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1. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution

Author

Abbosh, C, Birkbak, NJ, Wilson, GA, Jamal-Hanjani, M, Constantin, T, Salari, R, Quesne, JL, Moore, DA, Veeriah, S, Rosenthal, R, Marafioti, T, Kirkizlar, E, Watkins, TBK, McGranahan, N, Ward, S, Martinson, L, Riley, J, Fraioli, F, Bakir, MA, GrÖnroos, E, Zambrana, F, Endozo, R, Bi, WL, Fennessy, FM, Sponer, N, Johnson, D, Laycock, J, Shafi, S, Czyzewska-Khan, J, Rowan, A, Chambers, T, Matthews, N, Turajlic, S, Hiley, C, Lee, SM, Forster, MD, Ahmad, T, Falzon, M, Borg, E, Lawrence, D, Hayward, M, Kolvekar, S, Panagiotopoulos, N, Janes, SM, Thakrar, R, Ahmed, A, Blackhall, F, Summers, Y, Hafez, D, Naik, A, Ganguly, A, Kareht, S, Shah, R, Joseph, L, Quinn, AM, Crosbie, P, Naidu, B, Middleton, G, Langman, G, Trotter, S, Nicolson, M, Remmen, H, Kerr, K, Chetty, M, Gomersall, L, Fennell, DA, Nakas, A, Rathinam, S, Anand, G, Khan, S, Russell, P, Ezhil, V, Ismail, B, Irvin-sellers, M, Prakash, V, Lester, JF, Kornaszewska, M, Attanoos, R, Adams, H, Davies, H, Oukrif, D, Akarca, AU, Hartley, JA, Lowe, HL, Lock, S, Iles, N, Bell, H, Ngai, Y, Elgar, G, Szallasi, Z, Schwarz, RF, Herrero, J, Stewart, A, Quezada, SA, Van Loo, P, Dive, C, Lin, CJ, Rabinowitz, M, Aerts, HJWL, Hackshaw, A, Shaw, JA, Zimmermann, BG, Swanton, C, Bosshard-Carter, L, Goh, G, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Horswell, S, Al Bakir, M, Mitter, R, Escudero, M, Xu, H, Goldman, J, Stone, RK, Denner, T, Biggs, J, Costa, M, Begum, S, Phillimore, B, Nye, E, Graca, S, Joshi, K, Furness, A, Aissa, AB, Wong, YNS, Georgiou, A, Quezada, S, Simeon, C, Hector, G, Smith, A, Aranda, M, Novelli, M, Forster, M, Papadatos-Pastos, D, Carnell, D, Mendes, R, George, J, Navani, N, Taylor, M, Choudhary, J, Califano, R, Taylor, P, Krysiak, P, Rammohan, K, Fontaine, E, Booton, R, Evison, M, Moss, S, Idries, F, Bishop, P, Chaturved, A, Marie Quinn, A, Doran, H, leek, A, Harrison, P, Moore, K, Waddington, R, Novasio, J, Rogan, J, Smith, E, Tugwood, J, Brady, G, Rothwell, DG, Chemi, F, Pierce, J, Gulati, S, Bellamy, M, Bancroft, H, Kerr, A, Kadiri, S, Webb, J, Djearaman, M, Fennell, D, Le Quesne, J, Moore, D, Thomas, A, Walter, H, Monteiro, W, Marshall, H, Nelson, L, Bennett, J, Primrose, L, Amadi, A, Palmer, S, Miller, J, Buchan, K, Lester, J, Edwards, A, Morgan, F, Verjee, A, MacKenzie, M, Wilcox, M, Smith, S, Gower, N, Ottensmeier, C, Chee, S, Johnson, B, Alzetani, A, Shaw, E, Lim, E, De Sousa, P, Tavares Barbosa, M, Bowman, A, Jordan, S, Rice, A, Raubenheimer, H, Proli, C, Elena Cufari, M, Ronquillo, JC, Kwayie, A, Bhayani, H, Hamilton, M, Bakar, Y, Mensah, N, Ambrose, L, Devaraj, A, Buderi, S, Finch, J, Azcarate, L, Chavan, H, Green, S, Mashinga, H, Nicholson, AG, Lau, K, Sheaff, M, Schmid, P, Conibear, J, Light, T, Horey, T, Danson, S, Bury, J, Edwards, J, Hill, J, Matthews, S, Kitsanta, Y, Suvarna, K, Fisher, P, Keerio, AD, Shackcloth, M, Gosney, J, Postmus, P, Feeney, S, Asante-Siaw, J, Constatin, T, Zimmermann, B, Dentro, S, Dessimoz, C, Shiu, K-K, Bridgewater, J, Hochauser, D, Beck, S, Parker, P, Walczak, H, Enver, T, Proctor, I, Sinclair, R, Lok, C-W, Mitchison, M, Trevisan, G, Lynch, M, Brandner, S, Gishen, F, Tookman, A, Stone, P, Sterling, C, Larkin, J, Attard, G, Eeles, R, Foster, C, Bova, S, Sottoriva, A, Chowdhury, S, Ashish, C, Spicer, J, Stares, M, Lynch, J, Caldas, C, Brenton, J, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Stewart, G, Watts, C, Gilbertson, R, McDermott, U, Tavare, S, Maughan, T, Tomlinson, I, Campbell, P, McNeish, I, Biankin, A, Chambers, A, Fraser, S, Oien, K, Krebs, M, Marais, R, Carter, L, Nonaka, D, Dhomen, N, Shaw, J, Baijal, S, Tanchel, B, Collard, M, Cockcroft, P, Taylor, J, Colloby, P, Olisemeke, B, Wilson, R, Harrison, D, Loda, M, Flanagan, A, McKenzie, M, Lederman, J, Sharp, A, and Farrelly, L

