Molecular Profiling Drives Progress in GI Cancers
Surgery, radiotherapy, and chemotherapy have been the mainstay of treatment for GI cancers but have limited effect and can take a heavy toll on quality of life. The development of more effective therapies for GI cancers has lagged. Molecular profiling has helped change the outlook for patients with GI cancer by identifying the molecular and genetic signatures that allow oncologists to deliver treatments that are highly specific to a tumor. For these reasons, ASCO selected molecular profiling driving progress in GI cancers as the 2021 Advance of the Year. This selection recognizes the treatment advances made possible by molecular testing for patients with GI cancers.
GI cancers include cancers of the esophagus, stomach, small bowel, gallbladder and biliary tract, pancreas, colon, rectum, and anus and account for 26% of the global cancer incidence burden and 35% of all cancer-related deaths.6 The ability to molecularly profile a tumor has expanded the treatment options for individual patients with GI cancers— extending survival, while minimizing adverse effects. Specific genetic mutations, amplifications or fusions, epigenetic profile, protein expression, or other molecular features allow oncologists to choose targeted therapies matched to the molecular profile of their patient’s disease. In the past year, research has shown that targeting HER2 improves survival in gastric cancer and shows promise for patients with HER2-positive colorectal cancer. Therapy is now approved that targets specific DNA mutations in metastatic colorectal cancer. These advances are moving the treatment of GI cancers closer to personalized medicine.
Antibody-Drug Conjugate Shows Promise in GI Cancers
HER2 is a protein that promotes the growth of cancer cells. Overexpression of HER2 occurs among patients with breast, lung, gastric, and gastroesophageal junction cancers, among others. Trastuzumab is a monoclonal antibody that targets HER2, tamping down accelerated cancer cell growth and promoting cell death.
Trastuzumab plus chemotherapy is the standard initial treatment for HER2-positive gastric and gastroesophageal cancers, which account for around 20% of these types of cancers.27 Standard secondary therapy consists of chemotherapy with paclitaxel plus the monoclonal antibody ramucirumab, which acts on vascular endothelial growth factor 2, reducing blood supply to tumors.28 A number of treatments have been investigated for the treatment of gastric and gastroesophageal junction cancers following progression after standard first- and second-line therapies.29-31
Trastuzumab deruxtecan is a novel antibody-drug conjugate that links anti-HER2 trastuzumab with deruxtecan— an anticancer drug that interrupts DNA replication in cancer cells. Essentially, trastuzumab deruxtecan delivers a highly targeted payload of the replication-interrupting drug into tumor cells, further triggering cell death.32
Following the promising results in a phase I trial of trastuzumab deruxtecan, researchers evaluated efficacy and safety in a phase II trial of patients with HER2-positive gastric or gastroesophageal cancers that progressed despite treatment with trastuzumab. In the DESTINY Gastric01 study (ClinicalTrials.gov identifier: NCT03329690),33 patients were randomly assigned to receive trastuzumab deruxtecan (125 patients) or the treating clinician’s choice of chemotherapy (62 patients). Among patients who received the antibody-drug conjugate, 51.3% experienced an objective response compared with 14.3% of patients who received chemotherapy. Overall survival was also improved with trastuzumab deruxtecan (12.5 months) compared with chemotherapy (8.4 months). The most common grade 3 or greater adverse events were decreased neutrophil count, anemia, and decreased WBC count, all of which were more frequent among patients receiving trastuzumab deruxtecan. Twelve patients (10%) who received the antibody-drug conjugate developed drug-related interstitial lung disease or pneumonitis, mostly grade 1 or 2; no cases occurred in the chemotherapy group.
Additional data were presented at the virtual scientific program of the 2020 ASCO Annual Meeting. A study of trastuzumab deruxtecan in HER2-positive colorectal cancer showed similarly promising results. The phase II DESTINY-CRC01 trial (ClinicalTrials.gov identifier: NCT03384940)34 included patients with HER2-expressing metastatic colorectal cancer that had progressed after two or more treatment regimens. In this trial, nearly half of patients (45.3%) experienced an objective response—one patient had complete response and 23 had partial response. The most common grade 3 or greater adverse events were decreased neutrophil count and anemia. Five patients developed interstitial lung disease.
If approved, trastuzumab deruxtecan could fill a significant unmet need for patients with previously treated HER2- positive metastatic gastric and/or colorectal cancer.
Pembrolizumab Doubles Time to Disease Progression in Patients With Advanced Colorectal Cancer With DNA Mismatch Repair Deficiency
Approximately 5% of patients with metastatic colorectal cancer have high microsatellite instability with deficient mismatch repair (MSI-H/dMMR),35 which can be detected when a cell is unable to repair mistakes that are made during the process of copying DNA. When this happens, mutations in the DNA start accumulating and may cause cancer. Pembrolizumab is an immune checkpoint inhibitor that blocks the activity of a receptor called PD-1, a protein that helps keep the immune system in check, thereby allowing the immune system to attack cancer cells.
In the phase III KEYNOTE-177 trial (ClinicalTrials.gov identifier: NCT02563002),36 first-line treatment with pembrolizumab doubled the time to disease progression (16.5 months) compared with patients who received conventional chemotherapy (8.2 months). The findings come from an interim analysis presented during the virtual scientific program of the 2020 ASCO Annual Meeting. Severe treatment-related adverse events (grade 3 or greater) were less common with pembrolizumab (22%) than chemotherapy (66%). The FDA approved pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in June 2020.35
ASCO’s Targeted Agent and Profiling Utilization Registry Study (TAPUR; ClinicalTrials.gov identifier: NCT02693535), now in its fifth year, continues to enroll patients with advanced cancer with tumors that harbor a potentially actionable genomic alteration and report findings on patient outcomes. TAPUR evaluates antitumor activity of commercially available, targeted anticancer drugs when used outside of their FDA-approved indications. The study identifies potential new uses for existing, effective treatments that target a tumor genomic alteration.
More than 3,000 participants have been registered and more than 2,000 treated with a TAPUR study therapy. Based on treatment responses in the first stage of the enrollment, patient cohorts are either expanded to stage II for further study or permanently closed. This past year alone, TAPUR researchers have presented or published findings for 10 cohorts. Of these 10 cohorts, six reported positive findings, including positive cohorts for patients with HER2-amplified metastatic colorectal cancer (mCRC) treated with trastuzumab plus pertuzumab and patients with BRAF-mutant mCRC treated with cobimetinib plus vemurafenib. For the latest updates of all available results, closures, expansions, and listing of publications and presentations, visit the TAPUR website at tapur.org.