Dwight Owen

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O 6 -methylguanine DNA methyltransferase as a biomarker for response

Recent advances in the treatment of neuroendocrine tumors (NET), including the combination regimen of capecitabine and temozolomide (CAPTEM), have mostly focused on grade 1 and 2 pancreatic neuroendocrine tumors (pNET). We undertook a retrospective review of 38 patients with advanced NET treated with CAPTEM, including patients with non-pancreatic tumors as well as grade 2 and 3 tumors. O6-methylguanine DNA methyltransferase (MGMT) expression was assessed as a predictive biomarker. We found that CAPTEM demonstrated activity in patients with all grades and in pNET and non-pNET. Median progression free survival (mPFS) was 13.0 months (95% CI: 5.6-17.0) and median overall survival (mOS) 29.3 months (95% CI 17.7 - 45.3). Among evaluable patients, there were 11 (38%) partial responses, 15 (52%) stable disease, and 3 (10%) progressive disease for a disease control rate of 90%. A higher rate of partial responses occurred in patients whose tumors had low levels of MGMT expression (63%) compared to intermediate-high (17%) (p=0.19). Our results show that CAPTEM therapy is active in patients with NET including in previously treated patients and in those with poorly-differentiated histology. We observed a trend towards increased response rate, median PFS, and median OS in patients whose tumors had low MGMT protein expression.

Immunotherapy in surgically resectable non-small cell lung cancer

Surgical resection is the mainstay of therapy for patients with resectable and operable early stage non-small cell lung cancer (NSCLC). Surgery alone yields an unacceptably high rate of lung cancer recurrence. The addition of chemotherapy to surgery as adjuvant or neoadjuvant treatment can improve survival rates by roughly 5% at 5 years. Recently, major advances in cancer immunotherapy have led to better outcomes for many patients with lung cancer. Monoclonal antibodies to programmed death 1 and its ligand are now approved for both first and second line treatment patients with metastatic lung cancer. In this review, we will outline the rationale and current research strategies investigating the role of immunotherapy in resectable NSCLC.

Frequency, Morbidity, and Mortality of Bone Metastases in Advanced Hepatocellular Carcinoma

Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%-9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52-2.97; P<.01) in the multivariable model. Conclusions: Patients with AJCC stage IV HCC and bone metastases that are clinically evident on routine radiography or on clinical examination at presentation are apt to develop frequent, morbid, and mortal SREs, whereas those without evident bone metastasis at presentation are unlikely to develop these complications.

Brief Report: Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients with RET-Rearranged Lung Cancers

Introduction: In ret proto‐oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods: A global, multi‐institutional registry (cohort A, n = 114) and a bi‐institutional data set (cohort B, n = 71) of RET‐rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET‐, ROS1‐, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression‐free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression‐free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions: Brain metastases occur frequently in RET‐rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET‐directed targeted therapy strategies are needed.

Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon

Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAFV600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAFV600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.

New treatment options and challenges for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer with brain metastases

Up to a third of patients with non-small cell lung cancer (NSCLC) may develop brain metastases, typically portending a poor prognosis (1). Data suggest that median overall survival (OS) for patients who develop brain metastases after diagnosis is 10 months, and even shorter for patients who present with brain metastases at time of diagnosis (as low as 5 months) (2).

Abstract 3116: MGMT immunohistochemistry (IHC) as a biomarker for response to combination therapy with capecitabine and temozolomide (C/T) in patients (pts) with advanced neuroendocrine carcinomas (aNEC):

Introduction: Tumor O6-methylguanine-methyltransferase (MGMT) reverses temozolomide-induced DNA injury, and low MGMT tumor expression has been shown as a predictor of response to temozolomide in glioblastoma. C/T therapy induces partial responses in up to 70% of pts with grade 1-2 pancreatic NEC but the role of MGMT expression as a predictor is unclear. We evaluated MGMT expression by IHC as a prognostic and predictive biomarker for pts with aNEC of all grades and primary sites treated with C/T. Methods: A retrospective review was carried out at Ohio State University of 29 pts with aNEC who received C/T therapy from 2009 to 2013 and who were evaluable for RECIST response. MGMT expression was assessed when available by IHC on pre-treatment tumor samples to test the hypothesis that low MGMT expression ( Results: Of 29 pts, primary NEC site was pancreas in 18 pts, and non-pancreas in 11 pts. Objective response, progression-free survival (PFS) and overall survival (OS) data are outlined in the Table. Partial response (PR) rate was 50% in pts with pancreas primary vs 18% for non-pancreas primary. High PRs were observed in pts with grade 3 NEC (57%). Median PFS in the MGMT-low group was 16.6 months vs 9.5 months in the MGMT-high group (p = 0.19). Median OS in the MGMT low group was 42.9 months vs 18.1 months in the MGMT-high group (p = 0.16). There was a trend toward higher rate of PR (63%) in pts whose tumors had low levels of MGMT expression compared to those with high levels (17%) (p = 0.18). Conclusion: We observed a trend towards increased PR, median PFS, and median OS in aNEC pts whose tumors had low MGMT protein expression by IHC. The small sample size likely limited the statistical significance of the data. Results of this trial serve as strong rationale for future prospective trials to clarify role of MGMT expression in choosing C/T therapy for pts with NEC. Citation Format: Dwight Owen, Andrew J. Alexander, Lai Wei, Jessica Hemminger, Manisha H. Shah. MGMT immunohistochemistry (IHC) as a biomarker for response to combination therapy with capecitabine and temozolomide (C/T) in patients (pts) with advanced neuroendocrine carcinomas (aNEC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3116.