Subjects
0301 basic medicine, Oncology, Lung Neoplasms, IMPACT, Biopsy, DNA Mutational Analysis, Drug resistance, Metastasis, 0302 clinical medicine, Limit of Detection, Carcinoma, Non-Small-Cell Lung, Medicine, Neoplasm Metastasis, Early Detection of Cancer, Multidisciplinary, medicine.diagnostic_test, Phylogenetic tree, DNA, Neoplasm, STATISTICS, 3. Good health, Tumor Burden, Multidisciplinary Sciences, Cell Tracking, PEACE consortium, 030220 oncology & carcinogenesis, Disease Progression, Science & Technology - Other Topics, medicine.medical_specialty, CARCINOMA, Tumour heterogeneity, General Science & Technology, Early detection, Evolution, Molecular, 03 medical and health sciences, Internal medicine, MD Multidisciplinary, Carcinoma, Humans, Cell Lineage, Lung cancer, Postoperative Care, Science & Technology, MUTATIONS, TRACERx consortium, business.industry, CIRCULATING TUMOR DNA, Reproducibility of Results, medicine.disease, R1, NEGATIVE BREAST-CANCER, Clone Cells, 030104 developmental biology, Drug Resistance, Neoplasm, UPTAKE RATIO, Immunology, FDG PET, Neoplasm Recurrence, Local, business, Multiplex Polymerase Chain Reaction
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Published
2017

2. Immune checkpoint blockade for non–small cell lung cancer: What is the role in the special populations?

Author

Califano, R., Gomes, F., Ackermann, C.J., Rafee, S., Tsakonas, G., and Ekman, S.

Subjects
*THERAPEUTIC use of monoclonal antibodies, *HIV infection complications, *ELDER care, *AUTOIMMUNE diseases, *CANCER chemotherapy, *CANCER patients, *HEALTH care teams, *IMMUNOTHERAPY, *LUNG cancer, *TRANSPLANTATION of organs, tissues, etc., *DECISION making in clinical medicine, *AT-risk people, *TREATMENT effectiveness, *PATIENT selection, *CHRONIC hepatitis B, *CHRONIC hepatitis C, *DISEASE complications, MORTALITY risk factors
Abstract

