 months (95% CI, 4.6-9.3) and the 6-month PFS rate was 56.2%. Iams noted that PFS was improved proportionally to PD-L1 expression levels. The median PFS was 16.7 months (95% CI, 4.0-16.8) in those with a PD-L1 TPS of 50% or greater, 8.3 months (95% CI, 4.4-15.7) in those with a PD-L1 TPS between 1% and 49%, 4.2 months (95% CI, 3.6-6.1) in those with a PD-L1 TPS of less than 1%, and 9.3 months (95% CI, 6.1-15.7) in those with a PD-L1 TPS of 1% or greater.

The median treatment exposure for the combination was 24.7 weeks (range, 1-58) and 24.2 weeks (range, 0.1-103.3) for maintenance pembrolizumab. Six patients completed the 2 years of treatment, whereas 24 were still on therapy at the data cutoff date.

The safety profi le was consistent with prior reports on the combination. Adverse effects (AEs) of Grade 3 or above occurred in 12.3% of patients, and serious AEs occurred in 10.5% of patients. AEs that led to treatment discontinuation occurred in 9.6% of patients, and AEs that led to death occurred in 3 patients.

AEs of any grade by preferred term were pruritus (20.2%), asthenia (19.3%), rash (13.2%), diarrhea (10.6%), and fatigue (10.5%). Grade 3 diarrhea and fatigue were reported in 1 patient each.

Data from part B of the trial were presented during the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer in Vienna, Austria. Here, efti plus pembrolizumab showed encouraging PFS and OS in the second-line setting in patients with NSCLC who showed progression on anti–PD-1/ PD-L1 therapy. The median OS was 9.7 months, and the 18-month OS rate was 36.5%.

1. Iams W, Felip E, Majern M, et al. Combining the antigen-presenting cell activator eftilagimod alpha (soluble LAG-3) and pembrolizumab: effi cacy results from the 1st line non-small cell lung cancer cohort of TACTI-002 (phase II). Abstract presented at: Society for Immunotherapy of Cancer 37th Annual Meeting & Pre-Conference Programs; November 8-12, 2022; Boston, MA. Abstract 1470.

2. Immutep receives FDA fast track designation for LAG-3 therapeutic eftilagimod alpha for fi rst line non-small cell lung cancer. News release. Immutep. October 4, 2022. Accessed November 11, 2022. h ps://bit.ly/3C5MuTD

3. Immutep reports new positive interim data from its phase II study of LAG-3 candidate, eftilagimod alpha, in 2nd line PD-X refractory NSCLC. News release. Immutep. August 1, 2022. Accessed November 10, 2022. h ps://bit.ly/3JnIWPU

Updated findings from the TACTI-002 trial of pembrolizumab and eftilagimod alpha in non–small cell lung cancer were presented during the Society for Immunotherapy of Cancer 37th Annual Meeting & Pre-Conference.

Eftilagimod Alpha Combination Demonstrates Durable Responses in Frontline NSCLC

The investigational allogeneic CRISPR-Cas9 gene-edited, anti-CD70 chimeric antigen recep-tor (CAR) T-cell therapy, CTX130, led to an objective response rate of 8%, a stable disease (SD) rate of 69%, and a disease control rate of 77% in patients with advanced clear cell renal cell carcinoma (RCC). Findings from the phase 1 COBALT-RCC trial (NCT04438083) were presented during the Society for Immunotherapy of Cancer’s 37th Annual Meeting.

In 13 evaluable patients, 1 had a partial response that became a complete response (CR) by 3 months, with a maintained CR at 18 months. As of 4 months, 4 patients had SD. The therapy had an acceptable safety profile across all dose levels, with no dose-limiting toxicities (DLTs). Of the 14 patients in the study, 50% had grade 1/2 cytokine release syndrome (CRS), 3 of which were related to CTX130. The median time to CRS onset was 1 day, with a median duration of 2 days.  Three patients had serious adverse events (AEs) that were infec-tions, all of which were unrelated to CTX130. There was 1 death of pneumonia with grade 4 dyspnea, which was not considered to be related to treatment.

“This first-in-human clinical trial exploring CD70 CAR T-cell therapy in clear cell renal cell carcinoma showed a tolerable safety profile, with no unexpected on-target, off-tumor toxicities and encouraging antitumor activity,” lead study author Sumanta K. Pal, MD, a professor in the Department of Medical Oncology and Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope in Duarte, California, said in a presentation during the meeting. “To our knowledge, this durable [CR] is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed/refractory solid tumors.”

