Esophageal cancer presents as a localized disease, defined as adenocarcinoma or squamous cell carcinoma confined to the esophagus, in approximately 22% of all cases [13]. Regional disease, which includes spread to regional lymph nodes, accounts for another 30% of patients with esophageal cancer. Locally advanced, unresectable, and metastatic esophagogastric cancers are not curable, and therapy goals are symptom palliation and prolongation of survival. While systemic therapy is the most effective treatment modality for patients with metastatic disease and may adequately palliate dysphagia and other symptoms (such as nausea, pain, obstruction, perforation, or bleeding from a locally advanced or locally recurrent primary tumor), it often requires multidisciplinary management using endoscopic, surgical, radiotherapeutic, or other approaches. Despite active clinical research on the treatment of esophageal squamous cell carcinoma (ESCC), the long-term survival rate of advanced patients is still very low, with a five-year survival rate of 30-40%. NXCEL1311 is a prospective, randomized-controlled, double-blinded, multicenter Phase 3 study designed to investigate the efficacy and safety of nimotuzumab (Nimo), an anti-epidermal growth factor receptor (EGFR) humanized monoclonal antibody, plus concurrent chemo-radiotherapy compared with placebo plus chemo-radiotherapy in unresectable locally advanced ESCC [14]. The patients were randomized (1:1) to receive Nimo or placebo in combination with concurrent chemo-radiotherapy (paclitaxel and cisplatin and 3D-CRT/IMRT) for seven weeks. The ORR was significantly higher in the Nimo group (93.8%) than with placebo (72.0%). Twenty-six patients (32.5%) in the Nimo group reached the complete response versus 10 in the placebo group (12.2%). The safety profile was similar with the incidence of grade 3-5 drug-related AEs of 11.1% vs. 10.9%, correspondingly. The most common drug-related AEs were leucopenia, neutrophilic granulocytopenia, thrombocytopenia, hemoglobin, bone marrow inhibition, and anemia.
More than 62,000 people develop exocrine pancreatic cancer each year in the US [15]. Because of its aggressive character and the fact that most patients present with advanced disease, the five-year survival rate is about 8%. Surgical resection offers the only chance of cure, but only 15-20% of patients have resectable disease at initial diagnosis. For patients with metastatic cancer, palliative systemic chemotherapy can improve disease-related symptoms and prolong survival. For patients who have a germline BRCA or PALB2 pathogenic variant, Poly (ADP-ribose) polymerase (PARP) inhibitor maintenance therapy can be used after at least 16 weeks of initial platinum-based chemotherapy for those without disease progression. CodeBreaK100 is an international, single-arm, Phase 1/2 study evaluating the efficacy and safety of sotorasib in patients with KRASG12C-mutated advanced solid tumors with ≥ 1 prior systemic therapy unless intolerant or ineligible for available therapies [16]. KRAS mutation is present in 90% of pancreatic ductal adenocarcinomas. Sotorasib is a small molecule that specifically and irreversibly inhibits KRASG12C. The study showed an ORR of 21.1% and a favorable safety profile with the incidence of treatment-related adverse events of any grade of 42.1%. Sotorasib demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer who have limited treatment options and poor prognoses.
Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. It is typically diagnosed late in its course, and the median survival following diagnosis is approximately 6 to 20 months. Although the mainstay of therapy is surgical resection, most patients are not eligible because of tumor extent or underlying liver dysfunction. Several other treatment options are available, including liver transplantation, various modalities of radiotherapy and embolization, chemotherapy, and immunotherapy. The choice of therapy is determined by disease extent and the severity of the underlying liver disease. Yuk Ting Ma (University of Birmingham, United Kingdom) presented the first randomized study to demonstrate efficacy using dendritic cells in HCC. The ImmunoTACE trial is a randomized Phase 2 clinical trial of low-dose cyclophosphamide and transarterial chemoembolization (TACE) with or without vaccination with dendritic cells pulsed with HepG2 lysate ex vivo in patients with hepatocellular carcinoma (HCC) [17]. A previous study using autologous monocyte-derived DC pulsed ex vivo with HepG2 cell lysate showed some clinical benefit with evidence of antigen-specific T-cell responses in patients with advanced HCC. The current trial reports the activity of this vaccine in combination with TACE in patients with HCC. All patients also received low-dose cyclophosphamide to deplete regulatory T cells and enhance vaccination. Patients with intermediate-stage HCC (performance status 0-2, Child-Pugh score A/B7) were randomized 1:1 to TACE plus low-dose cyclophosphamide (Group 1) or TACE plus low-dose cyclophosphamide plus dendritic cell vaccination (Group 2). Median PFS with RECIST 1.1 criteria was significantly longer in Group 2 compared to Group 1 (18.6 versus 10.4 months). Median PFS using mRECIST criteria showed a similar magnitude of benefit (18.6 versus 10.8 months). Median OS was 25.7 months in Group 2 versus 21.5 months in Group 1. Group 2 showed a higher ORR (complete and partial response) with RECIST 1.1 (54% versus 29%) and mRECIST (75% versus 54%) and a higher disease control rate (complete and partial response and stable disease). Treatment with DC infusions was well tolerated; the most common adverse events were chills (30%), fatigue (22%), and nausea (22%). Further investigation of the role of DC infusions in the treatment of HCC is warranted but will need to consider the evolving immunotherapy landscape.
Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer in the world, with roughly 2 million new cases and about 1 million deaths occurring annually, and these numbers are steadily increasing. A significant proportion of CRC occurs in the rectum – so-called rectal cancer. Rectal cancers are typically treated with a combination of chemotherapy, radiation, and surgery, and while cure is frequently achieved, radiation and surgery significantly influence the quality of life.
Approximately 5-10% of rectal cancers are locally advanced mismatch repair-deficient (MMRd) with an annual incidence of 40,000-75,000 cases."
Being resistant to chemotherapy, these tumors could be effectively treated with checkpoint blockers as in a single-arm Phase 2 study reported by Andrea Cercek, MD (Memorial Sloan Kettering Cancer Center, New York, USA) [18]. The study plans to enroll 30 patients with clinical stage II-III MMRd rectal cancer. All patients had MMRd and BRAF V600E wild-type tumors and received dostarlimab (anti-PD-1 monoclonal antibody) at 500 mg intravenously every three weeks for six months and then underwent radiologic and endoscopic evaluation.
Fourteen patients have been treated and completed at least six months of follow-up. All 14 achieved a complete clinical response with no evidence of tumor on magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG)-positron emission tomography (PET), endoscopic visualization, digital rectal exam, or biopsy. As of June 2022, no patients have required chemoradiation or surgery, and no cases of progression or recurrence have been noted during follow-up. No serious adverse events higher than grade 3 were observed. Median follow-up is currently only 6.8 months, but four patients have been followed for nearly two years, and only four have received less than six months of the required treatment. Longer follow-up is needed to assess response duration, as it is well known that 88% of tumor regrowth can happen up to two years after treatment completion. There are limitations in the study design, including the lack of a control arm or historical control data, the fact this was a single-center study performed in an institution with extensive expertise in non-operative management of rectal cancer, and the restriction of only a single endpoint available at the moment (overall response) with no data on survival or other clinically relevant outcomes (for example, 3-year OS/disease-free survival and organ preservation rates). However, the results are clinically significant due to the 100% clinical complete response rate, even if observed in a small number of patients. The study has a significant potential to change the clinical practice and to decrease morbidity by eliminating pelvic radiation and surgery, which, in turn, is particularly relevant as the incidence of rectal cancer is increasing steadily in young people. It also has the potential to be translated rapidly into areas around the world without access to modern chemotherapy, radiation, and surgery. The PARADIGM Phase 3 clinical trial enrolled more than 800 patients with RAS wild-t ype metastatic colorectal left-sided cancer in Japan who were randomly assigned to receive either panitumumab (anti-EGFR antibody) or bevacizumab (anti-VEGF antibody) [19]. All patients also received mFOLFOX6 (modified leucovorin, fluorouracil, and oxaliplatin) and were followed up for a median of 61 months. The study showed that patients who received panitumumab lived for 37.9 months from the start of treatment in the trial compared with 34.3 months for those who received bevacizumab. PFS was 13.7 versus 13.2 months, respectively, but this difference was statistically insignificant. The response rate and the curative resection rate were higher with panitumumab than with bevacizumab. The results from PARADIGM highlight the importance of RAS testing at the initial diagnosis of metastatic disease in left-sided CRC. The study also showed adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves OS, and the combination of panitumumab with FOLFOX chemotherapy is superior for patients with RAS wild-type and left-sided mCRC than the combination of bevacizumab with FOLFOX chemotherapy. This study is not the first to show the same result of increased OS and ORR with no difference in progression-free survival. This challenges the choice of a PFS as a surrogate endpoint when dealing with upfront and EGFR-containing regimens, which must be considered when planning future clinical trials.