Kyle Doherty

An investigational CAR-T cell therapy, BNT211-01, showed promise in treating patients with CLDN6-positive, relapsed/refractory solid cancers, according to findings from phase 1/2a trial, that showed that BNT211-01 was efficacious when given alone or in combination with a vaccine.

the 2022 European Society for Medical Oncology Congress

, showed that at the June 15, 2022, data cutoff, 21 patients were able to be evaluated. Among them, the overall response rate (percentage of patients whose disease shrunk because of treatment) was 33%, including one patient who experienced a complete response (total disappearance of disease) and six patients who achieved a partial response (decrease in disease). Additionally, seven patients achieved stable disease and the disease control rate was 67%.

“BNT211-01 is a CAR-T cell product candidate that targets the CLDN6 … protein,” Dr. Andreas Mackensen, a professor in the Department of Internal Medicine 5—Hematology/Oncology at the University Hospital Erlangen in Germany, said during the presentation. “CLDN6 is an ideal CAR antigen (because) it has an (outside-of-the-cell) loop that can be targeted by T cells, is absent in healthy adult tissue since … and is expressed in various cancers, such as testicular cancer and ovarian cancer.”

Patients with testicular cancer expressed CLDN6 at a rate of approximately 93%, and it is present in a little over half (56%) of patients with ovarian cancer.

Researchers on the trial defined CLDN6-positivity as at least 50% of tumor cells being CLDN6-high.

In part 1 of the phase 1 portion, patients received BNT211-01 monotherapy at two different doses. In part 2 of phase 1, four patients received dose level 1 of BNT211-01 plus the CLDN6-encoding mRNA vaccine and nine patients received dose level 2 (which was higher) in combination with the vaccine.

The patient population had received an average of four prior lines of therapy.

The manufacturing of the CAR-T cell therapy, which included a process known as apheresis, where blood is drawn and plasma is removed, occurred at day 18 or more prior to infusion. Patients then underwent lymphodepletion (chemotherapy given to kill T cells) with cytarabine plus fludarabine five and three days before infusion.

Patients also given the vaccine were administered the first dose four days after the CAR-T cell infusion. The first five vaccine treatments occurred every three weeks, followed by a treatment every six weeks thereafter.

Study Findings Highlight CAR-T Cell Therapy’s Potential

Additional findings from the trial showed that patients with testicular cancer treated at dose level 2 with lymphodepletion (seven patients) experienced a better response than the overall population, achieving an overall response rate of 57% with a disease control rate of 85%.

The overall response rate for the total population of patients with testicular cancer who received either BNT211-01 dose with lymphodepletion was 45% with a DCR of 54%.

One patient with testicular cancer who previously underwent six lines of treatment with chemotherapy was still in an ongoing complete response at the time the study data were collected. This was a patient with a large tumor mass at baseline that displayed an impressive regression at six weeks following CAR-T cell therapy and over time, the disease was not able to be seen on PET scans, Mackensen noted.

Regarding safety, 20 patients in the safety population experienced a serious or worse treatment-emergent side effect. A single case of mild immune effector cell-associated neurotoxicity syndrome was reported, and it quickly resolved.

Cytokine release syndrome, a common side effect accompanying CAR-T cell treatments that involves a dangerously high concentration of cytokines (proteins involved in the immune system) being released into the blood, was present in 10 patients (45%). Increased levels of interleukin-6 (cytokines involved with inflammation) were present in patients with cytokine release syndrome. All instances of cytokine release syndrome were mild, moderate or serious and were treated with Actemra (tocilizumab), if needed.

Dose-limiting side effects were observed in two patients, including one who was treated at dose level 2 alone and one treated at dose level 2 in combination with the CLDN6-encoding mRNA vaccine. The dose-limiting side effects consisted of prolonged pancytopenia (deficiency of red cells, white cells and platelets) after lymphodepletion for the patient treated with the CAR-T cell monotherapy and hemophagocytic lymphohistiocytosis (a dangerous and excessive activation of the immune system) for the patient treated with the combination, though this toxicity occurred before administration of the CLDN6-encoding mRNA vaccine.

Eight total patients died during the trial, all from disease progression.

A strong persistence of CAR-T cells was reported for over 100 days. A few patients also displayed persistence for over 200 days.

“Some patients showed long-term CAR-T cell persistence for more than 200 days post CAR-T cell infusion,” Mackensen said. “The process of generation of CLDN6 CAR T cells has now been switched to an automated process and dose escalation is ongoing. The recommended phase 2 dose will be identified for the automated product (in the future).”

