SUMMARY: The FDA on February 25, 2020, approved NERLYNX® (Neratinib) in combination with XELODA® (Capecitabine) for adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.
NERLYNX® (Neratinib) is a potent, irreversible, oral Tyrosine Kinase Inhibitor, of HER1, HER2 and HER4 (pan-HER inhibitor). NERLYNX® interacts with the catalytic domain of HER1, HER2, and HER4 and blocks their downstream signaling pathways, resulting in decreased cell proliferation and increased cell death. Clinical data has suggested that NERLYNX® has significant activity in suppressing HER-mediated tumor growth and is able to overcome tumor escape mechanisms experienced with current HER2-targeted and chemotherapeutic agents. It has been well known that hormone receptor positive breast cancer patients, who are also HER2-positive, have relative resistance to hormone therapy. Preclinical models had suggested that the addition of NERLYNX® could improve responses in ER positive, HER2-positive breast cancer patients. Further, NERLYNX® has clinical activity in patients with HER2-positive metastatic breast cancer. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly reduced the proportion of clinically relevant breast cancer relapses that might lead to death, such as distant and locoregional recurrences outside the preserved breast.
TYKERB® (Lapatinib) is a Tyrosine Kinase Inhibitor of HER2 and EGFR, and in a previously published Phase III study, a combination of TYKERB® plus XELODA® (Capecitabine) was found to be superior to XELODA® alone in women with HER2-positive advanced breast cancer, that has progressed after treatment with regimens that included an Anthracycline, a Taxane, and HERCEPTIN®. (N Engl J Med 2006; 355:2733-2743)
NALA is a multinational, randomized, open-label, Phase III trial of NERLYNX® plus XELODA® in patients with heavily pretreated Stage IV HER2-positive metastatic breast cancer. In this study, 621 patients with metastatic HER2-positive breast cancer who received two or more prior anti-HER2 based regimens in the metastatic setting were randomly assigned in a 1:1 to receive NERLYNX® 240 mg given orally once daily on days 1-21 along with XELODA® 750 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=307) or TYKERB® 1250 mg given orally once daily on days 1-21 along with XELODA® 1000 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=314). Approximately 80% had visceral metastases, and about 30% had received at least three anti-HER2 therapies. Patients in the NERLYNX® group also received antidiarrheal prophylaxis with Loperamide. Patients were treated until disease progression or unacceptable toxicity. The Co-Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR) and Duration of Response, Clinical Benefit Rate (CBR), time to intervention for symptomatic metastatic Central Nervous System (CNS) disease and Safety.
It was noted that the median PFS was 5.6 months for patients who received NERLYNX® with XELODA® and 5.5 months for those receiving TYKERB® with XELODA® (HR=0.76; P=0.006). This represented a 24% reduction in the risk of disease progression or death for those receiving a combination of NERLYNX® and XELODA®. The PFS rate at 12 months was 29% versus 15% respectively. The median OS was 21 months for patients receiving NERLYNX® and XELODA® compared to 18.7 months for those receiving TYKERB® and XELODA® (HR=0.88; P=0.20). The ORR was numerically higher with NERLYNX® and XELODA® combination in patients with measurable disease (32.8% versus 26.7%), and there was a statistically significant improvement in the Clinical Benefit Rate (45% versus 36%; P=0.03). The median Duration of Response was 8.5 versus 5.6 months respectively (HR=0.50; P=0.0004), favoring the NERLYNX® combination. The time to intervention for symptomatic CNS disease was significantly delayed with NERLYNX® combination versus TYKERB® combination, with an overall cumulative incidence of 22.8% versus 29.2% respectively (P= 0.043). Treatment related toxicities were similar between arms, but there was a higher rate of Grade 3 diarrhea with the NERLYNX® combination (24.4% versus 12.5% respectively). Discontinuation due to treatment related toxicities were lower with NERLYNX® combination versus TYKERB® combination (10.9% versus 14.5%).
It was concluded from this study that a combination of NERLYNX® and XELODA® significantly improved Progression Free Survival, with a trend towards improved Overall Survival, and also resulted in a delayed time to intervention for symptomatic CNS disease, among patients with heavily pretreated advanced HER2-positive breast cancer. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Saura C, Oliveira M, Feng Y-H, et al. J Clin Oncol. 2019;37 (suppl; abstr 1002).
Author: RR
LONSURF® Plus AVASTIN® Combination for Chemo-Refractory Metastatic Colorectal Cancer
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease.
LONSURF® is a combination of two agents – a novel oral nucleoside, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride. In a pivotal, global, Phase III trial (RECOURSE), LONSURF® significantly improved Overall Survival (OS) compared to placebo, with a 32% reduction in the risk of death, among patients with chemo-refractory metastatic CRC. AVASTIN® (Bevacizumab) is a humanized anti-VEGF monoclonal IgG1 antibody that directly binds Vascular Endothelial Growth Factor (VEGF) to inhibit angiogenesis.
In a previously published multicenter Phase I/II study (C-TASK FORCE), the combination of LONSURF® in combination with AVASTIN® showed promising antitumor activity with acceptable toxicity among patients with metastatic CRC. Based on the encouraging results of this study, the authors conducted an open-label, randomized, Phase II study in which the efficacy of LONSURF® plus AVASTIN® was compared with LONSURF® monotherapy in patients with refractory metastatic CRC. This study enrolled and randomly assigned 93 patients in 1:1 ratio to LONSURF® plus AVASTIN® (N=46) or LONSURF® alone (N=47). The main inclusion criteria were histopathologically confirmed metastatic CRC, refractory or intolerant to a Fluoropyrimidine (5-FU), Irinotecan (CAMPTOSAR®), Oxaliplatin (ELOXATIN®), and Cetuximab (ERBITUX®) or Panitumumab (VECTIBIX®), with the latter two agents offered only for RAS wild-type tumors. Patients had a WHO performance status of 0 or 1 and previous therapy with AVASTIN®, ZALTRAP® (Aflibercept), CYRAMZA® (Ramucirumab), or STIVARGA® (Regorafenib) was allowed. Randomized patients received LONSURF® 35 mg/m2 orally twice daily on days 1-5 and 8-12 every 28 days alone, or in combination with AVASTIN® 5 mg/kg IV on days 1 and 15 of each treatment cycle, until disease progression or unacceptable toxicity. Patients were stratified by institution and RAS mutation status. The Primary endpoint was Progression Free Survival (PFS).
After a median follow up of 10.0 months, the median PFS was 4.6 months in the LONSURF® plus AVASTIN® group versus 2.6 months in the LONSURF® monotherapy group (HR=0.45; P=0.0015). This represented a 55% reduction in the risk of progression or death. This benefit remained significant when analysis was adjusted for the stratification factors of study center and RAS mutation status (HR = 0.47, P =0.0015). The median Overall Survival was 9.4 months versus 6.7 months (HR=0.55, P =0.03) and Disease Control Rates were 67% versus 51% (P=0.14), in favor of the combination therapy. The most common treatment-related Grade 3 or more adverse events in the combination group were neutropenia and diarrhea.
It was concluded that among patients with chemo-refractory metastatic CRC, a combination of LONSURF® and AVASTIN® was associated with a significant and clinically relevant improvement in Progression Free Survival with tolerable toxicity, compared with LONSURF® monotherapy. The authors added that this could be a new treatment option and practice-changing development for patients with refractory metastatic CRC. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Pfeiffer P, Yilmaz M, Möller S, et al. THE LANCET Oncology. Published:January 27, 2020DOI:https://doi.org/10.1016/S1470-2045(19)30827-7
Neoadjuvant KEYTRUDA® Plus Chemotherapy Improves Pathological Complete Response in Triple Negative Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.
Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.
KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. Cytotoxic chemotherapy releases tumor-specific antigens and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Preliminary results from Phase I and II trials have shown that in patients with TNBC, KEYTRUDA® given along with chemotherapy in a neoadjuvant setting resulted in a high rate of pCR.
