Virtual Library

Abstract:
The traditional obstacles to approval of oncologic therapeutic agents, especially targeted therapies that address a rare-biomarker defined group of patients are the long processes from initial drug discovery to clinical implementation, the difficulties in recruitment for these clinical trials and high number of screen failures and the overall low rate of enrollment in clinical trials. The Lung Master Protocol (Lung-MAP, S1400) is a precedent-setting clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer of the lung (SCCA). There are few new effective therapeutic options for patients with advanced lung SCCA. Immunotherapies, including nivolumab, have already shown clear benefit for patients with SCCA in 2015 leading to approval by the FDA which has been an unprecedented step forward for the treatment of patients, however we are still lacking predictive markers for these therapies that are reliably selecting patients more likely to benefit. Lung-MAP (S1400) is aiming to identify biomarker-drug pairs that will lead to successful therapeutic outcomes and registration of new agents. It is a registration-intent master protocol that includes a screening component and clinical trial component; the clinical trial component includes multiple sub-studies which independently evaluate investigational therapies. The clinical trial component is designed to be modular such that new sub-studies can be added either as other sub-studies close or as new biomarker-drug pairs are identified for testing in this patient population. Lung-MAP is utlilizing a broad NGS screening platform capitalizing on the expanding application of genomic sequencing in oncology that has through the Cancer Genome Atlas and other sequencing initiatives revealed targetable genetic aberrations including gene mutations, rearrangements, amplifications, and deletions, and creating an immense opportunity to implement personalized therapy with a high potential to improve patients outcomes. Immunotherapy has been integrated in the design of Lung-MAP from its launch in June of 2014. The original study design and structure is shown in the figure. Figure 1 The modular design of the study has allowed for the flexibility to adapt to the approval of nivolumab and the hault in further development of AMG102 (rilotumumab) with discontinuation of the corresponding sub-study by implementing timely modifications which include the following:1)Eligibility has changed from exclusively second line therapy to second-or more line therapy 2)Pre-screening, while patient receive first line therapy has been added to boost accrual 3)the unmatched arm has been changed to a single (not randomized) arm study with the anti-PD-L1 agent MEDI-4736. Theses changes are reflected in the figure. Each independently conducted and analyzed sub-study specifies investigator-assessed progression-free survival (IA-PFS) and overall survival (OS) as the co-primary endpoints for the phase 3 primary objectives. The primary objectives for the phase 3 are to determine if there is a statistically significant difference in OS and to determine if there is both a clinically meaningful and statistically significant difference in IA-PFS. The conduct of Lung-MAP relies on close collaboration (a public-private partnership) among the NCI and NCTN (spearheaded by SWOG), the pharmaceutical industry, the Foundation for the NIH (FNIH), Friends of Cancer Research, advocates, and FDA. This Master Protocol will improve genomic screening of SCC patients for clinical trial entry, and improve time lines for drug-biomarker testing, allowing for inclusion of the maximum numbers of otherwise eligible patients. The clinical trial continues to be updated following science and alterations in the therapeutic landscape, with adaptations in design and incorporation of new agents against matched targets and the implementation of novel immunotherapy approaches for the unmatched arm. Figure 2

Abstract:
Lung-MAP, a “multi-drug, multi-study bio-marker driven squamous cell lung cancer clinical trial” [i] is, as the song says – a new day . . . a new life . . . and the old world is a new world.[ii] It represents an exciting and radical new paradigm for lung cancer research and with that a potential for new, life-saving treatment protocols for lung cancer. Lung-Map was borne of a National Cancer Institute (NCI) sponsored two-day workshop with the NCI Thoracic Steering Committee and the Federal Drug Administration (FDA) “to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer.”[iii] The objectives of the “workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents and molecularly defined lung cancer subsets and to facilitate generations of data leading to approval of these new therapies.”