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Rushing will not help to choose the best combination
Correspondence
Rushing will not help to choose the best combination We read with great interest and welcome the publication of the CheckMate 012 trial1 in The Lancet Oncology, in which the authors assessed the safety and efficacy of nivolumab plus ipilimumab as firstline therapy for metastatic non-smallcell lung cancer (NSCLC). Initial cohorts that assessed the combination of nivolumab (1 or 3 mg/kg) plus ipilimumab (1 or 3 mg/kg) given every 3 weeks followed by nivolumab 3 mg/kg every 2 weeks were characterised by poor tolerability with 51% (25/49) patients having grade 3–4 treatment-related adverse events. Four additional regimens evaluated lower doses of both agents or less frequent dosing. Only two of them were fully presented in the paper because they were the two cohorts considered for clinical development: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg given either every 12 weeks or every 6 weeks. Grade 3–4 treatment-related toxicity occurred in 37% patients in the every-12-weeks cohort and in 33% in the every 6-weeks-cohort. Confirmed objective responses (all partial responses) were achieved by 47% patients in the every 12-weeks cohort and 38% in the every-6-weeks cohort (all partial responses). These two schedules seem to be active even in patients with low expression of programmed death ligand 1 (PD-L1) and in patients carrying an EGFR activating mutation. Notably, the results of the other two regimens (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks, followed by nivolumab 3 mg/kg every 2 weeks vs nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/ kg every 6 weeks) were presented in the appendix (grade 3–4 treatmentrelated toxicities 29% vs 40%; www.thelancet.com/oncology Vol 18 April 2017
objective response rate 19% vs 33%). Overall, the trial results certainly confirm the fact that increasing the dose or frequency of ipilimumab negatively affects the safety of the combination without necessarily increasing the response rate. However, we find it difficult to understand why the combination of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks was chosen as the regimen for further development in the ongoing phase 3 Checkmate 012 trial. Use of a 12-week ipilimumab dosing schedule, in view of the results, would have seemed more logical to us. The primary issue for us with the study design of the CheckMate 012 trial is the potential for confounding because it is a cohort study. Because patients are not randomly assigned to treatment groups, some patient characteristics might not be evenly distributed between the two groups. For example, the number of patients who were EGFR mutation positive and amount of PD-L1 expressed was not balanced across groups. Confounding occurs when these characteristics are linked to the outcomes of interest. In our opinion, it is strongly debatable to move from a phase 1 cohort straight into a phase 3 randomised trial, especially since the method of selecting the better regimen in this trial seems rather controversial. We are fully convinced that the combination of anti-PDL1 plus antiCTLA4 inhibition could represent an advance in the treatment of NSCLC, but we are concerned that not fit for purpose trial designs and the lack of phase 2 trial could jeopardise the possibilities to show clinical benefit in phase 3 trials.
1
Hellman MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017; 18: 31–41.
We declare no competing interests.
*Alfredo Addeo, Bishal Gyavali [email protected] Bristol Cancer Centre, Bristol, BS8 2XR, UK (AA); and Department of Hemato-oncology, Nobel Hospital, Kathmandu, Nepal (BG)
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Rushing will not help to choose the best combination We read with great interest and welcome the publication of the CheckMate 012 trial1 in The Lancet Oncology, in which the authors assessed the safety and efficacy of nivolumab plus ipilimumab as firstline therapy for metastatic non-smallcell lung cancer (NSCLC). Initial cohorts that assessed the combination of nivolumab (1 or 3 mg/kg) plus ipilimumab (1 or 3 mg/kg) given every 3 weeks followed by nivolumab 3 mg/kg every 2 weeks were characterised by poor tolerability with 51% (25/49) patients having grade 3–4 treatment-related adverse events. Four additional regimens evaluated lower doses of both agents or less frequent dosing. Only two of them were fully presented in the paper because they were the two cohorts considered for clinical development: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg given either every 12 weeks or every 6 weeks. Grade 3–4 treatment-related toxicity occurred in 37% patients in the every-12-weeks cohort and in 33% in the every 6-weeks-cohort. Confirmed objective responses (all partial responses) were achieved by 47% patients in the every 12-weeks cohort and 38% in the every-6-weeks cohort (all partial responses). These two schedules seem to be active even in patients with low expression of programmed death ligand 1 (PD-L1) and in patients carrying an EGFR activating mutation. Notably, the results of the other two regimens (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks, followed by nivolumab 3 mg/kg every 2 weeks vs nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/ kg every 6 weeks) were presented in the appendix (grade 3–4 treatmentrelated toxicities 29% vs 40%; www.thelancet.com/oncology Vol 18 April 2017
objective response rate 19% vs 33%). Overall, the trial results certainly confirm the fact that increasing the dose or frequency of ipilimumab negatively affects the safety of the combination without necessarily increasing the response rate. However, we find it difficult to understand why the combination of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks was chosen as the regimen for further development in the ongoing phase 3 Checkmate 012 trial. Use of a 12-week ipilimumab dosing schedule, in view of the results, would have seemed more logical to us. The primary issue for us with the study design of the CheckMate 012 trial is the potential for confounding because it is a cohort study. Because patients are not randomly assigned to treatment groups, some patient characteristics might not be evenly distributed between the two groups. For example, the number of patients who were EGFR mutation positive and amount of PD-L1 expressed was not balanced across groups. Confounding occurs when these characteristics are linked to the outcomes of interest. In our opinion, it is strongly debatable to move from a phase 1 cohort straight into a phase 3 randomised trial, especially since the method of selecting the better regimen in this trial seems rather controversial. We are fully convinced that the combination of anti-PDL1 plus antiCTLA4 inhibition could represent an advance in the treatment of NSCLC, but we are concerned that not fit for purpose trial designs and the lack of phase 2 trial could jeopardise the possibilities to show clinical benefit in phase 3 trials.
1
Hellman MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017; 18: 31–41.
We declare no competing interests.
*Alfredo Addeo, Bishal Gyavali [email protected] Bristol Cancer Centre, Bristol, BS8 2XR, UK (AA); and Department of Hemato-oncology, Nobel Hospital, Kathmandu, Nepal (BG)
e186