Keith D. Eaton

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

BACKGROUND Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the hosts immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non-Small-Cell Lung Cancer

PURPOSE Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have had a significant impact on non-small-cell lung cancer (NSCLC) outcomes, particularly for patients with EGFR mutations. Resistance emerges after 9 to 12 months, primarily mediated by the T790M resistance mutation. We studied neratinib, an irreversible pan-ErbB TKI that may overcome T790M. PATIENTS AND METHODS Patients with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with > or = 12 weeks of prior TKI therapy were placed in arm A if they were EGFR mutation positive or arm B if they were wild-type. Arm C included TKI-naïve patients with adenocarcinoma and light smoking histories (< or = 20 pack-years). All patients received daily oral neratinib, initially at 320 mg but subsequently reduced to 240 mg because of excessive diarrhea. The primary end point was objective response rate (RR). RESULTS One-hundred sixty-seven patients were treated: 91 in arm A, 48 in arm B, and 28 in arm C. Diarrhea was the most common toxicity; grade 3 incidence was 50% at 320 mg but improved to 25% after dose reduction. The RR was 3% in arm A and zero in arms B and C. No patients with known T790M responded. Notably, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks. CONCLUSION Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.

Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation.

Purpose: We conducted a phase II study to assess the efficacy of continuous dosing of sunitinib in patients with flurodeoxyglucose positron emission tomography (FDG-PET)–avid, iodine-refractory well-differentiated thyroid carcinoma (WDTC) and medullary thyroid cancer (MTC) and to assess for early response per FDG-PET. Experimental Design: Patients had metastatic, iodine-refractory WDTC or MTC with FDG-PET–avid disease. Sunitinib was administered at 37.5 mg daily on a continuous basis. The primary end point was response rate per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included toxicity, overall survival, and time to progression. We conducted an exploratory analysis of FDG-PET response after 7 days of treatment. Results: Thirty-five patients were enrolled (7 MTC, 28 WDTC), and 33 patients were evaluable for disease response. The primary end point, objective response rate per RECIST, was 11 patients (31%; 95% confidence interval, 16-47%). There were 1 complete response (3%), 10 partial responses (28%), and 16 patients (46%) with stable disease. Progressive disease was seen in 6 patients (17%). The median time to progression was 12.8 months (95% confidence interval, 8.9 months-not reached). Repeat FDG-PET was done on 22 patients. The median percent change in average standardized uptake values was −11.7%, −13.9%, and 8.6% for patients with RECIST response, stable disease, and progressive disease, respectively. Differences between response categories were statistically significant (P = 0.03). The most common toxicities seen included fatigue (11%), neutropenia (34%), hand/foot syndrome (17%), diarrhea (17%), and leukopenia (31%). One patient on anticoagulation died of gastrointestinal bleeding. Conclusion: Continuous administration of sunitinib was effective in patients with iodine-refractory WDTC and MTC. Further study is warranted. Clin Cancer Res; 16(21); 5260–8. ©2010 AACR.

Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens

Recent years have seen development and implementation of anticancer therapies targeted to particular gene mutations, but methods to assay clinical cancer specimens in a comprehensive way for the critical mutations remain underdeveloped. We have developed UW-OncoPlex, a clinical molecular diagnostic assay to provide simultaneous deep-sequencing information, based on >500× average coverage, for all classes of mutations in 194 clinically relevant genes. To validate UW-OncoPlex, we tested 98 previously characterized clinical tumor specimens from 10 different cancer types, including 41 formalin-fixed paraffin-embedded tissue samples. Mixing studies indicated reliable mutation detection in samples with ≥ 10% tumor cells. In clinical samples with ≥ 10% tumor cells, UW-OncoPlex correctly identified 129 of 130 known mutations [sensitivity 99.2%, (95% CI, 95.8%-99.9%)], including single nucleotide variants, small insertions and deletions, internal tandem duplications, gene copy number gains and amplifications, gene copy losses, chromosomal gains and losses, and actionable genomic rearrangements, including ALK-EML4, ROS1, PML-RARA, and BCR-ABL. In the same samples, the assay also identified actionable point mutations in genes not previously analyzed and novel gene rearrangements of MLL and GRIK4 in melanoma, and of ASXL1, PIK3R1, and SGCZ in acute myeloid leukemia. To best guide existing and emerging treatment regimens and facilitate integration of genomic testing with patient care, we developed a framework for data analysis, decision support, and reporting clinically actionable results.

