Combination of Durvalumab and Tremelimumab May Prolong OS in CRC

A phase II trial published in JAMA Oncology suggested that combination immune checkpoint inhibition with durvalumab (Imfinzi) plus tremelimumab may be associated with prolonged overall survival (OS) in patients with advanced refractory colorectal cancer (CRC).¹

Even further, exploratory analysis suggested that tumor mutation burden (TMB) from cell-free DNA (cfDNA) analysis could be a possible biomarker for benefits from immune checkpoint inhibitors. 

“Although single-agent immune checkpoint inhibition has not shown meaningful clinical activity in [microsatellite stable; MSS] colorectal cancer, emerging data indicate that combining these agents with others with different mechanisms of action can potentially overcome resistance,” the authors wrote. “The results of this study further lend support to this strategy.”

The trial was conducted in 27 cancer centers across Canada between August 2016 and June 2017. Patients who were eligible for the study had histologically confirmed adenocarcinoma of the colon or rectum, and received all available standard systemic therapies, including:

• fluoropyrimidines, oxaliplatin, irinotecan (Camptosar), and bevacizumab (Avastin), if appropriate

• cetuximab (Erbitux) or panitumumab (Vectibix), if the patient has RAS wild-type tumors

• regorafenib (Stivarga), if available

Moreover, they had to be at least 18 years or older, had adequate organ function, had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. 

Patients were randomized 2:1 to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg of durvalumab every 28 days, or best supportive care alone. The primary endpoint was OS and a 2-sided P < 0.10 was considered statistically significant. Moreover, circulating cfDNA from baseline plasma was used to identify microsatellite instability (MSI) and TMB.

Overall, 180 patients were enrolled and 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC ([HR, 0.72; 90% CI, 0.54-0.97; P = 0.07). Progression-free survival (PFS) was 1.8 months and 1.9 months, respectively (HR, 1.01; 90% CI, 0.76-1.34). 

Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In those who were MSS, OS was significantly improved with the combination of durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = 0.02). However, patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) saw the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = 0.004). 

Grade 3 or 4 adverse events (AEs) were found to be significantly more frequent with immunotherapy – 75 (64%) patients in the treatment group had at least 1 grade 3 or higher AE vs 12 (20%) in the BSC group. Additionally, incidences of all grades were significantly higher in the treatment group for fatigue, nausea, constipation, insomnia, cough, diarrhea, and cutaneous eruption.

In an editorial written by Ryan B. Corcoran, MD, PhD, of Massachusetts General Hospital, and Axel Grothey, MD, of West Cancer Center, it was suggested that results seen with the combination of durvalumab and tremelimumab in treatment-refractory MSS colorectal cancer can only be considered hypothesis generating, and the likelihood of seeing actual efficacy from this immunotherapy combination is low.²

“The search for active immunotherapy approaches in MSS and/or MMR-P colorectal cancers has to move beyond the PD-(L)1 plus CTLA-4 inhibitor combination,” the editorial authors wrote. “However, the observation that a subset of patients with MSS colorectal cancer may derive some modest benefit from combined immune checkpoint blockade suggests that novel combinations of immune checkpoint inhibitors with agents that may further enhance the immune response may be a promising approach, and several clinical trials are ongoing.”

Furthermore, the editorial authors indicated that preclinical models to select rational combination therapies will be critical to moving the whole field of immunotherapy in colorectal cancer forward. The study authors suggested this as well, writing, “Given the lack of treatment options for this patient population, confirmation studies for combined immune checkpoint inhibitors are warranted.”

References:

1. 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. JAMA Oncology. doi:10.1001/jamaoncol.2020.0910.

2. Corcoran RB, Grothey A. Efficacy of Immunotherapy in Microsatellite-Stable or Mismatch Repair Proficient Colorectal Cancer. JAMA Oncology. doi:10.1001/jamaoncol.2020.0504.