Suresh S. Ramalingam

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

Background Osimertinib is an oral, third‐generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) that selectively inhibits both EGFR‐TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR‐TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small‐cell lung cancer (NSCLC). Methods In this double‐blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR‐TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator‐assessed progression‐free survival. Results The median progression‐free survival was significantly longer with osimertinib than with standard EGFR‐TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR‐TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR‐TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR‐TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR‐TKIs (34% vs. 45%). Conclusions Osimertinib showed efficacy superior to that of standard EGFR‐TKIs in the first‐line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature.

Monoclonal antibodies against programmed cell death protein 1 (PD‐1) and programmed death ligand 1 (PD‐L1) are effective therapies in patients with non‐small cell lung cancer (NSCLC). Herein, the authors performed a systematic review investigating differences in the toxicities of PD‐1 and PD‐L1 inhibitors.

Tumor Mutation Burden: Leading Immunotherapy to the Era of Precision Medicine?

Non–small-cell lung cancer (NSCLC) exemplifies precision medicine, with multiple Food and Drug Administration–approved targeted therapies that are based on genomic biomarkers such as EGFR, ALK, ROS1, and BRAF. Recently, immunotherapy became accepted broadly as an effective treatment modality for patients with cancer. However, the ability to select patients who will benefit from immunotherapy remains limited. Tumor mutational burden (TMB) is promising as a predictive biomarker and potentially could lead the way for immuno-oncology to enter the era of precision medicine.

CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation-many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell-like PD-1+ CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.

Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable Stage III Non–Small Cell Lung Cancer: A Phase I Study

Objectives: Stereotactic body radiation therapy (SBRT) is now the standard of care in medically inoperable stage I NSCLC, yielding high rates of local control. It is unknown whether SBRT can be safely utilized in the locally advanced NSCLC setting. This multi‐institution phase I study evaluated the safety of 44 Gy of conventionally fractionated thoracic radiation with concurrent chemotherapy plus dose‐escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary end point of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost. Methods: Inclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor 8 cm or smaller, and N1 or N2 lymph nodes 5 cm or smaller. Tumors were staged with positron emission tomography/computed tomography (CT), and four‐dimensional CT simulation was used for radiation planning. The treatment schema was 44 Gy of thoracic radiation (2 Gy/d) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy had been delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved mediastinal lymph nodes. Consolidation chemotherapy was given at the discretion of the treating medical oncologist. Four SBRT boost dose cohorts were tested: cohort 1 (9 Gy × 2), cohort 2 (10 Gy × 5), cohort 3 (6 Gy × 5), and cohort 4 (7 Gy × 5). Patients were treated in cohorts of three patients, and the Bayesian escalation with overdose control method was used to determine the MTD of the SBRT boost. Dose‐limiting toxicities (DLTs) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment. Results: The study enrolled 19 patients from November 2012 to December 2016. There were four screen failures, and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). DLT developed in one patient in dose cohort 3 (n = 3) and in 2 patients in dose cohort 4 (n = 3). The calculated MTD was 6 Gy × 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients at this dose level. Thus, the calculated MTD was 6 Gy × 5; however, 10 Gy × 2 is thought to be a reasonable dose as well, given that no grade 5 toxicities occurred with that dose. Conclusions: The MTD of a SBRT boost combined with 44 Gy of thoracic chemoradiation was 6 Gy × 5. A SBRT boost dose of 10 Gy × 2 could be considered safer, with no grade 3 or higher toxicities observed at this dose level during the follow‐up period in this study.

Overcoming acquired resistance to AZD9291, a third generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation

Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non–small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo. Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567–79. ©2017 AACR.

Guideline-concordant Care Improves Overall Survival for Locally Advanced Non–Small-cell Lung Carcinoma Patients: A National Cancer Database Analysis

Background Current evidence‐based guideline‐concordant care (GCC) for locally advanced non–small‐cell lung cancer (NSCLC) patients with good performance status is concurrent chemoradiation. In this study we evaluated factors associated with lack of GCC and its effects on overall survival (OS). Patients and Methods Unresectable stage III NSCLC patients, diagnosed from 2005 to 2013 with a Charlson–Deyo score of 0, were identified from the National Cancer Database. Primary outcomes were receipt of GCC, defined as concurrent chemoradiation (thoracic radiotherapy, starting within 2 weeks of chemotherapy, to at least 60 Gy), and OS. Multivariable logistic regression modeling identified variables associated with non‐GCC. Cox proportional hazard modeling was used to examine OS. Results Twenty‐three percent of patients (n = 10,476) received GCC. Uninsured patients were more likely to receive non‐GCC (odds ratio [OR], 1.54; P < .001) compared with privately insured patients. Other groups with greater odds of receiving non‐GCC included: patients treated in the western, southern, or northeastern United States (ORs, 1.39, 1.37, and 1.19, respectively; all Ps < .001) compared with the Midwest; adenocarcinoma histology (OR, 1.48; P < .001) compared with squamous cell carcinoma; and women (OR, 1.08; P = .002). Those who received non‐GCC had higher death rates compared with those who received GCC (hazard ratio [HR], 1.42; P < .001). The uninsured (HR, 1.53; P < .001), patients treated in the western, southern, or northeastern United States (HRs, 1.56, 1.41, and 1.34, respectively; P < .001), adenocarcinomas (HR, 1.39; P < .001), and women (HR, 1.44; P < .001) also all had lower OS for non‐GCC versus GCC. Conclusion Socioeconomic factors, including lack of insurance and geography, are associated with non‐GCC. Patient‐ and disease‐specific factors, including increasing adenocarcinoma histology and sex, are also associated with non‐GCC. Non‐GCC diminishes OS. Micro‐Abstract Several socioeconomic factors, including lack of insurance and geography, and patient‐ and disease‐specific factors, including increasing adenocarcinoma histology and sex, are associated with receipt of non–guideline‐concordant care. Non–guideline‐concordant care is associated with poorer survival outcomes.

HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium

Human epidermal growth factor receptor 2 (HER2) mutations have been reported in lung adenocarcinomas. Herein, the authors describe the prevalence, clinical features, and outcomes associated with HER2 mutations in 1007 patients in the Lung Cancer Mutation Consortium (LCMC).

Health Care Disparities Among Octogenarians and Nonagenarians With Stage III Lung Cancer

To the authors knowledge, the practice patterns for patients aged more than 80 years with stage III non–small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB).

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle–regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ. Mcl-1 also promoted DNA resection mediated by the Mre11 complex and HR-dependent DSB repair. Using the Mcl-1 BH1 domain as a docking site, we identified a small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1–stimulated HR DNA repair, leading to sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcomes.