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Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more?
Comment
Many studies are testing whether or not the combination of additional drugs with anti-programmed death 1 (PD-1) agents will improve survival outcomes. Among these approaches, anti-PD-1 drugs in combination with the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor ipilimumab is furthest along in clinical development. Nivolumab (1 mg/kg) plus standard-dose ipilimumab (3 mg/kg) is approved by regulatory agencies for treatment of patients with advanced melanoma and increases overall survival, progression-free survival, and the proportion of patients who achieve an objective response compared with ipilimumab monotherapy.1,2 The dose of this standard combination was selected partly because of similar side-effect profiles between nivolumab 1 mg/kg plus ipilimumab 3 mg/kg and nivolumab 3 mg/kg plus ipilimumab 1mg/kg in phase 1 assessment and the fact that ipilimumab at 3mg/kg had a known overall survival benefit as monotherapy.3,4 Nevertheless, adverse events remain a concern, and many studies of multiple malignancies are now testing whether or not reduction of the dose or frequency (ie, every 6 weeks or 12 weeks instead of the standard every 3 weeks) of ipilimumab would improve tolerability and maintain efficacy.5 In The Lancet Oncology, Georgina Long and colleagues6 report results of the KEYNOTE-029 study, which was an open-label, multicenter, phase 1b trial that assessed standarddose pembrolizumab (2 mg/kg) in combination with reduced-dose ipilimumab (1 mg/kg) for 153 patients with advanced melanoma. They conclude that this combination is feasible and has substantial anti-tumour activity. The primary endpoint of this phase 1 trial was, appropriately, safety. The authors report that the combination of standard-dose pembrolizumab plus reduced-dose ipilimumab was associated with 69 (45%) of patients having grade 3–4 treatment-related side-effects and no treatment-related deaths. Since this trial was not randomised, comparison of these results to other related studies is inherently difficult because of differing patient populations. Nonetheless, the combination of standard-dose pembrolizumab
with reduced-dose ipilimumab seems to be associated with somewhat more favourable tolerability than is the standard nivolumab plus ipilimumab combination (with about 55% of patients experiencing grade 3–4 side-effects and very rare treatment-related deaths).1,2 This result was expected since the occurrence of sideeffects with ipilimumab monotherapy is known to be dose dependent.7,8 Of additional consideration, combination of even a low dose of ipilimumab (1 mg/kg) with pembrolizumab is sufficient to lead to a much higher prevalence of side-effects than occurs with pembrolizumab alone at 2 mg/kg (grade 3–4 side-effect frequency of about 11%).9 Despite the increased occurrence of side-effects compared with pembrolizumab alone, the addition of reduced-dose ipilimumab to pembrolizumab was associated with an impressively high proportion of patients with an objective response of 61% (95% CI 53–69; 15% with a complete response). This proportion compares favourably with that of pembrolizumab alone (21–34%)9,10 and seems to be similar to that of other studies of the standard nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (58%).1,2 Cross-trial comparisons with the standard nivolumab plus ipilimumab combination should be made with caution, as the authors advise, since the patient population in this standard-dose pembrolizumab plus reduceddose ipilimumab trial (25% with elevated lactate dehydrogenase concentrations and 87% previously untreated) differed somewhat from that of the Checkmate 067 trial2 (37% and 100%, respectively). Although preliminarily encouraging, unlike anti-PD-1 monotherapy, ipilimumab monotherapy is known to have a dose-dependent effect, with 10 mg/kg of ipilimumab improving overall survival compared with 3 mg/kg of ipilimumab.8 Notably, this overall survival improvement was seen without an increase in obvious short-term efficacy, such as objective response. This finding serves as a reminder that even though the objective response in the trial of standard-dose pembrolizumab plus reduced-dose ipilimumab by Long and colleagues appeared similar to that of the standard nivolumab plus ipilimumab,1,2 longer-term follow-up
www.thelancet.com/oncology Published online July 17, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30518-1
Kevin Link/Science Photo Library
Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more?
