Kyle Doherty

A favorable safety profile and promising efficacy was seen with C-CAR066, a novel 2nd generation chimeric antigen receptor (CAR) T-cell therapy targeting the CD20 antigen, in adult patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) who failed with prior CD19 CAR T-cell therapy, according to results from a phase 1 study (NCT04036019) in China presented during the 2021 ASCO Annual Meeting.

In a population of 10 patients, at a median follow-up of 4.2 months (range, 1.2-11.7), C-CAR066 elicited an overall response rate (ORR) of 100%; 7 patients had a complete response, and 3 patients had a partial response. The median time to response was 1 month (range, 0.9-2.7) and the median time to CR was 2.7 months (range, 0.9-2.9). The median duration of response (DOR) was not reached (NR; range, 1.0-NR).

“I think these results are very amazing,” said Aibin Liang, MD, PhD, lead study author and professor of medicine at Tongji Hospital of Tongji University in Shanghai, China. “This population is very heavily [pre]treated.”

 reactivity than other anti-CD20 single-chain variable fragments, including Leu16, obinutuzumab (Gazyva), and rituximab (Rituxan). 

 anti-tumor activity was also greater with C-CAR066 compared with other CAR T therapies containing Leu16.

The agent is manufactured in a serum-free manner, utilizing a functionally closed and highly automated system. The manufacturing success rate in the trial was 100%. The median manufacture time of C-CAR066 was 7 days.

The study, which was conducted at 2 sites in China, was the first in human, open-label study of C-CAR066. In order to be eligible for the trial, patients had to be aged 18 to 75 years with a measurable lesion, no active infection, adequate organ function, and no central nervous system lesions.

Patients were administered a lymphodepletion regimen of 3-day cyclophosphamide (300 mg/m2) plus fludarabine (30 mg/m2); bridging therapy was permitted. C-CAR066 was given as a single infusion at a dose of 1.0 to 5.0 x 106/kg. The median vein to vein time was 20 days (range, 17-91). Assessments and follow-up occurred from day 1 to month 24 of the study.

The primary objective of the study was to determine the incidence and severity of treatment emergent adverse events (TEAE), per common terminology criteria for adverse events (CTCAE) v5.0 and American Society for Transplantation and Cellular Therapy guidelines. Secondary objectives included ORR, DOR, progression-free survival, and overall survival. CAR T expansion and persistence were considered exploratory objectives.

The study population was heavily pretreated, with patients receiving a median of 5 (range, 2-6) prior lines of therapy. The median age was 55.5 years (range, 41-67), with 2 patients over 65 years. Most patients (n = 9) had an ECOG performance score of 1, and 6 patients registered an International Prognostic Index score of 3 to 5. The study was evenly divided with 5 male patients and 5 female patients.

Patients with diffuse large B-cell lymphoma (DLBCL) made up a majority of the study population (n = 8); the remaining 2 patients had transformed follicular lymphoma. Additionally, there were 4 patients with double-expressor lymphoma and 9 with Ann Arbor stage III/IV disease.

The median DOR of prior CAR T therapy was 2.1 months (range, 0.7-12.6). All patients responded to prior therapy; 2 had CRs and 8 experienced a PR. A Bruton tyrosine kinase inhibitor was previously administered to 2 patients and 6 patients had prior lenalidomide therapy. Bridging therapy was used in 4 patients.

Regarding safety, 9 patients experienced cytokine release syndrome (CRS) of any grade and grade 4 CRS was reported for 1 patient. The median days to onset of CRS was 2 (range, 1-9), and the median time to resolution was 4 days (range, 2-17). The patient with grade 4 CRS presented with high fever, hypotension, and hypoxia on day 6 and resolved on day 10. This patient was treated with tocilizumab, steroids, noninvasive ventilation support, and was not admitted to the intensive care unit.

Other common AEs of any grade included neutropenia (100%), anemia (100%), thrombocytopenia (70%), and infection (70%). AEs grade 3 or higher included neutropenia (80%), anemia (50%), thrombocytopenia (30%), and infection (10%). Notably, there were no immune effector cell-associated neurotoxicity syndrome events.

“C-CAR066 showed very promising clinical benefits in patients with relapsed/refractory DLBCL following failure of C19 CAR T therapy,” Liang concluded. “These are patients with a high, unmet medical need. Many further studies are planned.”

Liang A, Ye S, Li P, et al. Safety and efficacy of a novel anti-CD20 chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) patients after failing CD19 CAR-T therapy. 

