Patrick M. Forde

HLA-Haploidentical Donor Lymphocyte Infusions for Patients with Relapsed Hematologic Malignancies after Related HLA-Haploidentical Bone Marrow Transplantation

Treatment of relapse after related HLA-haploidentical T cell-replete bone marrow transplantation (haploBMT) with post-transplantation cyclophosphamide (PTCy) using haploidentical donor lymphocyte infusion (haploDLI) is not documented. All patients who received haploDLI after haploBMT with PTCy between June 2003 and October 2012 were identified and assessed for graft-versus-host disease (GVHD) and outcomes. Forty patients received 52 haploDLI doses. Sixteen patients had acute myeloid leukemia, 11 had lymphomas, and 34 had nonmyeloablative conditioning before haploBMT. The median time from haploBMT to relapse was 183 (range, 0 to 1399) days. The median age at haploDLI was 48 (range, 3 to 70) years. The first haploDLI doses were 1 × 10(5) CD3(+) cells/kg with subsequent escalation. The most commonly used first haploDLI dose was 1 × 10(6) CD3(+) cells/kg. The median follow-up after haploDLI was 7 (mean, 15.4; range, .5 to 96) months for the entire cohort, and 17.5 (mean, 28; range, 2.4 to 96) months for the responders. Acute GVHD developed in 10 patients (25%), 6 patients had grade 3 to 4, and 3 developed chronic GVHD. Twelve (30%) patients achieved a complete response (CR) with a median duration of 11.8 (mean, 22.5; range, .4 to 94) months. At last follow-up, 8 responders were alive in CR; 6 for over a year. HaploDLI for relapse after haploBMT is associated with acceptable toxicities and can result in durable responses.

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

BACKGROUND Antibodies that block programmed death 1 (PD‐1) protein improve survival in patients with advanced non–small‐cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD‐1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD‐L1), mutational burden, and mutation‐associated, neoantigen‐specific T‐cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side‐effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD‐L1–positive and PD‐L1–negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T‐cell clones that were found in both the tumor and peripheral blood increased systemically after PD‐1 blockade in eight of nine patients who were evaluated. Mutation‐associated, neoantigen‐specific T‐cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD‐1 blockade. Treatment induced expansion of mutation‐associated, neoantigen‐specific T‐cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)

Crizotinib in the treatment of non-small-cell lung cancer

Introduction: Recent progress in identifying distinct subsets of lung cancer, based on critical driver mutations, has led to increasingly focused efforts in the development of selectively targeted therapies. The fusion oncogene, echinoderm microtubule-associated protein-like 4 – anaplastic lymphoma kinase (EML4-ALK), is present in approximately 5% of non-small-cell lung cancer (NSCLC) tumors. Crizotinib is an oral tyrosine kinase inhibitor (TKI), which silences the protein product of the ALK fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing ALK. Emerging data suggest that crizotinib may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the MET oncogene, or translocation of the ROS1 oncogene. Areas covered: This paper gives an overview of the molecular pathogenesis of ALK-associated NSCLC. It also reviews the pharmacokinetic and pharmacodynamic data on crizotinib and outlines the preclinical and clinical studies leading to the approval of crizotinib. In addition, it discusses its role in the treatment of NSCLC expressing ALK. Expert opinion: Crizotinib represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations. Crizotinib has demonstrated efficacy against ALK-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer.

Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy

Cancer cells employ several mechanisms to evade the immune system of their host, thus escaping immune recognition and elimination. Of particular interest is a cancer cells ability to co-opt the immune systems innate ligands and inhibitory receptors (also known as checkpoints), thus creating an immunosuppressive microenvironment that downregulates T-cell activation and cell signaling. The recent development of the checkpoint inhibitors anti-programmed death-1 and anti-programmed death ligand-1 has generated an enormous amount of interest as a potential new anticancer strategy in solid tumors, particularly in non-small-cell lung cancer, renal cell carcinoma and melanoma. Data suggest significant disease response rates using anti-programmed death-1 and anti-programmed death ligand-1 antibodies, even in heavily pretreated patients. Future directions include optimization of drug delivery sequence and combination of immunotherapy with other therapies including cytotoxic chemotherapy, radiation, antiangiogenic agents and small-molecule tyrosine kinase inhibitors.

Targeted therapy for non-small-cell lung cancer: past, present and future

Therapy for advanced non-small-cell lung cancer has developed significantly with new awareness of histologic subtype as an important factor in guiding treatment and the development of targeted agents for molecular subgroups harboring critical mutations that spur on cancer growth. In this comprehensive review, we look back at developments in targeted therapy for advanced non-small-cell lung cancer, reviewing in detail efforts, both successful and in some cases less so, to target EGFR, VEGF and ALK. This review provides an overview of where the field stands at present and the areas we feel are most likely to provide challenges and potential successes in the next 5 years including immune checkpoint inhibition, epigenetic therapy and driver mutation targeting.

