Argentine consensus recommendations for lung cancer screening programmes: a RAND/UCLA-modified Delphi study.

BACKGROUND: Lung cancer (LC) screening improves LC survival; the best screening method in terms of improving survival is low-dose CT (LDCT), outpacing chest X-ray and sputum cytology. METHODS: A consensus of experts in Argentina was carried out to review the literature and generate recommendations for LC screening programmes. A mixed-method study was used with three phases: (1) review of the literature; (2) modified Delphi consensus panel; and (3) development of the recommendations. The Evidence to Decision (EtD) framework was used to generate 13 evaluation criteria. Nineteen experts participated in four voting rounds. Consensus among participants was defined using the RAND/UCLA method. RESULTS: A total of 16 recommendations scored ≥7 points with no disagreement on any criteria. Screening for LC should be performed with LDCT annually in the population at high-risk, aged between 55 and 74 years, regardless of sex, without comorbidities with a risk of death higher than the risk of death from LC, smoking ≥30 pack-years or former smokers who quit smoking within 15 years. Screening will be considered positive when finding a solid nodule ≥6 mm in diameter (or ≥113 mm3) on baseline LDCT and 4 mm in diameter if a new nodule is identified on annual screening. A smoking cessation programme should be offered, and cardiovascular risk assessment should be performed. Institutions should have a multidisciplinary committee, have protocols for the management of symptomatic patients not included in the programme and distribute educational material. CONCLUSION: The recommendations provide a basis for minimum requirements from which local institutions can develop their own protocols adapted to their needs and resources.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

Immunotherapy in Lung Cancer: Are the Promises of Long-Term Benefit Finally Met?

Over the last few years, agents targeting immune checkpoints have shown potential to improve therapeutic outcomes in patients with lung cancer in multiple clinical settings. Inhibitors of PD-1/PD-L1 have been approved for the treatment of different types of lung cancer by the FDA either alone or in combination with chemotherapy or other immune checkpoint inhibitors, such as anti-CTLA-4 agents. The introduction of these agents in clinical practice has revolutionized the therapeutic approach to lung cancer, keeping the promises of long-term benefit in selected patient populations. The therapeutic indications of immunotherapy in lung cancer are rapidly growing, and multiple combinations entered clinical practice or are under active development. Furthermore, the quest for a reliable predictive biomarker is still ongoing to overcome the limits of currently approved tests for patients' selection. In this review, we summarized the current status and progress of anti-PD-1/PD-L1 agents in lung cancer treatment.

Recommendations for detection, prioritization, and treatment of thoracic oncology patients during the COVID-19 pandemic: the THOCOoP cooperative group.

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non-Small-Cell Lung Cancer.

BACKGROUND: Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. METHODS: Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. RESULTS: Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). CONCLUSION: Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression.

Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy.

Age-related genetic abnormalities: the Achilles' heel for customizing therapy in elderly lung cancer patients.

Aging and cancer are closely related, and DNA repair systems, mainly involving the nucleotide excision repair pathway, have an important caretaker function in both processes. More than half of non-small cell lung cancer patients are elderly, and the expression of some genes involved in the mitotic checkpoint, such as BubR1, declines with aging. Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer; if performance status is good, both elderly and younger patients can tolerate this treatment equally well. Customized cisplatin treatment, based on reduction of the nucleotide excision repair pathway function, could be an attractive approach, and the assessment of mitotic checkpoint genes can be used for selecting docetaxel treatment. Epidermal growth factor receptor (EGFR) mutations are particularly frequent in elderly lung cancer patients who are never-smokers and constitute an attractive target for treatment with EGFR tyrosine kinase inhibitors.