CD70 is a CD27 ligand that has transient expression on activated lymphocytes, and it is found to be highly expressed in clear cell RCC tumor samples. CTX130 is a first-in-class, CD70-targeting allogeneic CAR T-cell therapy that is being evaluated in patients with advanced clear cell RCC. The therapy has targeted disruption of the T-cell receptor α constant (TRAC), β2 microglobulin, and CD70 loci. With the use of an adeno-associated virus vector, an anti-CD70 CAR cassette is inserted into the TRAC locus by homology-directed repair. 

The CAR T-cell therapy is manufactured from healthy donor T cells that are then selected and edited prior to expansion and cryopreservation for off-the-shelf use. Preclinical data demonstrated encouraging signals in an RCC xenograft model, Pal noted.

In the open-label, multicenter, international, single-arm COBALT-RCC trial, investigators sought to evaluate the safety and efficacy of CTX130 in patients with advanced clear cell RCC (FIGURE

). The study had 2 parts: a dose-escalation portion (part A) and a cohort expansion portion (part B). 

Patients underwent lymphodepletion with fludarabine at 30 mg/m

 of cyclophosphamide for 3 days on days –5, –4, and –3. CTX130 infusion began on day +1, with the dose-escalation design: 3 × 10

To be eligible for enrollment, patients with unresectable or metastatic RCC with clear cell differentiation had to be at least 18 years old and have a body weight of 42 kg or higher. Prior exposure to a checkpoint inhibitor and VEGF inhibitor were required. Patients also had to have a Karnofsky performance status of at least 80%, as well as adequate renal, liver, cardiac, and pulmonary organ function. Those who had prior treatment with anti-CD70 therapy, CAR T cells, or any other modifi ed T or natural killer cells were excluded from enrollment, as well as those with a history of central nervous system, cardiac, or pulmonary conditions and prior solid organ transplantation or bone marrow transplant. 

The primary end point of part A of the trial was incidence of AEs via DLTs; in part B, the primary end point was objective response rate (ORR) per RECIST v1.1 criteria. Secondary end points were best overall response, progression-free survival, and overall survival. 

The median age was 64.5 years (range, 54-77), and 85.7% of patients were men. All patients had stage IV metastatic disease and previously received systemic therapy; 64.3% and 92.9% of patients received prior radiotherapy and surgery, respectively.

A total of 57.1% of patients had Inter-national Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease, whereas 42.9% of patients had high-risk disease. An estimated glomerular filtration rate of less than 60 mL/min/1.73 m

 was reported in 42.9% of patients. The median time from diagnosis was 4.9 years (range, 0.7-24.0), and the sum of diameters for target lesions was 64 mm (range, 12-141). 

Pal added that typical pharmacokinetics were seen, with peak time to expansion at a median of day 10 and peak concentration of approximately 3500 copies/μg. 

1. Pal SK, Tran B, Haanen JB, et al. CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcino-ma: results from the phase 1 COBALT-RCC study. Presented at: Society for Immunotherapy of Cancer’s 37th Annual Meeting; November 6-10, 2022; Boston, MA. Accessed December 5, 2022. https://bit.ly/3VNBum4

According to findings from the phase 1 COBALT-RCC trial, CTX130 led to an objective response rate of 8%, a stable disease rate of 69%, and a disease control rate of 77% in patients with advanced clear cell renal cell carcinoma.

Early Promise Is Seen With CTX130 for RCC

In MOMENTUM, momelotinib induces durable symptom, transfusion independence (TI), and splenic responses through 48 weeks of treatment in patients with myelofibrosis who have anemia and previously received a JAK inhibitor, according to data from the phase 3 open-label crossover phase in the study (NCT04173494).

Findings, which were presented during the 2022 ASH Annual Meeting, showed that in the open-label continuation phase where patients stayed on momelotinib or crossed over from danazol to receive momelotinib, the week 24 symptom responses were sustained through week 48 of treatment in 97% of patients on the momelotinib-to-momelotinib arm and 100% in the danazol-to-momelotinib arm.

Additionally, 29% of patients who did not have a Total Symptom Score (TSS) response to danazol and crossed over to momelotinib at week 24 achieved TSS responses at 48 weeks. Twenty percent of patients who continued momelotinib in the open-label phase from momelotinib in the double-blind phase were also new responders at week 48.

