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Helicobacter pylori, pathogenic variants associated with inherited cancer syndromes, and gastric cancer risk (April 2023)
Certain hereditary cancer syndromes and Helicobacter pylori infection are risk factors for gastric cancer, but their combined effect has not previously been studied. In an observational cohort study including 10,000 patients with gastric cancer and 38,000 controls, pathogenic variants in APC, ATM, BRCA1, BRCA2, PALB2, CDH1, MLH1, MSH2, and MSH6 were associated with an increased risk of gastric cancer.1 Carriers of these pathogenic variants with H. pylori infection also had a higher lifetime risk of gastric cancer compared with infected noncarriers (46 versus 14 percent). These data suggest that individuals with these pathogenic variants should be tested for H. pylori infection and offered eradication treatment if present.
Immune checkpoint inhibitors plus chemotherapy in advanced endometrial cancer (April 2023)
Although carboplatin and paclitaxel has been the standard initial treatment for advanced and recurrent endometrial cancer, trials are evaluating the addition of immune checkpoint inhibitors (ICIs) in this setting. In two randomized trials, the ICIs dostarlimab and pembrolizumab both improved progression-free survival (PFS) when added individually to carboplatin and paclitaxel; the addition of dostarlimab also demonstrated an overall survival (OS) benefit.2,3 Greatest PFS benefits were observed in both trials among those with mismatch repair-deficiency (dMMR), and the addition of dostarlimab also demonstrated an improvement in OS rates in this subset (83 versus 59 percent at 24 months). For advanced endometrial cancer with dMMR, we now suggest the addition of either dostarlimab or pembrolizumab to chemotherapy.
Retifanlimab for metastatic Merkel cell carcinoma (April 2023)
For patients with metastatic Merkel cell carcinoma (MCC), immune checkpoint inhibitors are an effective treatment option, and there is interest in investigating newer agents such as retifanlimab. In an open-label phase II trial (POD1UM-201) of over 60 patients with systemic therapy-naïve, recurrent locally advanced or metastatic MCC, the objective response rate was 52 percent at median follow-up of eight months.4,5 Based on these data, the US Food and Drug Administration approved retifanlimab for the treatment of adult patients with recurrent locally advanced or metastatic MCC.4 Although we consider it to be an acceptable option in this population, we favor pembrolizumab and avelumab, given longer follow up with these agents.
Intrathecal trastuzumab for HER2-positive leptomeningeal disease (April 2023)
Intrathecal (IT) delivery of trastuzumab is an emerging option for treatment of leptomeningeal disease (LMD) due to human epidermal growth factor receptor 2 (HER2)-positive cancers, particularly breast cancer. In the largest phase I/II study in 34 patients with HER2-positive cancers, only one grade 4 toxicity (arachnoiditis) was encountered at the 80 mg twice-weekly dose level.6 Among 23 patients with breast cancer treated at this dose, rates of partial response, stable disease, and progressive disease were 19, 50, and 30 percent, respectively. We consider IT trastuzumab to be a reasonable option in HER2-positive patients selected for IT therapy (algorithm 1), alongside other agents such as IT methotrexate.
1. Usui Y, Taniyama Y, Endo M, et al. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. N Engl J Med. 2023;388(13):1181.
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med. 2023.
3. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med. 2023.
4. Retifanlimab: US Food and Drug Administration (FDA) prescribing label https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761334s000lbl.pdf (Accessed on March 28, 2023).
5. Grignani G, Rutkowski P, Lebbe C. 545 A phase 2 study of retifanlimab in patients with advanced or metastatic merkel cell carcinoma (MCC) (POD1UM-201). J Immunother Cancer. 2021;9;2S
6. Kumthekar PU, Avram MJ, Lassman AB, et al. A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics. Neuro Oncol. 2023;25(3):557.
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