[iv] The result of this workshop led to the development of an unprecedented public-private collaboration called the Lung-MAP Master protocol. Lung-MAP is a unique research model in several respects. First, it will study five different experimental drugs at the same time for squamous cell lung cancer.[v] The approach stands in stark contrast to the long entrenched research approach whereby only one drug is tested and with that only those patients that might benefit from the treatment are involved in the trial. Second, Lung-MAP researchers will examine the DNA from each participating volunteer patient’s lung tumor to identify the genetic alterations or mutations that are causing the tumor to grow. They will match these results with sub-studies testing related investigative treatments. [vi] Figure 1 Third, while not entirely unique but nonetheless significant, is Lung-MAP’s broad collaborative approach. Those participating in Lung-MAP include NCI, public and private research and advocacy organizations together with five pharmaceutical companies.[vii] The importance of this new paradigm for lung cancer research is graphically illustrated by the treatment and research options that have traditionally been offered to lung cancer patients. In 2000, the only treatments offered and/or available to lung cancer patients were the same platinum chemotherapies, radiation and surgery which had been used to treat lung cancer patients for the prior 30 years. Neither the course of time, nor repeated use of these treatment therapies, offered much hope for survival to lung cancer patients as evidenced by a stagnant 13% five-year survival rate, which has only recently increased to 17% five-year survival rate. The underpinning of Lung-MAP has its genesis, in part, in the completion in 2003 of the Human Genome Project (HGP) which led to The Cancer Genome Atlas (TCGA) in 2005. The completion of the HGP and the TCGA resulted in refreshing and hopefully effective new ways of looking at lung cancer. Before the advent of the HGP and the TCGA, lung cancer tumors were viewed as homogeneous. Now they are viewed as unique biological entities – more like snowflakes, with no two tumors alike. Following the TCGA, the first treatable genomic mutation –EGFR – was identified in 2003. The mutation is found in 10% of non-small cell lung cancer (NSCLC) patients. It was quickly followed by FDA approved treatments gefitinib and erlotinib. In 2007, EML4-ALK fusion was identified. It too was quickly followed by an FDA approved treatment – crizotinib. Following in this vein, Lung-MAP portends the identification of additional genomic mutations and with it, a chance for faster research results and more effective treatment of lung cancer. There are now at least 15 significant identified and hopefully targetable lung cancer genomic mutations. Three of these, EGFR, EML4-ALK and ROS1 have received FDA approved treatments. There are more in clinical trials. In 2015, the first immuno-oncologic therapy received FDA approval for squamous cell lung cancer with many more immuno-oncologic therapies in the clinical trial pipeline that are expected to be approved for not only NCSLC but also small cell lung cancer (SCLC). The core of Lung-MAP is “rapid assessment.” This fast pace of discovery will hopefully render archaic established models requiring 10 to 15 years for development in clinical trials before receiving FDA approval. New approaches to clinical trial protocols such as Lung-MAP, are critical to keeping up with rapidly changing discoveries and changing the old order of research and development. Shortening the timeframe for translational research, from bench to bedside, in order to provide patients with the quickest and most effective benefit from these new therapies is critical and will save lives – especially for lung cancer patients. In order to continue to take advantage of this exciting period in the convergence of research and technology, it is equally imperative that we come together in a collaborative and open-sharing model that will deliver exciting, safe new therapies to patients as fast as possible and with that lead to a long overdue, exponential increase in the survival rate for lung cancer patients. [i] Consensus Report of a Joint NCI Thoracic Malignancies Steering Committee: FDA Workshop on Strategies for Integrating Biomarkers in to Clinical Development of New Therapies for Lung Cancer Leading to the Inception of “Master Protocols” in Lung cancer. Shakun M. Malik, MD, Richard Pazdur, MD, Jeffrey S. Abrams, MD, Mark A. Socinski, MD, William T. Sause, MD, David H. Harpole Jr., MD, John J. Welch, MD, PhD, Edward L. Korn, PhD, Claudio Dansky Ullmann, MD, and Fred R. Hirsch, MD PhD Journal of Thoracic Oncology, Vol. 9, Number 10, October 2014, p. 1443. [ii] Feeling Good, Michael Bublé, 2005 [iii] Consensus Report of a Joint NCI Thoracic Malignancies Steering Committee at p. 1443. [iv] Id. [v] Id. at 1443-1444 and www.lung-map.org/about - lung-map [vi] Id. [vii] Id.