In recent years, non–small cell lung cancer (NSCLC) entered in a new era of anticancer treatments with the success of checkpoint inhibitors (CPIs). These are now part of daily practice from locally advanced to metastatic NSCLC. However, the registration phase III trials are highly selective and not fully representative of the patients seen in real-world clinical practice. This is particularly obvious for older and frail patients, which represent the majority of NSCLC cases worldwide. The median age of the patients enrolled in clinical trials is 10 years younger than what is seen in clinic and patients with performance status (PS) ≥2 were excluded from registration studies. No strong conclusions can be drawn from the available trials where older and frail patients have been excluded. The majority of data on efficacy according to age are derived from underpowered subgroup analysis and there are no age-specific safety data published. Current data suggest that older patients may derive a similar benefit with no increased toxicity when compared with younger patients. However, the recent development of immunotherapychemotherapy combinations and the potential higher incidence of toxicity, raise additional concerns for these populations where adequate patient selection is paramount. CPI is not recommended for patients with PS 3–4 and should be considered with caution for those with PS 2. The evidence for patients with pre-existing autoimmune disease (AID), organ transplant or chronic viral infections (such us viral hepatitis B and C or human immunodeficiency virus) is less clear and low level. Although CPI are potentially safe in selected patients with AID with minimal activity and well-controlled chronic viral infections, patients with solid organ transplant face a significant risk of graft loss and death. Therefore, a decision to treat these groups of patients should always be discussed at a multidisciplinary level. • Checkpoint inhibitors revolutionised the treatment pathway for advanced non–small cell lung cancer (NSCLC). • There is increasing evidence supporting their use in older cancer patients. • Data on patients with a performance status score of 2 raise concerns on its efficacy within NSCLC. • Data is scarce for patients with autoimmune disease, organ transplant, or chronic viral infections. [ABSTRACT FROM AUTHOR]

Published
2020
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3. Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK.

Author

Califano, R., Tariq, N., Compton, S., Fitzgerald, D., Harwood, C., Lal, R., Lester, J., McPhelim, J., Mulatero, C., Subramanian, S., Thomas, A., Thatcher, N., and Nicolson, M.

Subjects
*ANTINEOPLASTIC agents, *DATABASES, *EPIDERMAL growth factor, *LUNG cancer, *META-analysis, *RESEARCH funding, *SYSTEMATIC reviews, *PROTEIN-tyrosine kinase inhibitors, *SOCIAL services case management, *CHEMICAL inhibitors, *THERAPEUTICS
Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings. [ABSTRACT FROM AUTHOR]

Published
2015
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5. Phase 3 Study of Pembrolizumab With Concurrent Chemoradiation Therapy Followed by Pembrolizumab With or Without Olaparib vs. Concurrent Chemoradiation Therapy in Patients With Newly Diagnosed Limited-Stage Small-Cell Lung Cancer: KEYLYNK-013.

Author

Rimner, A., Lai, V., Califano, R., Jabbour, S.K., Faivre-Finn, C., Cho, B.C., Kato, T., Yu, J., Yu, L., Zhao, B., Pietanza, M.C., and Byers, L.

Subjects
*DIAGNOSIS, *OLAPARIB, *CHEMORADIOTHERAPY, *LUNG cancer, *PROPORTIONAL hazards models, *SEMINOMA
Abstract