New Strategies in Lung Cancer: Translating Immunotherapy into Clinical Practice

Recent breakthroughs in translating the early development of immunomodulatory antibodies into the clinic, notably with the anti–cytotoxic T-lymphocyte antigen-4 antibody, ipilimumab, have led to durable benefits and prolonged survival for a subgroup of patients with advanced melanoma. Subsequent studies have shown that related immune checkpoint antibodies, specifically those targeting the programmed death-1 pathway, have activity in non–small cell lung cancer. Non–small cell lung cancer is the commonest cause of cancer death worldwide and this exciting avenue of clinical investigation carries with it great promise and new challenges. In this article, we discuss recent developments in lung cancer immunotherapy, reviewing recent findings from therapeutic vaccine studies and in particular we focus on the refinement of immunomodulation as a therapeutic strategy in this challenging disease. Clin Cancer Res; 20(5); 1067–73. ©2014 AACR.

New Strategies in Lung Cancer: Epigenetic Therapy for Non-Small Cell Lung Cancer

Recent discoveries that non–small cell lung cancer (NSCLC) can be divided into molecular subtypes based on the presence or absence of driver mutations have revolutionized the treatment of many patients with advanced disease. However, despite these advances, a majority of patients are still dependent on modestly effective cytotoxic chemotherapy to provide disease control and prolonged survival. In this article, we review the current status of attempts to target the epigenome, heritable modifications of DNA, histones, and chromatin that may act to modulate gene expression independently of DNA coding alterations, in NSCLC and the potential for combinatorial and sequential treatment strategies. Clin Cancer Res; 20(9); 2244–8. ©2014 AACR.

Chemotherapeutic and targeted strategies for locally advanced and metastatic esophageal cancer

Introduction: Esophageal cancer represents a major health care problem worldwide and its prevalence is rapidly increasing. A key challenge in the treatment of both locally advanced and metastatic disease is to improve our understanding of the underlying molecular biology. Herein we discuss the most active chemotherapies and targeted agents for esophageal cancer, and explore potential differences in the disease between Eastern and Western countries. Methods: We reviewed the literature for trials involving chemotherapy and targeted agents in locally advanced and metastatic disease in the last 20 years. The search was supplemented by a review of the abstracts presented at the annual American Society of Clinical Oncology meetings from 1992 to 2012. Results: Neoadjuvant chemo-radiation followed by surgery remains standard of care for operable disease. Definitive chemo-radiation can be considered for locally advanced squamous cell tumors. Platinum-based combination chemotherapy is preferable in the first-line metastatic setting. Recently, HER2, EGFR, and VEGF–targeted agents have been extensively investigated as single agents or in combination with chemotherapy. Several new targets are being explored. Conclusions: There have been incremental improvements in our understanding of the molecular biology of esophageal cancer, and ethnic differences between Asian and Western populations are becoming apparent. Next-generation sequencing has failed to demonstrate significant oncogenic drivers; however, the addition of trastuzumab to chemotherapy for HER2-amplified tumors has been validated in the metastatic setting and is undergoing investigation in operable disease. Epigenetic therapeutics may provide additional benefit in future years for this difficult-to-treat disease.

Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma

EGFR-mutated lung adenocarcinomas routinely develop resistance to tyrosine kinase inhibitors (TKI). To better characterize the relative frequencies of the resistance mechanisms, we analyzed 48 EGFR-mutated TKI-resistant specimens from 41 patients. Next-generation sequencing of post-treatment specimens detected EGFR p.T790M in 31 (79%) of 39 patients, PIK3CA mutations in 10 (26%), EGFR p.S768_V769delinsIL in one, and KRAS p.G12C in one. Five PIK3CA mutations were outside of codons 542, 545, and 1047. Three of four pre-treatment specimens did not carry the PIK3CA mutation found in the post-treatment sample. Small cell carcinoma transformation was identified in four patients; none had p.T790M, including two where p.T790M was identified in the co-existing adenocarcinoma. In p.T790M-mutated specimens, the allele frequency was less than 5% in 24% of cases. p.T790M allele frequency was usually lower than that of the sensitizing mutation indicating that the resistance mutation was present either in a subset of cells or, if the sensitizing mutation was amplified, in a subset of the sensitizing alleles of a dominant clone. Eight patients had multiple resistance mutations, suggesting either multiple separate resistant clones or a single clone harboring multiple resistance mechanisms. PIK3CA mutations appear to be a more significant resistance mechanism than previously recognized.

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype-Specific Therapies

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8-12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease.