In the Journals

Nintedanib fails to improve progression-free survival in mesothelioma

When added to combination therapy with cisplatin plus pemetrexed, nintedanib did not improve progression-free survival in patients with malignant pleural mesothelioma who had not been treated with chemotherapy, according to the phase 3 part of the LUME-Meso trial.

Specifically, after 250 events, there was no difference in median progression-free survival (PFS), as determined by investigator assessment, between patients randomly assigned cisplatin plus pemetrexed and nintedanib (Ofev, Boehringer Ingelheim) and those assigned cisplatin plus pemetrexed and placebo (6.8 vs. 7 months, respectively; HR = 1.01; 95% CI, 0.79-1.3).

PFS findings determined by independent central review were consistent with these results (6.8 months in both treatment groups; HR = 0.99; 95% CI, 0.77-1.28), and agreement between the investigator assessment and independent central review was greater than 80% in both treatment groups.

These results failed to confirm data from the phase 2 part of the LUME-Meso study, which showed that the addition of nintedanib, as compared with placebo, to standard chemotherapy prolonged PFS in chemotherapy-naive patients with unresectable malignant pleural mesothelioma, the researchers noted.

“Making significant improvements in the systemic therapy for malignant pleural mesothelioma has proven to be quite challenging. Despite promising data from the phase 2 part of the LUME-Meso study, the primary endpoint (progression-free survival) was not met in the phase 3 part,” the researchers wrote in The Lancet Respiratory Medicine.

Additional endpoints

Results also demonstrated no significant differences in median overall survival between the nintedanib and placebo groups (14.4 vs. 16.1 months, respectively; HR = 1.12; 95% CI, 0.79-1.58).

Additionally, scores on the mesothelioma version of the Lung Cancer Symptom Scale (LCSS-Meso), which was used to measure health-related quality of life, and the average symptom burden index scores did not differ significantly with vs. without treatment, although they slightly favored nintedanib. The same was also true for the LCSS-Meso global scales activity level and symptom distress scores and all individual symptoms scale scores except appetite loss. The likelihood of improvement also favored nintedanib vs. placebo for activity level (OR = 1.67; P = .0087) and symptom distress (OR = 1.58; P = .019).

Although PFS and overall survival were generally consistent across subgroups, exploratory analyses indicated that baseline platelet count may potentially predict which patients would benefit from nintedanib treatment.

For example, for overall survival, there was a positive treatment effect with nintedanib in patients with high platelet count at baseline (HR = 0.53; 95% CI, 0.3-0.92), but there was a negative treatment effect in patients with low platelet count at baseline (HR = 2.04; 95% CI, 1.21-3.45). For PFS, the predictive potential of baseline platelet count was less pronounced, with nintedanib conferring a slight benefit in patients with high (HR = 0.82; 95% CI, 0.53-1.27) but not low platelet counts (HR = 1.07; 95% CI, 0.77-1.49). However, the researchers emphasized that these analyses were exploratory, and therefore they could not include formal statistical testing.

Neutropenia was the most common grade 3 or worse adverse event in both the nintedanib group and the placebo group (32% vs. 24%). Serious adverse events were reported in 44% of the nintedanib group and 39% of the placebo group, and pulmonary embolism was the only serious adverse event occurring in at least 5% of patients in the nintedanib (6%) or placebo groups (3%).

“The overall safety profile of nintedanib in combination with chemotherapy was consistent with the known safety profile in combination with backbone chemotherapy from previous studies, and no major unexpected safety findings were reported in this study,” the researchers wrote.

However, they also noted that a higher proportion of patients in the treatment group vs. the placebo group experienced grade 3 or worse adverse events leading to dose reduction.

Future directions

For this international, multicenter, double-blind, randomized, placebo-controlled phase 3 trial, the researchers randomly assigned adults with unresectable epithelioid malignant pleural mesothelioma and Eastern Cooperative Oncology Group performance status of 0 to 1 to six 21-day cycles of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 followed by twice-daily nintedanib 200 mg (n = 229) or matched placebo (n = 229). Those without disease progression after six cycles received the study drug or placebo maintenance from days 1 to 21 of each cycle.

In looking at the phase 2 and 3 parts, the researchers noted that no major changes in trial design or patient population could account for the difference in findings between the two phases. The only change was the decision to include patients with epithelioid histology only in phase 3.

“This latest failure of an anti-angiogenetic drug in patients with mesothelioma fosters consistent doubts and skepticism and raises the questions of whether we should drop the anti-angiogenetic approach after so many trial failures; whether angiogenesis should still be considered an adequate therapeutic target in this disease and whether it should still be investigated in unselected patients; or whether identification and careful selection is needed of subgroups of patients who are the best candidates for this therapeutic approach on the basis of their pro-angiogenic tumor features,” Michele Maio, MD, PhD, and Luana Calabrò, MD, PhD, both from the department of oncology, medical oncology and immunotherapy at the Center for Immuno-Oncology, University Hospital of Siena, Italy, wrote in a linked comment.

They also highlighted a significant shift in research in this area, with a 2013 study showing the potential of an immune checkpoint blockade strategy directed to the CTLA-4 molecules and subsequent phase 1 or 2 studies showing additional potential from targeting PD-1 or its ligand PD-L1.

“Whether targeting of immune-checkpoints and their use in novel combinations or sequences will be the beginning of a new era in mesothelioma remains to be established. The final study results from the fully accrued CheckMate743 study (NCT02899299) comparing the co-targeting of CTLA-4 and PD-1 with cisplatin plus pemetrexed regimen will soon be available, hopefully providing clarity on whether immunotherapy will be the future standard treatment for patients with mesothelioma,” Maio and Calabrò wrote. – by Melissa Foster

Disclosures: This study was funded by Boehringer Ingelheim. Scagliotti reports he received fees for honoraria from AstraZeneca, Eli Lilly, Merck Sharp and Dohme (MSD), Pfizer and Roche; consulting or advisory roles from Eli Lilly; speakers bureau from Eli Lilly and MSD; and travel, accommodation and expenses from Bayer. Please see the study for all other authors’ relevant financial disclosures. Calabrò reports she has served as a consultant to Bristol-Myers Squibb. Maio reports she has served as a consultant, adviser or both to AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, MedImmune, MSD, Merck Serono and Roche-Genentech.

When added to combination therapy with cisplatin plus pemetrexed, nintedanib did not improve progression-free survival in patients with malignant pleural mesothelioma who had not been treated with chemotherapy, according to the phase 3 part of the LUME-Meso trial.

Specifically, after 250 events, there was no difference in median progression-free survival (PFS), as determined by investigator assessment, between patients randomly assigned cisplatin plus pemetrexed and nintedanib (Ofev, Boehringer Ingelheim) and those assigned cisplatin plus pemetrexed and placebo (6.8 vs. 7 months, respectively; HR = 1.01; 95% CI, 0.79-1.3).

PFS findings determined by independent central review were consistent with these results (6.8 months in both treatment groups; HR = 0.99; 95% CI, 0.77-1.28), and agreement between the investigator assessment and independent central review was greater than 80% in both treatment groups.

These results failed to confirm data from the phase 2 part of the LUME-Meso study, which showed that the addition of nintedanib, as compared with placebo, to standard chemotherapy prolonged PFS in chemotherapy-naive patients with unresectable malignant pleural mesothelioma, the researchers noted.

“Making significant improvements in the systemic therapy for malignant pleural mesothelioma has proven to be quite challenging. Despite promising data from the phase 2 part of the LUME-Meso study, the primary endpoint (progression-free survival) was not met in the phase 3 part,” the researchers wrote in The Lancet Respiratory Medicine.

Additional endpoints

Results also demonstrated no significant differences in median overall survival between the nintedanib and placebo groups (14.4 vs. 16.1 months, respectively; HR = 1.12; 95% CI, 0.79-1.58).

Additionally, scores on the mesothelioma version of the Lung Cancer Symptom Scale (LCSS-Meso), which was used to measure health-related quality of life, and the average symptom burden index scores did not differ significantly with vs. without treatment, although they slightly favored nintedanib. The same was also true for the LCSS-Meso global scales activity level and symptom distress scores and all individual symptoms scale scores except appetite loss. The likelihood of improvement also favored nintedanib vs. placebo for activity level (OR = 1.67; P = .0087) and symptom distress (OR = 1.58; P = .019).

