Breast Cancer Treatment: To tARget or Not? That Is the Question.

To assess AR's role in TNBC treatment, various existing and completed clinical trials targeting AR or co-targeting AR with other pertinent signaling molecules were analyzed. Cyclin-dependent kinase 4/6 (CDK4/6), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17 lyase), and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were some of the most prevalent biomarkers used in combination therapy with AR inhibitors in these trials. Studying how AR functions in tandem with these molecules can have increasing breakthroughs in the treatment options for TNBC. Previous studies have been largely unsuccessful in utilizing AR as the sole drug target for systemic targeted treatment in TNBC. However, there is a lack of other commonly used drug target biomarkers in the treatment of this disease, as well. Thus, analyzing the clinical benefit rate (CBR) within clinical trials that use combination therapy can prove to be imperative to the progression of improving treatment options and prognoses.

Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data.

BACKGROUND: Adjuvant chemotherapy (AC) is indicated for stage II and stage III lung adenocarcinomas (ADC). Using the LACE Bio II database, we analyzed the distribution of various mutations across the subtypes of ADCs and studied the prognostic and predictive roles of PD-L1, TMB, and Tumor Infiltrating Lymphocytes (TILs). MATERIALS AND METHODS: Clinical and genomic data from the LACE Bio II data were extracted. Patients were divided into ADC subtypes, in which the grouping was done based on their known clinical behavior (Lepidic [LEP], Acinar/Papillary [ACI or PAP], Micropapillary/Solid [MIP or SOL], Mucinous [MUC] and Others). Kaplan-Meier (KM) and log-rank test were used to compare survival based on PD-L1, TMB, TILs and combinations of TMB with PD-L1 and TILs. Adjusted Hazard Ratios (HR) were analyzed with Overall Survival (OS), Disease-Free Survival (DFS) and Lung Cancer-Specific Survival (LCSS) as endpoints. RESULTS: A total of 375 ADC patients were identified. MIP/SOL was the subtype most commonly positive for various biomarkers. PD-L1 Negative/high TMB was associated with better outcomes in terms of OS (HR = 0.46 [0.23-0.89], P = .021) and DFS (HR = 0.52 [0.30-0.90], P = .02), relative to PD-L1 Negative/low TMB. High TMB predicted worse outcome with AC use in terms of OS (ratio of hazard ratio rHR = 2.75 [1.07-7.04], P = .035). Marked TILs had better outcome with AC for DFS (rHR = 0.22 [0.06-0.87], P = .031 and LCSS (rHR = 0.08 [0.01-0.66], P = .019) respectively. There was also a beneficial effect of AC among patients with Marked TILs/low TMB in terms of DFS (rHR = 0.06 [0.01-0.53], P = .011). CONCLUSION: High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy.

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.

Introduction: KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA. Methods: Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed. Results and discussion: Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

Metabolic syndrome is independently associated with improved overall survival to first-line therapy with immune checkpoint inhibitors in non-small cell lung cancer.

Background: Many co-existing medical conditions may affect the outcome in patients treated with immune checkpoint inhibitors for advanced cancer. There is currently not any information on whether metabolic syndrome (MetS) impacts the clinical outcome in patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell line cancer (NSCLC). Methods: We carried out a single-center retrospective cohort study to determine the effects of MetS on first-line ICI therapy in patients with NSCLC. Results: One hundred and eighteen consecutive adult patients who received first-line therapy with ICIs and had adequate medical record information for the determination of MetS status and clinical outcomes were included in the study. Twenty-one patients had MetS and 97 did not. There was no significant difference between the two groups in age, gender, smoking history, ECOG performance status, tumor histologic types, pre-therapy use of broad-spectrum antimicrobials, PD-L1 expression, pre-treatment neutrophil:lymphocyte ratio, or proportions of patients who received ICI monotherapy or chemoimmunotherapy. With a median follow-up of 9 months (range 0.5-67), MetS patients enjoyed significantly longer overall survival (HR 0.54, 95% CI: 0.31-0.92) (p = 0.02) but not progression-free survival. The improved outcome was only observed in patients who received ICI monotherapy and not chemoimmunotherapy. MetS predicted for higher probability of survival at 6 months (p = 0.043) and 12 months (p = 0.008). Multivariate analysis indicated that, in addition to the known adverse effects of use of broad-spectrum antimicrobials and the beneficial effects of PD-L1 (Programmed cell death-ligand 1) expression, MetS was independently associated with improved overall survival but not progression-free survival. Conclusions: Our results suggest that MetS is an independent predictor of treatment outcome in patients who received first-line ICI monotherapy for NSCLC.

Genomic landscape of non-small-cell lung cancer with methylthioadenosine phosphorylase (MTAP) deficiency.

INTRODUCTION: New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP). METHODS: Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay). RESULTS: 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD-L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups. CONCLUSIONS: MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

Single Cell RNA Sequencing: A New Frontier in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma is a malignancy with a high mortality rate. It exhibits significant heterogeneity in metabolic pathways which are associated with its progression. In this review, we discuss the role of single cell RNA sequencing in unraveling the metabolic and clinical features of these highly malignant tumors.