KEYNOTE-522 is an international, placebo controlled Phase III trial, conducted to evaluate the safety and efficacy of neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® or placebo, in patients with early stage TNBC. In this study, 1,174 patients were randomly assigned in a 2:1 ratio to receive neoadjuvant KEYTRUDA® 200 mg IV every 3 weeks (N=784) or placebo (N=390). All patients received 4 cycles of Carboplatin plus Paclitaxel, followed by 4 cycles of Doxorubicin or Epirubicin plus Cyclophosphamide, in the neoadjuvant setting. Following definitive surgery, adjuvant KEYTRUDA® or placebo was continued every 3 weeks for 9 cycles or until disease recurrence or unacceptable toxicity. Enrolled TNBC patients were newly diagnosed, treatment naïve, and included both node-negative and node-positive patients with nonmetastatic disease (Tumor Stage T1c, Nodal Stage N1-N2 or Tumor Stage T2-T4, Nodal Stage N0-N2, per AJCC criteria). Treatment groups were well balanced and patients were stratified according to nodal status, tumor size, and Carboplatin schedule (weekly versus every 3 weeks). The two Primary endpoints were pathological Complete Response (pCR) at the time of definitive surgery and Event Free Survival (EFS). The median follow up was 15.5 months.
At the first interim analysis, the pCR among the first 602 patients who underwent randomization was 64.8% in the KEYTRUDA® plus chemotherapy group, compared with 51.2% in the placebo plus chemotherapy group (P<0.001). This pCR benefit was consistent across subgroups including PD-L1 expresssion subgroups. In the PD-L1-positive population, the pCR was 68.9% in the KEYTRUDA® plus chemotherapy group compared with 54.9% in the placebo plus chemotherapy group. In the PD-L1 negative group, the pCR in the KEYTRUDA® plus chemotherapy group was 45.3% and 30.3% in the placebo plus chemotherapy group. Neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® showed a favorable trend for Event Free Survival compared with chemotherapy alone, although these data are still premature. Across all treatment phases, Grade 3 or higher treatment-related toxicities were 78.0% in the KEYTRUDA® plus chemotherapy group and 73.0% in the placebo plus chemotherapy group.
It was concluded that among patients with early stage Triple Negative Breast Cancer, the addition of KEYTRUDA® to neoadjuvant chemotherapy significantly increased the pathological Complete Response rate, compared to those who received placebo plus neoadjuvant chemotherapy, with a favorable trend in Event Free Survival. Pembrolizumab for Early Triple-Negative Breast Cancer. Schmid P, Cortés J, Pusztai L, et al. for the KEYNOTE-522 Investigators. N Engl J Med 2020;382:810-821
Improved Quality of Life and Efficacy with BRAFTOVI®, MEKTOVI® and ERBITUX® Triplet Therapy in Patients with BRAF V600E-Mutant Metastatic Colorectal Cancer
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab), as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC), whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 5-20% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. However, BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than melanoma. BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The combination of BRAFTOVI® along with anti-EGFR monoclonal antibody ERBITUX® (Cetuximab) showed promising activity in early-phase clinical trials.
The BEACON CRC (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) trial is an international, multicenter, randomized, open-label, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI® (Binimetinib), was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC, whose disease has progressed after one or two prior regimens. In this trial, 665 patients were randomly assigned in a 1:1:1 ratio to receive either triplet therapy of BRAFTOVI® 300 mg orally daily, MEKTOVI® 45 mg orally twice daily, and ERBITUX® 400 mg/m2 IV as an initial dose, then 250 mg/m2 IV weekly (N=224), doublet-therapy of BRAFTOVI® and ERBITUX® administered in the same doses and on the same schedule as the triplet regimen (N=220) or investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan (N=221). Patients were stratified according to previous Irinotecan use and treatment was administered in 28-day cycles until disease progression. The co-Primary end points were Overall Survival (OS) in the triplet-therapy group as compared with the control group and Secondary end points included OS in the doublet-therapy group as compared with the control group, as well as PFS, Duration of Response, and Safety in all groups. This study was not powered to compare the triplet-therapy group against the doublet-therapy group.