Abstract:
Thymic malignancies represent a heterogeneous group of rare thoracic cancers [1, 2]. The histopathological classification distinguishes thymomas from thymic carcinomas. Thymomas are further subdivided into different types (so-called A, AB, B1, B2, and B3) based upon the atypia of tumor cells, the relative proportion of the associated non-tumoral lymphocytic component, and resemblance to the normal thymic architecture [3]. Thymic carcinomas are similar to their extra-thymic counterpart, the most frequent subtype being squamous cell carcinoma. The diagnosis of any thymic epithelial tumour relies on making the differential diagnosis with other anterior mediastinal tumours and non-malignant thymic lesions. Thymic epithelial tumours are routinely staged according to the Masaoka-Koga staging system, which is correlated with overall survival. Masaoka-Koga staging is a surgical pathology system that is assessable only after surgical resection of the tumour [4]. Recently, the International Association for the Study of Lung Cancer (IASLC) Staging Prognostic Factors Committee, together with the International Thymic Malignancy Interest Group (ITMIG), proposed a Tumour-Node-Metastasis (TNM)-based staging system for thymic malignancies, based on overall survival analyses of a retrospective international database of more than 10,000 cases [5]. The TNM-based approach has the advantage of being more appropriate both for thymoma and thymic carcinomas, which present with a higher propensity towards nodal and distant metastatic invasion. The management of thymic epithelial tumours is a paradigm of multidisciplinary collaboration. Systematic immunological check-up is recommended when a diagnosis of thymic epithelial tumour is suspected, including complete blood cells count with reticulocytes and serum protein electrophoresis, as well as anti-acetylcholine receptor and antinuclear antibodies tests. This is to make the diagnosis of the most frequent immune disorders associated with thymoma, the most frequent being myasthenia gravis, that may impact any therapeutic intervention, including surgery, radiotherapy, and chemotherapy. The treatment strategy is based on the resectability of the tumour [6]. The assessment of resectability is mostly based on the surgeon’s expertise; it is recommended to discuss indications for surgery in a multidisciplinary tumour board setting. The new TNM staging may even better help to formalize resectability: T1-3 level of invasion refers to structures amenable to surgical resection, when T4 level of invasion includes unresectable structures. If complete resection is deemed to be achievable upfront, as it is the case in Masaoka-Koga stage I/II and some stage III tumours, surgery represents the first step of the treatment, possibly followed by postoperative radiotherapy, and for carcinomas, chemotherapy. Standard approach is median sternotomy; minimally-invasive surgery is an option for presumed stage I and possibly stage II tumours in the hands of appropriately-trained thoracic surgeons. Current practices for postoperative radiotherapy are highly variable and there is paucity of prospective, multicentre evidence. The global trend over the past years has been towards a less frequent use of postoperative radiotherapy in thymoma, and to keep it in reserve for high-risk cases. This is based on recent reports from large databases, as well as pooled analyses of retrospective studies, indicating: 1) the absence of survival benefit after radiotherapy in stage I thymoma, or after R0/1 resection of stage II-III thymoma; 2) a similar rate of recurrence in patients who received postoperative radiotherapy or not after complete resection of thymoma; and 3) a recurrence-free and overall survival benefit with postoperative radiotherapy after resection of thymic carcinoma. If complete resection is deemed not to be achievable upfront on the basis of imaging studies, as it is frequently the case in Masaoka-Koga stage III/IVA tumours, a biopsy should be taken, followed by primary/induction chemotherapy as part of a curative-intent sequential strategy that integrates subsequent surgery or radiotherapy. Patients not eligible for local treatment receive palliative chemotherapy only. Cisplatin-based combination regimens should be administered; combinations of cisplatin, adriamycin