. 2021;39(suppl 15):2508. doi:10.1200/JCO.2021.39.15_suppl.2508

Articles

A favorable safety profile and promising efficacy was seen with C-CAR066, a novel 2nd generation chimeric antigen receptor T-cell therapy targeting the CD20 antigen, in adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma who failed with prior CD19 CAR T-cell therapy. 

In R/R B-NHL, High Marks Achieved by C-CAR066

Neoadjuvant nivolumab in combination with platinum-doublet chemotherapy significantly improved pathological complete response (pCR) rates and had a greater depth of pathological response compared with chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), according to data presented during the 2021 virtual ASCO Annual Meeting.

Results from the phase 3 CheckMate 816 study (NCT02998528) showed that nivolumab plus chemotherapy elicited a pCR of 23% in patients with stage IIIA disease (n = 113), compared with 1% in the chemotherapy arm (n = 115). Patients with stage 1B NSCLC who received nivolumab plus chemotherapy (n = 10) had a pCR of 40% vs 0% in the chemotherapy group (n = 8). Patients with stage IIA disease registered pCRs of 23% and 3% in the nivolumab plus chemotherapy (n = 30) and chemotherapy (n = 32) arms, respectively. Patients with stage IIB NSCLC experienced a pCR of 24% in the nivolumab plus chemotherapy cohort (n = 25) vs 9% for those treated with chemotherapy (n = 23).

“In CheckMate 816, the primary endpoint of pCR was met,” said Jonathan Spicer, MD, PhD lead study author and assistant professor of surgery at McGill University Health Center in Montreal, Canada. “Patients had improved response rates and greater depth of pathological response, regardless of disease stage.”

Additionally, patients with stage IB or IIB disease treated with nivolumab plus chemotherapy (n = 52) had a median residual viable tumor of 28% vs 79% in those treated with chemotherapy alone (n = 49); median residual viable tumor was reported for patients with stage IIIA NSCLC at 8% in the nivolumab plus chemotherapy arm (n = 89) and 70% in chemotherapy treated patients (n = 77).

Investigators randomized a total of 358 patients in a 1:1 ratio to receive either nivolumab plus chemotherapy (n = 179) or chemotherapy alone (n = 179). Patients had newly diagnosed, resectable stage IB-IIIA NSCLC, an ECOG performance status of 0 to 1, and no known sensitizing 

 alterations. Patients were stratified by disease stage, PD-L1 expression, and sex.

Three cycles of therapy were planned in the neoadjuvant window. Nivolumab was administered at a dose of 360 mg. Surgery was performed within 6 weeks following the last dose of neoadjuvant treatment. After surgery, patients had the option to receive adjuvant chemotherapy or radiotherapy per local standard of care and no adjuvant immunotherapy was permitted.

The primary end points of the study were pCR by blinded independent committee review (BICR) and event free survival (EFS) by BICR. Secondary end points included major pathological response (MPR) by BICR, overall survival (OS), and time to death or distant metastases. The trial also examined exploratory endpoints including objective response rate (ORR) by BICR, the feasibility of surgery, and surgery-related adverse effects (AE).

Baseline characteristics were well balanced between the 2 arms. The median age in the nivolumab plus chemotherapy arm was 64 (range, 41-82) vs 65 (range, 34-84) in the chemotherapy arm. Patients in the nivolumab plus chemotherapy group were 28% female compared with 29% of patients in the chemotherapy cohort. The majority of patients in both groups had stage IIIA disease; 63% and 64%, respectively.

Neoadjuvant treatment was administered to 98% of patients in both arms; 94% of patients in the nivolumab plus chemotherapy arm completed the prescribed 3 cycles compared with 85% in the chemotherapy arm. Surgery was cancelled for 16% of patients in the nivolumab plus chemotherapy group vs 21% in the chemotherapy group. Reasons for cancellation included patients declining surgery, unresectable disease, and poor lung function. Cancellation of surgery due to neoadjuvant therapy toxicity occurred in 1% of patients in both arms.

Patients treated with nivolumab plus chemotherapy proceeded to surgery 83% of the time compared with 75% of those treated with chemotherapy alone. The median duration of operation was 184 minutes in the nivolumab plus chemotherapy group vs 217 minutes in the chemotherapy arm. Of note, 8% more surgical cancellations were reported for patients with stage IIIA disease in the chemotherapy arm than in the nivolumab combination arm (25% vs 17%, respectively).

