Immunotherapy improves survival for people with liver cancer
A combination of two immune checkpoint inhibitors, Imfinzi (durvalumab) and tremelimumab, improved overall survival in people with advanced liver cancer, while Imfinzi plus chemotherapy prolonged survival in people with bile duct cancer, studies show. will be presented this week at the 2022 ASCO Symposium on Gastrointestinal Cancers. Another test showed that Keytruda (pembrolizumab) also improved the survival of patients with liver cancer.
Over time, hepatitis B or chronic hepatitis C, fatty liver disease, excessive alcohol consumption, and other causes of liver damage can lead to the development of hepatocellular carcinoma (HCC), the most common type most common of liver cancer. HCC is often detected late and difficult to treat. Bile duct cancerthat originates in the bile ducts (cholangiocarcinoma) or the gallbladder, is also difficult to treat.
Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center, and colleagues conducted the Phase III HIMALAYA trial (NCT03298451) to evaluate a single dose of tremelimumab added to Imfinzi for the treatment of advanced liver cancer.
Imfinzi is a monoclonal antibody that blocks the PD-L1 protein on cancer cells. PD-1 is an immune checkpoint protein on T cells that helps regulate immune function. Some tumors can hijack PD-1 to disable immune responses against them. Drugs that block the interaction between PD-1 and PD-L1, its binding partner, release the brakes and restore T-cell activity. Tremelimumab, not yet approved by the Food and Drug Administration (FDA), blocks CTLA-4, a different checkpoint protein that suppresses T cell multiplication. Another immune checkpoint combo – PD-1 inhibitor Opdivo (nivolumab) plus CTLA-4 inhibitor Yervoy (ipilimumab)— is currently approved for liver cancer.
This open international trial included 1,171 people with inoperable stage III or IV HCC who had not used previous systemic therapies and were not eligible for local therapies. These patients have a five-year survival rate of only 7%. Participants were randomly assigned to receive a single priming dose of tremelimumab plus Imfinzi given by IV infusion every four weeks (known as the STRIDE regimen), Imfinzi alone, or oral targeted therapy Nexavar (sorafenib).
Tremelimumab plus Imfinzi led to a significant improvement in overall survival compared to Nexavar, while Imfinzi alone was non-inferior, meaning it worked at least as well as Nexavar. Patients treated with the STRIDE regimen had a 22% lower risk of death than those who received Nexavar. The median overall survival times were 16.4 months for the STRIDE regimen, 16.6 months for Imfinzi alone and 13.8 months for Nexavar. At two years, 41% of STRIDE recipients, 40% of Imfinzi monotherapy recipients and 33% of Nexavar recipients were still alive. At three years, the overall survival rates were 31%, 25%, and 20%, respectively. However, progression-free survival, ie patients were alive without their disease getting worse, was not statistically superior with the combination or Imfinzi alone compared to Nexavar.
Additionally, the Imfinzi combination demonstrated a higher overall response rate (20%), or likelihood of tumor shrinkage, than Imfinzi alone (17%) or Nexavar (5%), and had a duration of longer response (22.3, 16.8 and 18.4 months, respectively).
The STRIDE diet was generally safe, but it resulted in more treatment-related side effects and deaths than Imfinzi alone. The rates of serious side effects (grade 3 or 4) were 26% with STRIDE, 13% with Imfinzi monotherapy and 37% with Nexavar. But fewer patients who received the combination or Imfinzi alone discontinued treatment due to side effects compared to Nexavar recipients (8%, 4% and 11%, respectively).
Based on these findings, the STRIDE diet could become a new standard of first-line care for inoperable HCC, the researchers suggested.
“Patients with unresectable liver cancer face a grim prognosis, and new treatment options are essential to improve long-term survival,” Abou-Alfa said in a statement. Astra Zeneca press release. “The three-year overall survival rate and favorable safety profile seen with the STRIDE regimen set a new benchmark in this setting and underscore the potential of this innovative therapeutic approach.
The researchers plan to examine whether outcomes differ depending on the cause of liver cancer (eg, hepatitis B or C) as well as quality of life outcomes, according to Abou-Alfa.
Another international phase III trial, TOPAZ-1 (NCT03875235), evaluated Imfinzi plus chemotherapy for the first-line treatment of advanced biliary tract cancer.