At the time of prespecified interim analysis, with a median duration of follow up for survival at 7.8 months across the three groups, the median OS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR for death=0.52; P<0.001). This represented 48% reduction in the risk of death in the triplet-therapy group. The confirmed Response Rate was 26% in the triplet-therapy group and 2% in the control group (P<0.001). The median OS in the doublet-therapy group was 8.4 months (HR for death versus control=0.60; P<0.001).
The authors in this updated analysis focused on the patient-reported Quality of Life (QOL) assessments from this study. QOL assessments using 4 validated QOL measures were secondary endpoints in the trial. They included EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The risk of QOL deterioration was reduced by 45% (HR=0.55) and 44% (HR=0.56), using EORTC QLQ C30 and FACT C assessments respectively, in favor of the triplet regimen over control. Similar findings were observed when the doublet-therapy regimen was compared with the regimen in the control group, and when QOL assessments were made using the other two QOL measures (EuroQol 5D 5L and PGIC). There was however no significant differences in QOL when the triplet and doublet regimen groups were compared.
It was concluded based on this updated analysis of the BEACON CRC trial, that among patients with BRAF V600E-mutant metastatic Colorectal Cancer, a combination of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI®, demonstrated longer maintenance of QOL on patient-reported assessments, compared to the current standard of care. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Kopetz S, Grothey A, Van Cutsem E, et al. J Clin Oncol. 2020;38(suppl 4; abstr 8).
Blood-Based Screening Test Identifies Gastrointestinal Cancers
SUMMARY: It is estimated that cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum account for approximately 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US. There are currently no screening tests available for cancers of the gallbladder, bile duct, and pancreatic cancer. Although screening tests do exist for other types of GI malignancies such as colorectal and stomach cancer, many of them are invasive. Further, when GI malignancies are diagnosed, they are frequently at advanced stages and are more difficult to treat.
A noninvasive, liquid biopsy assay based on circulating tumor DNA (ctDNA) has the potential to detect cancer in early stages among asymptomatic individuals. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. ctDNA can detect almost all molecular alterations present in cancer cells and genotyping circulating cell-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape. The proportion of cfDNA that originates from a tumor depends on the anatomic location, tumor burden and cell turnover. cfDNA also allows real-time monitoring for treatment response and resistance.
The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community, and helped advance health and science technologies.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, case-control, observational study with longitudinal follow up, and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection based on cell-free DNA (cfDNA). This study completed enrollment of approximately 15,000 participants with and without cancer (56% with more than 20 tumor types and all clinical stages), across 142 sites in the US and Canada. The purpose of this study is to collect biological samples from patients with a new diagnosis of cancer (blood and tumor tissue) and from individuals who do not have a diagnosis of cancer (blood), in order to characterize the population heterogeneity in cancer and non-cancer participants, and to develop models for distinguishing cancer from non-cancer. The principal goal is to develop a noninvasive cancer detection assay and the CCGA was designed to characterize the landscape of genomic cancer signals in the blood and to detect and validate GRAIL, Inc.’s multi-cancer early detection blood test through three pre-planned sub-studies.
GRAIL, Inc., is a healthcare company focused on the early detection of cancer by using the power of Next-Generation Sequencing, population-scale clinical studies, and state-of-the-art computer science and data science to enhance the scientific understanding of cancer biology, and to develop its multi-cancer early detection blood test. GRAIL’s high efficiency methylation technology preferentially targets the most informative regions of the genome, and is designed to use its proprietary database and machine-learning algorithms to both detect the presence of cancer and identify the tumor’s Tissue of Origin. GRAIL’s sequencing database of cancer and non-cancer methylation signatures is believed to be the largest of its kind, and covers approximately 30 million methylation sites across the genome, with more than 20 cancer types across stages represented within the database.
