Rina Lokaj

The phase 3 CheckMate 914 clinical trial missed one of its primary endpoints of improved disease-free survival (DFS) with Opdivo (nivolumab) compared with placebo in patients with localized renal cell carcinoma at high risk of relapse after nephrectomy (removal of the kidney), according to findings from part B of the trial that were presented at the 2024 

At a median follow-up of 27 months, the median DFS, which is the time patients live without progression or complications from their cancer, was not reached in either the Opdivo arm or the placebo arm. The 18-month DFS rates by blinded review were 78.4% in the Opdivo arm and 75.4% in the placebo arm. There was no statistically significant difference among the two DFS rates, meaning that the researchers could not say with certainty that one truly outperformed the other.

When evaluated by researchers, the median DFS was also not reached in either arm, and the 18-month rates of DFS were 81.1% and 75.0%, respectively.

The phase 3 CheckMate 914 clinical trial investigated the effectiveness of Opdivo in patients with localized renal cell carcinoma at high risk of relapse after partial or complete removal of the kidney.

The trial did not meet one of its primary endpoints, which was to show improved disease-free survival (DFS) with Opdivo compared to placebo. DFS is the time patients live without progression or complications from their cancer.

At a median follow-up of 27 months, the median DFS was not reached in either the Opdivo or placebo arm, and there was no statistically significant difference in DFS rates between the two groups.

Despite the overall results, certain patient subgroups, including those with sarcomatoid features, PD-L1 expression of 1% or greater and lower baseline hemoglobin, showed a preference for Opdivo over placebo.

The trial had secondary endpoints, including DFS for Opdivo/Yervoy versus Opdivo alone, overall survival (OS) for Opdivo versus placebo, and safety. However, due to the primary endpoint not being met, no formal overall survival analysis will be performed.

Because the primary endpoint of DFS per BICR was not met, no formal overall survival (OS; time from treatment until death of any cause) analysis will be performed, lead study author, Dr. Robert J. Motzer, said in an oral presentation during the meeting.

However, patient subgroups that favored Opdivo vs placebo included patients with sarcomatoid features, PD-L1 expression of 1% or greater, and those with a lower limit of normal hemoglobin at baseline.

“Subgroup analysis from CheckMate 914 part A, which has been published previously, and presented previously, and part B suggest that there are tumor-specific characteristics that may influence outcomes for adjuvant (Opdivo) plus (Yervoy [ipilimumab]) and (Opdivo) monotherapy treatment,” said Motzer, section head, Kidney Cancer, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center.

Part A of the CheckMate 914 study was designed to evaluate the efficacy of adjuvant Opdivo plus Yervoy compared with placebo in patients with surgically resected stage 2/3 clear cell RCC with a high risk of relapse. At a median follow-up of 37 months, part A did not meet the primary endpoint of DFS for the treatment combination, with a median DFS of NR with Opdivo/Yervoy and 50.7 months with placebo. The 18-month DFS rates were 78.8% and 76.6%, respectively.

Part B of the double-blind, randomized, phase 3 CheckMate 914 trial included 825 patients with radical or partial nephrectomy with negative surgical margins, predominant clear cell histology, no clinical or radiological evidence of residual disease or distant metastases after nephrectomy, and an ECOG performance status of 0 or 1, indicating that they can perform all of most of their daily tasks independently.

Patients were randomly assigned to receive either 240 mg of intravenous (IV) Opdivo every two weeks for 12 doses plus placebo every six weeks for four doses (411 patients), IV placebo every two weeks for 12 doses plus placebo every six weeks for four doses (208 patients), or 240 mg of IV Opdivo every two weeks for 12 doses plus Yervoy every six weeks for four doses (206 patients). Randomization occurred between 4 and 12 weeks after surgery.

Patients were analyzed in groups based on the stage of their disease and the type of nephrectomy they underwent.

Secondary endpoints for this trial included DFS for Opdivo/Yervoy versus Opdivo alone, OS for Opdivo versus placebo and Opdivo/Yervoy versus Opdivo alone, and safety. An exploratory outcome was health-related quality of life. The data cutoff date was Sept. 8, 2023.

The median ages of patients in the Opdivo monotherapy, placebo, and Opdivo/Yervoy arms were 59 years (range, 25-86), 59 years (range, 25-80) and 60 years (range, 29-81), respectively. Ninety-three percent, 93%, and 94% of patients in each respective arm had a radical nephrectomy. In addition, most patients had pathological TNM staging of pT3, G any, N0 M0 at 82%, 81% and 82%, respectively. Most patients also had a PD-L1 expression of less than 1% or not evaluable (85%, 89% and 86%, respectively).

