Brielle Benyon

Improved survival outcomes were reported with the addition of nivolumab (Opdivo) to either ipilimumab (Yervoy) or chemo-therapy vs chemotherapy alone in the frontline treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC). Updated data from the phase 3 CheckMate 648 trial (NCT03143153) were presented at the 2021 American Society of Clinical Oncology Annual Meeting.

“Advanced [ESCC] carries a poor prognosis, with a median survival of around 10 months,” said Ian Chau, MD, consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom.

CheckMate 648 is a randomized phase 3 trial evaluating the efficacy of the following treatment regimens in adult patients with histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus that is deemed inoperable and cannot be treated with chemoradiation with curative intent:

Nivolumab plus chemotherapy: nivolumab 240 mg on day 1 and day 15; fluorouracil 800 mg/m² per day on day 1 -5 for 5 days; and cisplatin 80 mg/m² on day 1 of the 4-week cycle (n = 321).

Nivolumab plus ipilimumab: nivolumab 3 mg/kg every 2 weeks, followed by ipilimumab 1mg/kg every 6 weeks until unacceptable toxicity or disease progression (n = 325).

Chemotherapy alone: cisplatin and fluorouracil (n = 324).

Eligible patients had an ECOG performance score of 0 to 1, measurable disease, and no prior systemic treatment for advanced disease. The primary end points in the trial were overall survival (OS) and progression-free survival (PFS) in patients whose tumors had PD-L1 expression greater than or equal to 1%.

Secondary end points were OS and PFS in all patients, as well as objective response rate (ORR), both in patients with PD-L1 greater than or equal to 1% and all patients.

At a minimum follow-up of 12.9 months, median OS in patients with PD-L1 greater than or equal to 1% in the nivolumab plus chemotherapy arm (n = 158) was 15.4 months (95% CI, 11.9-19.5), and was 13.7 months (95% CI, 11.217.0) in the nivolumab plus ipilimumab arm (n = 158). In the patients who were PD-L1 positive in the chemotherapy alone arm (n = 157) median OS was 9.1 months (95% CI, 7.7-10.0; 

“This translates into over 6 months improvement in median OS when comparing nivolumab plus chemotherapy to chemotherapy alone,” Chau said. “But importantly, if you look at the latter parts of the [OS] curve, they’re widely separated in favor of nivolumab plus chemo-therapy, meaning that there were more patients with prolonged [OS].”

In the overall study population, the median OS in the nivolumab plus chemotherapy arm was 13.2 months (95% CI, 11.1-15.7); 12.8 months in the nivolumab plus ipilimumab arm (95% CI, 11.3-15.5 months); and 10.7 months in the chemo arm (95% CI, 9.4-11.9; 

The primary end point of PFS per blind independent committee review was not met in patients whose tumors were PD-L1 positive (HR, 1.02; 95% CI, 0.73-1.43). The ORR in patients with PD-L1–positive tumors given nivolumab plus ipili-mumab was 35% (95% CI, 28-43). In the chemotherapy arm it was 20% (95% CI, 14-27). In all patients, ORR was 28% (95% CI, 23-33) and 27% (95% CI, 22-32) in the nivolumab plus ipilimumab and nivolumab plus chemotherapy arms, respectively.

Regarding safety, the most common (occur-ring in 10% or more) treatment-related adverse events (TRAEs) for the chemotherapy-contain-ing arms were nausea, decreased appetite, and stomatitis. For the nivolumab/ipilimumab arm, common TRAEs were rash, pruitis, and hypothyroidism. Notably, incidence of TRAEs was consistent with all treated patients across all arms for patients whose tumor cell had PD-L1 expression greater than or equal to 1%.

Ultimately, these regimens have the potential to drastically improve outcomes in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma—a group that tends to have poor prognoses.

“Nivolumab plus chemotherapy [and] nivolumab plus ipilimumab each represent a new potential first-line standard of care for patients with advanced [ESCC], based on the results of CheckMate 648, the largest randomized control trial conducted in this setting to date,” Chau said.

1. Chau I. First results from the CheckMate 648 study evaluating nivolumab plus ipilimumab or nivolumab plus chemotherapy versus che-motherapy as first-line treatment for advanced esophageal squamous cell carcinoma. Presented at: 2021 ASCO Annual Meeting Press Program, May 28, 2021.

2. A study to evaluate efficacy in subjects with esophageal cancer treat-ed with nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin (CheckMate 648). Clinical-Trials.gov. Updated May 7, 2021. Accessed June 1, 2021. https://clinical-trials.gov/ct2/show/NCT03143153

Articles

Improved survival outcomes were reported with the addition of nivolumab to either ipilimumab or chemo-therapy vs chemotherapy alone in the frontline treatment of patients with unresectable advanced or meta-static esophageal squamous cell carcinoma.

Survival in Advanced ESCC Improved With Frontline Nivolumab Plus Ipilimumab or Chemotherapy

The frequency of neurologic toxicities from ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) can be reduced with management strategies for patients with relapsed or refractory multiple myeloma treated with the chimeric antigen receptor (CAR) T-cell therapy, findings from CARTITUDE-2 show. 

