Wayne Kuznar

For the treatment of patients with newly diagnosed acute graft-versus-host disease (GVHD, itolizumab, a humanized IgG1 monoclonal antibody that modulates the activated leukocyte cell adhesion molecule (ALCAM) pathway, has demonstrated promise in part A of the multicenter dose-ascending phase 1b/2 EQUATE study, according to results presented during the virtual 2021 Transplantation & Cellular Therapy Meetings.

Data showed that administration of itolizumab resulted in a dose-dependent reduction of CD6 expression on T-effector cells and a 100% overall response rate (ORR) at the 2 highest dose levels at day 29, with almost all responses being complete responses, said lead study author John Koreth, MBBS, PhD.

“The dose-dependent reduction of CD6 expression on CD4+ and CD8+ T cells is consistent with the expected mechanism of action [of itolizumab],” said Koreth, director of translational research, stem cell transplantation, Dana-Farber Cancer Institute, Boston.

The CD6 ALCAM pathway is central to immune infiltration, he explained. “CD6 is a costimulatory receptor that is upregulated and expressed on CD4+ and CD8+ effector T cells. There are multiple CD6 ligands, most prominently ALCAM that is expressed on both antigen-presenting cells and tissues, including the skin and the GI [gastrointestinal] tract,” Koreth said. “ALCAM overexpression leads to the increased infiltration of CD6high cells. The CD6 ALCAM pathway, therefore, potentially can modulate both the activity of T cells and the trafficking of T cells to sites of inflammation.”

CD6high cells adopt a pathogenic phenotype to secrete high amounts of gamma interferon and high amounts of interleukin-17. Itolizumab acts by causing antigenic modulation of cell surface CD6, a pathogenic CD6high cell, resulting in a switch to a CD6 low phenotype in a dose-dependent manner.

Part A of EQUATE is an open-label 3+3 dose escalation design evaluating 4 itolizumab doses ranging from 0.4 mg/kg to 2.4 mg/kg. Patients received intravenous itolizumab administered every 2 weeks for 5 doses, with corticosteroids tapered over the treatment period. At the time of data cutoff, 4 patients were enrolled in cohort 1 (0.4 mg/kg), 3 in cohort 2 (0.8 mg/kg), and 3 in cohort 3 (1.6 mg/kg).

All patients are adult recipients of first allogeneic hematopoietic stem cell transplant with grade III/IV acute GVHD at screening or baseline. Primary disease was acute myeloid leukemia in 4 patients, acute lymphoblastic leukemia in 2, myelofibrosis in 2, and other in 2. The graft source was peripheral blood in 8 of the 10 patients.

Nine patients had lower gastrointestinal (GI) involvement and 2 had upper GI involvement. Eight of the 10 were high risk based on the MacMillan risk score and all patients had Ann Arbor scores of 2 (30%) or 3 (70%). All patients received either methotrexate (70%), tacrolimus (70%), or sirolimus (60%) prophylaxis.

As early as day 15, an ORR of 100% was observed for the 0.8 and 1.6-mg/kg dose level cohorts, all but 1 being a complete response. These responses were sustained through day 57 in the 2 highest dose cohorts. One patient in cohort 1 experienced acute GVHD progression and required rescue therapy at day 7.

The overall CR rate was 100% in cohort 2. In cohort 3, 1 patient who had a partial response at day 15 improved to a CR by day 85 but then experienced grade 2 acute GVHD on steroid taper and drug discontinuation beyond day 57, indicating durability on treatment and the need for potentially longer-term treatment in some patients, said Koreth.

Itolizumab was associated with a reduction in the dose of systemic steroids by 93%, 87%, and 91% at day 85 for cohorts 1, 2, and 3, respectively. A dose-dependent reduction in cell surface CD6 levels, on both CD4 and CD8 T cells, as early as 24 hours after the initiation of therapy was also observed. At the 0.8- and 1.6-mg/kg dose levels, the suppression of CD6 levels was sustained though day 15.