Lancet Oncol 2017 Published Online July 17, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30518-1 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30428-X
1
Comment
than reported by Long and colleagues for reduced-dose ipilimumab and standard-dose pembrolizumab and randomised data will be needed to truly assess whether or not the reduced ipilimumab dose affects overall survival in combination with anti-PD-1. Long and colleagues should be congratulated for the first trial of reduced-dose ipilimumab in combination with pembrolizumab, showing that the known dosedependent toxicity of ipilimumab seems to extend to the combinatorial setting with anti-PD-1. Their results come at an opportune time as 2 year overall survival results from the Checkmate 067 trial2 of the standard nivolumab plus ipilimumab combination (64%), nivolumab (59%), and ipilimumab (45%) were reported in April, 2017. Although additional follow-up is needed, the generally similar 2 year overall survival results between the standard nivolumab plus ipilimumab combination and nivolumab-alone groups stresses the need to continue to refine and improve the combination of ipilimumab with anti-PD-1. A more substantial difference in 2 year overall survival outcomes than that of the Checkmate 067 trial might have otherwise more firmly established the standard nivolumab plus ipilimumab combination. So what is next? The first obvious step will be completion of ongoing randomised trials testing various doses and schedules of the combination of reduceddose ipilimumab with standard-dose pembrolizumab. Immunotherapy combinations blocking both CTLA-4 and PD-1 are the most developed combinations because studies targeting these checkpoints individually were the first to show clinical success. Multiple other anti-PD-1 combinations are now being tested, and the principles that are learnt from refining of the combination of
2
anti-CTLA-4 with anti-PD-1 immunotherapy will be instrumental to improve our understanding of how best to assess this growing list of promising additional combination strategies. Michael Postow Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; and Weill Cornell Medical College, New York, NY, USA [email protected] I report being on the advisory board for and receiving honoraria and research grants from Bristol-Myers Squibb, being on the advisory board for Novartis and Array Biopharma, and being on the advisory board for and receiving honoraria from Merck. 1
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006–17. 2 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients with advanced melanoma (CheckMate 067). 2017 Annual Meeting of the American Association for Cancer Research; Washington DC, USA; April 1–5, 2017. Abstract CT075. 3 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–33. 4 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23. 5 Hellmann 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. 6 Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 2017; published online July 17. http://dx.doi.org/10.1016/S14702045(17)30428-X. 7 Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11: 155–64. 8 Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017; 18: 611–22. 9 Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigatorchoice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015; 16: 908–18. 10 Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372: 2521–32.
www.thelancet.com/oncology Published online July 17, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30518-1
Many studies are testing whether or not the combination of additional drugs with anti-programmed death 1 (PD-1) agents will improve survival outcomes. Among these approaches, anti-PD-1 drugs in combination with the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor ipilimumab is furthest along in clinical development. Nivolumab (1 mg/kg) plus standard-dose ipilimumab (3 mg/kg) is approved by regulatory agencies for treatment of patients with advanced melanoma and increases overall survival, progression-free survival, and the proportion of patients who achieve an objective response compared with ipilimumab monotherapy.1,2 The dose of this standard combination was selected partly because of similar side-effect profiles between nivolumab 1 mg/kg plus ipilimumab 3 mg/kg and nivolumab 3 mg/kg plus ipilimumab 1mg/kg in phase 1 assessment and the fact that ipilimumab at 3mg/kg had a known overall survival benefit as monotherapy.3,4 Nevertheless, adverse events remain a concern, and many studies of multiple malignancies are now testing whether or not reduction of the dose or frequency (ie, every 6 weeks or 12 weeks instead of the standard every 3 weeks) of ipilimumab would improve tolerability and maintain efficacy.5 In The Lancet Oncology, Georgina Long and colleagues6 report results of the KEYNOTE-029 study, which was an open-label, multicenter, phase 1b trial that assessed standarddose pembrolizumab (2 mg/kg) in combination with reduced-dose ipilimumab (1 mg/kg) for 153 patients with advanced melanoma. They conclude that this combination is feasible and has substantial anti-tumour activity. The primary endpoint of this phase 1 trial was, appropriately, safety. The authors report that the combination of standard-dose pembrolizumab plus reduced-dose ipilimumab was associated with 69 (45%) of patients having grade 3–4 treatment-related side-effects and no treatment-related deaths. Since this trial was not randomised, comparison of these results to other related studies is inherently difficult because of differing patient populations. Nonetheless, the combination of standard-dose pembrolizumab