and cyclophosphamide, and cisplatin and etoposide, are the recommended options [7]. Primary chemoradiotherapy with platin and etoposide is an option for thymic carcinomas. Innovative options may include KIT sequencing in the setting of potential access to specific inhibitors, particularly clinical trials; sunitinib may represent an off-label option as second-line treatment for thymic carcinomas, independently from KIT status, through antiangiogenic effects [8]. mTOR is emerging as a potential target in thymic epithelial tumours, following tumour responses observed in phase I-II trials. Ongoing trials are assessing immune checkpoint inhibitors for refractory thymic carcinoma. No prospective data are available to build recommendations about post-treatment oncological follow-up of patients. Follow-up may be continued for 10-15 years given the possible occurrence of late recurrences. Clinicians should be aware of the possible late onset of new autoimmune disorders. REFERENCES 1. Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P. Thymoma: a focus on current therapeutic management. J Thorac Oncol 2009;4:119-126. 2. Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S; ESMO Guidelines Committee. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; in press 3. Marx A, Ströbel P, Badve SS, et al. ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting. J Thorac Oncol. 2014;9:596-611. 4. Detterbeck F, Nicholson AG, Kondo K, et al. The Masaoka-Koga Stage Classification for Thymic Malignancies: Clarification and Definition of Terms. J Thoracic Oncol 2011; 6:S1710-6. 5. Detterbeck FC, Stratton K, Giroux D, et al; Staging and Prognostic Factors Committee; Members of the Advisory Boards; Participating Institutions of the Thymic Domain. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014;9:S65-72. 6. Detterbeck FC, Moran C, Huang J, et al. Which Way is Up? Policies and Procedures for Surgeons and Pathologists Regarding Resection Specimens of Thymic Malignancy. J Thoracic Oncol 2011;6:S1730-1738. 7. Girard M, Lal R, Wakelee H, et al. Chemotherapy definitions and policies for thymic malignancies. J Thorac Oncol 2011;6: S1749-1755. 8. Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol 2014;9:S131-136

Abstract:
The clinical benefits of biomarker-driven targeted cancer therapy are clear in many tumor types, particularly in lung adenocarcinoma. At this time, use of targeted agents is predicated on access to tumor tissue; in lung cancer patients this tissue is often limited in quantity, a product of minimally invasive procedures using narrow-gauge biopsy needles intended to reduce complications. Current clinical practice has forced pathology labs to revisit approaches to tissue handling, diagnosis, and molecular platform selection. Coordinated efforts are critical to optimizing the handling of small biopsies, from the time of request, to the actual procedure, to receipt in the pathology lab. Ideally, the requesting physician clearly communicates the need for genomic studies to both the operator, who may consider the need/feasibility of multiple biopsies, and pathologist, who may perform rapid on site evaluation. Interventional techniques designed to improve the chances of obtaining material amenable to molecular diagnostics should be implemented whenever possible, including combined core biopsy and fine needle aspiration,[1]and preferential sampling of soft tissue components of bony metastases when possible, in order to avoid the need for specimen decalcification. In the future, in vivo microscopy may be used to guide the biopsy location.[2] Routine histology practices, such as cutting slides from a paraffin block in an iterative fashion only after a pathologist’s review, often requires “refacing” to optimize the plane of section and can waste valuable tumor tissue. The need for genomics studies should be clearly indicated to the receiving pathology laboratory, thereby facilitating histology protocols designed to conserve tissue. Such protocols may include embedding each tissue core in an individual block, delivering “up-front” unstained sections for use in immunohistochemistry and molecular studies, and/or triaging slides to a dedicated molecular diagnostics workflow. As an example, from a single 18-gauge core needle biopsy containing 30% tumor, 15-20 unstained slides can typically generate enough material to perform a diagnostic workup, immunohistochemistry and/or FISH for ALK and ROS1 rearrangements, and adequate DNA for hybrid capture next generation sequencing.