The Lung Microbiota and Lung Cancer: A Growing Relationship.

The lung is home to a dynamic microbial population crucial to modulating immune balance. Interest in the role of the lung microbiota in disease pathogenesis and treatment has exponentially increased. In lung cancer, early studies suggested an important role of dysbiosis in tumor initiation and progression. These results have helped accelerate research into the lung microbiota as a potential diagnostic marker and therapeutic target. Microbiota signatures could represent diagnostic biomarkers of early-stage disease. Lung microbiota research is in its infancy with a limited number of studies and only single-center studies with a significant methodological variation. Large, multicenter longitudinal studies are needed to establish the clinical potential of this exciting field.

Radioimmunoconjugates in the age of modern immuno-oncology.

Immunotherapy was first investigated as a therapeutic option for treating cancer more than a century ago. During this period, it has gone through numerous disappointments when the successes obtained in the laboratory were not matched clinically. However, recent advances in immuno-oncology have provided the impetus to revisit this therapeutic option. Unlike previous efforts, modern immunotherapy is now a realistic and formidable therapeutic option for patients with relapsed/refractory malignancies. Unfortunately, most of the successes obtained thus far have primarily been in patients with hematologic malignancies. While the results of immunotherapy with immune check-point inhibitors for solid tumors such as non-small cell lung cancer and melanoma are encouraging, more effective treatment methods are desirable. Many intrinsic and extrinsic factors pose as obstacles to successful immunotherapy of solid tumors. They include heterogeneity of tumor antigens, limitation in the trafficking and accessibility of the effector mechanisms to the tumor sites, the adverse anti-inflammatory tumor microenvironment, and the on-target off tumor and off-target off-tumor effects of some of these approaches. In this review, we will discuss these obstacles and examine the evidence that support the notion that radioimmunotherapy, using radioimmunoconjugates, may be the answer to overcome these obstacles in patients with metastatic cancer. Finally, we will discuss how the efficacy of radioimmunotherapy using radioimmunoconjugates might further be harnessed to maximize successes in these patients.

Systemic Cancer Therapy Does Not Significantly Impact Early Vaccine-Elicited SARS-CoV-2 Immunity in Patients with Solid Tumors.

mRNA vaccines have been shown to be safe and effective in individuals with cancer. It is unclear, however, if systemic anti-cancer therapy impacts the coordinated cellular and humoral immune responses elicited by SARS-CoV-2 mRNA vaccines. To fill this knowledge gap, we assessed SARS-CoV-2 mRNA vaccine-elicited immunity in a cohort of patients with advanced solid tumors either under observation or receiving systemic anti-cancer therapy. This analysis revealed that SARS-CoV-2 mRNA vaccine-elicited cellular and humoral immunity was not significantly different in individuals with cancer receiving systemic anti-cancer therapy relative to individuals under observation. Furthermore, even though some patients exhibited suboptimal antibody titers after vaccination, SARS-CoV-2 specific cellular immune responses were still detected. These data suggest that antibody titers offer an incomplete picture of vaccine-elicited SARS-CoV-2 immunity in cancer patients undergoing active systemic anti-cancer therapy, and that vaccine-elicited cellular immunity exists even in the absence of significant quantities of SARS-CoV-2 specific antibodies.

Asymptomatic Tumor Thrombus in the Left Atrium from Squamous Cell Carcinoma.

A 67-year-old female patient presented asymptomatically for further evaluation of a chest mass. Other than significant smoking history, the patient had been healthy with a recently treated case of uncomplicated pneumonia. The mass originated in the aortopulmonary window of the left mediastinum and invaded proximally into the left superior pulmonary vein and subsequently into the left atrium. The mass protrusion into the mitral valve occupied 50% of the left atrium space but showed no clinical symptoms of a valvular blockade. Poorly differentiated squamous cell carcinoma was identified upon biopsy. These findings of a primary lung tumor with atrial extension in an asymptomatic patient point to the importance of age-appropriate screening and standardization treatment modalities.

Alliance Foundation Trial 09: A Randomized, Multicenter, Phase 2 Trial Evaluating Two Sequences of Pembrolizumab and Standard Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a "pick a winner" design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68-1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63-1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted.

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer patients.