“In this updated analysis of open-label momelotinib, the patients maintained week 24 symptom, transfusion, and spleen responses and continued with a safety profile that was very consistent with the overall [intent-to-treat] analysis,” lead study author Aaron T. Gerds, MD, an assistant professor in medicine (hematology and medical oncology), Cleveland Clinic Taussig Cancer Institute, said in a presentation of the data. “These findings support the potential use of momelotinib as an effective treatment in patients with myelofibrosis, particularly in patients with anemia and thrombocytopenia.”

Momelotinib is a JAK1, JAK2, and ACVR1 inhibitor designed to address myelofibrosis symptoms, spleen, and anemia. In August 2022, the FDA accepted a new drug application for momelotinib for the treatment of patients with myelofibrosis, based on preliminary MOMENTUM findings.

In the prior results, which comprised data at week 24, the Myelofibrosis Symptom Assessment Form TSS response rate achieved with momelotinib was 24.6% vs 9.2% with danazol (

 = .0095); the TI response rates were 30.8% vs 20.0%, respectively (noninferior 1-sided 

 = .0064), and the splenic response rate (SRR) with a 35% reduction (SRR35) was 23.1% vs 3.1%, respectively (

The double-blind, international, ongoing, phase 3 MOMENTUM trial enrolled patients with myelofibrosis who were symptomatic (TSS ≥100), anemic (hemoglobin [HgB] <10 g/dL), and platelet levels at least 25 x 10

/L. Patients were randomly assigned 2:1 to receive momelotinib at 200 mg daily plus placebo (n = 130) or danazol at 600 mg daily plus placebo (n = 65). All patients had to have received prior treatment with a JAK inhibitor.

Early crossover to momelotinib was permitted if disease progression was confirmed. In the open-label crossover phase after 24 weeks of treatment, momelotinib was given at 200 mg daily.

Patients were stratified by TSS, palpable spleen length, transfused units in prior 8 weeks, and study site.

Regarding baseline characteristics, the median age was 70.6 years, and 64.3% of patients were male. The mean HgB was 8.0 g/dL, and approximately 48% of patients had a HgB greater than 8 g/dL. Approximately half of patients across both arms (50.4%) were transfusion dependent and the transfusion receiving rate was 35.4%.

As of May 17, 2022, 40 of the patients who were initially on the danazol arm crossed over to receive momelotinib. In the next 24 weeks of treatment in the open-label phase, 20.0% of these patients (n = 27) discontinued momelotinib therapy due to investigator’s discretion (n = 3), adverse effects (AEs; n = 1), patient decision (n = 3), insufficient efficacy (n = 2), death (n = 2), leukemic transformation (n = 1), and disease progression (n = 1). Of those who were on momelotinib in both phases, 20.8% (n = 13) discontinued momelotinib due to investigator’s discretion (n = 3), AEs (n = 11), patient decision (n = 3), insufficient efficacy (n = 3), death (n = 6), and disease progression (n = 1).

The primary end point of the trial was TSS response rate at week 24. Secondary end points included TI and SRR at week 24.

Further data showed that through week 48, the week 24 TI response was maintained in 90% of patients on the momelotinib-to-momelotinib arm and 77% of those in the danazol-to-momelotinib arm. All patients who had splenic responses that were reported at week 24 maintained their spleen volume below baseline on both arms.

An additional analysis of momelotinib presented during the 2022 ASH Annual Meeting looked at the consecutive 12-week TI-response rate with the 2 arms, which was 44.6% and 29.2% with momelotinib to momelotinib and danazol to momelotinib, respectively.

Gerds noted that no new safety signals were reported in the open-label phase of momelotinib treatment and were similar between arms. In the momelotinib-to-momelotinib arm, grade 3 or higher AEs and serious AEs occurred in 49.5% and 31.2% of patients, respectively. The grade 3 or higher AEs were comprised of thrombocytopenia (8.6%), anemia (8.6%), neutropenia (5.4%), COVID-19 (pneumonia; 5.4%), asthenia (3.2%), and diarrhea (1.1%).

In the danazol-to-momelotinib arm, 46.3% and 29.3% of patients experienced grade 3 or higher and serious AEs, respectively. Grade 3 or higher AEs included thrombocytopenia (14.6%), hypertension (2.4%), and anemia (2.4%).