Purpose/objective(s): Concurrent chemoradiotherapy (CCRT) with etoposide and platinum (carboplatin/cisplatin) plus the anti‒PD-1 antibody pembrolizumab (pembro) has shown antitumor activity and acceptable safety in patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has shown activity in combination with checkpoint inhibitors in SCLC. KEYLYNK-013 (NCT04624204) is a randomized, placebo-controlled, double-blind phase 3 trial of pembro plus CCRT followed by pembro with or without olaparib in pts with newly diagnosed LS-SCLC.Materials/methods: Eligible pts are those aged ≥18 years with previously untreated LS-SCLC, ECOG PS 0/1, and adequate pulmonary function. Pts are randomized 1:1:1 to receive pembro 200 mg Q3W (groups A and B) or pembro placebo (saline) Q3W (group C) during the chemoradiation phase. All pts also receive 4 cycles of chemotherapy (etoposide 100 mg/m2 on days 1, 2, and 3 of each cycle and investigator's choice of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 on day 1 of each cycle) with definitive thoracic radiotherapy (total dose of 45 Gy in 30 fractions twice daily over 3 weeks or 66 Gy in 33 fractions once daily over 6.5 weeks starting on day 1 of cycle 2). After chemoradiation, prophylactic cranial irradiation is strongly recommended for pts with CR/PR or at investigator's discretion for pts with SD. Postchemoradiation pts receive pembro 400 mg Q6W plus olaparib placebo (group A), or pembro 400 mg Q6W plus olaparib 300 mg BID (group B), or pembro placebo plus olaparib placebo (group C) for 9 cycles/12 months. Randomization is stratified by ECOG PS (0 vs 1), SCLC stage (I/II vs III), radiation fractionation (twice vs once daily), and region (east Asia vs North America/western Europe/UK/Australia vs rest of world). Tumor imaging occurs at baseline, within 12 weeks of cycle 1 day 1, followed by Q9W to the end of year 2, Q12W in year 3, Q16W in year 4, every 6 months in year 5, and annually thereafter. Imaging is assessed per RECIST v1.1 by blinded independent central review. AEs are made per NCI-CTCAE v5.0. Health-related quality of life is assessed using EORTC-QLQ-C30 and QLQ-LC13. Primary endpoints are OS and PFS per RECIST v1.1 by blinded independent central review. OS and PFS are estimated by the Kaplan-Meier method. Between-group differences will be evaluated with stratified log-rank tests and Cox proportional hazard models with Efron's method of tie handling. Secondary endpoints include ORR, duration of response, safety, and pt-reported outcomes. Enrollment began in Dec 2020 and is ongoing at 43 sites in 11 countries as of Feb 24, 2021.Results: TBD CONCLUSION: TBD. [ABSTRACT FROM AUTHOR]

Published
2021
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6. Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) – A decision-making analysis amongst European lung cancer experts.

Author

Früh, M., Panje, C.M., Reck, M., Blackhall, F., Califano, R., Cappuzzo, F., Besse, B., Novello, S., Garrido, P., Felip, E., O'Brien, M., Paz Ares, L., de Marinis, F., Westeel, V., De Ruysscher, D., and Putora, P.M.

Subjects
*SMALL cell lung cancer, *INTRAVENOUS therapy, *LUNG cancer
Abstract

• Second-line therapy of stage IV SCLC is heterogeneous among European experts. • After 6 months from first-line treatment, 92 % recommend platinum re-challenge. • 3–6 months after first-line treatment no consensus was found. • In very early recurrence CAV for fit & topotecan for unfit patients was recommended. Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3–6 months since the end of first-line therapy. Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in. [ABSTRACT FROM AUTHOR]

Published
2020
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7. Position of an international panel of lung cancer experts on the decision for expansion of approval for pembrolizumab in advanced non-small-cell lung cancer with a PD-L1 expression level of ≥1% by the USA Food and Drug Administration.

Author

Mountzios, G, Remon, J, Novello, S, Blais, N, Califano, R, Cufer, T, Dingemans, A M, Liu, S V, Peled, N, Pennell, N A, Reck, M, Rolfo, C, Tan, D, Vansteenkiste, J, West, H, and Besse, B

Subjects
*NON-small-cell lung carcinoma, *LUNG cancer
Published
2019
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8. Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: The United Kingdom Named Patient Programme.

Author

Khan, F., Ottensmeier, C., Popat, S., Dua, D., Dorey, N., Ellis, S., Szabo, M., Upadhyay, S., Califano, R., Chan, S., Lee, L., Ali, C.W., Nicolson, M., Bates, A.T., Button, M., Chaudhuri, A., Mulvenna, P., Shaw, H.M., and Danson, S.J.