Plasma Processing Conditions Substantially Influence Circulating microRNA Biomarker Levels

Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4–30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

Salvage Lung Resection After Definitive Radiation (>59 Gy) for Non-Small Cell Lung Cancer: Surgical and Oncologic Outcomes

BACKGROUND Isolated local relapse occurs in 24% to 35% of patients after definitive chemoradiation for locally advanced non-small cell lung cancer. Although originally considered inoperable, select patients are referred for surgical salvage. We describe a series of salvage lung resection after curative-intent radiation. METHODS Twenty-four consecutive patients from 1997 to 2005 were identified retrospectively. Medical records reviewed. Patients were grouped by surgical indication: A, obvious relapse by computed tomography (CT), 7 patients; B, abnormal fluorodeoxyglucose-positron emission tomography (FDG-PET), 12; C, delayed conversion to trimodality, 4; and D, chronic bronchopleural fistula, 1. RESULTS All patients received definitive radiation (median, 63.9 Gray), 22 with concurrent chemotherapy. Original staging included cardiothoracic surgical consultation in 4. Median time from radiation to resection was 21 weeks. Twenty-four patients underwent 25 resections: one wedge, 10 lobectomies, 4 bilobectomies, and 10 pneumonectomies. Nineteen flaps were performed, 16 omental. Fourteen had complications, including one death from adult respiratory distress syndrome. Viable tumor was found in 19 patients. Median overall survival was 30 months (12 months, group A; 43 months, group B). Estimated 3-year survival was 47%. The Kaplan-Meier survival curve for group B was superior to that for group A (p = 0.019). CONCLUSIONS Salvage lung resection after definitive chemoradiation is feasible, with encouraging survival. Surgical indication is predictive, with higher survival among patients undergoing resection for abnormal FDG-PET than for obvious relapse by CT. FDG-PET should be studied prospectively in selecting patients for salvage lung resection. Systematic staging may have increased primary incorporation of surgery, minimizing the need for late salvage.

Antagonism of platelet-derived growth factor receptor in non small cell lung cancer: rationale and investigations.

Molecules that target growth and survival pathways in cancer cells have revolutionized the treatment of cancer. Imatinib mesylate is one such agent inhibiting the tyrosine kinase that results from the Bcr-Abl translocation. Imatinib is also a potent inhibitor of the platelet-derived growth factor receptor. The platelet-derived growth factor receptor is crucial in the regulation of interstitial fluid pressure, as well as in the function of pericytes. Increased interstitial fluid pressure is a common feature of solid tumors and is thought to impede transcapillary transport of chemotherapy. Preclinical data show that platelet-derived growth factor receptor antagonism decreases interstitial fluid pressure, augments intratumoral concentration of chemotherapy, and impairs tumor growth. Pericytes are important cells in the vascular support structure of tumors regulating endothelial cell survival and directing capillary growth. Preclinical data suggest that dual targeting of pericytes and endothelial cells is a more effective antiangiogenic strategy than antiendothelial monotherapy. Two phase II studies in advanced non–small cell lung cancer are currently under way with imatinib. The first trial evaluates the use of intermittent imatinib and weekly paclitaxel in elderly patients. The second trial evaluates a novel maintenance strategy of imatinib and the antivascular endothelial growth factor antibody bevacizumab after first-line chemotherapy with bevacizumab. These trials should indicate whether encouraging preclinical data can be translated into clinical benefit in non–small cell lung cancer.

Intradural intramedullary spinal cord metastasis due to mesothelioma

To report the occurrence of intramedullary spinal cord metastases in a patient with a mesothelioma. A case report. Setting: University medical center. A 67-year old man with mesothelioma developed paraparesis 6-months after diagnostic thoracotomy. MR spine imaging revealed an intramedullary spinal cord metastases. Cyberknife radiotherapy. Intramedullary spinal cord metastases, although rare, is increasingly recognized with spinal cord MRI. Treatment remains unsatisfactory as treatment with surgery or irradiation is only partially effective.

Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy

Lung cancer is the leading cause of cancer death in U.S. and represents a major public health burden. Epidemiologic data have suggested that lung cancer in women may possess different biological characteristics compared to men, as evidenced by a higher proportion of never-smokers among women with lung cancer. Emerging data indicate that female hormones such as estrogen and progesterone play a significant role in lung carcinogenesis. It has been reported that estrogen and progesterone receptors are expressed in lung cancer cell lines as well as in patient-derived tumors. Hormone related risk factors such as hormone replacement therapy have been implicated in lung carcinogenesis and several preclinical studies show activity of anti-estrogen therapy in lung cancer. In this review, we summarize the emerging evidence for the role of reproductive hormones in lung cancer and implications for lung cancer therapy.