Additional data showed that TI response with momelotinib at 24 weeks was associated with overall survival (OS) and leukemia-free survival. However, Gerds cautioned that due to this being a crossover study, OS is difficult to analyze.

Efficacy was also analyzed in patients with thrombocytopenia. For patients whose baseline platelet counts were less than 100 x 10

/L, week 24 responses in TSS at 50% reduction, TI-R, and SRR35 were also well maintained during the open-label period. For these patients with thrombocytopenia on momelotinib-to-momelotinib (n = 46) and danazol-to-momelotinib (n = 24), grade 3 or higher bleeding events occurred in 15% and 4%, respectively; major adverse cardiovascular events were reported in 7% and 0% of patients, respectively. Overall, Gerds said that the safety findings in this subset, which included 47.9% grade 3 or higher AEs and 28.8% serious AEs, were consistent with what was observed the intent-to-treat population.

OS was also analyzed up to 48 weeks in the thrombocytopenic patients whose baseline platelet counts were less than 50 x 10

/L (HR, 0.123; 95% CI, 0.014-1.062) and less than 100 x 10

/L (HR, 0.958. 95% CI, 0.424-2.212). While encouraging, Gerds noted the small sample size for this subgroup and that it warrants further investigation.

1. Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in sympatomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 627

2. US FDA accepts new drug application for GSK’s momelotinib for the treatment of myelofibrosis. News release. GSK. August 17, 2022. Accessed December 12, 2022. https://bit.ly/3K4Azcq

3. Verstovsek S, Vannucchi A, Gerds AT, et al. MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S195

4. Verstovsek S, Oh ST, Kiladjian J-J, et al. Transfusion independence response as a potential surrogate for overall survival in JAKi-experienced patients with myelofibrosis from Momentum.Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 3028

The MOMENTUM trial continues to show positive results for momelotinib fro the treatment of anemic myelofibrosis. 

Momelotinib Responses Last for Up to 11 Months Patients With Anemic Myelofibrosis 

Three-year follow-up results from 2 a phase 2 trials, olverembatinib (HQP1351) upheld clinical benefit and continued to have an acceptable safety profile in patients with 

 T315I-mutant chronic myeloid leukemia (CML)-chronic phase (CP) or -acute phase (AP) that is resistant to TKIs, according a presentation during the 2022 ASH Annual Meeting.

Updated results for cumulative incidence of response showed that, in patients with T315I-mutant CML-CP, the major cytogenetic response (MCyR) at 3 years was 80% (95% CI, 64%-90%), the complete cytogenetic response (CCyR) was 71% (95% CI, 54%-83%), and the major molecular response (MMR) was 59% (95% CI, 42%-72%). The molecular response (MR) 4.0 and the MR 4.5 were both 51% (95% CI, 35%-66%).

In those with T315I-mutant CML-AP, the MCyR was 52% (95% CI, 30%-71%), the CCyR was 52% (95% CI, 29%-71%), and the MMR was 48% (95% CI, 25%-68%). The MR 4.0 and the MR 4.5 were both 35% (95% CI, 16%-55%).

“Olverembatinib is efficacious and well tolerated in TKI-resistant CML-CP and CML-AP patients with a 

 T315I mutation,” said Yifan Zhai, of Ascentage Pharma Group, the developer of the third-generation BCR-ABL inhibitor, in a presentation during the meeting. “The responses and safety profile of these studies are consistent with the T315I mutation subgroup in a phase 1 study.”

In November 2021, olverembatinib was granted conditional approval for the treatment of patients with CML-CP and CML-AP with a T315I mutation by the National Medical Products Administration in China.

In the single-arm, open-label, multicenter, registrational phase 2 HQP1351CC201 (NCT03883087) and HQp1351CC202 (NCT03883100) trials, patients with TKI-resistant CML-CP and CML-AP, respectively, who had T315I-mutant disease, were treated with oral olverembatinib at 40 mg every other day in 28-day cycles.

To be eligible for enrollment, patients had to be at least 18 years old, have T315I-mutant CML in either CP or AP via MD Anderson Cancer Center criteria, an ECOG performance status of 0 to 2, and adequate organ function.

Those who received prior ponatinib (Iclusig), olverembatinib, or similar agents were excluded from enrollment, as well as those with uncontrolled cardiovascular diseases, pulmonary arterial pressure greater than 50 millimeters of mercury, and those who have CP disease with CCyR and AP disease with major hematologic response (MaHR).