Subjects
*LUNG cancer, *PHOSPHOTRANSFERASES, *RETROSPECTIVE studies, *DESCRIPTIVE statistics, *CHEMICAL inhibitors
Abstract

Abstract: Introduction: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. Patients and methods: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. Results: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. Conclusions: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial. [Copyright &y& Elsevier]

Published
2014
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9. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

Author

Rafael Rosell, Alice T. Shaw, Ali Zeaiter, Shirish M. Gadgeel, Emmanuel Mitry, Bogdana Balas, Jin S. Ahn, Maurice Perol, Johannes Noe, Sai-Hong Ignatius Ou, Peter N. Morcos, D. Ross Camidge, Solange Peters, Tony Mok, Dong Wan Kim, Rafal Dziadziuszko, Sophie Golding, ALEX Trial Investigators, Nordman, I., Pittman, K., Dear, R., Lwin, Z., Briggs, P., Pavlakis, N., Ceric, T., Mehic, B., Stanetic, M., Franke, F.A., Castro, G., Santo Borges, G., Pereira, J., Brust, L., Santos, L., Cruz, M., Ribeiro, R., De Azevedo, S., Neron, Y.V., Sangha, R., Cohen, V., Burkes, R., Abdelsalam, M., Yadav, S., Cheema, P., Yanez, E., Aren, O., Zhou, C., Zhang, L., Liu, X., Corrales Rodriguez, L., Meldgaard, P., Soerensen, J.B., McCulloch, T., Rodriguez, N., Gaafar, R., Abdel Azeem, H., Coudert, B., Moro-Sibilot, D., Lena, H., Bennouna, J., Cortot, A., Veillon, R., Cadranel, J., Barlesi, F., Reck, M., Mezger, J., von Pawel, J., Fischer, J.R., Dickgreber, N.K., Zarogoulidis, K., Syrigos, K., Georgoulias, V., Agelaki, S., Castro-Salguero, H., Ho, J., Chan, S.H., Cheng, C.K., Ng, A., Stemmer, S., Wollner, M., Gottfried, M., Dudnik, J., Cyjon, A., Heching, N., Novello, S., Tiseo, M., Platania, M., Misino, A., Gridelli, C., Ciardiello, F., Favaretto, A., De Marinis, F., Longo, F., Bordonaro, R., Dazzi, C., Chiari, R., Mercuri, E., Macedo, E., Rodriguez Cid, J.R., McKeage, M., Vera, L., Morón Escobar, H.D., Rodriguez, M., Mas, L., Ramlau, R., Kowalski, D., Szczesna, A., Kazarnowicz, A., Milanowski, J., Luboch-Kowal, J., Oliveira, J., Barata, F., Almodovar, T., Lee, J.S., Cho, B.C., Kim, S.W., Han, J.Y., Karaseva, N., Stroyakovskii, D., Kuzmin, A., Smolin, A., Laktionov, K., Ragulin, Y., Filippov, A., Levchenko, E., Jovanovic, D., Perin, B., Andric, Z., Soo, R., Tan, E.H., De Castro Carpeno, J., Provencio Pulla, M., Garrido Lopez, P., Felip Font, E., Morano Bueno, T., Sanchez, A., Isla Casado, D., Ponce Aix, S., Reguart Aransay, N., Viteri Ramirez, S., Rodriguez Abreu, D., Sanchez Torres, J.M., Massuti Sureda, B., Ramos Vazquez, M., Tabernero, J.M., Curioni, A., Rothschild, S., Scherz, A., Chiu, C.H., Su, W.C., Yang, CHJ, Chang, G.C., Hsia, T.C., Yang, C.T., Tharavichitkul, E., Pongthai, P., Arpornwirat, W., Geater, S., Srimuninnimit, V., Sriuranpong, V., Demirkazik, A., Goker, E., Harputluoglu, H., Cicin, I., Kose, F., Erman, M., Bondarenko, I., Vinnyk, Y., Shparyk, Y., Golovko, Y., Lal, R., Forster, M., Califano, R., Skailes, G., Thompson, J., Mekhail, T., Polikoff, J., Spigel, D., Waqar, S., Hermann, R., Deo, E., Simon, G., Rybkin, I., Kaywin, P.R., Uyeki, J., Gubens, M., Limaye, S., Gerber, D.E., Leal, T., Spira, A.I., Bazhenova, L., Cetnar, J., Socinski, M., Jahanzeb, M., Kabbinavar, F., Lawler, W.E., Hancock, M.R., Raez, L.E., DiCarlo, B.A., Lowe, T.E., Fidler, M., Ross, H., Davidson, S.J., Sanchez, J.D., Hamm, J., Kerr, S., Belman, N., Baker, S., Naraev, B., Jung, G., Edelman, M., Feldman, L., Belani, C., and Pakkala, S.

