SPOTLIGHT protein PD-L1. Combined targeting of the two checkpoints, CTLA-4 and PD-1/PD-L1, has shown clinical benefit in a number of cancer types. HCC is the most commonly diagnosed liver cancer in adults and the third leading cause of cancer-related deaths worldwide (428). Most HCC cases are diagnosed at an advanced stage when surgical removal is not an option, and many patients experience cancer recurrence after initial treatment (429). Patients with HCC that is not removable surgically are treated with systemic therapy, including anti-angiogenic treatments that block the development of blood vessels or with ICIs, often as combination therapy. While these treatments have led to some improvement in survival for patients with HCC not surgically removable, additional treatment options are needed for this globally diverse patient population, highlighting the importance of FDA approval of the tremelimumab and durvalumab combination. The efficacy of tremelimumab plus durvalumab was tested in a randomized, phase III clinical trial in patients with unresectable HCC who had not received prior systemic treatment. The study compared the efficacy of tremelimumab plus durvalumab to the standard of care, which is treatment with the molecularly targeted antiangiogenic therapeutic sorafenib (Nexavar). Findings from the trial showed that patients who received the ICI combination experienced a 22 percent reduction in the risk of death during the course of the study compared to patients who received sorafenib (429). In the 12 months covered in this report, FDA also expanded the approval of the tremelimumab and durvalumab combination for certain patients with lung cancer. In November 2022, FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for treatment of adult patients with metastatic NSCLC whose tumors do not have mutations in the EGFR or ALK genes. Patients with NSCLC with tumors that have alterations in EGFR or ALK are usually treated with molecularly targeted therapeutics that specifically target the EGFR or ALK proteins. The approval was based on results from a phase III randomized clinical trial that compared the efficacy of the tremelimumab, durvalumab, and chemotherapy combination to chemotherapy alone, among patients with NSCLC who had not received prior systemic treatment. The data from the clinical trial showed that patients receiving the ICI combination experienced a 23 percent reduction in the risk of death during the course of the trial compared to those receiving chemotherapy alone (430). The median overall survival (see Sidebar 32, p. 80) was 14 months in patients treated with the combination versus 11.7 months in patients treated with chemotherapy alone (430). In September 2022, FDA approved durvalumab in combination with the chemotherapeutics gemcitabine and cisplatin for adult patients with locally advanced or metastatic cancer of the biliary tract. Biliary tract cancers include various rare but aggressive epithelial malignancies (see Sidebar 5, p. 26), including bile duct cancer and gallbladder cancer, among others and account for three percent of all gastrointestinal cancers. Surgical removal of the entire tumor is currently the only curative treatment for biliary tract cancer. Unfortunately, many patients are diagnosed at an advanced stage when surgery is no longer an option. For over a decade, the combination of gemcitabine and cisplatin has remained the standard initial treatment for patients with advanced biliary tract cancer, including those whose cancer returned after the initial treatment. Research has shown that the tumor microenvironment of biliary tract cancers may suppress the immune system, indicating that there may be limited benefit from immunotherapeutics, if used alone. Chemotherapeutics are known to modulate the immune system, leading researchers to hypothesize that a combination of ICIs with chemotherapy could improve response to immunotherapy. Recent data from two clinical trials supported this hypothesis and showed that patients with advanced biliary tract cancer benefit when ICIs such as durvalumab or pembrolizumab are administered as a combination with gemcitabine and cisplatin (431,432). One of these trials provided the basis for the approval of durvalumab in biliary tract cancer. The study, a phase III randomized clinical trial, found that adding durvalumab to standard chemotherapy modestly extended how long patients with advanced biliary tract cancer lived (431). The FDA approval was based on the fact that patients who received chemotherapy plus durvalumab had a 20 percent reduction in the risk of death during the course of the trial compared to patients who received chemotherapy alone (431). While these data offer hope for patients with a very aggressive disease, there is urgent need for continued research to identify more effective treatments for this difficult-to-treat group of cancers. In addition to combinations with other ICIs, researchers are combining ICIs with molecularly targeted therapeutics to maximize the potential of precision medicine. As one example, in April 2023, FDA approved a combination of a molecularly targeted therapeutic, called enfortumab vedotin-ejfv (Padcev) and pembrolizumab to treat patients with bladder cancer. The approval was based on findings of a clinical study that showed According to the National Cancer Institute, a locally advanced cancer is one that has spread from where it started to nearby tissue or lymph nodes. Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 107
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