BACKGROUND: In the current analysis, we characterize the prognostic significance of KRAS mutations with concomitant copy number aberrations (CNA) in early stage non-small cell lung cancer (NSCLC), and evaluate the ability to predict survival benefit from adjuvant chemotherapy. METHODS: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; KRAS status was defined as wild type (WT) or mutant (MUT). The following groups were compared in all patients and the adenocarcinoma subgroup, and were correlated to survival endpoints using a Cox proportional hazards model: WT + Neut/Loss (reference), WT + Gain, MUT + Gain and MUT + Neut/Loss. A treatment-by-variable interaction was added to evaluate predictive effect. RESULTS: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in KRAS MUT + Gain patients relative to KRAS WT + Neut/Loss patients. A negative prognostic effect of KRAS MUT + Neut/Loss was observed for LCSS (HR =1.32; 95% CI, 1.01-1.71, P=0.038) relative to KRAS WT + Neut/Loss on univariable analysis, but to a lesser extent after adjusting for covariates (HR =1.28; 95% CI, 0.97-1.68, P=0.078). KRAS MUT + Gain was associated with a greater beneficial effect of chemotherapy on DFS compared to KRAS WT + Neut/Loss patients (rHR =0.33; 95% CI, 0.11-0.99, P=0.048), with a non-significant trend also seen for LCSS (rHR =0.41; 95% CI, 0.13-1.33, P=0.138) and OS (rHR =0.40; 95% CI, 0.13-1.26, P=0.116) in the adenocarcinoma subgroup. CONCLUSIONS: A small prognostic effect of KRAS mutation was identified for LCSS, and a trend towards worse LCSS, DFS and OS was noted for KRAS MUT + Gain. A potential predictive effect of concomitant KRAS mutation and copy number gain was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require validation.

Smoking Behavior in Patients With Early-Stage NSCLC: A Report From ECOG-ACRIN 1505 Trial.

INTRODUCTION: Smoking cessation has been reported to benefit patients even after a diagnosis of lung cancer. We studied the smoking behavior of patients who participated in a phase 3 trial of adjuvant therapy following resection of stages IB-IIIA NSCLC. METHODS: The ECOG-ACRIN 1505 was conducted to determine whether the addition of bevacizumab to adjuvant chemotherapy would improve overall survival (OS) for patients with early-stage NSCLC. Studying the association between smoking status and OS was a secondary end point. Patients completed a questionnaire on their smoking habits at baseline, 3, 6, 9, and 12 months. RESULTS: A total of 1501 patients were enrolled, and 99.8%, 95%, 94%, 93%, and 93% responded to the questionnaire at baseline, 3, 6, 9, and 12 months, respectively. A total of 90% reported a current or previous history of cigarette smoking. In addition, 60% of nonsmokers at enrollment reported smoking after diagnosis (before randomization); however, 1% of them reported smoking at 12 months. Furthermore, 94% of the respondents smoked none/fewer cigarettes daily at 12 months. The incidence of grades 3-5 toxicity on treatment was 68%, 76%, and 72% in never, former, and current smokers, respectively (p = 0.05). The disease-free survival for never-smokers relative to current and former smokers was (hazard ratio [HR] 0.93, p = 0.64 and HR 1.05, p = 0.72), and OS was (adjusted HR for death 0.54, p = 0.005 and adjusted HR for death 0.68, p = 0.03), respectively. CONCLUSIONS: This is the first comprehensive, prospective report of smoking habits in patients with NSCLC patients from a phase III early-stage trial. There was a high rate of smoking reduction and cessation following study entry. The disease-free survival did not differ significantly between smokers and never smokers, though there were less grade 3-5 toxicities and more favorable OS in never-smokers.

Use of Immunotherapy in Extensive-Stage Small Cell Lung Cancer.

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60-80%, the prognosis is poor, with overall survival of 10-12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6-12% in chemorefractory disease and 15-37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.

Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. OBJECTIVE: To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. INTERVENTIONS: Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). RESULTS: Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. CONCLUSIONS AND RELEVANCE: Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01532089.

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer.

BACKGROUND: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection. MATERIALS AND METHODS: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested. RESULTS: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and ß-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches. CONCLUSIONS: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.

Tumor Mutation Burden as a Biomarker in Resected Non-Small-Cell Lung Cancer.

PURPOSE: The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non-small-cell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). METHODS: A total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens were sequenced using a targeted panel of 1,538 genes. Stringent filtering criteria were applied to exclude germline variants and artifacts related to formalin fixation. Disease-free survival, overall survival, and lung cancer-specific survival (LCSS) were assessed in Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage. RESULTS: Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. High nonsynonymous TMB (> 8 mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in patients with low nonsynonymous TMBs (≤ 4 mutations/Mb). Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was neither prognostic nor predictive. Statistically significant effect of mutations in individual genes was difficult to determine due to high false-discovery rates. CONCLUSION: High nonsynonymous TMB was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on LCSS was more pronounced in patients with low nonsynonymous TMBs. Studies are warranted to confirm these findings.

Overview of the LUX-Lung clinical trial program of afatinib for non-small cell lung cancer.

Tyrosine kinase inhibitors (TKIs) have emerged as first-line treatment for the management of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib were the initial TKIs to be approved for lung cancer and showed improved response rates compared with chemotherapy. Afatinib is an irreversible ErbB family blocker that has also been shown to be active in EGFR-mutated NSCLC. Afatinib has been tested as first-line treatment of advanced NSCLC in the LUX-Lung trial program, as well as in the second- and third-line settings. In this article, we will review the data from the 8 reported LUX-Lung trials.