The adverse event (AE) rate was 100%, which was “consistent with this high-risk acutely sick patient population,” he said. Five patients experienced serious AEs; only 2 were considered treatment related. Four patients had serious infections, 1 was grade 4 sepsis deemed to be a dose-limiting toxicity. Three patients, 2 in cohort 2 and 1 in cohort 3, had AEs that led to discontinuation of itolizumab. One patient in cohort 3 had an AE leading to death, unrelated to the study intervention.

Patients experienced a transient decline in absolute lymphocyte count, most commonly with the first dose of itolizumab. “Importantly, there were no infectious or clinical sequelae during this period of transient lymphopenia,” he said.

Koreth J, Loren AW, Nakamura R, et al. Preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed severe acute graft-versus-host disease: interim results from Equate study. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract LBA4.

Articles

For the treatment of patients with newly diagnosed acute graft-versus-host disease, itolizumab has demonstrated promise in part A of the multicenter dose-ascending phase 1b/2 EQUATE study.

Itolizumab Induces Durable Clinical Responses in Newly Diagnosed aGVHD

Treatment with axicabtagene ciloleucel (axi-cel; Yescarta) is less likely to induce response in patients with refractory large B-cell lymphoma (LBCL) who have never achieved a complete response (CR) to any line of prior therapy, according to findings from a single-center retrospective analysis.

The analysis comprised 171 patients with LBCL treated with axi-cel at the academic center between January 2018 and April 2020. At a median follow-up of 9 months, the median progression-free survival (PFS) was 6 months (95% CI, 4-8) in patients who never attained a CR to prior therapy. There was a trend toward shorter PFS in the group that never attained a CR compared with patients who achieved a CR with any prior line of therapy (5 vs 26 months, respectively; 

The data were presented virtually by Sairah Ahmed, MD, and Paolo Strati, MD, at The University of Texas MD Anderson Cancer Center during the 2021 Transplantation & Cellular Therapy Meetings.

“In our large cohort, we identified lack of prior complete response to any line of therapy to predict for inferior outcomes with axi-cel CAR T-cell therapy,” the investigators noted in their poster. “Despite CAR T-cell therapy having a non-overlapping mechanisms with standard cytotoxic chemotherapy, it appears that disease refractoriness may be therapy agnostic.”

Additional data showed that the median overall survival (OS) showed a similar trend to median PFS. Median OS was not reached in the cohort without a prior CR. However, the 1-year OS rate was shorter at 60% in this group versus those who attain a CR to a prior treatment, at 75%, although the difference missed statistical significance (

Axi-cel is currently approved for the treatment of patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and high-grade B-cell lymphoma after at least 2 lines of systemic therapy. In the phase 2 portion of the ZUMA-1 trial,

 which was the basis for the approval in this setting, there was no significant difference in outcomes in patients with refractory LBCL based on prior lines of treatment, noted the researchers.

“Beyond tumor volume, there is a lack of data in predicting response outcomes,” they wrote.

Of the 171 patients who received axi-cel as standard of care as part of the analysis, 134 did not attain a CR to any prior line of therapy and 37 did achieve a CR.

There was no statistically significant difference in age, gender, histology, ECOG performance status, stage, or International Prognostic Index (IPI) between the 2 groups at baseline. The median age of the overall cohort was 59 years (range, 18-85), 70% were male, 82% had Ann Arbor stage III or IV LBCL, 64% had more than 1 extra-nodal site, 56% had an IPI score of 3 to 5. The median level of lactate dehydrogenase at baseline was 323 U/L. The median number of prior therapies was 4 (range, 2-15). About one-fourth (n = 45; 26%) had received previous autologous stem cell transplant (SCT) and 3 (2%) received prior allogeneic SCT. Fifty percent had bridging therapy, including 30% with chemotherapy as a bridge, 12% with radiation therapy, and 8% with biologic therapy.

The need for bridging therapy, which was 54% in those never attaining a CR versus 35% in those who attained a CR to prior therapy (

 = .04), and lack of prior autologous SCT (22% vs 43%, respectively; 

 = .01) were identified as significant factors associated with lack of a CR to prior therapy.

The findings from this analysis should be explored in larger registry studies and targeted in future clinical trials, the authors concluded.

In September 2020, a supplemental biologics license application was filed with the FDA for axi-cel for the treatment of patients with relapsed/refractory follicular lymphoma and marginal zone lymphoma following 2 or more previous lines of systemic treatment.

1. Ahmed S, Strati P, Fayad LE, et al. Efficacy of chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma (LBCL). Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 493.

2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-Cell lymphoma. 

Treatment with axicabtagene ciloleucel is less likely to induce responses in patients with refractory large B-cell lymphoma who have never achieved a complete response to any line of prior therapy, according to findings from a single-center retrospective analysis. 

Axi-Cel Treatment Outcomes Correlate With Response to Prior Therapy in Refractory Large B-Cell Lymphoma

Most patients with metastatic renal cell carcinoma (RCC) whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. When administered post-immunotherapy, cabozantinib (Cabometyx) is associated with superior median progression free survival (PFS), according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Of 162 patients with metastatic RCC who were referred to centers that were part of the Meet-Uro group, 111 (68.5%) were treated after progression on immuno-oncology drugs. Of the 79 patients (71.2%) who received subsequent cabozantinib, median PFS was 7.6 months (95% CI, 5.2-10.1 months), compared with a median of 3.2 months (95% CI, 1.8-4.5 months) in the 11 patients (9.9%) who received everolimus as subsequent therapy (

= .001 for cabozantinib vs. everolimus) and a median of 4.3 months (95% CI, 1.3-7.4 months) in the 21 who received other drugs as subsequent therapy.

Median overall survival from first-line therapy was 41.1 months (95% CI, 30.4-51.8 months).

The data were reported at the 2020 Genitourinary Cancer Symposium by investigators led by Daniele Santini, MD, co-chief and professor in the Department of Medical Oncology, Campus Bio-Medico University of Rome, Italy.

They undertook this project because little real-world data exist on safety and outcomes of metastatic RCC patients after progression on immuno-oncology drugs.

Previously, using data from 8 international cancer centers, Graham et al assessed outcomes of patients with metastatic RCC who were treated with targeted therapy after prior immuno-oncology therapy. Their study found an advantage of VEGF-TKIs over mTOR inhibitors on the end points of time to treatment discontinuation (adjusted HR, 0.46; 95% CI, 0.30-0.71;

<.01), 1-year probability of survival (65% vs 47%;

<.01), and objective response rate (29.8% vs 3.6%;

The study presented here included 104 men and 58 women. A total of 136 (83.9%) had prior nephrectomy. About two thirds (65.4%) had received sunitinib (Sutent) as first-line therapy, 29.6% received pazopanib (Votrient), and 5% other agents as first line. Metastatic sites were lymph nodes in 70.3%, visceral in 25.3%, and bone in 76.5%. At baseline, Sixty-six percent of patients had an ECOG performance status of 0-1 and 44% had an ECOG performance status of 2. Histology was clear cell in 87.6% and non-clear cell in 12.4%. Sarcomatoid histology was present in 15.5%.

The median PFS was 4 months in patients pretreated with pazopanib (95% CI, 2.4-5.5 months) versus 3.9 months in those pretreated with sunitinib (95% CI, 2.9-4.9 months).

= .004) in patients reporting adverse events of any grade (5.03 months; 95% CI, 3.8-6.1 months) compared with those not reporting adverse events (2.99 months; 95% CI, 2.4-3.5 months). Median PFS also trended longer among patients without nephrectomy (4.1 months vs. 2.9 months among those with prior nephrectomy;

Physician-assessed best response was stable disease (SD) or partial response (PR) in 55 patients (49.5%) and progressive disease in 26 (23.4%). A total of 42 patients (53.1%) who received cabozantinib as subsequent therapy had SD/PR as best response compared with 2 (18.1%) who received everolimus as treatment subsequent to immune-oncologic therapy and 6 patients (5.4%) who received other agents as subsequent treatment.

