Denise Myshko

A small clinical trial of pediatric patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) showed efficacy and safety with anti-C-type lectin-like molecule (CLL1)-based chimeric antigen receptor (CAR) T cells, according to data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

In an interim analysis from the phase 1/2 trial (ChiCTR1900027684), 10 of 11 patients completely responded to anti-CLL1–based CAR-T cell therapy, with CLL1-positive AML blasts eliminated within 1 month. Six patients achieved complete remission with minimal residual disease (MRD) negativity, added lead investigator Hui Zhang, MD, PhD, an assistant professor at Shanghai Children’s Medical Center and director of Guangzhou Women and Children’s Medical Center at China’s Guangzhou Medical University.

“From all the research shown, we can say that anti-CLL1 based CAR T-cells is a safe therapeutic candidate with manageable CAR T-cell­–associated toxicity for children with R/R AML,” he said. “It is highly effective in targeting CLL1-positive AML cells with superior overall response rate (ORR) relative to conventional/novel targeting compounds.”

In this study, 11 pediatric R/R AML patients aged 2 to 16 years were infused between October 2019 and January 2021 with a second-generation CLL1 CAR-T created in Zhang’s laboratory. Investigators administered a single dose of CLL1 or CLL1-CD33 dual CAR-T cells (target dose: 0.3-1x10

/kg) following lymphodepleting conditioning with a cyclophosphamide/fludarabine combination.

Zhang said all 11 patients experienced CAR T-cell expansion 

 during the first month. Five patients demonstrated persistence of T-cell expansion.

All patients experienced grade 1 to 3 cytokine release syndrome (CRS) but there were no lethal events, Zhang said. All patients experienced myelosuppression, which he said might be due to chemotherapy. Three patients experienced a grade 1/2 hepatic event. No patient experienced cardiac, renal, or gastrointestinal adverse events.

Investigators have suggested that CLL1 is a promising target because it not expressed on normal hematopoietic stem cells (HSCs), but is expressed on 85% to 92% of AML blasts cells and leukemia stem cells.

 In a humanized mouse model, investigators demonstrated that CAR Ts specific for CLL-1 exhibit potent cytokine production and cytotoxicity against CLL-1-expressing AML cell lines without disrupting normal HSCs.

Investigators theorized that developing an anti-CLL1 CAR T therapy would help patients avoid the need for HSC transplant.

In 2020, Zhang published a case study of a 10-year-old girl who presented with an elevated peripheral blood blast percentage while undergoing maintenance treatment for a B-cell ALL relapse. Investigators developed a CAR containing a CLL1-specific single chain variable fragment.

The patient received lymphodepleting chemotherapy for 4 days before CAR T-cell transfer to enhance 

 expansion of CAR T-cells. This was followed by a single dose anti-CLL1 CAR-T cells infusion. She experienced Grade 1 to CRS.

After completing CAR T-cell therapy, the patient achieved a complete response and was negative for MRD (<0.1%) on day 29. But the CLL1+ cells were not completely eliminated until 6 months after CAR T-cell therapy. The patient achieved a 10-month response using 1 dose of anti-CLL1 CAR-T monotherapy.

Zhang H, Bu C, Pen Z, et al. The efficacy and safety of anti-CLL1 based CAR-T cells in children with relapsed or refractory acute myeloid leukemia: A multicenter interim analysis. 

 2021;39(suppl 15):10000. doi:10.1200/JCO.2021.39.15_suppl.10000

Tashiro H, Sauer T, Shum T, et al. Treatment of acute myeloid leukemia with T cells expressing chimeric antigen receptors directed to C-type lectin-like molecule 1. 

. 2017;25(9):2202-2213. doi:10.1016/j.ymthe.2017.05.024

Zhang H, Gan WT, Hao, WG, et al. Successful ant-CLL1 CAR T-cell therapy in secondary acute myeloid leukemia. 

. 2020;10:685. Doi:10.3389/fonc.2020.00685

Articles

A small clinical trial of pediatric patients with relapsed/refractory acute myeloid leukemia showed efficacy and safety with anti-C-type lectin-like molecule-based chimeric antigen receptor T cells.

Early Trial Targeting CLL1-Positive Cells Demonstrates Efficacy in Pediatric AML

After 4 years of treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), the therapy showed durable, long-term overall survival (OS) benefit compared with chemotherapy in patients with advanced non‒small cell lung cancer (NSCLC) regardless of PD-L1 expression or histology, according to a presentation at the 2021 ASCO Annual Meeting.

Progression-free survival (PFS) and duration of response (DOR) benefits were also maintained at 4 years, said lead author Luis Paz-Ares, MD, PhD, head of the H12O-CNIO Lung Cancer Clinical Research Unit of the Spanish National Cancer Research Centre (CNIO), in Madrid, Spain.