[3]With careful histology embedding and sectioning, material will still remain in the block for future studies. International guidelines have recognized the centrality of molecular testing to the clinical management of lung cancer patients and have responded with recommendations for judicious use of immunohistochemical studies in pathology workups and introduced new diagnostic categories intended to eliminate ambiguous classifications, particularly for small biopsy specimens.[4]These guidelines advise against use of the term “non small cell lung carcinoma” whenever possible and recommend use of TTF-1 and p63 or p40 immunohistochemical stains as first line markers for distinguishing between adenocarcinoma and squamous cell carcinoma.[5] Simultaneous evaluation of fine needle aspirates and core biopsies with an optimized IHC protocol may significantly reduce rates of the NSCLC diagnosis and generate additional “testable” material.[6] In institutions that use touch imprints for rapid evaluation of core needle biopsies, careful specimen handling is required to maintain tumor cell adequacy in the needle biopsy specimen.[7] When cytology material is available for testing, cell blocks are preferred because a physical record of the sample can be retained in the form of a stained glass slide.[4] However, in many circumstances the most cellular material is in the form of a smear; these preps can generate abundant and high quality DNA and so should be considered for use in molecular testing, particularly if the slide can be scanned and a digital image archived. Validation of alternative specimens such as cytology smears for FISH can provide additional tissue for in situ assays when core needle or cell block specimens are inadequate.[8] In the molecular diagnostics lab, a plethora of testing platforms are available, many of which are evolving to accept low DNA inputs. Many targeted amplicon-sequencing based assays can accept as little as 10ng of input DNA, whereas hybrid capture approaches typically require around 50ng or more for targeted sequencing panels and whole exome sequencing. However, in today’s practice, it is rare that a single test can provide comprehensive analysis of all the desired targets; indeed, confirmation of individual events detected by sequencing by FISH or immunohistochemistry may be needed. Therefore, an interdisciplinary effort to optimize tumor sampling and conserve tissue is required to ensure successful and comprehensive molecular profiling of lung tumors. References 1. Poulou LS, Tsagouli P, Ziakas PD, Politi D, Trigidou R, Thanos L. Computed tomography-guided needle aspiration and biopsy of pulmonary lesions: A single-center experience in 1000 patients. Acta Radiol. 2013;54(6):640-645. 2. Hariri LP, Mino-Kenudson M, Applegate MB, et al. Toward the guidance of transbronchial biopsy: Identifying pulmonary nodules with optical coherence tomography. Chest. 2013;144(4):1261-1268. 3. Austin MC, Smith C, Pritchard CC, Tait JF. DNA yield from tissue samples in surgical pathology and minimum tissue requirements for molecular testing. Arch Pathol Lab Med. 2015. 4. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the college of american pathologists, international association for the study of lung cancer, and association for molecular pathology. Arch Pathol Lab Med. 2013;137(6):828-860. 5. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: Implications of the 2011 international association for the study of lung cancer/american thoracic society/european respiratory society classification. Arch Pathol Lab Med. 2013;137(5):668-684. 6. Sigel CS, Moreira AL, Travis WD, et al. Subtyping of non-small cell lung carcinoma: A comparison of small biopsy and cytology specimens. J Thorac Oncol. 2011;6(11):1849-1856. 7. Rekhtman N, Kazi S, Yao J, et al. Depletion of core needle biopsy cellularity and DNA content as a result of vigorous touch preparations. Arch Pathol Lab Med. 2015;139(7):907-912. 8. Betz BL, Dixon CA, Weigelin HC, Knoepp SM, Roh MH. The use of stained cytologic direct smears for ALK gene rearrangement analysis of lung adenocarcinoma. Cancer Cytopathol. 2013;121(9):489-499.