Search

PurposeEganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.Patients and methodsDose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).ResultsThe most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.ConclusionsOn the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.

BackgroundEntrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.MethodsAn integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).FindingsPatients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.InterpretationEntrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.FundingIgnyta/F Hoffmann-La Roche.

Simple Summary: Sinonasal carcinoma and olfactory neuroblastoma have very limited therapeutic options. The expression of the somatostatin receptor 2 (SSTR2) gene has been described in these patients, and the successful use of SSTR2-targeted treatments have been reported. This study investigates the association of SSTR2 expression with genomic features, immune biomarkers, and the tumor immune microenvironment in a cohort of patients with sinonasal malignancies. Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (SSTR2), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed SSTR2 gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database. SSTR2 gene expression was high in neural-type ONB and low in basal-type ONB and in most of the SNUC and SNEC cases; there was no difference in expression between primary and metastatic tumors. The T cell-inflamed (TCI) score analysis classified 38.5% of SNUC cases as T cell-inflamed compared to only 3.9% of ONB and 0% of SNEC cases; 26.9% of ONB cases were classified as intermediate TCI; and SNEC had the lowest relative immune cell infiltration by deconvolution. In high SSTR2-expressing ONB, there was a higher proportion of infiltrating of Natural Killer cells and dendritic cells by deconvolution. Additionally, high SSTR2-expressing ONB was enriched for proliferation pathways, including E2F and Myc targets and G2M checkpoints. In conclusion, our findings delineate significant differences between these three types of sinonasal malignancies that were examined. In ONB, relative to SNUC and SNEC, the SSTR2 expression profile, combined with its immune profiles, indicates potential novel therapeutic strategies and combinations for this unmet clinical need. Conversely, the inflammatory microenvironment of SNUC may be targetable using immuno-oncologic therapies. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma. Methods: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi‐square tests and overall survival rates were estimated using Kaplan–Meier method. Results: A total of 17 642 patients were included in the study. The 5‐year overall survival rates were 82.0% (95% CI: 79.8%–84.0%) in younger patients versus 67.5% (95% CI: 66.7%–68.3%, p‐value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2–NA) versus 129.8 (95% CI: 125.4–138.7, p‐value <0.0001) in males. Conclusions: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR-mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR-mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration:NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number). In some patients with non-small-cell lung cancer, changes (or mutations) in the DNA sequence can alter a protein called EGFR and allow tumors to grow and survive. Drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs for short) are used to treat these tumors by interfering with the abnormal EGFR protein. Treatment with these drugs can work well at first, but some tumors never respond, and for tumors that do respond, the cancer eventually becomes resistant to the EGFR TKI and the drug stops working. Platinum-based chemotherapy is often prescribed after an EGFR TKI stops working; however, platinum-based chemotherapy can provide only temporary control of the tumor growth. Most patients with non-small-cell lung cancer have a protein called HER3 on the surface of their tumor cells. A new drug candidate called patritumab deruxtecan (HER3-DXd) finds tumor cells and attaches to the HER3 protein on their surface. HER3-DXd then moves inside the cancer cells, where a novel antitumor payload is released and kills the tumor cells. This article describes the phase III clinical trial HERTHENA-Lung02 (NCT05338970) that compares the benefit of HER3-DXd to platinum-based chemotherapy for patients who have non-small-cell lung cancer with the abnormal EGFR protein and whose disease stopped responding or never responded to EGFR TKI therapy. [ABSTRACT FROM AUTHOR]

Objectives: Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. Methods: A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. Results: Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile‐onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5–70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre‐treatment baseline, 9 (75.0%) patients experienced a stable‐to‐partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial‐to‐complete responses in the larynx and trachea. Conclusion: Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable‐to‐partial response of pulmonary involvement in a majority of patients. Level of Evidence: 4 Laryngoscope, 134:577–581, 2024 [ABSTRACT FROM AUTHOR]

Background: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard‐of‐care in patients with stage III or unresectable non–small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real‐world evaluation of the PACIFIC regimen in these patients. Methods: This single‐institution, multi‐site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression‐free survival (PFS), and grade ≥3 pneumonitis‐free survival (PNFS) were compared between Black and non‐Black patients using Kaplan–Meier and Cox regression analyses. Results: A total of 105 patients with a median follow‐up of 22.8 months (interquartile range, 11.3–37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non‐Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p =.031), but other treatment characteristics were balanced between groups. The median OS (not‐reached vs. 39.7 months; p =.379) and PFS (31.6 months vs. 19.3 months; p =.332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non‐Black patients (p =.096). The grade ≥3 pneumonitis rate was similar between Black and non‐Black patients (12.3% vs. 12.5%; p =.973), and there was no significant difference in time to grade ≥3 PNFS (p =.904). Three (5.3%) Black patients and one (2.1%) non‐Black patient developed grade 5 pneumonitis. Conclusions: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non‐Black patients. Consolidative durvalumab after concurrent chemoradiation has similar efficacy and tolerability between Black and non‐Black patients with unresectable stage II/III non–small cell lung cancer. [ABSTRACT FROM AUTHOR]