“Taken together, these updated results continue to support the use of nivolumab/ipilimumab as a first-line treatment of advanced NSCLC,” he said.

Paz-Ares presented updated 4-year efficacy and safety results for Part 1 of CheckMate-227 (NCT02477826) and a post-hoc efficacy analysis in patients who discontinued the nivolumab/ipilimumab combination because of treatment-related adverse events (TRAEs). The database was locked in February 2021 at a median follow up 54.8 months.

The median 4-year OS in patients with PD-L1 greater than or equal to 50% who received nivolumab/ipilimumab was 21.2 months (95% CI, 15.5-31.6). The hazard ratio (HR) compared with chemotherapy was 0.66 (95% CI, 0.52-0.84). For patients receiving nivolumab alone, the median OS was 18.1 months (95% CI, 14.4-22.1) with an HR of 0.64 (95% CI, 0.51-0.81) compared with chemotherapy. For patients receiving chemotherapy, the OS was 14.0 months (95% CI, 10.0-18.6).

Median 4-year OS in patients with PD-L1 less than 1% who received nivolumab/ipilimumab was 17.2 months (HR, 0.64; 95% CI, 0.51-0.81). For patients receiving nivolumab plus chemotherapy, the OS was 15.2 months (95% CI, 12.3-19.8). For patients receiving chemotherapy, the OS was 12.2 months (95% CI, 9.2-14.3)

Four-year updated DOR in patients with PD-L1 greater than or equal to 1% who received nivolumab/ipilimumab was 23.2 months (95% CI, 15.5-33.9). The DOR for patients with PD-L1 ≥ 1% who received nivolumab alone was 15.5 months (95% CI, 12.7-20.8). DOR was 6.7 months (95% CI, 5.6-7.6) for patients who received chemotherapy.

For patients with PD-L1 ≥ 50%, the 4-year updated DOR in patients who received nivolumab/ipilimumab was 31.8 months (95% CI, 20.7-51.2). For those who received nivolumab alone, the DOR was 16.8 months (95% CI, 13.5-29.6). DOR was 5.8 months (95% CI, 4.5-6.9) for patients receiving chemotherapy.

Four-year updated DOR in patients with PD-L1 < 1% who received nivolumab/ipilimumab was 18.0 months (95% CI, 12.4-33.2) compared with 8.3 months (95% CI, 5.9-9.4) for those who received nivolumab plus chemotherapy. For patients receiving chemotherapy only, the DOR was 4.8 months (95% CI, 3.7-5.8).

Sixty-six patients (17%) with PD-L1 ≥ 1 discontinued nivolumab/ipilimumab because of TRAEs. The median DOR after discontinuation was 52.6 months. Ninety-seven patients with PD-L1 ≥ 1% and < 1% discontinued nivolumab/ipilimumab because of TRAEs. The median DOR after discontinuation was 34.2 months in this group.

“In a post-hoc analysis, discontinuation of nivolumab/ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients,” Paz-Ares said. “Approximately half of the responders who had a TRAE leading to discontinuation maintained their responses for at least 3 years after treatment discontinuation.”

The FDA approved the combination of nivolumab/ipilimumab in May 2020 as a first-line treatment for patients with metastatic NSCLC with PD-L1 ≥ 1% based on the CheckMate-227 study (NCT02477826). The most common (20% or more) adverse reactions in patients receiving the combination were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, pruritis, nausea, and hepatitis.

The agency also approved the combination of nivolumab/ipilimumab plus chemotherapy in May 2020 as a first-line treatment for patients with metastatic NSCLC. This based on the CheckMate-9LA study (NCT03215706). OS for patients treated with nivolumab plus ipilimumab plus chemotherapy compared to those who received chemotherapy. The median OS was 14.1 months in the experimental arm versus 10.7 months with chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87). The most common (20% or more) AEs were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

1. Paz-Ares LG, Ciuleanu TE, Lee JS, et al. Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227. 

2021;39(suppl 15):9016. doi:10.1200/JCO.2021.39.15_suppl.9016

2. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥ 1%). News release. FDA. May 15, 2020. Accessed June 4, 2021. https://bit.ly/2SYFQLY

3. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment mNSCLC. News release. FDA. May 26, 2020. Accessed June 4, 2021. https://bit.ly/3wZaO5u

After 4 years of treatment with the combination of nivolumab and ipilimumab, the therapy showed durable, long-term overall survival benefit compared with chemotherapy in patients with advanced non‒small cell lung cancer regardless of PD-L1 expression or histology.