This study included 685 participants with previously untreated advanced or metastatic gallbladder cancer (25%) or cholangiocarcinoma inside (55%) or outside of the liver (19%). They were randomly assigned to receive Imfinzi, given every three weeks for a maximum of three cycles, then every four weeks, or placebo with standard IV chemotherapy (gemcitabine plus cisplatin).
An interim analysis showed that patients treated with Imfinzi plus chemotherapy had a 20% reduction in mortality compared with those who received chemotherapy alone. Although the difference in median overall survival time was small (12.8 months versus 11.5 months), the proportion of patients still alive at two years was greater with the combination than with chemotherapy alone (25% against 10%). In addition, Imfinzi plus chemotherapy resulted in a 25% reduction in the risk of disease progression or death. Median progression-free survival times were 7.2 months versus 5.7 months, respectively. The combination also had a higher overall response rate (27% versus 19%).
Imfinzi combination treatment was generally safe and caused no more side effects than chemotherapy alone. Rates of treatment-related serious adverse events were similar in the two treatment groups (63% versus 65%, respectively), as were discontinuation rates due to adverse events (9% versus 11%), which which suggests that most of the side effects were attributable to the chemotherapy. The most common adverse events were anemia, neutropenia (low white blood cell count) and nausea.
“After minimal progress for more than a decade in advanced biliary tract cancer, TOPAZ-1 results are a huge step forward for our patients, showing a clear survival benefit for Imfinzi added to chemotherapy compared to standard treatment. with a remarkable safety profile,” lead researcher Do-Youn Oh, MD, PhD, of Seoul National University College of Medicine in South Korea, said in a Astra Zeneca press release. “This combination will provide a desperately needed and potentially practice-changing new treatment option in a setting where the current prognosis is devastating.”
“TOPAZ-1 is the first phase III trial to demonstrate the benefit of immunotherapy in improving overall survival [for inoperable biliary tract cancer]in combination with chemotherapy, creating a new standard of care,” commented Cathy Eng, MD, of Vanderbilt-Ingram Cancer Center, in a ASCO press release. “Patients have more reason to be hopeful given the positive results seen with the use of immunotherapy in bile duct cancers.”
Finally, a third phase III study, KEYNOTE-394 (NCT03062358), evaluated Keytruda, a PD-1 checkpoint inhibitor, as a second-line treatment for advanced liver cancer.
This indication received accelerated approval based on overall response data, but these drugs need further testing to confirm that they provide clinical benefits, such as improved survival, with longer follow-up. It was one of many indications for immunotherapy reviewed at an FDA advisory committee meeting in April 2021 to decide whether they should remain in force. Councilors voted unanimously to maintain the indication pending the results of KEYNOTE-394.
This trial recruited 453 patients in Asia who had advanced HCC previously treated with Nexavar or platinum-based chemotherapy. They were randomly assigned to receive Keytruda, given by IV infusion every three weeks for up to two years, or placebo plus best supportive care (eg, pain management).
According to a Merck press release. The median overall survival time was 14.6 months in the Keytruda group versus 13.0 months in the placebo group. At two years, 34% of Keytruda recipients and 25% of placebo recipients were still alive. Keytruda also reduced the risk of disease progression or death by 26%, with median progression-free survival times of 2.6 months and 2.3 months, respectively. The overall response rate with Keytruda was 13% compared to only 1% in the placebo group, and the duration of response was 23.9 months compared to 5.6 months.
Keytruda treatment was generally safe and well tolerated. The rates of treatment-related serious adverse events were 14% in the Keytruda group and 6% in the placebo group. Therapies that release the immune system can lead to excessive inflammation that harms healthy tissue; 18% of Keytruda recipients experienced immune-mediated adverse reactions (3% serious), but 11% of placebo recipients did the same.
“Hepatocellular carcinoma is one of the leading causes of cancer death worldwide, and there are limited treatment options that prolong patient survival after sorafenib treatment,” lead researcher Shukui Qin said in press release. , MD, from Nanjing University of Chinese Medicine. Release. “These overall survival data are very encouraging for HCC patients previously treated with sorafenib and show the potential of Keytruda to prolong the lives of these patients.”
Click here to read the Summary of the Himalayas (abstract 379).
Click here to read the TOPAZ-1 summary (abstract 378)
Click here to read the KEYNOTE-394 summary (abstract 383).
Click here to more liver cancer news.