Patients with an ECOG performance status of 0 after immuno-oncologic therapy compared with ECOG performance status of 1 or 2.

All-grade adverse events were reported in 83 patients (74%), with grade 3-4 adverse events reported by 39 (35%).

Santini D, Stellato M, De Giorgi U, et al. Clinical outcomes of metastatic renal carcinoma following disease progression to programmed death (PD)-1 or PD-L1 inhibitors (I-O): a Meet-URO group real-world study (Meet-Uro 7). Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 69

Graham J, Shah AY, Wells JC, et al. Outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy after immuno-oncology checkpoint inhibitors.[published online ahead of print, 2019 Nov 27].

. 2019;S2588-9311(19)30160-9. doi:10.1016/j.euo.2019.1001

Most patients with metastatic renal cell carcinoma whose disease progresses after immunotherapy given either alone or in combination with other agents receive subsequent treatment with VEGF tyrosine kinase inhibitors or mTOR inhibitors. When administered post-immunotherapy, cabozantinib is associated with superior median progression free survival, according to retrospective data from a real-world study of patients treated at 16 Italian referral centers.

Patients With Metastatic RCC Receive TKIs or mTOR Inhibitors After Immunotherapy

Stereotactic body radiotherapy (SBRT) combined with nivolumab (Opdivo) was associated with &ldquo;high&rdquo; disease control and overall survival (OS) rates in a phase II study of pretreated patients with metastatic renal cell carcinoma (RCC), according to lead investigator Cristina Masini, MD, who presented the data at the 2020 Genitourinary Cancers Symposium.

In the single-arm, multicenter NIVES study, the objective response rate (ORR) to the SRBT/nivolumab combination was 17.4% in the intent-to-treat (ITT) analysis and 19.0% in the per protocol analysis,

which fell short of the hypothesized rate of 40% on ITT analysis. Among the 69 patients enrolled, there was 1 complete response and 11 partial responses. Stable disease was the best response in 28 patients, for a disease control rate of 58.0% (40 of 69) on ITT analysis.

The median duration of response was 9.7 months, with 9 of the 12 responses ongoing. Six patients have ongoing stable disease.

The median progression-free survival (PFS) was 4.1 months (95% CI, 2.8-7.1), with a 12-month PFS rate of 32.6% (95% CI, 21.0%-44.6%). Median OS was 22.07 months (95% CI, 18.1-not reached), with a 12-month OS rate of 73.4% (95% CI, 60.6%-82.6%).

The investigators were looking to improve upon the dismal prognosis of metastatic RCC, which carries a 5-year survival rate of only about 10%. SBRT is a focused radiation therapy thought to effectively kill tumor cells while minimizing damage to adjacent healthy tissue and enhancing antitumor immune responses, said Masini, from the Medical Oncology unit, Clinical Cancer Centre, Azienda Unit Sanitaria Locale di Reggio EmiliaInstituto di Ricovero e Cura Carattere Scientifico, Reggio Emilia, Italy. &ldquo;Several preclinical studies have documented an increase in peripheral antitumor immunity with an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in the irradiated tumor,&rdquo; she said.

Tumor PD-L1 expression can also be induced by radiation; inhibition of the PD-1/PD-L1 axis with nivolumab has been shown to improve antitumor immunity by blocking tumor-mediated suppression of cytotoxic T cells. In addition, radiation may have an abscopal effect on metastases.

On the trial, eligible patients had progressive disease after &le;2 prior antiangiogenic therapies and measurable metastatic sites with at least 1 suitable for SBRT.

Patients received hypofractionated radiation in 1 tumor at a dose of 10 Gy &times; 3 fractions, started 7 days after the first infusion of nivolumab. Nivolumab was given as a fixed dose of 240 mg on day 1 of every 14 days for 6 months. In responding patients, the nivolumab dosage was then increased to 480 mg every 4 weeks until progressive disease or unacceptable toxicity.

A total of 69 patients were treated with at least 1 dose of nivolumab, 2 of whom didn&rsquo;t receive SBRT and 4 of whom did not complete the first cycle of treatment. Twelve centers in Italy participated in the study.