No clinically meaningful differences were observed in time to surgery; median time to definitive surgery was 5.3 weeks (range, 4.6-6.0) in the nivolumab plus chemotherapy arm and 5.0 weeks (range, 4.6-5.9) in the chemotherapy cohort. Surgical procedures were delayed or occurred beyond the 6-week protocol window for 21% of patients in the nivolumab plus chemotherapy arm vs 18% for those in the chemotherapy group.

Thoracotomy was the most frequent surgical approach in both arms. Minimally invasive procedures were favored more frequently for patients with stage IIIA disease treated with nivolumab plus chemotherapy (30%; N = 94) vs chemotherapy alone (19%; N = 83). Lobectomy was the most common type of surgery across all stage subgroups and was more frequent in the nivolumab plus chemotherapy arm (n = 149) than in the chemotherapy arm (n = 135) at 77% vs 61%, respectively. Spicer noted that patients with stage IIIA disease treated with chemotherapy alone went on to pneumonectomy at a higher rate than those who received the nivolumab combination (30% vs 17%, respectively).

Regarding safety, nivolumab was tolerable and the addition to chemotherapy did not increase postsurgical complications. The median length of hospital stay was 10 days (range, 7.0-14.0) in both arms. Finally, the addition of nivolumab did not increase surgery-related AEs. Any grade surgery–related AEs occurred at a rate of 41% in the nivolumab plus chemotherapy arm vs 42% in the chemotherapy arm. Grade 3/4 AEs occurred in 11% of patients treated with nivolumab plus chemotherapy and 15% of those treated with chemotherapy alone.

The most common any-grade AEs 90-days after surgery for nivolumab plus chemotherapy and chemotherapy alone were anemia (12% and 12%, respectively), pain (8% and 16%), and wound complications (8% and 6%). Grade 3/4 postsurgical anemia occurred in 2% of each arm.

“The safety and surgical outcome data reported thus far from CheckMate 816, along with significant improvement in pCR, support nivolumab in combination with chemotherapy as an attractive neoadjuvant option for patients with resectable NSCLC,” Spicer concluded.

Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503

Data presented at the 2021 virtual ASCO Annual Meeting showed the benefits of adding nivolumab to chemotherapy treatment compared to chemotherapy alone, in patients with resectable non-small cell lung cancer. 

Nivolumab Plus Chemotherapy Shows Significant Improvements in Resectable NSCLC 

The novel agent, zenocutuzumab (MCLA-128) demonstrated promise as treatment of patients with 

positive cancers, in the phase 1/2 eNRGy study (NCT02912949), according to results presented during the 

In 45 evaluable patients treated with zenocutuzumab the confirmed overall response rate (ORR) was 29%. Specifically, the ORRs for 12 patients with pancreatic adenocarcinoma (PDAC), 24 patients with non–small cell lung cancer (NSCLC), and 9 patients with other 

 fusion–positive cancers were 42%, 25%, and 22%, respectively. Additionally, tumor reduction was reported for 34 patients (76%).

“Zenocutuzumab is highly effective in pretreated 

 fusion-positive pancreatic cancer, with rapid and durable responses,” said Alison M. Schram, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “There is activity across multiple 

 fusion-positive cancer types and an extremely well tolerated safety profile.”

NRG1, a ligand that binds to HER3, has been shown to be a clinically active target and tumors harboring 

 fusions are sensitive to HER2-, HER3-directed therapies. Zenocutuzumab is a bispecific, humanized, full-length IgG1 antibody with enhanced antibody-dependent cell-mediated cytotoxic activity that inhibits the HER3 signaling pathway. The agent has previously shown single-agent antitumor activity in several tumor types, specifically in heavily pretreated patients with metastatic breast cancer whose disease progressed on HER2 therapies in a phase 1/2 trial (NCT02912949).

eNRGy enrolled a total of 61 adult patients with locally advanced, unresectable, or metastatic sold tumors that harbor 

 gene fusions. Patients were previously treated with, or unable to receive, standard therapy and had an ECOG performance status of 2 or less. The data cutoff date was April 13, 2021, at which point 47 patients were included in the primary analysis population.

The primary end point was investigator-assessed ORR. Secondary end points included ORR per central independent radiologist review, duration of response, and safety. Zenocutuzumab was administered at a dose of 750 mg intravenously every 2 weeks until disease progression. Tumor assessments occurred every 8 weeks. Patients included in the primary analysis population were those who had the opportunity for at least 1 post baseline tumor assessment at the time of cutoff.