Previously reported data from the first sub-study of CCGA showed GRAIL’s prototype technology could detect the presence of multiple deadly cancer types with a low rate of false positive results (high specificity). In this analysis blood samples from 166 participants who had a cancer diagnosis at the time of enrollment were evaluated, and cancer was detected using the methylation technology. Results showed that GRAIL’s prototype technology correctly identified the tumor’s Tissue of Origin in 87% of the blood samples evaluated (N=144/166), including 96% of breast cancer cases (N=22/23), 88% of lung cancer cases (N=29/33), 90% of liver cancer cases (N=9/10) and 100% of pancreatic cancer cases (N=17/17).
GRAIL has since selected methylation as its preferred approach and evaluated its refined methylation blood test in the second pre-planned sub-study of CCGA. It was determined that whole-genome bisulfite sequencing for DNA methylation was the most effective approach for early cancer detection. DNA methylation is a natural epigenetic mechanism used by cells to regulate gene expression with some regions of hypermethylation and some regions of hypomethylation, and is a chemical modification to DNA, that can change how a gene’s function is carried out by the body without changing the order of the DNA bases. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth (hypermethylation can cause tumor-suppressor genes to be inactivated). Methylation patterns or signatures, are unique to the tumor DNA, enabling tumor detection and localization, but are not of value when it comes to precision therapies. This is unlike mutations and copy number changes, which can be detected in white blood cells in individuals without cancer as well, leading to false-positives.
The researches in this second substudy reported the performance of methylation-based cfDNA early multi-cancer detection test, for GastroIntestinal (GI) tract cancers, and also provided data from individuals without known cancer (non-cancer controls). To test the current assay, the second substudy included approximately 4,500 individuals, both with and without cancer, who were split into a training cohort and a validation cohort. Of the 2,185 patients with newly-diagnosed cancer in the second substudy, 447 patients were diagnosed with GI malignancies. Plasma cfDNA was subjected to targeted methylation analysis to develop an algorithm that could identify the presence or absence of cancer, as well as the Tissue of Origin of the cancer. The GI malignancies included Esophagus/Stomach (N=67), Pancreas/Gallbladder/Extrahepatic bile duct (N=95), Liver/Intrahepatic bile duct (N=29), and Colon/Rectum (N=121). To minimize the likelihood of false-positives, the targeted methylation assay was pre-set to yield greater than 99% specificity.
The test showed a sensitivity level of approximately 82% for detecting GI cancers of all stages in the independent validation set. The predicted Tissue of Origin accuracy across all GI cancers was 92%.
It was concluded that this assay performed using a single noninvasive blood sample, has the potential to diagnose a variety of gastrointestinal cancers earlier, when they are more treatable, with good sensitivity and with a low rate of false positives. Performance of a blood-based test for the detection of multiple cancer types. Wolpin BM, Richards DA, Cohn AL, et al. J Clin Oncol. 2020;38(suppl 4; abstr 283).
Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma
Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma
SUMMARY: It is estimated that in the US, approximately 100,350 new cases of malignant melanoma will be diagnosed in 2020 and about 6850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in Phase III trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.
TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. Long term survival data pooled from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic melanoma patients, with BRAFV600E or V600K mutation who had received TAFINLAR® along with MEKINIST® showed PFS rates of 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal LDH level plus fewer than three metastatic organ sites at baseline.
With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians based on the long term data supporting the durability of responses with immunotherapies. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.
COMBI-AD is an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected, Stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. At a median follow up of 2.8 years, the estimated 3-year Relapse Free Survival (RFS) rate was 58% with a combination of TAFINLAR® and MEKINIST® and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). A prespecified exploratory outcome of this trial was assessment of biomarkers. The authors assessed intrinsic tumor genomic features in 368 patients using Next-Generation DNA sequencing, and tumor microenvironment characteristics were assessed in 507 patients by use of a NanoString RNA assay, in an attempt to provide prognostic and predictive information. Median follow up at data cutoff was 44 months in the TAFINLAR® plus MEKINIST® group and 42 months in the placebo group.