Histology was clear cell in 79.7% of patients and nonclear cell in 14.5%, with unknown histology in 5.8%. Some 82.6% of patients enrolled were male. Median age at therapy initiation was 67 years (range, 43-85). The International Metastatic RCC Database Consortium risk score was intermediate in 68.1%, good in 20.3%, and poor in 11.6%. More than half of patients (50.7%) had &ge;3 metastatic sites and 33.4% had 2 metastatic sites. In total, 56 patients (81.2%) received nivolumab as second-line therapy and 13 (18.8%) received it in the third line. The most common first-line therapy was sunitinib (65.2%). About three-fourths of those included on the study (76.9%) had prior nephrectomy.

The most frequent sites of SBRT were lung (37.7%), lymph nodes (11.6%), and bone (11.6%). At the time of this analysis and with a median follow-up of 15 months (range, 0-25.6), the median number of nivolumab doses received was 12 (range, 1-32). Fifty-four patients (78.3%) discontinued treatment, most often due to disease progression (55.2%).

When sites of metastases were stratified by whether they received SRBT, the ORR was 26.9% in irradiated sites and 17.4% in nonirradiated sites. Masini said what was &ldquo;interesting was the very high disease control rate in the irradiated metastases, 82%, whereas in the past, metastatic kidney cancer has been considered resistant to therapy,&rdquo; said Masini. The disease control rate in nonirradiated sites was 59.4%.

The ORR was significantly higher in patients with clear cell versus nonclear cell histology (20.4% vs 0%;

Grade 3/4 toxicities related to nivolumab were experienced by 17 patients (24.6%), with the most frequent events being diarrhea (5.8%), an increase in amylase/lipase (4.3%), and fatigue (4.3%). Six patients (8.7%) were hospitalized due to treatment-related serious adverse events.

Analysis of the correlation between efficacy with PD-L1 expression and molecular alterations in tumor tissue samples as well as in circulating tumor DNA is ongoing, she said.

Randomized perioperative trials of radiation therapy for kidney cancer have been negative, but SBRT is a different approach that &ldquo;has established a footprint in renal cancer,&rdquo; although the data to support it are weak, said discussant Thomas Powles, MD, director of Barts Cancer Center in London, United Kingdom. &ldquo;If this was a drug, we probably wouldn&rsquo;t be using SBRT the same way as we are now. The robustness of the data in renal cancer is not there.&rdquo;

The median PFS in NIVES is not much different from the 4.6-month median PFS in the CheckMate 025 study with nivolumab alone, he pointed out.

The immunogenic effect of SBRT may be different in kidney cancer and other tumor types in which it has shown efficacy, such as in lung and bladder cancer, said Powles.

&ldquo;We are in an era where I think we are keen to believe that this [the effect of radiotherapy on the immune cycle] exists, but that doesn&rsquo;t mean that we should be adopting it just because we can give radiation therapy and SBRT,&rdquo; he said. &ldquo;Just because we can do it, doesn&rsquo;t mean we should be doing it without robust data.&rdquo;

Masini C, Iotti C, De Giorgi U, et al. Nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): First results of phase II NIVES study. Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 613.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma.

. 2015;373(19):1803-1813. doi: 10.1056/NEJMoa1510665.

Stereotactic body radiotherapy combined with nivolumab was associated with &ldquo;high&rdquo; disease control and overall survival rates in a phase II study of pretreated patients with metastatic renal cell carcinoma, according to lead investigator Cristina Masini, MD, who presented the data at the 2020 Genitourinary Cancers Symposium.

Wayne Kuznar | Authors

Articles

Itolizumab Induces Durable Clinical Responses in Newly Diagnosed aGVHD

Axi-Cel Treatment Outcomes Correlate With Response to Prior Therapy in Refractory Large B-Cell Lymphoma

Patients With Metastatic RCC Receive TKIs or mTOR Inhibitors After Immunotherapy

Effects of SBRT Plus Nivolumab Result in Responses for Certain RCC Subgroups