Frontline Nivolumab Plus Ipilimumab Show Long-Term Benefit in mNSCLC

Findings from a A phase 3 trial (NCT02632409) evaluating adjuvant nivolumab (Opdivo) following surgery versus placebo demonstrated an improvement in median disease-free survival (DFS) in patients with muscle-invasive urothelial cancer (MIUC), according to results from the CheckMate 274 trial presented at the 2021 Genitourinary Cancers Symposium. 

Investigators found that nivolumab conferred a median DFS benefit in both the intention-to-treat (ITT) and PD-L1–positive populations. In the ITT population, DFS in those treated with nivolumab (n = 353) was 21.0 months, compared with 10.9 months with placebo (n = 356; HR, 0.70; 98.31% CI, 0.54-0.89; 

“This corresponds to a 30% reduction in the risk of disease recurrence or death with nivolumab,” said lead author Dean Bajorin, MD, the Frederick R. Adler senior faculty chair at Memorial Sloan Kettering Cancer Center in New York. “The median DFS is nearly double with nivolumab compared to placebo.”

In the PD-L1–positive population, the median DFS in those treated with nivolumab (n = 140)  was not reached, compared with 10.8 months in the placebo arm (n = 142; HR, 0.53; 98.87% CI, 0.34-0.84; 

 < .001). “This corresponds to a 47% reduction in the risk of disease recurrence or death with nivolumab,” Bajorin said.

A subgroup analysis of the ITT population found no differences related to age, sex, region, or performance status, he added.

The monoclonal antibody also improved median non–urothelial tract recurrence-free survival (NUTRFS), a secondary end point of the study, as well as distant metastasis free survival (DMFS), an exploratory end point, in both the ITT and the PD-L1–positive patient populations

In the ITT population, those treated with nivolumab experienced NUTRFS of 24.6 months versus 13.7 months in the placebo group (HR, 0.72; 95% CI, 0.58-0.89). In the PD-L1– positive population, NUTRFS in those treated with nivolumab was not reached versus 10.9 months in the placebo group (HR, 0.54; 95% CI, 0.38-0.77).

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma,” Bajorin said. “These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy.”

The randomized, double-blind CheckMate 274 study evaluated the efficacy and safety of adjuvant nivolumab versus placebo in patients with high-risk MIUC after radical surgery. Patients were randomized 1:1 to receive nivolumab 240 mg administered once every 2 weeks or placebo for up to 1 year of adjuvant treatment.

Eligible patients had radical surgery within 120 days with or without neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemotherapy and were disease-free as evidenced by imaging.

The primary end point of the study, according to investigators, was DFS in the ITT population and in patients with tumor PD-L1 expression of at least 1%. The median follow-up was 20.9 months for nivolumab and 19.5 months for placebo.

In total, 353 patients were randomized to receive nivolumab and 356 patients received placebo. In the nivolumab arm, 53.3% of patients discontinued treatment and in the placebo arm, 56.3% of patients discontinued. This was most commonly due to disease recurrence.

Among patients in the nivolumab arm, the tumor of origin was urinary bladder carcinoma in 79% of patients and upper tract disease in 21% of patients. In the placebo arm, the tumor of origin was the bladder in 78.9% of patients and upper tract disease in 21.1% of patients. About 40% patients in both arms were PD-L1 positive and about 43% had received prior cisplatin based neoadjuvant chemotherapy.

The safety of nivolumab was consistent with previously reported studies in patients with solid tumors. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 17.9% of patients in the nivolumab arm and 7.2% of patients in the placebo arm.

Any-grade TRAEs leading to discontinuation occurred in 12.8% in the nivolumab arm and 2% of patients in the placebo arm. The most common TRAEs in the nivolumab arm were pruritis, fatigue, diarrhea, and rash.

Nivolumab is approved by the FDA as a monotherapy for the treatment of platinum-resistant urothelial carcinoma.

Bajorin DF, Witjes JA, Gschwend J, Schenker M. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). 

Findings from a A phase 3 trial evaluating adjuvant nivolumab following surgery versus placebo demonstrated an improvement in median disease-free survival in patients with muscle-invasive urothelial cancer, according to results from the CheckMate 274 trial presented at the 2021 Genitourinary Cancers Symposium. 





Adjuvant Nivolumab Confers 30% Reduction in Disease Recurrence in MIUC

After treatment with savolitinib, undetectability of 

ex14) in the circulating tumor DNA (ctDNA) of patients with non‒small cell lung cancer (NSCLC) was found to be associated with prolonged progression-free survival (PFS), and overall survival (OS), according to a poster presented during the virtual AACR Annual Meeting 2021.

ex14 clearance upon savolitinib treatment was correlated with significantly longer PFS and OS compared with those who had detectable 

ex14,” said lead author Yongfeng Yu, MD, of the Shanghai Chest Hospital, Shanghai Jiao Tong University in Shanghai, China.

He cautioned the sample size was small and confirmation of the finding with a larger sample size was needed.

The median PFS for patients treated with savolitinib who had undetectable 

ex14 (n = 14) was 30.3 months (95% CI, 6.8-NC) with a hazard ratio (HR) of 0.72 (95% CI, 0.28-1.87; 

 = .501). The median OS for these patients was 35.8 months (95% CI, 14-NC) with an HR of 0.89 (95% CI, 0.25-3.18; 

ex14 following treatment (n = 10), the median PFS was 5.5 months (95% CI, 0.66-5.6) with an HR of 4.94 (95 CI, 1.83-13.36; 

 = .002). The median OS for these patients was 8.7 months (95% CI, 0.8-10.6). HR was 7.06 (95% CI, 2.39-20.89; 

For patients treated with savolitinib who were non-evaluable for 

ex14 (n = 22), the median PFS was 4.1 months (95% CI, 4.0-6.9). HR was 3.45 (95% CI, 1.48-8.03; 

 = .006). The median OS for these patients was 10.6 months (95% CI, 4.8-12.0). HR was 5.88 (95% CI, 2.24-15.47; 

ex14 was undectable for 20 patients at baseline. The median PFS for those patients was 13.8 months (95% CI, 4.2-22.1) and the median OS was not calculable.

Investigators also studied concurrent gene alterations with METex14 and noted alterations with likely resistance to savolitinib including 

 tyrosine kinase inhibitor. The agent previously demonstrated clinical efficacy and a manageable safety profile in Chinese NSCLC patients with METex14 alterations in a phase 2 study (NCT02897479).

In the analysis presented at AACR, investigators studied ctDNA analysis of 

ex14 at baseline and clearance upon treatment using next generation sequencing, QIAamp Circulating Nucleic Acid Kit from Qiagen. They collected plasma samples pre-dose and at tumor assessment visits, until disease progression or end of treatment. Data cut-off was August 2020.

Sixty-six patients provided baseline plasma samples, of which 

ex14 ctDNA was detectable in 46 (70%) patients. Of these patients, investigators were able to evaluate 24 patients for clearance of 

ex14. Fourteen of those 24 achieved ctDNA clearance with a median time to clearance of 1.4 months of treatment.

In a previously published analysis of patients in this phase 2 study, savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in 

 As of October 31, 2019, 593 patients were pre-screened/screened and 87 were identified as having 

ex14+; 70 of these patients were treated.

Sixty-one patients in this study were efficacy evaluable by independent review committee assessment. The objective response rate was 47.5% (95% CI, 34.6%-60.7%) with a disease control rate of 93.4% (95% CI, 84.1%-98.2%). The median duration of response has not been reached. The median PFS was 6.8 months (95% CI, 4.2-13.8) among all treated patients.

The most common (greater than or equal to 20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of grade 3 or higher TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% patients, the most common of which are liver injury and hypersensitivity (2.9% each).

The therapy’s developer, Hutchinson China MediTech, has applied for regulatory approval in China for the treatment of NSCLC with 

Ex14 skipping mutations, the first application globally and the first for a selective 

 inhibitor in China. China’s National Medical Products Administration has granted the therapy priority review status.

1. Yu Y, Ren Y, Fan J, et al. ctDNA analysis in the savolitinib phase II study in non‒small cell lung cancer (NSCLC) patients (pts) harboring 

ex14). Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT158

2. Lu S, Fang J, Li X, et al. Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring 

 2020; 38, no. 15_suppl:9519-9519. doi: 10.1200/JCO.2020.38.15_suppl.9519

3. Chi-Med’s NDA for savolitinib in non‒small cell lung cancer granted priority review in China. Hutchinson China MediTech Limited. News release. July 28, 2020. Accessed April 10, 2020. https://www.hutch-med.com/nda-for-savolitinib-in-nsclc-granted-priority-review-in-china/

After treatment with savolitinib, undetectability of MET Exon 14 in the circulating tumor DNA of patients with non‒small cell lung cancer was found to be associated with prolonged progression-free survival, and overall survival.

Denise Myshko | Authors

Articles

Early Trial Targeting CLL1-Positive Cells Demonstrates Efficacy in Pediatric AML

Frontline Nivolumab Plus Ipilimumab Show Long-Term Benefit in mNSCLC

Adjuvant Nivolumab Confers 30% Reduction in Disease Recurrence in MIUC

Undetectable METex14 After Savolitinib Correlates With Positive Outcomes in NSCLC