with reduced-dose ipilimumab seems to be associated with somewhat more favourable tolerability than is the standard nivolumab plus ipilimumab combination (with about 55% of patients experiencing grade 3–4 side-effects and very rare treatment-related deaths).1,2 This result was expected since the occurrence of sideeffects with ipilimumab monotherapy is known to be dose dependent.7,8 Of additional consideration, combination of even a low dose of ipilimumab (1 mg/kg) with pembrolizumab is sufficient to lead to a much higher prevalence of side-effects than occurs with pembrolizumab alone at 2 mg/kg (grade 3–4 side-effect frequency of about 11%).9 Despite the increased occurrence of side-effects compared with pembrolizumab alone, the addition of reduced-dose ipilimumab to pembrolizumab was associated with an impressively high proportion of patients with an objective response of 61% (95% CI 53–69; 15% with a complete response). This proportion compares favourably with that of pembrolizumab alone (21–34%)9,10 and seems to be similar to that of other studies of the standard nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (58%).1,2 Cross-trial comparisons with the standard nivolumab plus ipilimumab combination should be made with caution, as the authors advise, since the patient population in this standard-dose pembrolizumab plus reduceddose ipilimumab trial (25% with elevated lactate dehydrogenase concentrations and 87% previously untreated) differed somewhat from that of the Checkmate 067 trial2 (37% and 100%, respectively). Although preliminarily encouraging, unlike anti-PD-1 monotherapy, ipilimumab monotherapy is known to have a dose-dependent effect, with 10 mg/kg of ipilimumab improving overall survival compared with 3 mg/kg of ipilimumab.8 Notably, this overall survival improvement was seen without an increase in obvious short-term efficacy, such as objective response. This finding serves as a reminder that even though the objective response in the trial of standard-dose pembrolizumab plus reduced-dose ipilimumab by Long and colleagues appeared similar to that of the standard nivolumab plus ipilimumab,1,2 longer-term follow-up
www.thelancet.com/oncology Published online July 17, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30518-1
Kevin Link/Science Photo Library
Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more?
Lancet Oncol 2017 Published Online July 17, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30518-1 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30428-X
1
Comment
than reported by Long and colleagues for reduced-dose ipilimumab and standard-dose pembrolizumab and randomised data will be needed to truly assess whether or not the reduced ipilimumab dose affects overall survival in combination with anti-PD-1. Long and colleagues should be congratulated for the first trial of reduced-dose ipilimumab in combination with pembrolizumab, showing that the known dosedependent toxicity of ipilimumab seems to extend to the combinatorial setting with anti-PD-1. Their results come at an opportune time as 2 year overall survival results from the Checkmate 067 trial2 of the standard nivolumab plus ipilimumab combination (64%), nivolumab (59%), and ipilimumab (45%) were reported in April, 2017. Although additional follow-up is needed, the generally similar 2 year overall survival results between the standard nivolumab plus ipilimumab combination and nivolumab-alone groups stresses the need to continue to refine and improve the combination of ipilimumab with anti-PD-1. A more substantial difference in 2 year overall survival outcomes than that of the Checkmate 067 trial might have otherwise more firmly established the standard nivolumab plus ipilimumab combination. So what is next? The first obvious step will be completion of ongoing randomised trials testing various doses and schedules of the combination of reduceddose ipilimumab with standard-dose pembrolizumab. Immunotherapy combinations blocking both CTLA-4 and PD-1 are the most developed combinations because studies targeting these checkpoints individually were the first to show clinical success. Multiple other anti-PD-1 combinations are now being tested, and the principles that are learnt from refining of the combination of
2
anti-CTLA-4 with anti-PD-1 immunotherapy will be instrumental to improve our understanding of how best to assess this growing list of promising additional combination strategies. Michael Postow Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; and Weill Cornell Medical College, New York, NY, USA [email protected] I report being on the advisory board for and receiving honoraria and research grants from Bristol-Myers Squibb, being on the advisory board for Novartis and Array Biopharma, and being on the advisory board for and receiving honoraria from Merck. 1
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006–17. 2 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival (OS) results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients with advanced melanoma (CheckMate 067). 2017 Annual Meeting of the American Association for Cancer Research; Washington DC, USA; April 1–5, 2017. Abstract CT075. 3 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–33. 4 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23. 5 Hellmann 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. 6 Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 2017; published online July 17. http://dx.doi.org/10.1016/S14702045(17)30428-X. 7 Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11: 155–64. 8 Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017; 18: 611–22. 9 Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigatorchoice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015; 16: 908–18. 10 Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372: 2521–32.
www.thelancet.com/oncology Published online July 17, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30518-1