Impact of EML4-ALK variants and co-occurring TP53 mutations on duration of first-line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion-positive NSCLC: Real-world outcomes from the GuardantINFORM database.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Factors such as variant allele frequencies (VAF), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting. METHODS: Adults with advanced/metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated. RESULTS: 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n=280), brigatinib (n=15), lorlatinib (n=9), or ceritinib (n=3); 150 patients (49%) had ALK-fusion VAF ≥1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF <1% versus ≥1% had median TTD of 32.2 (95% CI: 20.7-NE) versus 14.7 months (10.4-19.9; HR: 1.57 [95% CI: 1.09-2.26]; P=0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-not estimable [NE]) in patients with versus without TP53mt detected (HR: 1.53 [1.07-2.19]; P=0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR: 1.29 [0.83-2.01]; P=0.2641). Patients with TP53mt and v3 had median TTD of 7.4 months (95% CI: 4.2-31.1). CONCLUSION: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

T-Cell Engagers in Solid Cancers-Current Landscape and Future Directions.

Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host's immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop 'off-the-shelf' anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.

Immunotherapy in pancreatic cancer and the importance of tumour testing.

Advanced pancreatic cancer carries a poor prognosis and has traditionally been treated with chemotherapy. However, immunotherapy has made great strides in a subset of patients depending on mismatch repair/microsatellite status. We present a patient with locally advanced pancreatic cancer treated with neoadjuvant chemotherapy followed by surgery and additional adjuvant chemotherapy whose disease progressed while on adjuvant chemotherapy. Tumour testing showed a mismatch repair mutation and high microsatellite instability, making her eligible for treatment with immunotherapy. Germline genetic testing confirmed the clinical suspicion of Lynch syndrome. She has had isolated sites of progression treated with radiation but overall has been receiving immunotherapy for more than 3 years, highlighting the importance of tumour testing as it may allow for additional treatment options and improved survival.

Mushroom Poisoning Mimicking Painless Progressive Jaundice: A Case Report with Review of the Literature.

Mushroom poisoning is common in the United States. The severity of mushroom poisoning may vary, depending on the geographic location, the amount of toxin delivered, and the genetic characteristics of the mushroom. Though they could have varied presentation, early identification with careful history could be helpful in triage. We present a case of a 69-year-old female of false morel mushroom poisoning leading to hepatotoxicity with painless jaundice and biochemical pancreatitis.

Giant-cell tumor of bone with pathological evidence of blood vessel invasion.

Giant cell tumor of bone is a rare but aggressive benign tumor that arises at the end of long tubular bones. The tumor rarely metastasizes; however, we report a case in which a giant cell tumor of bone presented with progressive pulmonary metastases. There has been no clear pathologic evidence of the definitive cause or route of metastasis. In our case, the primary tumor site was located in the left femur with pathological evidence of blood vessel invasion. The histological and pathological features of this entity are discussed in this letter to the editor.

Dasatinib-Induced T-Cell-Mediated Colitis: A Case Report and Review of the Literature.

Dasatinib is a potent inhibitor of the altered tyrosine kinase activity in disease states associated with BCR/ABL1. This agent has been shown to exhibit broad off-target kinase inhibition and immunomodulating properties. These effects may be responsible for dasatinib's unique side effects including a distinctive form of hemorrhagic colitis. We report a case of hemorrhagic colitis associated with dasatinib use in a patient with chronic myelogenous leukemia. Colon biopsies at the time of symptomatic colitis confirmed CD3+CD8+ T cell infiltration. The process rapidly resolved following drug discontinuation, but relapsed when rechallenged with a reduced dose of dasatinib. Colitis did not recur when the patient was treated with an alternative agent. A literature review of prior cases involving dasatinib-induced T-cell mediated colitis provides insight into commonalities that may facilitate the recognition and management of this entity. Most incidences occurred after a 3-month drug exposure and may be accompanied by large granular lymphocytes. The process uniformly resolves within a few days following drug discontinuation and will generally recur in a shorter period of time if the drug is reintroduced. Most patients will require an alternative agent, although select patients could be continued on dasatinib if other options are limited.