Sukhmani K. Padda

Diffuse High Intensity PD–L1 Staining in Thymic Epithelial Tumors

Introduction: Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA). Methods: The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1high and the remaining as PD-L1low. Results: PD-L1high scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1high TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13–25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94–9.24; p = 0.064). Conclusions: PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394-403. ©2017 AACR.See related commentary by Comino-Mendez and Turner, p. 1368This article is highlighted in the In This Issue feature, p. 1355.

Early-Stage Non-Small Cell Lung Cancer: Surgery, Stereotactic Radiosurgery, and Individualized Adjuvant Therapy

Despite cures in early stage (IA-IIB) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 36%-73%. Surgical resection via lobectomy is the treatment of choice in early-stage NSCLC, with the goal being complete anatomic resection of the tumor and mediastinal lymph node evaluation. Newer technologies, including the minimally invasive thoracoscopic approach and the many techniques available to stage the mediastinum, have introduced advantages over traditional approaches in achieving this goal. The advent of stereotactic ablative radiotherapy (SABR) has changed how we treat those patients who cannot undergo surgery secondary to comorbidities or patient preference. SABR allows for precise radiation delivery in a short course and at high doses. Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected high-risk stage IB and stage II NSCLC based on a ~5% improvement in 5-year overall survival. The concept of customized adjuvant chemotherapy is emerging, and we will explore the potential value of targeting tumor mutations with available drugs (ie, epidermal growth factor receptor [EGFR] mutations with erlotinib), a strategy that for the moment should be restricted to clinical trials.

A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non–Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements

c-ros oncogene 1 (ROS1), an orphan receptor tyrosine kinase, is a recently defined molecular subset of lung cancer identified in approximately 1% to 2% of screened patients.1,2 Like anaplastic lymphoma receptor tyrosine kinase (ALK) translocations, ROS1 rearrangements lead to constitutive kinase activation and commonly arise in young nonsmokers with adenocarcinoma tumor histology.3 Crizotinib (Pfizer), recently approved by the US Food and Drug Administration for treatment of metastatic non–small-cell lung cancer (NSCLC) patients with ALK rearranged tumors, has potent activity in cell lines with ROS1 translocations and recently demonstrated clinical activity in patients whose tumors harbor ROS1 rearrangements.3,4 Because of the recently discovered importance of ROS1 trans-locations in a small subset of NSCLC, we know little regarding the response to specific chemotherapeutics in patients whose tumors harbor these molecular alterations. Pemetrexed (Lilly) inhibits thymidylate synthase (TS) and other folate-dependent enzymes, and is a chemotherapeutic agent commonly used to treat nonsquamous NSCLC.5 Our institution conducted a retrospective case series of all meta-static lung cancer patients with ROS1 rearrangements. We recently began testing for ROS1 gene rearrangements using break-apart fluorescence in situ hybridization (FISH) in patients with lung adenocarcinoma and no other known mutations. A total of 129 ROS1 assays using FISH have been completed at Stanford with 5 ROS1 rearrangements identified; 1 additional patient treated at Stanford tested positive using FISH at an outside institution. Four of the 6 patients with detectable ROS1 rearrangements have metastatic cancer; and all 4 patients have a strikingly long progression-free survival (PFS) using pemetrexed—given as either single-agent second-line treatment or as part of front-line chemotherapy (Table 1). Table 1 Summary of ROS1 Cases Case 1 The patient is a 35-year-old never smoking woman who presented with dyspnea. Imaging revealed confluent pulmonary nodules in the left lung with a fluorine-18 fluorodeoxyglucose-avid pleural effusion. Mediastinoscopy showed N3 disease with right-sided mediastinal nodes positive for lung adenocarcinoma. The patient received 6 cycles of carboplatin, pemetrexed, and bevacizumab with a partial response followed by continuation maintenance with pemetrexed and bevacizumab for 21 cycles (Figure 1). During maintenance treatment, FISH was performed and revealed a ROS1 rearrangement. Bevacizumab was eventually discontinued because of nonspecific neurologic complaints. She continues on pemetrexed alone as maintenance therapy for > 14 cycles with minimal disease burden. Total time using pemetrexed is now > 36 months. Figure 1 Computed Tomography Scan of a NSCLC Patient With a ROS1 Gene Rearrangement Before Treatment (Left) and More Than 26 Months Later (Right) During Pemetrexed Continuation Maintenance Case 2 The patient is a 64-year-old man with a distant light smoking history who presented with a palpable left supraclavicular lymph node. Biopsy of this node revealed lung adenocarcinoma. The patients NSCLC was initially stage IIIB and he was treated with concurrent chemoradiation with carboplatin and paclitaxel. He developed biopsy-proven recurrence of disease 1 year later with multiple bilateral pulmonary nodules. He then received 6 cycles of carboplatin, pemetrexed, and bevacizumab with a partial response, followed by continuation maintenance pemetrexed and bevacizumab for 37 cycles. During maintenance treatment, a ROS1 rearrangement was detected by FISH. Proteinuria eventually led to discontinuation of bevacizumab. He continues taking pemetrexed alone as maintenance therapy for additional > 19 cycles. Total time taking pemetrexed is now > 47 months.

A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer

Background: Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab. Methods: Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m2 on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity. Results: From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1–42) with 37 patients (78.7%) completing ≥4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8–7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0–16.5). The OS is 57% at 1 year and 10% at 2 years. Conclusions: Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

MET inhibitors in combination with other therapies in non-small cell lung cancer

MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.

Pemetrexed in patients with thymic malignancies previously treated with chemotherapy

PURPOSE Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies. METHODS Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis. RESULTS A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months). CONCLUSIONS This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases.

Complications of Ablative Therapies in Lung Cancer

Two cases of complications secondary to the use of microwave ablation (MWA) in non-small-cell lung cancer (NSCLC) are discussed herein. The first case involves a 62-year-old man with stage IB NSCLC who declined surgery and pursued MWA. Within 7 months, he had residual disease at the MWA treatment site, and surgery was performed. The patient was found to have pleural and chest wall involvement, making complete resection impossible. The second case involves an 86-year-old woman with a second local recurrence of NSCLC and previous treatment including surgery and chemoradiation therapy. She was initially a surgical candidate but declined surgery and pursued MWA. Within 6 months, she had residual disease at the MWA treatment site. A second MWA was performed, and she developed a large cavitary abscess at the MWA site and had subsequent clinical decline. Less invasive ablation therapies and stereotactic radiosurgery are being developed for patients with inoperable lung cancer. Because these modalities have recently been developed, trials that clearly show efficacy and survival benefit are yet to be completed. Ablation procedures can result in complications, including residual disease and cavitary lesions susceptible to infection. These cases highlight the caution that should still be observed when recommending lung ablation strategies and the importance of selecting appropriate patients.

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction

INTRODUCTION Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer. METHODS Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib+300 mg dovitinib) and cohort -1 (150 mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure. RESULTS Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698 ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration. CONCLUSIONS This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry

Introduction: Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short‐term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database. Methods: The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi‐square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed. Results: A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity‐matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection. Conclusions: The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.