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Unleashing the immune system to fight cancer has been a major breakthrough in cancer therapeutics since 2014 when anti-PD-1 antibodies (pembrolizumab and nivolumab) were approved for patients with metastatic melanoma. Therapeutic indications have rapidly expanded for many types of advanced cancer, including lung cancer. A variety of antibodies targeting the PD-1/PD-L1 checkpoint are contributing to this paradigm shift. The field now confronts two salient challenges: first, to improve the therapeutic outcome given the low response rate across the histologies; second, to identify biomarkers for improved patient selection. Pre-clinical and clinical studies are underway to evaluate combinatorial treatments to improve the therapeutic outcome paired with correlative studies to identify the factors associated with response and resistance. One of the emerging strategies is to combine epigenetic modifiers with immune checkpoint blockade (ICB) based on the evidence that targeting epigenetic elements can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). We will briefly review pleotropic biological functions of enhancer of zeste homolog 2 (EZH2), the enzymatic subunit of polycomb repressive complex 2 (PRC2), clinical developments of oral EZH2 inhibitors, and potentially promising approaches to combine EZH2 inhibitors and PD-1 blockade for patients with advanced solid tumors, focusing on lung cancer.

BACKGROUND: Now that immunotherapy plus chemotherapy (CT) is one standard option in first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT. METHODS: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses. RESULTS: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR = 0.93 [95% confidence interval {CI}: 0.89; 0.98], p = 0.005) and PFS (0.80 [0.77; 0.84], p < 0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [-0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR = 0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients

Patients from historically underrepresented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the United States 1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than twelve-thousand consent events at a large Cancer Center and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays translation costs) than for industry sponsored studies (for which this cost is covered by the sponsor). Here, we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient’s primary language in studies without industry sponsorship was approximately half of that seen in industry sponsored studies. Our results suggest that the cost of consent document translation in trials not sponsored by industry is a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

SummaryImmune checkpoint inhibitors have revolutionized the treatment of multiple solid malignancies, but their role in the treatment of neuroendocrine neoplasms (NEN) is unclear. The accompanying article reports on a study combining the programmed cell death (PD-1) inhibitor nivolumab with the alkylating agent temozolomide in patients with advanced NENs.See related article by Owen et al., p. 731

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Background: Although immune checkpoint blockade (ICB) targeting Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) alone or in combination with chemotherapy is now a first-line option for patients with advanced NSCLC, the majority of patients do not benefit from anti-PD-1/PD-L1 monotherapy, and the combination with chemotherapy is often associated with toxicity. For patients who initially respond to PD-1/PD-L1 inhibition, many relapse after an initial response and are in need for innovative strategies to overcome the resistance to ICB. One possible approach is to utilize in situ vaccination with functional chemokine gene-modified antigen presenting cells (APCs) that take advantage of the full repertoire of tumor antigens in the tumor microenvironment (TME) in order to restore tumor antigen presentation, promote tumor infiltration of immune cells driven by chemokine gradient, and facilitate tumor-specific T cell activation, both locally and systemically. The chemokine CCL21 is a therapeutic candidate due to its ability to promote infiltration and co-localization of naïve T cells and antigen-experienced dendritic cells (DCs) and facilitate T cell activation. In preclinical studies as well as a phase I clinical trial, we observed that intratumoral (IT) injection of CCL21-DC induces the infiltration of autologous DC and T cells into the TME, and generates systemic tumor-specific immune responses against multiple tumor antigens. We also observed tumoral PD-L1 upregulation following CCL21-DC injection, which may hinder T cell function. Similarly, the lack of efficacy of PD-1/PD-L1 inhibitors could potentially be combated by enhanced T cell infiltration and augmented APC function in the TME following in situ vaccination with CCL21-DC. Therefore, we are currently evaluating the safety and efficacy of combining IT CCL21-DC and intravenous (IV) pembrolizumab in advanced NSCLC patients following progression on ICB or tyrosine kinase inhibitor (TKI) therapy in a phase I trial (NCT03546361). Methods: Phase I, dose-escalating, multi-cohort trial followed by dose expansion. Maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or EGFR/ALK mutant after progression on TKI. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC when combined with pembrolizumab. Primary objective of dose expansion is objective response rate at MTD. Secondary objectives include adverse event profiling and immune monitoring studies. [B.L. and A.L. contributed equally to this work as first authors.] Citation Format: Bin Liu, Aaron Lisberg, Ramin Salehi-Rad, Jay Lee, Linh M. Tran, Kostyantyn Krysan, Raymond Lim, Camelia Dumitras, Zhe Jing, Michael Oh, Fereidoun Abtin, Robert Suh, Scott Genshaft, Scott Oh, Gregory Fishbein, Ciara M. O'Higgins, Anita Kaul, Kanwarpal Kahlon, Shahryar Ashouri, Jonathan Goldman, David Elashoff, Edward Garon, Steven Dubinett. Phase I trial of in situ vaccination with autologous CCL21 gene-modified dendritic cells (CCL21-DC) combined with pembrolizumab for advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT219.

Rociletinib is a new third generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer. Known side effects include hyperglycemia and QT prolongation. We describe the first case of rociletinib associated macroscopic pseudo-T wave alternans with