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BNT211-01, a novel CAR-T cell therapy, was efficacious in treating patients with CLDN6-positive, relapsed/refractory solid cancers, according to a small clinical trial. 

CAR-T Cell Therapy Shows Promise in Relapsed/Refractory Solid Cancers

Patients with Ewing sarcoma, a rare type of bone or soft tissue cancer, derived a small benefit from treatment with the chemotherapy ifosfamide over the combination of Hycamtin (topotecan) and cyclophosphamide.

Findings from the phase 2/3 rEECur trial — which were presented at the 2022 American Society of Clinical Oncology Annual Meeting — demonstrated that at a median follow-up of 40 months, patients treated with ifosfamide experienced a median event-free survival (time after treatment stops where a patient remains free of the cancer returning or the onset of certain symptoms, such as bone pain) of 5.7 months compared with 3.5 months for patients who received the Hycamtin plus cyclophosphamide combination.

The six-month event-free survival rates were 47% and 37%, respectively.

Additionally, patients who received ifosfamide achieved a median overall survival (time a patient is alive until death from any cause) of 15.4 months compared with 10.5 among patients treated with Hycamtin plus cyclophosphamide. The one-year overall survival rates were 55% and 45%, respectively.

“Given the observed data, there is a 96% probability that ifosfamide is better than topotecan plus cyclophosphamide for (event-free survival),” Martin McCabe, a clinical senior lecturer at the University of Manchester in England, said during a presentation of the data. “(However), the numbers (of patients) beyond six months are extremely small. There was a 94% probability that ifosfamide is better than topotecan plus cyclophosphamide for (overall survival). Again, (there are) very small numbers (of patients) beyond about two years. The benefits of ifosfamide over topotecan plus cyclophosphamide were more obvious in children than in adolescents and adults.”

Patients enrolled onto the rEECur trial were randomly assigned to receive Hycamtin plus cyclophosphamide (163 patients), irinotecan plus temozolomide (127 patients), gemcitabine and docetaxel (72 patients), or ifosfamide (83 patients). The phase 3 comparison between ifosfamide and Hycamtin plus cyclophosphamide reported in the presentation included 73 patients in both treatment groups.

he median age of patients in the trial was 19 years (range, 4 to 49). Most patients had first recurrent disease (66%) and 18% had refractory disease. Seventy percent of patients had bone as their initial disease site. Sites of progression included pleuropulmonary metastases (disease that has spread to an organ in the chest cavity) only (34%), primary site only (15%), and other metastatic (51%).

Measuring event-free survival was the main goal of the study. The investigators also aimed to analyze overall survival, toxicity and quality of life.

In terms of safety, both ifosfamide and Hycamtin plus cyclophosphamide caused similar rates of neutropenic infection (infection caused by a decrease in white blood cells). Ifosfamide caused more severe kidney toxicity and brain toxicity compared with the combination therapy, however both were observed in less than 10% of patients. Common serious or severe side effects for Hycamtin plus cyclophosphamide versus ifosfamide, respectively, included, but were not limited to, vomiting (1% vs. 1%), nausea (0% vs 3%), diarrhea (1% vs 1%) and kidney toxicity (0% vs 8%).

“This is the first ever randomized, controlled trial of chemotherapy in this disease setting,” McCabe concluded. “Importantly, we now have data both to inform patients and to develop future studies. The differences (between these regimens) are quite subtle. What we actually need are better drugs to cure more patients.”

The use of the chemotherapy ifosfamide was associated with small improvements in survival outcomes in a group of patients with relapsed/refractory Ewing sarcoma, a rare type of bone or soft tissue cancer.

Ifosfamide Induces ‘Subtle’ Survival Improvement Over Hycamtin-Cyclophosphamide Combo in Ewing Sarcoma

When given after one line of platinum-based chemotherapy, Zejula (niraparib) plus Avastin (bevacizumab) was shown to improve outcomes for patients with newly diagnosed, advanced ovarian cancer, according to findings from the phase 2 OVARIO study that was presented at the 2022 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.

Dr. Melissa Hardesty added that the combination had a safety profile consistent with the known side effects of each treatment.