Baseline MAPK pathway genomic alterations did not affect treatment benefit or outcomes in either treatment groups. An Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Tumor Mutational Burden (TMB) was independently associated with better RFS in the placebo group (HR for top third versus bottom third of TMB values=0.56; P=0.0056), but this benefit was not seen in the TAFINLAR® plus MEKINIST® group (HR= 0.83; P=0.44). However, patients with TMB in the lower two terciles who received TAFINLAR® plus MEKINIST® combination had improved RFS compared to those who received placebo (HR=0.49: P<0.0001). Patients with high TMB appeared to have a less pronounced benefit with TAFINLAR® plus MEKINIST® targeted therapy, compared to placebo, especially if they had an Interferon Gamma gene expression signature lower than the median.
It was concluded from this biomarker analysis that high Tumor Mutational Burden was independently associated with better Relapse Free Survival in the placebo group but not in the TAFINLAR® plus MEKINIST® combination group, and an Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Dummer R, Brase JC, Garrett J, et al. The Lancet Oncology. Published:January 30, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30062-0
KISQALI® plus FASLODEX® Improve Overall Survival in Advanced Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies.
Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.
KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized Phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS and OS, compared with placebo plus endocrine therapy.
MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR), and Safety.
In the primary analysis of the trial, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The authors now report the results of the second interim analysis of Overall Survival and an updated analysis of Progression Free Survival. The median duration of follow up for all patients was 39.4 months, and the median duration of treatment was 15.8 months in the KISQALI® group and 12.0 months in the placebo group.
There was a significant Overall Survival benefit with KISQALI® plus FASLODEX® compared to placebo plus FASLODEX®. The estimated Overall Survival at 42 months was 57.8% in the KISQALI® group compared to 45.9% in the placebo group, and this represented a 28% reduction in the relative risk of death with the KISQALI® combination (HR=0.72; P=0.00455). The survival benefit was consistent across most subgroups. The median PFS among patients receiving first line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the KISQALI® group and 19.2 months in the placebo group. No new safety signals were observed during this longer follow up period.
It was concluded that KISQALI® plus FASLODEX® significantly improved Overall Survival compared to placebo plus FASLODEX® in patients with HR-positive, HER2-negative advanced breast cancer, regardless of whether they received their treatment in the frontline setting or subsequently. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. Slamon DJ, Neven P, Chia S, et al. N Engl J Med 2020;382:514-524
NELSON Trial Confirms that Low-Dose CT Screening Reduces Lung Cancer Mortality
SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST and NCCN issued guideline in 2011, the United States Preventive Services Task Force (USPSTF) recommended Lung Cancer screening with Low Dose CT scan in high risk patients. CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service.
Despite the evidence and recommendation along with supportive public policies, screening with LDCT has not been adequately implemented in the US healthcare system. Low Health Care Provider knowledge of the Lung Cancer Screening (LCS) guidelines represents a potential barrier to implementation. Additionally, despite the unequivocal findings from the NLST, several countries have not adopted this guideline due to early publication of inconclusive results from a number of smaller trials in Europe. Further, there are limited data from randomized trials regarding whether nodule volume-based, low-dose CT screening can reduce lung cancer mortality among male former and current smokers.
The Dutch-Belgian lung cancer screening trial, NELSON (Nederlands–Leuvens Longkanker Screenings Onderzoek ) is a population-based, randomized, controlled trial initiated in 2000. The goal of the study was to show a 25% or more reduction in lung cancer mortality, in high-risk male participants at 10 years of follow-up, utilizing volume-based, low-dose CT lung cancer screening. The authors in this publication reported the incidence of lung cancer, associated mortality, and the performance of the four rounds of low-dose CT screening for lung cancer in the this trial, among male participants (main analysis) and female participants (subgroup analyses).