The median age in the PDAC cohort was 47.5 years (range, 22-72) and was 58 years (range, 32-84) and 63 years (range, 31-81) in the NSCLC and basket/other groups, respectively. The basket cohort encompassed patients with breast (n = 3), unknown primary (n = 2), and other (n = 5) cancers. The median duration of exposure to zenocutuzumab was 5.7 months (range, 1-19), 4.6 months (range, 1-12), and 5.0 months (range, 2-10) in the PDAC, NSCLC, and basket cohorts respectively.

Patients had a median of 2 prior lines of therapy (range, 0-6). Nearly all patients in the primary analysis population had metastatic disease (n = 46) and 8 patients (17%) were previously treated with afatinib (Gilotrif). At the time of data cutoff 19 patients remained on treatment, including 7 with PDAC, 6 with NSCLC, and 6 with other cancers. The most common reason for treatment discontinuation was disease progression (53%).

In a more detailed analysis of the PDAC cohort, the confirmed partial response rate was 42% (90% CI, 18%-69%), stable disease was reported in 50% of patients and 9 patients experienced tumor shrinkage. These patients were heavily pretreated and had a median of 2.5 (range, 1-4) prior lines of therapy. Further, 100% of patients with CA 19-9 measurements (n = 11) had a decline of greater than 50% in follow-up analysis from baseline.

In addition to patients with PDAC, Schram presented a case study of a male patient aged 48 years with -

-positive cholangiocarcinoma with metastases in the liver, lung, and lymph nodes. The patient received zenocutuzumab as third-line therapy following 2 lines of chemotherapy. “The patient had rapid tumor shrinkage and CA 19-9 normalization with an ongoing PR [partial response] of over 5 months into treatment,” Schram said.

Specifically, there was a 32% tumor reduction and an 84% reduction in CA 19-9 was observed (120 U/mL to 20 U/mL). At the time of data cutoff, the patient had received 7 cycles of zenocutuzumab and treatment was ongoing.

In terms of safety, the most common all-grade adverse effects (AEs) included asthenia/fatigue (35%), diarrhea (30%), and anemia (20%). Most AEs were grade 1 or 2 and no patients required dose reduction because of toxicity. There was a notable absence of severe gastrointestinal toxicity, skin toxicities, and clinical cardiotoxicity, Schram noted.

In January 2021, the FDA granted fast track designation to

 zenocutuzumab for the treatment of patients with metastatic solid tumors

 gene fusions and have progressed on standard-of-care treatment.

“This is the first prospective clinical validation of 

fusions as actionable oncogenic drivers,” Schram said. “[It’s also] the first demonstration of effective targeting of a genomically-altered ligand and the first proof-of-concept that antibody-based therapy can target a fusion oncoprotein. Zenocutuzumab is the first genome-directed therapy for 

fusion–positive cancer offering a potential new standard of care.”

1. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. 

. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003

2. Schram A, Macarulla T, O’Reilly E, et al. Phase 2 study of zenocutuzumab (MCLA-128), a bispecific HER2/HER3 antibody in NRG1 fusion-positive advanced solid tumors. 

. 2021;16(suppl 3):S675. doi:10.1016/j.jtho.2021.01.1237

The novel agent, zenocutuzumab demonstrated promise as treatment of patients with NRG1 fusion–positive cancers, in the phase 1/2 eNRGy study.

Zenocutuzumab Displays Promising Activity in NRG1-Positive Malignancies

Progression-free survival (PFS) and disease control in patients with advanced synovial sarcoma (SS) was improved by catequentinib (Anlotinib), according to data from the phase 3 APROMISS study (NCT03016819) presented during the 

Results from a single arm of the trial showed that patients treated with catequentinib achieved a median PFS of 2.89 months (95% CI, 2.73-6.87) compared with 1.64 months (95% CI, 1.45-2.70) in those treated with dacarbazine (HR, 0.449; 95% CI, 0.270-0.744). More patients treated with catequentinib (n = 52) had PFS of at least 12 months at 29.6% vs 3.7% of patients treated with dacarbazine (n = 27).

“The difference in PFS was significant, and the risk of disease progression was reduced by 67%,” said Brian A. Van Tine, MD, PhD, lead study author and an associate professor of medicine at Washington University School of Medicine, Siteman Cancer Center, in St Louis, Missouri. “Catequentinib is effective for the treatment of patients with SS.”

Catequentinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor targeting VEGFR1-3, FGFR1-3, PDGFRβ, c-Kit and RET. The agent has previously demonstrated efficacy across several tumor types and is approved in China for the treatment of patients with non–small cell lung cancer based on results from the randomized phase 3 ALTER303 trial (NCT02388919) and for patients with soft tissue sarcoma based on results from the phase 2/3 ALTER0203 trial (NCT02449343).

APROMISS enrolled adult patients with metastatic or recurrent advanced SS. Patients had an ECOG performance status of 1 or less, measurable lesions by RECIST 1.1, and progressed on at least 1 line of therapy that must have included an anthracycline-containing regimen. Prior pazopanib use was permitted. The study was an intention-to-treat analysis and the primary end point was PFS.

Patients were randomized 2:1 to receive either catequentinib or dacarbazine. Catequentinib was administered orally at a dose of 12 mg once daily, 2-weeks on and 1-week off in a 3-week cycle. Dacarbazine was given intravenously. Patients with disease progression while being treated with dacarbazine were allowed to cross over to catequentinib at the time of progression.

The median age of patients in the catequentinib arm was 42.0 years (range, 20-80) and 40.5 years (range, 20-73) in the dacarbazine arm. Nearly three-quarters of patients treated with catequentinib (73%) received more than 1 prior line of therapy compared with 65.4% in the dacarbazine cohort. The majority of patients in both groups were White, 81.5% and 82.7%, respectively.

PFS rates were also reported for patients at 4-, 6-, and 12-month intervals. Patients in the catequentinib arm had response rates of 48.1%, 42.3%, and 26.9%, respectively. Those in the dacarbazine arm had response rates of 14.9%, 11.1%, and 3.7%, respectively. Van Tine noted that there was a statistically significant difference between those receiving catequentinib and those receiving dacarbazine (

“Of note, there were 3 partial responses to catequentinib on study and 6 patients who [did not experience progression] greater than 1 year. In comparison no patients [treated with] dacarbazine had a partial response and only 1 patient made it to 1 year [progression-free],” Van Tine said.

In an analysis of patients based on prior pazopanib 40 patients who did not have prior pazopanib and were treated with catequentinib had a median PFS of 2.79 months (95% CI, 1.58-6.97) compared with 1.64 months (95 % CI, 1.45-1.78) in the 21 patients who went on to receive dacarbazine (HR, 0.347; 95% CI, 0.189-0.639; log-rank 

 = 0.0004). In those who were treated with prior pazopanib and went on to receive catequentinib (n = 12) the median PFS was 3.02 (95% CI, 1.55-not evaluable [NE]) compared with 2.14 months (95% CI, 1.28-NE) in 6 patients treated with dacarbazine (HR, 0.826; 95% CI, 0.266-2.566; log-rank 

 = 0.7683). Van Tine highlighted that those who received dacarbazine and had prior pazopanib saw an improved PFS compared with those who did not.

Finally, an observed benefit was observed with catequentinib across all subgroups.

In terms of safety, 23.1% of patients in the catequentinib group had an adverse effect (AE) of grade 3 or higher compared with 25.9% of those treated with dacarbazine. Notable grade 3 or greater AEs in the catequentinib cohort included diarrhea (5.8%) and hypertension (3.8%). In the 21 patients who crossed over from dacarbazine to catequentinib grade 3 or higher pneumothorax (4.8%) and hypertension (4.8%) were AEs of note.

“Catequentinib was well tolerated,” concluded Van Tine. “The most common AEs observed in the catequentinib group were hypertension, increased TSH, hypertriglycefidemia, diarrhea, and hand-foot syndrome.”

Van Tine BA, Chawla SP, Trent JC, et al. A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma. 

. 2021;39(suppl 15):11505. doi:10.1200/JCO.2021.39.15_suppl.11505

Gao Y, Liu P, Shi R. Anlotinib as a molecular targeted therapy for tumors. 

. 2020;20(2):1001-1014. doi:10.3892/ol.2020.11685

Progression-free survival and disease control in patients with advanced synovial sarcoma was improved by catequentinib. 

Kyle Doherty | Authors

Articles

In R/R B-NHL, High Marks Achieved by C-CAR066

Nivolumab Plus Chemotherapy Shows Significant Improvements in Resectable NSCLC

Zenocutuzumab Displays Promising Activity in NRG1-Positive Malignancies

Catequentinib May be Effective in Treating Advnaced Synovial Sarcoma