The median duration of therapy for all three arms was 5.1 months (range, <0.1-8.3). Overall, 327, 182 and 118 patients completed treatment in each respective arm. Discontinuations occurred in 20% of the Opdivo-alone arm, 12% of the placebo arm, and 42% of the combination arm; 11%, 1% and 31% of patients discontinued due to study drug toxicity, respectively.

All-grade treatment-related side effects occurred in 73% of patients in the monotherapy arm, 52% of patients in the placebo arm, and 85% in the combination arm. Grade 3/4 (moderate to severe) side effects occurred in 9%, 2% and 20% of patients in each respective arm. No patients died due to study drug toxicity.

The most common all-grade side effect in the Opdivo monotherapy, placebo, and combination arm, respectively, were itching (21% versus 15% versus 25%), fatigue (19% versus 16% versus 22%), hyperthyroidism (11% versus 1% versus 16%), hypothyroidism (11% versus 3% versus 21%), diarrhea (11% versus 9% versus 19%), rash (10% versus 6% versus 17%), weakness (9% versus 8% versus 8%), joint pain (8% versus 8% versus 11%), muscle aches/pain (5% versus 6% versus 9%), nausea (5% versus 5% versus 7%), headache (5% versus 3% versus 4%), alanine aminotransferase increase, which could indicate liver disease (5% versus 1% versus 10%), and maculopapular rash (5% versus <1% versus 7%).

Motzer noted that 6% of patients in the Opdivo monotherapy arm required corticosteroids to manage any grade immune-mediated side effects, compared with 2% in the placebo arm and 19% in the nivolumab/ipilimumab arm.

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Opdivo failed to improve disease-free survival in patients with localized renal cell carcinoma at high risk of relapse, according to findings from CheckMate 914. 

Opdivo Misses Disease-Free Survival Goal in Kidney Cancer Trial

Opdivo (nivolumab) plus chemotherapy demonstrated significant improvements in survival in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma when compared with chemotherapy treatment alone, according to a phase 3 trial.

Findings from the phase 3 CheckMate-649 trial were presented at the 

This randomized study included a total of 2,031 patients, 789 of whom were in the Opdivo plus chemotherapy arm and 792 of whom were in the chemotherapy alone arm.

The median age of patients enrolled in each arm was 62 and 61, respectively. Most of the population identified as male (68% versus 71%), had gastric cancer at initial diagnosis (70% versus 70%), had metastatic disease (96% versus 95%) and had an ECOG performance status of 1 (58% versus 57%), meaning patients were restricted in strenuous activities.

Patients with previously untreated, unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma with no known HER2-positive status and an ECOG performance status of 0 or 1 were eligible to enroll in the trial.

Patients were grouped based on tumor cell PD-L1 expression, region, ECOG performance status and type of chemotherapy received.

Opdivo with chemotherapy improves survival in GI cancers, compared to chemotherapy alone.

Patients in the Opdivo-chemo group lived longer without disease worsening.

Opdivo is the first treatment of its kind showing long-term benefits and safety over four years.

Opdivo-chemo resulted in a positive response in 58% of patients, with manageable side effects.

Although some side effects led to treatment discontinuation, the overall safety was considered acceptable for the survival benefits observed.

Results reflected survival improvements, specifically with overall survival (OS; time from diagnosis or start of treatment when a patient is still alive) and progression-free survival (PFS; time during and after treatment when patients live with disease but it does not worsen).

The median OS in the overall population was 13.7 months in the Opdivo-chemotherapy arm and 11.6 months in the chemotherapy-alone arm. The median PFS in the overall population was 7.7 months in the Opdivo-chemotherapy arm and 6.9 months in the chemotherapy-alone arm.

“(Opdivo) is the first PD-1 inhibitor plus chemotherapy combination to demonstrate long-term efficacy versus chemotherapy and acceptable safety after four years of follow-up in patients with previously untreated advanced (gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma),” Dr. Kohei Shitara, lead study author, said during the presentation.

Shitara is a medical oncologist and the chief of the department of gastrointestinal oncology of the National Cancer Center Hospital East in Kashiwa, Japan.

Adding Opdivo to Frontline Chemo Boosts Survival in Advanced GI Cancers

At the data cutoff, the minimum follow-up was 48.1 months. Three patients in the combination arm and nine in the chemotherapy arm were still receiving treatment at the cutoff.

The objective response rate (ORR; percentage of patients who had a partial or complete response to treatment) in the total population was 58% in the Opdivo-chemotherapy arm and 46% in the chemotherapy-alone arm, with most patients experiencing a partial response (47% versus 39%), as well as complete responses (11% versus 7%) and stable disease (28% versus 33%).