“To date, more than 100 patients across the CARTITUDE study program have been dosed with cilta-cel. So when implemented, patient management strategies have reduced the incidence of neurotoxicity, including movement and neurocognitive events,” said Hermann Einsele, MD, FRCP, professor of internal medicine at the Julius Maximillians University of Würzburg in Germany, while presenting the study findings during the European Hematology Association 2021 Virtual Meeting.

The open-label, phase 2, multicohort CARTITUDE-2 (NCT04133636) trial evaluated the efficacy and safety of cilta-cel in patients with myeloma. For the purpose of studying adverse events, the researchers analyzed cohort A, which involved patients with myeloma that progressed after 1-3 lines of therapy, including a proteasome inhibitor and an immunomodulary drug.

Eligible patients were adults with measurable disease and ECOG performance status of 0 or 1. Their disease was refractory to lenalidomide (Revlimid) and was not previously treated with another BCMA-targeted drug.

Patients received cilta-cel (0.75×10 6 [range: 0.5–1.0×10

] CAR+ viable T cells/kg) as a single infusion 5–7 days after the initiation of lymphodepletion (cyclophosphamide 300 mg/m

“Patient management strategies included more effective bridging therapy to reduce baseline tumor burden, early aggressive treatment of [cytokine release syndrome] and [immune effector cell-associated neurotoxicity], as well as handwriting assessment for early detection of symptoms of neurotoxicity,” Einsele said. “These strategies have been successfully implemented across the CARTITUDE proves.”

At a median follow-up of 5.8 months (range, 2.5-9.8), 20 patients in cohort A received cilta-cell, and 4 (20%) experienced at least 1 neurotoxicity. Three patients had grade 1/2 immune effector cell-associated neurotoxicity (ICANS) alongside cytokine release syndrome. The median time to symptom onset was 8 days (range, 7-11), and, on average, symptoms lasted 2 days. Two patients received supportive measure for their ICANS, including levetiracetam and steroids.

There was 1 patient who experienced isolated grade 2 facial paralysis on day 29. The patient recovered 51 days later after being treated with dexamethasone for 28 days. Overall, there were no movement or neurocognitive disorders that were reported within Cohort A of the study.

“Importantly, none of the patients in the cohort A of the CARTITUDE study experienced other neurotoxicities that were seen in CARTITUDE-1,” Einsele said.

Einsele H, Parekh S, Madduri D, et al. Incidence, mitigation, and management of neurologic adverse events in the phase 2 CARTITUDE-2 study of ciltacabtagene autoleucel in patients with multiple myeloma. Presented at: 2021 European Hematology Association Congress. June 9-17, 2021. Virtual. Abstract EP1003.

The frequency of neurologic toxicities from ciltacabtagene autoleucel can be reduced with management strategies for patients with relapsed or refractory multiple myeloma treated with the chimeric antigen receptor T-cell therapy, findings from CARTITUDE-2 show. 

Management Strategy Helps to Mitigate Neurotoxicity Concerns With Cilta-Cel in Multiple Myeloma

In patients with relapsed/refractory multiple myeloma, treatment with higher doses of subcutaneous elranatamab (PF-06863135), a BCMA-targeting humanized bispecific monoclonal antibody, was found to be effective, according to findings from a phase 1 clinical trial (NCT03269136) presented at the 2021 ASCO Annual Meeting.

“We recently reported on the intravenous dosing of elranatamab and demonstrated evidence of anti-myeloma activity in heavily pretreated relapsed/refractory multiple myeloma. We now extend these findings and report the results of subcutaneous elranatamab,” said Nizar J. Bahlis, MD, of the Arnie Charbonneau Cancer Institute at the University of Calgary, while reporting the findings.

“The primary objective was to assess the safety [and] tolerability of elranatamab administered and determine recommended phase 2 doses. The secondary objectives include the evaluation of anti-myeloma activity, as well as the duration of response,” he added.


 The trial tested weekly subcutaneous elranatamab in 30 patients across the following doses:

On average, patients had received 8 prior treatments. The majority (87%) had triple-refractory disease, with nearly all patients (97%) having received prior anti-CD38 therapy. Twenty-three percent of patients received BCMA-directed antibody drug conjugate or chimeric antigen receptor (CAR) T-cell therapy.

Response was measured by IMWG criteria, and the data cutoff was February 4, 2021.

Doses at or above 215 μg/kg had the best outcomes, with an overall response rate (ORR) of 70% (n = 14). Out of the 215-, 360-, 600-, and 1000-μg/kg dose groups, the highest dose had the best outcomes, with an 83.3% ORR, including 16.7% of patients with a complete response, 50% with a very good complete response, and 16.7% with a partial response. Median time to response was 22 days, ranging from 21 to 50 days.

There were 14 patients with IMWG-confirmed response; in this cohort, median duration of response was not reached. There was a 92.3% probability (95% CI, 56.7-98.9) of responders being event-free at 6 months.