At the June 16, 2021, data cutoff point, patients who received the PARP inhibitor Zejula plus the vascular endothelial growth factor-A inhibitor Avastin (105 patients) achieved a median progression-free survival (PFS; the time from treatment until a patient’s disease progresses) of 19.6 months. Eighteen months after treatment, 62% of patients still were without disease progression, and at the 24-month mark, 53% of patients’ disease did not progress.

“OVARIO enrolled a high-risk population,” said Hardesty, a gynecologic oncologist with Alaska Women’s Cancer Care in Anchorage. “More than half of the patients remained progression-free at 24 months. Clinical benefit (by PFS) was observed in the overall population, and across biomarker subgroups in a continuum.”

Patients with high-grade serous or endometrioid stage 3b to 4 epithelial ovarian, fallopian tube or peritoneal cancer were enrolled onto the trial. Eligible patients achieved a complete response (CR; when there is no more detectable cancer after the treatment), partial response (PR; when cancer shrinks but does not completely disappear) or no evidence of disease (NED) result after treatment with front-line platinum-based chemotherapy plus Avastin.

Patients weighing less than 77 kg (169.8 pounds) and/or with a platelet count below 150,000 per µL (82 patients) received 200 mg of daily Zejula plus 15 mg/kg of Avastin once every three weeks. The 23 other patients who were 77 kg or heavier received 300 mg of Zejula each day plus Avastin at 15 mg/kg once every three weeks.

The main goal of the trial was PFS rate at 18 months. Secondary end points included median PFS, overall survival (OS), time to first therapy after the Zejula/Avastin combination and safety. The researchers also analyzed PFS rate at six and 12 months.

All patients underwent tissue testing for homologous recombination deficiency (HRD) at study enrollment. Prior research has shown the patients with HRD-positive disease may be more likely to benefit from certain types of treatments, including PARP inhibitors.

Investigators observed HRD positivity at a rate of 47%, and 63% of patients underwent prior treatment with presurgical chemotherapy or interval debulking surgery. Most patients had a CR or NED to their prior surgery or chemotherapy (58%) and 42% experienced a PR.

The average age of patients included in the trial was 60 (range, 37 to 82).Most patients had and ECOG performance status of 0, meaning that their disease had no impact on their daily activities (63%), stage 3c disease at diagnosis (68%) and serous histology, meaning that the cancer originated from the serous membrane (95%).

Study results showed that the median time to first subsequent treatment was 17.5 months. Notably, median time to second progression was not evaluable. OS data was immature at the time of the analysis, with an event rate of 23.8%.

Investigators noted a higher median PFS in patients in the HRD subgroup compared with the homologous recombination proficient (HRP) and homologous recombination not determined (HRnd) subgroups, 28.3 months (49 patients) versus 14.2 months (38 patients) and 12.1 months (18 patients), respectively.

Within the HRD subgroup, patients with BRCAalterations (29 patients) had a median PFS that was not evaluable, while patients with BRCAwild-type mutations (16 patients) had a median PFS of 28.3 months.

No new safety signals were observed with the combination; all patients experienced a treatment-related side effect of any grade. Most patients (80%) experienced a side effect that was considered serious or worse, with 77% of these determined to be related to Zejula and 51% attributed to Avastin.

Side effects leading to treatment interruption occurred in 88% of patients, while 74% underwent dose reduction due to side effects. Forty percent of patients discontinued treatment due to side effects.

The most common side effects of any severity included thrombocytopenia (70%), fatigue (57%), anemia, and nausea (both 52%). Commonly occurring side effects considered serious or worse included thrombocytopenia (39%), anemia (34%) and hypertension (27%), among others.

Investigators also noted that treatment with Zejula plus Avastin resulted in no clinically meaningful impact on patient quality of life.

“There was no impact on quality of life as assessed by change in FOSI (Functional Assessment of Cancer Therapy-Ovarian Symptom Index) score,” Hardesty concluded.

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A version of this article was originally published on OncLive as, “Niraparib Plus Bevacizumab Shows Promise in High-Risk Ovarian Cancer Population.”

Zejula plus Avastin led to promising progression-free survival rates with no new side effects for patients with newly diagnosed, advanced ovarian cancer. 

Kyle Doherty

CAR-T Cell Therapy Shows Promise in Relapsed/Refractory Solid Cancers

Ifosfamide Induces ‘Subtle’ Survival Improvement Over Hycamtin-Cyclophosphamide Combo in Ewing Sarcoma

Zejula-Avastin Combo Improves Outcomes, With ‘No Impact on Quality of Life’ in High-Risk Ovarian Cancer

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