The median duration of response (DOR; time from start of study until disease progression or death in patients with a partial or complete response) in the overall population was 8.5 months and 6.9 months in each respective arm.

No new safety signals were reported, according to the study. Any grade treatment-related side effects occurred in 95% of patients in the Opdivo-chemotherapy arm and 89% of patients in the chemotherapy-alone arm.

Treatment-related side effects leading to discontinuation occurred in 42% and 26% of patients in each respective arm, with 19% and 10% in each arm resulting from severe to life-threatening treatment-related side effects.

The most common severe to life-threatening treatment-related side effects in the Opdivo-chemotherapy arm included neutropenia (lower levels of white blood cells; 16%), anemia (6%) and increased lipase (enzymes that break down fats in food; 6%).

In the chemotherapy-alone arm, the most common severe to life-threatening treatment-related side effects included neutropenia (13%), diarrhea (3%), peripheral neuropathy (numbness or pain in hands and feet; 3%), anemia (3%) and vomiting (3%). A total of 16 patients in the Opdivo-chemotherapy arm and four patients in the chemotherapy-alone arm experienced treatment-related deaths.

Treatment with Opdivo and chemotherapy improved survival in patients with gastrointestinal cancers, compared with chemotherapy alone, according to a phase 3 trial. 

Opdivo-Chemo Combination Improves Survival in GI Cancers

Yescarta boosted survival in patients with pretreated large B-cell lymphoma, research showed. 

Yescarta (axicabtagene ciloleucel) showed an improvement in overall survival (OS; the time a patient lives following treatment regardless of disease status) and progression free survival (PFS, the time a patient lives without their disease worsening) in patients 65 and older with large B-cell lymphoma who previously underwent one line of therapy compared with standard of care, according to subgroup findings from the phase 3 ZUMA-7 trial presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.

In the subgroup of patients 65 and older, the median OS in those receiving Yescarta versus standard of care was 43.5 months and 19.5 months, respectively. In the subgroup of patients 70 and older, the median OS in patients receiving Yescarta versus standard of care was 24.7 months and 11.2 months, respectively.

In the subgroup of patients 65 and older, the median PFS in patients receiving Yescarta versus standard of care was 28.6 months and five months, respectively. In the subgroup of patients 70 and older, the median OS in each arm was 11.4 months and 2.7 months, respectively.

“In the subgroup analysis, (Yescarta) as second-line therapy showed prolonged survival over standard of care in patients aged 65 years or older, including in patients aged 70 years or older,” said presenting author Dr. Marie José Kersten, professor of hematology at Amsterdam University Medical Centers. “These findings confirm that age alone should not be a barrier for consideration of CAR-T cell therapy and support the use of (Yescarta) as a curative intense second-line therapeutic option for elderly patients with relapsed refractory large B-cell lymphoma.”

In the international phase 3 trial, patients with refractory large B-cell lymphoma or who had relapsed no more than 12 months after first-line chemoimmunotherapy were randomly assigned to receive Yescarta or standard care, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy.Patients were able to receive cellular immunotherapy if they did not experience a response to standard of care. A total of 109 patients 65 and older were included in the subgroup analysis.

The primary endpoint of the study was event-free survival (EFS; the time a patient lives without complications from their disease). Secondary endpoints included OS, PFS and safety.

Improved OS in patients 65 years and older who received Yescarta was also associated with a greater proportion of naive T cells.

Any-grade and grade 3 or higher side effects of interest in the experimental arm versus control arm, respectively, were cytokine release syndrome (CRS, a systemic inflammatory response; 98% and 8% versus not evaluable), neurological events (67% and 27% versus 25% and 2%), hypogammaglobulinemia (low immunoglobin levels, 20% and 0% versus 2% and 0%), cytopenia (reduced blood cell counts, 84% and 84% versus 82% and 76%) and infections (61% and 29% versus 38% and 16%).

Death occurred in 51% of patients receiving Yescarta and 53% of patients receiving standard of care. Reasons for death included progressive disease (41% versus 36%), grade 5 side effects (4% versus 2%), new or secondary malignancies (2% versus 0%) and definitive therapy-related mortality (0% versus 2%).

Data from the ZUMA-7 trial shows that age alone should not be a barrier of consideration of administering CAR-T cell therapy to patients with large B-cell lymphoma, says Dr. Marie José Kersten.

Rina Lokaj

Opdivo Misses Disease-Free Survival Goal in Kidney Cancer Trial

Opdivo-Chemo Combination Improves Survival in GI Cancers

Yescarta Improves Survival for Patients With Large B-Cell Lymphoma

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