Durvalumab Plus Tremelimumab Trialled for Advanced CRC

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Phase II trial findings suggest there could be a potential role for combination immune checkpoint inhibitor therapy for patients with metastatic DNA mismatch repair proficient/microsatellite-stable (pMMR/MSS) colorectal cancer (CRC), although no significant benefit was found for patients in the full study population. 

The study included 180 patients who had received at least one prior fluoropyrimidine-containing chemotherapy regimen for advanced disease, with many having also received bevacizumab (79%), regorafenib (26%) and 97% of the subgroup of  patients with RAS wild-type disease had received cetuximab or panitumumab. 

After a median 15.2 months of follow-up, overall survival (OS) was a median of 6.6 months for the 119 patients given the PD-L1 inhibitor durvalumab 1500 mg every 28 days, with the CTLA-4 inhibitor tremelimumab 75 mg also given every 28 days for the first four cycles, in addition to best supportive care (BSC). 

This compared with median OS of 4.1 months for the 61 patients who instead received BSC only, although the hazard ratio (HR) for death of 0.72 was above the 0.65 required to show a significant difference between the groups, say Eric Chen, from the Princess Margaret Cancer Center in Toronto, Ontario, Canada, and co-authors in JAMA Oncology.  

And progression-free survival was comparable between the treatment groups, at a median of 1.8 and 1.9 months, respectively. 

However, when circulating cell-free DNA analysis was performed in samples taken from 168 of the participants, subgroup analysis identified a significant OS benefit with the combination regimen for patients with MSS disease, giving a HR for death of 0.66. 

The greatest OS benefit with the combination regimen was found among the 21% of MSS patients who had a plasma tumour mutation burden (TMB) of 28 variants/Mb or more, with a median OS of 5.5 versus 3.0 months with BSC, and a significant HR of 0.34. 

In an accompanying editorial, Ryan Corcoran (Massachusetts General Hospital Cancer Center, Boston, USA) and Axel Grothey (West Cancer Center and Research Institute, Germantown, Tennessee, USA) note that the combination treatment group had fewer markers of poor prognosis than those given BSC only and were more likely to receive further treatment after progression. 

And they caution that “[a]lthough the TMB data are important, in particular in view of the larger OS difference observed in the TMB-high cases, the improved HR is mainly driven by the fact that patients with higher TMB did worse in the BSC arm.”

Moreover, the editorialists highlight that within the combination arm, patients with high TMB had a shorter OS than those with a low TMB (5.5 vs 6.9 months). “This is a very important point because the way the results were presented leaves the suggestion that high TMB is a positive predictive marker for improved immunotherapy combination efficacy compared with low TMB, but this is quite obviously not the case.”

Safety analysis showed a significantly higher rate of grade 3 or more severe adverse events in the combination therapy group than the BSC arm (64 vs 20%), with abdominal pain and fatigue both significantly more common at grade 3 and above. 

But Eric Chen et al found no evidence of a “significant deterioration” of physical function or global health status after 8 or 16 weeks of treatment with add-on durvalumab plus tremelimumab compared with BSC alone. 

“Given the lack of treatment options for this patient population, confirmation studies for combined immune checkpoint inhibitors are warranted”, the investigators conclude.

Ryan Corcoran and Axel Grothey believe that the study’s results “can only be considered hypothesis generating and the likelihood of true efficacy of this immunotherapy combination in MSS cancers is low”.  

But they admit that the “modest benefit” from durvalumab plus tremelimumab indicates that “novel combinations of immune checkpoint inhibitors with agents that may further enhance the immune response may be a promising approach.” 

References 

Chen EX, Jonker DJ, Loree JM, et al. Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer. The Canadian Cancer Trials Group CO.26 study. JAMA Oncol; Advance online publication 7 May 2020. doi:10.1001/jamaoncol.2020.0910 

Corcoran RB, Grothey A. Efficacy of immunotherapy in microsatellite-stable or mismatch repair proficient colorectal cancer–fact or fiction? JAMA Oncol; Advance online publication 7 May 2020. doi:10.1001/jamaoncol.2020.0504