In this study, a total of 13,195 men aged 50-74 years were randomly assigned to undergo CT screening at baseline, year 1, year 3, and year 5.5 (N = 6,583) or no screening (N=6,612). At the time of initiation of this trial, only a small number of women were eligible, as smoking was much less prevalent and intense among women, than among men. Because of the relevance and importance of the inclusion of women in this study, high-risk women were later allowed to participate (N=2594). Participants were current or former smokers who had quit 10 or fewer years ago, who had smoked more than 15 cigarettes a day for more than 25 years, or more than 10 cigarettes a day for more than 30 years. About 45% of the male participants were former smokers.
At 10 years of follow up, lung cancer mortality among men was 24% lower in the screening group than in the control group (Rate Ratio=0.76; P=0.01), and 33% lower among women (Rate Ratio=0.67). The CT screening compliance among men was 90% and approximately 9.2% of the screened participants underwent at least one additional CT scan due to an indeterminate screening test. Screening-detected lung cancers were substantially more often diagnosed in Stage IA or IB (58.6%) and were Adenocarcinomas (52.0% in the screening group and 43.8% in the control group).
It was concluded that in this trial involving high-risk individuals, lung cancer mortality was significantly lower among those who underwent CT screening with determination of nodule volume, than among those who underwent no screening. Adherence to CT screening was very high, with low rates of follow up procedures for results suggestive of lung cancer. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. de Koning H.J., van der Aalst C.M., de Jong P.A., et al. N Engl J Med 2020;382:503-513
Assessment of Molecular Relapse Detection in Early Stage Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. Majority of the breast cancer patients present with early stage disease without macroscopic metastatic disease. Several small proof of principle studies have shown that detection of circulating tumor DNA (ctDNA) in the peripheral blood may identify patients at risk of relapse following definitive therapy. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. ctDNA can detect almost all molecular alterations present in cancer cells and the proportion of ctDNA that originates from a tumor depends on the anatomic location, tumor burden and cell turnover. ctDNA allows real-time monitoring for treatment response and resistance.
To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer, the authors conducted a multicenter, prospective study in the UK over a 5 year period, and included patients, irrespective of their hormone receptor or HER2 status, who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. All patients had primary breast cancer without evidence of distant metastatic disease and patients scheduled to receive standard neoadjuvant chemotherapy followed by surgery consented for plasma sample collection before chemotherapy, and patients scheduled to receive adjuvant chemotherapy consented for plasma sample collection after surgery and before chemotherapy. This study enrolled 170 women, and somatic mutations were identified in 101 patients, and this formed the primary analysis cohort and secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study (N=101+43). Tumor DNA extracted from the primary tumor was sequenced to identify somatic mutations to track in plasma, and personalized tumor-specific digital Polymerase Chain Reaction (dPCR) assays were designed to monitor these somatic mutations in serial plasma samples collected from patients every 3 months during the first year of follow up, and subsequently every 6 months for 5 years. ctDNA testing can identify genetic alterations unrelated to the lesion of interest (Clonal Hematopoiesis of Indeterminate Potential- CHIP). The authors analyzed buffy coat DNA to control for CHIP, which is common with increasing age and can potentially cause false-positive results in ctDNA analysis. The mean patient age was 54 years and the median follow up was 35.5 months. The Primary objective of the study was to assess whether patients with ctDNA detected in follow-up blood samples had worse Relapse Free Survival than patients without detectable ctDNA. Secondary end points included lead time between ctDNA detection and relapse, and association between detection of ctDNA in the diagnosis sample before neoadjuvant chemotherapy and relapse.
Results from the combined cohort of 144 patients showed that detection of ctDNA during follow up was associated with relapse (88.4% of patients who experienced relapse had antecedent ctDNA detection- P<0.001). Detection of ctDNA at diagnosis, before any treatment, was associated with larger tumor size and higher tumor grade, and patients with Triple Negative Breast Cancer (TNBC) had the highest level of ctDNA, likely due to high proliferative rates and cell turnover. This patient group was at a higher risk to relapse. Further, ctDNA detection had a median lead time of 10.7 months before clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 96% of patients. Brain-only metastasis however was less commonly detected by ctDNA, suggesting that cranial metastases are less readily detectable by ctDNA analysis.