Within the entire study population, the most common all causality treatment-emergent adverse events (AEs) were lymphopenia (83.3%; grade 3, 20% and grade 4, 60%), cytokine release syndrome (CRS; 73%; all grade 1 and 2); anemia (57%; grade 3, 43% and grade 4, 3%); injection site reaction (53%; none above grade 2); thrombocytopenia (53%; grade 3, 23% and grade 4, 17%); and neutropenia (40%; grade 3, 17% and grade 4, 17%). There were no dose-limiting toxicities.

The researchers also found that body weight or baseline soluble BCMA were not a significant variant on total exposure, “therefore, this supports a fixed-dosing approach,” Bahlis said.

Ultimately, he added, that these findings should lead to future studies of elranatamab alone and in combination with other drugs.

“These results clearly support the further development of elranatamab, both as monotherapy or in combination with other anti-myeloma agents,” he said.

Bahlis NJ, Raje NS, Costello C, et al. Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM). Presented at: 2021 ASCO Annual Meeting. June 4-8, 2021.

In patients with relapsed/refractory multiple myeloma, treatment with higher doses of subcutaneous elranatamab was found to be effective, according to findings from a phase 1 clinical trial.

Subcutaneous Elranatamab Demonstrates Efficacy in Relapsed/Refractory Myeloma 

In previously treated patients with chronic lymphocytic leukemia (CLL) who have del(17p) or del(11q) in theirs tumors, treatment with acalabrutinib (Calquence) was found to be noninferior but better tolerated compared with ibrutinib (Imbruvica), according to research presented at the 2021 ASCO Annual Meeting.

“Acalabrutinib is a more selective inhibitor of [Bruton tyrosine kinase (BTK)] and has been known to have less adverse events (AEs) when compared across trials. [Until] today, no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this,” said John C. Byrd, MD, professor of hematology at The Ohio State University.

Byrd presented findings from an open-label, randomized, noninferiority, phase 3 trial that compared acalabrutinib and ibrutinib in 533 patients.

 Patients were randomized to receive the BTK inhibitor acalabrutinib or ibrutinib until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS), and secondary endpoints were (in hierarchical order): all-grade atrial fibrillation, grade 3 or higher infection, Richter transformation, and overall survival (OS).

Overall, 268 patients received acalabrutinib and 265 received ibrutinib. Median age was 66 years and on average patients had 2 prior lines of therapies; 45.2% of patients had del(17p) and 64.2% had del(11q).

At a median follow-up of 40.9 months, acalabrutinib was noninferior to ibrutinib, with a PFS of 38.4 months in both arms (HR 1.00; 95% CI, 0.79-1.27).

Acalabrutinib was superior in all-grade atrial fibrillation incidence compared to ibrutinib (9.4% versus 16.0%, respectively; 

“When considering de-novo atrial fibrillation flutter occurring in patients who had never had this before, the difference between ibrutinib and acalabrutinib was greater,” Byrd explained. “Patients with acalabrutinib had a 6.2% incidence, whereas ibrutinib was 14.9%. Among patients developing atrial fibrillation and flutter, prior history of this and other risk factors were more common in the acalabrutinib arm.”

Other end points were comparable between the 2 treatments: 30.8% of patients on acalabrutinib and 30.0% of patients on ibrutinib experienced grade 3 or higher infection; 3.8% of patients on acalabrutinib versus 4.9% of those on ibrutinib had Richter transformation.

Average OS was not reached in either arm. There were 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm.

When it came to frequent (≥20%) all-grade AEs, the acalabrutinib arm had a lower instance of hypertension than ibrutinib (9.4% vs 23.2%, respectively), arthralgia (15.8% vs 22.8%), and diarrhea (34.3% vs 46.0%). Acalabrutinib, however, did have a higher incidence of headache (34.6% vs 20.2%, respectively) and cough (28.9% vs 21.3%) than ibrutinib.

“Despite a similar [independent review committee] progression-free survival, survival non-statistically favored acalabrutinib with 10 fewer deaths,” Byrd said. “These results demonstrate that acalabrutinib is better tolerated and safer than ibrutinib [and has] similar efficacy in previously treated patients with CLL.”

1. Byrd JC, Hillmen P, Ghia P, et. Al. First results of head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 7501.

2. Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. ClinicalTrials.gov Updated May 20, 2021. Accessed June 2, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02477696

In select previously treated patients with chronic lymphocytic leukemia, treatment with acalabrutinib was found to be noninferior but better tolerated compared with ibrutinib.

Brielle Benyon | Authors

Articles

Survival in Advanced ESCC Improved With Frontline Nivolumab Plus Ipilimumab or Chemotherapy

Management Strategy Helps to Mitigate Neurotoxicity Concerns With Cilta-Cel in Multiple Myeloma

Subcutaneous Elranatamab Demonstrates Efficacy in Relapsed/Refractory Myeloma

Acalabrutinib Shows Noninferiority to Ibrutinib With Better Safety in Previously Treated CLL