In HQP1351CC201, MCyR ( ≥40% vs 15%) was the primary end point; this was MaHR (≥40% vs 10%) in the HQP1351CC202 trial.

Regarding baseline characteristics between the HQP1351CC201 and HQP1351CC202 studies, the median age was 47 years (range, 22-70) and 41 years (range, 21-74), respectively. Moreover, the time from diagnosis to starting olverembatinib was 5.3 years (range, 0.6

23.2) and 5.0 years (range, 0.4-10.2), respectively. In HQP1351CC201, patients had received 1 (22%), 2 (61%), or 3 (17%) prior lines of therapy; these rates were 17%, 61%, and 22%, respectively, in the HQP1351CC202 trial.

The data cutoff date was September 30, 2022, for both studies. The median duration of treatment was 38 months (range, 3-41) in HQP1351CC201 and 20 months (range, 1-41) in HQP1351CC202. Sixty-six percent and 44% of patients, respectively, continued treatment.

In HQP1351CC201 and HQP1351CC202, 34% and 57% of patients, respectively, discontinued treatment due to disease progression (5% and 22%), treatment failure (7% and 9%), intolerant adverse effects (AEs; 10% and 17%), withdrawn consent (7% and 0%), death (0% and 4%), or other unspecified reasons (5% and 4%).

Regarding duration of response, additional findings in HQP1351CC201 showed that at 36 months, the MCyR in patients with CML-CP was 80% (95% CI, 61%-91%), the CCyR was 81% (95% CI, 60%-92%), and the MMR was 85% (95% CI, 61%-95%). In the CML-AP population, the MCyR was 81% (95% CI, 44%-95%), the CCyR was 66% (95% CI, 32%-86%), and the MMR was 22% (95% CI, 4%-50%).

Progression-free survival (PFS) and (OS) at 3 years were also assessed. In the CML-CP population, the 3-year PFS and OS rates were 92% (95% CI, 77%-97%) and 95% (95% CI, 82%-99%), respectively. In the CML-AP population, these rates were 62% (95% CI, 38%-79%) and 70% (95% CI, 47%-84%), respectively.

When stratified by mutational status, investigators noted that response rates were similar regardless of whether patients harbored T315I single mutation or T315l and additional mutations, which included F317L, M244V, E459k, F359V, Y253H, E255V, E450A, and E459Q.

 mutation dynamic changes, it was found that while some patients did not have any changes or lost their T315I mutation with no response or loss of response to olverembatinib, 1 patient gained G250E and E255K mutations at 3 months and 8 months after treatment.

The study also included a multivariate analysis of responses pertaining to number of prior TKIs and interruption within 3 months, both of which were associated with lower response rates. Prior TKI use impacted olverembatinib response as it related to CCyR (HR, 0.5; 95% CI, 0.3-0.9; 

 = .015), MMR (HR, 0.4; 95% CI, 0.2-0.6; 

 = .001), and MR4.5 (HR, 0.6; 95% CI, 0.3-1.2; 

Regarding interruption within 3 months, the HR for CCyR was 0.4 (95% CI, 0.2-0.7; 

 = .001), and 0.4 for MR4.5 (95% CI, 0.2-0.9; 

 = .024). Sixty-nine percent of patients experienced treatment interruption due to grade 3/4 thrombocytopenia, which occurred at 1.2 years (range, 1.0-1.4) from diagnosis to starting olverembatinib treatment (

Zhai noted that the prevalence of treatment-related AEs decreased over time, with skin pigmentation being the main AE that remains. She noted that any-grade and grade 3 or higher arterial occlusive events and venous thrombotic events occurred in 3% and less than 2% of patients, respectively.

1. Jiang Q, Chen Zi, Niu Q, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP) with T315I mutation. 

. 2022;140(suppl 1):203-204. doi:10.1182/blood-2022-170698

2. Jiang Q, Shi D, Li z, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant BCR-ABL1 T315I-mutated chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP). 

. 2021;138(1):3598. doi:10.1182/blood-2021-153937

Olverembatinib is efficacious and well tolerated in tyrosine kinase inhibitor-resistant CML-CP and CML-AP patients with a BCR-ABL1 T315I mutation.

Gina Mauro | Authors

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