Nivolumab–Ipilimumab Proposed For Advanced Merkel Cell Carcinoma

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: Nivolumab plus ipilimumab has achieved a “high” objective response rate (ORR) for unresectable, recurrent or metastatic Merkel cell carcinoma, say US researchers, but use of stereotactic body radiotherapy (SBRT) does not provide additional benefit. 

The findings of the phase II trial were reported simultaneously at the ESMO Congress 2022 in Paris, France, by Sungjune Kim, from the H Lee Moffitt Cancer Center in Tampa, Florida, USA, and in The Lancet. 

“The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma”, summarise the authors. 

Study participants with stage IIIB or IV disease were given nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks with (n=25) or without SBRT delivering 24 Gy in three fractions over week 2 of the study (n=25). 

The patients were aged a median 73 years, around 78% were men and all were White. And there was a “reasonable balance of demographic and clinical factors in both groups”, the researchers say. 

“Patients had to have a least two measurable sites of disease so one non-irradiated site could be followed for response”, explain the investigators, and they note that participants were also stratified by prior use of pembrolizumab or avelumab immune checkpoint inhibitor (ICI) therapy (52%). 

After a median follow-up of 14.6 months, the ORR was assessed in 48 of the patients and there was no significant difference in the ORR in patients who did and did not receive SBRT (72 vs 52%), the investigators say. 

However, 100% of the 22 patients who had not previously received ICI therapy achieved an objective response compared with 31% of the 26 patients who had previously received ICI therapy. This included a complete response in 41% and 15% of the groups, respectively, and partial responses in 59% versus 15%. 

The researchers say that the median duration of response was not reached among patients with no prior ICI therapy and 10.8 months for those who had previously received ICI agents. 

Median progression-free survival was unreached for the ICI therapy-naïve treatment arm regardless of SBRT receipt, whereas for the patients with prior ICI therapy the durations were 4.2 months for nivolumab plus ipilimumab alone and 2.7 months with additional SBRT. 

And the corresponding values for overall survival were unreached, 14.9 and 9.7 months. 

Safety analysis of all 50 patients showed that the rate of grade 3 or 4 treatment-related adverse events was comparable in the ICI-only and ICI plus SBRT treatment arms (40 vs 32%), mostly attributable to the ICI regimen and with “minimal SBRT-related toxicities”, the researchers say. 

Grade 4 events occurred in five patients, with four cases of pancreatic enzyme elevations and one incidence of hyponatraemia and acute kidney injury. 

Sungjune Kim et al admit that their study is limited by the small number of patients and lack of independent assessment, but note that the rarity of Merkel cell carcinoma and its occurrence in older patients, who frequently have comorbidities, “renders large, phase 3 studies difficult.” 

The authors of a linked comment agree that the study findings “make combined nivolumab and ipilimumab an attractive new strategy in this population” but emphasize that “multiple issues should be addressed before doing a confirmatory phase 3 trial”. 

In particular, they highlight the lack of independent review and the “scarce” information on patient prognostic factors, such as metastatic sites and Merkel cell carcinoma polyomavirus status. 

Philippe Saiag and Astrid Blom, from the University of Paris-Saclay in France, also note the short duration of follow-up – which they say is “clear from the Kaplan-Meier curves in ICI naïve patients, in which the numbers at risk drop abruptly after month 12” – and question whether response continued after treatment ended. 

They also query which ICI agents had previously been used in the responding patients with prior ICI therapy, noting that a “simple switch from PD-L1 to PD-1 blockage could also cause a refractory patient to respond.” 

The commentators conclude that “we need more information before routinely using combined nivolumab and ipilimumab in patients with Merkel cell carcinoma.” 

References  

LBA42 - Kim S, Wuthrick E, Blakaj DM, et al. Combined nivolumab and ipilimumab with or without sterotectic body radiation therapy for advanced Merkel cell carcinoma. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089

Kim S, Wuthrick E, Blakaj D, et al. Combined nivolumab and ipilimumab with or without stereotactic radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet; Advance online publication 11 September 2022. DOI: https://doi.org/10.1016/S0140-6736(22)01659-2

Saiag P, Blom A. Combined nivolumab and ipilimumab in non-resectable Merkel cell carcinoma. Lancet; Advance online publication 11 September 2022. DOI: https://doi.org/10.1016/S0140-6736(22)01749-4