Updated data from the phase 3 trial KEYNOTE-240 (NCT02702401) presented at the Gastrointestinal Cancer Symposium 2021 indicated that single-agent pembrolizumab (Keytruda) consistently resulted in greater overall survival (OS) results and improved survival (no improvement). PFS) compared with the best supportive care in the second-line setting for HCC, despite not meeting statistical significance.1
At a mean follow-up of 39.6 months for pembrolizumab (n = 278) and 39.8 months for placebo (n = 135), the mean OS was 13.9 months (95% CI, 11.6–16.0) with pembrolizumab versus 10.6 months (95% CI, 8.3-13.5) and placebo (HR, 0.77; 95% CI, 0.62–0.96; P. = .0112). Moreover, the estimated 24-month OS levels were 28.8% and 20.4% for pembrolizumab and placebo, respectively. At 36 months, the estimated OS rates were 17.7% and 11.7%, respectively.
The median PFS was 3.3 months (95% CI, 2.8–4.1) with pembrolizumab compared with 2.8 months (95% CI, 1.6–3.0) with placebo (HR, 0.70; 95% CI, 0.56–0.89; P. = .0011). The 24-month SDP rates were estimated at 11.8% and 4.8%, respectively. 36-month SDP rates were estimated at 9% and 0%, respectively.
“Patients with Sorafenib treatment saw an improvement in OS and PFS maintained over time with pembrolizumab compared with placebo,” said Philippe Merle, MD, PhD, professor of hepato-gastroenterology and digestive oncology at the Research Center in Cancerology at the University of Lyon and Croix-Rousse Hospital in Lyon, France, at a meaningful presentation of the data. “The safety profile of pembrolizumab remained stable over time with no recent or unforeseen adverse events. These data support the benefit / risk profile of pembrolizumab. ”
The study enrolled adult patients with confirmed diagnoses of advanced HCC who experienced postoperative progression or intolerance to sorafenib (Nexavar). Patients were randomized at 2: 1 to 200 mg of intravenous pembrolizumab every 3 weeks in addition to optimal placebo-controlled supportive care as well as optimal supportive care for 35 cycles or until progressive, inappropriate toxic, induced patient consent leave, or researcher decision.
Patients were confirmed by geographical area (Asia without Japan versus non-Asia with Japan), macrovascular aggression (yes no), and alpha-fetoprotein level (AFP; <200 ng / mL versus ≥ 200 ng / mL).
To be eligible for enrollment, patients had to be diagnosed with RECIST v1.1 criteria, Child-Pugh class A liver disease, Barcelona C Clinic Cancer C (BCLC) disease, or BCLC grade B disease who were unable to receive local or salvage therapy to locoregional therapy, and who are incapable of therapeutic treatment, and an ECOG (PS) performance rating of 0 or 1.
Previous results of the KEYNOTE-240 trial showed that the endpoints associated with OS and PFS were statistically improved but not statistically significant with pembrolizumab as well as optimal supportive care versus placebo. on optimal supportive care.2
KEYNOTE-240 was a pilot for pembrolizumab, which received accelerated FDA approval in November 2018 for the treatment of patients with HCC previously treated with sorafenib.3 The control decision was based on data from the KEYNOTE-224 phase 2 test.
The numerical improvements in OS and PFS were consistent and maintained, favoring pembrolizumab, with longer follow-up across predefined subgroups, including age, sex, geographic area, ECOG PS , macrovascular attack, AFP, reason for discontinuation of sorafenib, extrahepatic transmission, and etiology.
Other results from the updated study showed that the target response rate was 18.3% (95% CI, 14.0% –23.4%) with pembrolizumab compared with 4.4% (95% CI, 1.6% –9.4%) with placebo. The median response time was 2.7 months (95% CI, 1.2–16.9) and 2.9 months (95% CI, 1.1–6.9), respectively. The median length of response (DOR) was 13.9 months (range, 1.5+ – 41.9+) compared to 15.2 months (range, 2.8–21.9), respectively. In addition, 53.7% of respondents in the pembrolizumab arm had a DOR of at least 12 months versus 50% of respondents in the placebo arm.
Moreover, the disease control rate (DCR) was 61.9% with pembrolizumab versus 53.3% with placebo.
The best overall responses among patients who received pembrolizumab included 10 total responses (CRs), 41 partial responses (PR), and 121 examples of chronic disease (SD). CR patients did not perform with placebo, 6 had PR, and 66 had SD.
In addition, 85 patients in the pembrolizumab arm and 54 patients in the placebo arm developed advanced disease. The median time for improvement was 4.0 months (95% CI, 2.8–5.3) and 2.8 months (95% CI, 1.6–3.0), respectively.
In terms of safety, 61.3% (n = 171) of patients who received pembrolizumab and 48.5% (n = 65) of patients who received placebo developed adverse effects at any treatment-related stage (TRAEs). TRAE Level 3/4 has occurred in 19% (n = 53) and 7.5% (n = 10) of patients, respectively. In the pembrolizumab arm, 6.8% (n = 19) of TRAE patients experienced discontinuation of treatment, and 1 TRAE resulted in death. The death was due to the progression of a malignant neoplasm. In the placebo arm, 0.7% of patients experienced TRAEs that resulted in discontinuation of treatment.
AEs of special interest were observed in 17.9% (n = 50) of patients with pembrolizumab and 8.2% (n = 11) of patients with placebo. Of these, 7.2% (n = 20) and 0.7% (n = 1), rated 3/4. In the pembrolizumab group, 3.6% (n = 10) of AEs with special interest resulted in cessation of treatment.
Moderate hepatitis occurred in 3.6% (n = 10) of patients who received pembrolizumab or any patients who received placebo. Of those 10 patients, 8 (2.9%) received systemic corticosteroids. In addition, no patients in each arm experienced a flared episode of viral hepatitis.
References
1. Merle P, Edeline J, Bouattour M, et al. Pembrolizumab versus placebo in patients with advanced hepatocellular carcinoma previously treated with sorafenib: updated data from the randomized, placebo-controlled study KEYNOTE-240. J Clin Oncol. 2021; 39 (solair 3): 268. http://bit.ly/39DGqU9.
2. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as a second-line treatment in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, stage III trial. J Clin Oncol. 2020; 38 (3): 193-202. doi: 10.1200 / JCO.19.01307
3. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. November 8, 2018. Accessed January 18, 2021. https://bit.ly/2LWDTMC