Although PFS and overall survival were generally consistent across subgroups, exploratory analyses indicated that baseline platelet count may potentially predict which patients would benefit from nintedanib treatment.

For example, for overall survival, there was a positive treatment effect with nintedanib in patients with high platelet count at baseline (HR = 0.53; 95% CI, 0.3-0.92), but there was a negative treatment effect in patients with low platelet count at baseline (HR = 2.04; 95% CI, 1.21-3.45). For PFS, the predictive potential of baseline platelet count was less pronounced, with nintedanib conferring a slight benefit in patients with high (HR = 0.82; 95% CI, 0.53-1.27) but not low platelet counts (HR = 1.07; 95% CI, 0.77-1.49). However, the researchers emphasized that these analyses were exploratory, and therefore they could not include formal statistical testing.

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Neutropenia was the most common grade 3 or worse adverse event in both the nintedanib group and the placebo group (32% vs. 24%). Serious adverse events were reported in 44% of the nintedanib group and 39% of the placebo group, and pulmonary embolism was the only serious adverse event occurring in at least 5% of patients in the nintedanib (6%) or placebo groups (3%).

“The overall safety profile of nintedanib in combination with chemotherapy was consistent with the known safety profile in combination with backbone chemotherapy from previous studies, and no major unexpected safety findings were reported in this study,” the researchers wrote.

However, they also noted that a higher proportion of patients in the treatment group vs. the placebo group experienced grade 3 or worse adverse events leading to dose reduction.

Future directions

For this international, multicenter, double-blind, randomized, placebo-controlled phase 3 trial, the researchers randomly assigned adults with unresectable epithelioid malignant pleural mesothelioma and Eastern Cooperative Oncology Group performance status of 0 to 1 to six 21-day cycles of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 followed by twice-daily nintedanib 200 mg (n = 229) or matched placebo (n = 229). Those without disease progression after six cycles received the study drug or placebo maintenance from days 1 to 21 of each cycle.

In looking at the phase 2 and 3 parts, the researchers noted that no major changes in trial design or patient population could account for the difference in findings between the two phases. The only change was the decision to include patients with epithelioid histology only in phase 3.

“This latest failure of an anti-angiogenetic drug in patients with mesothelioma fosters consistent doubts and skepticism and raises the questions of whether we should drop the anti-angiogenetic approach after so many trial failures; whether angiogenesis should still be considered an adequate therapeutic target in this disease and whether it should still be investigated in unselected patients; or whether identification and careful selection is needed of subgroups of patients who are the best candidates for this therapeutic approach on the basis of their pro-angiogenic tumor features,” Michele Maio, MD, PhD, and Luana Calabrò, MD, PhD, both from the department of oncology, medical oncology and immunotherapy at the Center for Immuno-Oncology, University Hospital of Siena, Italy, wrote in a linked comment.

They also highlighted a significant shift in research in this area, with a 2013 study showing the potential of an immune checkpoint blockade strategy directed to the CTLA-4 molecules and subsequent phase 1 or 2 studies showing additional potential from targeting PD-1 or its ligand PD-L1.

PAGE BREAK

“Whether targeting of immune-checkpoints and their use in novel combinations or sequences will be the beginning of a new era in mesothelioma remains to be established. The final study results from the fully accrued CheckMate743 study (NCT02899299) comparing the co-targeting of CTLA-4 and PD-1 with cisplatin plus pemetrexed regimen will soon be available, hopefully providing clarity on whether immunotherapy will be the future standard treatment for patients with mesothelioma,” Maio and Calabrò wrote. – by Melissa Foster

Disclosures: This study was funded by Boehringer Ingelheim. Scagliotti reports he received fees for honoraria from AstraZeneca, Eli Lilly, Merck Sharp and Dohme (MSD), Pfizer and Roche; consulting or advisory roles from Eli Lilly; speakers bureau from Eli Lilly and MSD; and travel, accommodation and expenses from Bayer. Please see the study for all other authors’ relevant financial disclosures. Calabrò reports she has served as a consultant to Bristol-Myers Squibb. Maio reports she has served as a consultant, adviser or both to AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, MedImmune, MSD, Merck Serono and Roche-Genentech.