It was concluded that detection of ctDNA during follow up of early-stage breast cancer is associated with a high risk of future relapse. A clinical trial is underway evaluating the benefit of treatment initiation at molecular relapse, before clinical development of metastatic disease. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. Garcia-Murillas I, Chopra N, Comino-Méndez I, et al. JAMA Oncol.2019;5:1473-1478.
H. pylori Eradication Treatment Reduces the Risk of Gastric Cancer in High Risk Population
SUMMARY: The American Cancer Society estimates that in the US, about 27,600 new cases of stomach cancer will be diagnosed in 2020 and about 11,010 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. The incidence of gastric cancer in the US has been on the decline and has been attributed to increased use of refrigeration for food storage, making fresh fruits and vegetables more available, and decreased the use of salted and smoked foods. In the United States, Asians and Hispanics have a much higher incidence of gastric cancer.
Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. HDGC however, is the most common genetic predisposing syndrome for gastric cancer, with germline mutations of the E-cadherin gene (CDH1), detected in 30-50% of diffuse-type gastric cancers. Women with CDH1 mutations are also at an increased risk for breast cancer, and the follow up is similar to BRCA1/BRCA2 mutation carriers. A family history of gastric cancer in a first-degree relative is associated with double to triple the risk of gastric cancer. Gastric cancer overall has a poor prognosis and the 5 year Overall Survival rate is about 25%.
The strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium. This bacterial species colonizes the stomach and the overall estimate of H. pylori prevalence in adults is 76% in developing countries and 58% in developed countries. The association between H.pylori and gastric cancer has been shown in observational and case-control studies. In a recently published randomized trial (NEJM 2018;378:1085-1095), treatment of H. pylori infection in patients with early gastric cancer reduced the risk of metachronous gastric cancer by 50%.
It has been unclear whether treatment to eradicate H. pylori can reduce the risk of gastric cancer in individuals with a family history of gastric cancer in first-degree relatives. To address this question, the authors in this single-center, double-blind, placebo-controlled trial, randomly assigned 1838 participants with H. pylori infection and at least one first-degree relative with gastric cancer, in a 1:1 ratio to receive either H.pylori eradication therapy with Amoxicillin 1000 mg, Clarithromycin 500 mg, and Proton-Pump Inhibitor Lansoprazole 30 mg, each taken twice daily for 7 days or placebo. Eligible participants were 40-65 years of age and key exclusion criteria included a history of gastric cancer, peptic ulcer, or other malignancy, and previous eradication therapy for H. pylori. Surveillance endoscopies were performed every 2 years and suspicious lesions were biopsied for gastric cancer. A closeout endoscopy, with H. pylori evaluation, was performed at the end of the trial period. The Primary outcome was development of gastric cancer. A prespecified Secondary outcome was development of gastric cancer according to H. pylori eradication status, assessed during the follow-up period after receipt of H. pylori treatment or placebo. A total of 1676 participants (832 in the treatment group and 844 in the placebo group) were included in the primary outcome analysis.
During a median follow up of 9.2 years, the risk of gastric cancer was 55% lower among those who received H. pylori eradication treatment than among those who received placebo (HR=0.45; P=0.03). Among those who received treatment for H. pylori, the risk of gastric cancer was 73% lower among persons in whom H. pylori eradication was achieved than among those in whom infection was persistent (HR=0.27). Adverse events were common in the treatment group than in the placebo group (53% versus 19.1%; P<0.001), but were mild.
It was concluded that among individuals with H. pylori infection and a family history of gastric cancer in first-degree relatives, H. pylori eradication treatment significantly reduced the risk of gastric cancer. Family History of Gastric Cancer and Helicobacter pylori Treatment. Choi IJ, Kim CG, Lee JY, et al. N Engl J Med 2020;382:427-436