Subjects
Adult, Male, 0301 basic medicine, Oncology, Alectinib, medicine.medical_specialty, Pathology, Lung Neoplasms, Brigatinib, Pyridines, medicine.drug_class, Carbazoles, Antineoplastic Agents, Kaplan-Meier Estimate, Aged, 80 and over, Animals, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, Carbazoles/adverse effects, Carbazoles/therapeutic use, Carcinoma, Non-Small-Cell Lung/drug therapy, Carcinoma, Non-Small-Cell Lung/mortality, Central Nervous System Neoplasms/drug therapy, Central Nervous System Neoplasms/secondary, Disease-Free Survival, Female, Follow-Up Studies, Humans, Intention to Treat Analysis, Lung Neoplasms/drug therapy, Lung Neoplasms/mortality, Middle Aged, Piperidines/adverse effects, Piperidines/therapeutic use, Protein Kinase Inhibitors/adverse effects, Protein Kinase Inhibitors/therapeutic use, Pyrazoles/adverse effects, Pyrazoles/therapeutic use, Pyridines/adverse effects, Pyridines/therapeutic use, Receptor Protein-Tyrosine Kinases/analysis, Receptor Protein-Tyrosine Kinases/antagonists & inhibitors, Young Adult, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Carcinoma, Non-Small-Cell Lung, hemic and lymphatic diseases, Internal medicine, medicine, Anaplastic lymphoma kinase, Lung cancer, Protein Kinase Inhibitors, Crizotinib, Ceritinib, business.industry, Receptor Protein-Tyrosine Kinases, General Medicine, medicine.disease, Lorlatinib, ALK inhibitor, 030104 developmental biology, 030220 oncology & carcinogenesis, Pyrazoles, business, medicine.drug
Abstract

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P

Published
2017
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10. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Author

Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton, Mariam Jamal-Hanjani, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard-Carter, Pat Gorman, Robert E. Hynds, Gareth Wilson, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin Hiley, Christopher Abbosh, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Sergio Quezada, John A. Hartley, Helen L. Lowe, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Teresa Marafioti, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky Thakrar, Martin Forster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Leena Joseph, Paul Bishop, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean Fennell, Jacqui A. Shaw, John Le Quesne, David Moore, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, Marianne Nicolson, Keith Kerr, Shirley Palmer, Hardy Remmen, Joy Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Jason Lester, Alison Edwards, Fiona Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie Green, Hillaria Mashinga, Andrew G. Nicholson, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Hugo J.W.L. Aerts, Stefan Dentro, Christophe Dessimoz, TRACERx Consortium, Swanton, C., Jamal-Hanjani, M., Veeriah, S., Shafi, S., Czyzewska-Khan, J., Johnson, D., Laycock, J., Bosshard-Carter, L., Rosenthal, R., Gorman, P., Hynds, R.E., Wilson, G., Birkbak, N.J., Watkins, TBK, McGranahan, N., Horswell, S., Mitter, R., Escudero, M., Stewart, A., Van Loo, P., Rowan, A., Xu, H., Turajlic, S., Hiley, C., Abbosh, C., Goldman, J., Stone, R.K., Denner, T., Matthews, N., Elgar, G., Ward, S., Costa, M., Begum, S., Phillimore, B., Chambers, T., Nye, E., Graca, S., Al Bakir, M., Joshi, K., Furness, A., Ben Aissa, A., Wong, YNS, Georgiou, A., Quezada, S., Hartley, J.A., Lowe, H.L., Herrero, J., Lawrence, D., Hayward, M., Panagiotopoulos, N., Kolvekar, S., Falzon, M., Borg, E., Marafioti, T., Simeon, C., Hector, G., Smith, A., Aranda, M., Novelli, M., Oukrif, D., Janes, S.M., Thakrar, R., Forster, M., Ahmad, T., Lee, S.M., Papadatos-Pastos, D., Carnell, D., Mendes, R., George, J., Navani, N., Ahmed, A., Taylor, M., Choudhary, J., Summers, Y., Califano, R., Taylor, P., Shah, R., Krysiak, P., Rammohan, K., Fontaine, E., Booton, R., Evison, M., Crosbie, P., Moss, S., Idries, F., Joseph, L., Bishop, P., Chaturved, A., Quinn, A.M., Doran, H., Leek, A., Harrison, P., Moore, K., Waddington, R., Novasio, J., Blackhall, F., Rogan, J., Smith, E., Dive, C., Tugwood, J., Brady, G., Rothwell, D.G., Chemi, F., Pierce, J., Gulati, S., Naidu, B., Langman, G., Trotter, S., Bellamy, M., Bancroft, H., Kerr, A., Kadiri, S., Webb, J., Middleton, G., Djearaman, M., Fennell, D., Shaw, J.A., Le Quesne, J., Moore, D., Nakas, A., Rathinam, S., Monteiro, W., Marshall, H., Nelson, L., Bennett, J., Riley, J., Primrose, L., Martinson, L., Anand, G., Khan, S., Amadi, A., Nicolson, M., Kerr, K., Palmer, S., Remmen, H., Miller, J., Buchan, K., Chetty, M., Gomersall, L., Lester, J., Edwards, A., Morgan, F., Adams, H., Davies, H., Kornaszewska, M., Attanoos, R., Lock, S., Verjee, A., MacKenzie, M., Wilcox, M., Bell, H., Hackshaw, A., Ngai, Y., Smith, S., Gower, N., Ottensmeier, C., Chee, S., Johnson, B., Alzetani, A., Shaw, E., Lim, E., De Sousa, P., Barbosa, M.T., Bowman, A., Jordan, S., Rice, A., Raubenheimer, H., Proli, C., Cufari, M.E., Ronquillo, J.C., Kwayie, A., Bhayani, H., Hamilton, M., Bakar, Y., Mensah, N., Ambrose, L., Devaraj, A., Buderi, S., Finch, J., Azcarate, L., Chavan, H., Green, S., Mashinga, H., Nicholson, A.G., Lau, K., Sheaff, M., Schmid, P., Conibear, J., Ezhil, V., Ismail, B., Irvin-Sellers, M., Prakash, V., Russell, P., Light, T., Horey, T., Danson, S., Bury, J., Edwards, J., Hill, J., Matthews, S., Kitsanta, Y., Suvarna, K., Fisher, P., Keerio, A.D., Shackcloth, M., Gosney, J., Postmus, P., Feeney, S., Asante-Siaw, J., Aerts, HJWL, Dentro, S., and Dessimoz, C.

Subjects
Male, immune-editing, 0301 basic medicine, DOWN-REGULATION, immune-escape, Lung Neoplasms, Loss of Heterozygosity, Cohort Studies, Loss of heterozygosity, HLA Antigens, Carcinoma, Non-Small-Cell Lung, Chromosome instability, MUTATIONAL PROCESSES, 11 Medical and Health Sciences, Aged, 80 and over, Antigen Presentation, cancer evolution, Manchester Cancer Research Centre, bioinformatics, Middle Aged, 3. Good health, Female, loss of heterozygosity, SENSITIVITY, Life Sciences & Biomedicine, Adult, Biochemistry & Molecular Biology, chromosomal instability, Antigen presentation, Locus (genetics), NEOANTIGENS, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, copy number, medicine, Humans, Lung cancer, Aged, Science & Technology, ResearchInstitutes_Networks_Beacons/mcrc, CTLA-4 BLOCKADE, Cell Biology, 06 Biological Sciences, medicine.disease, PD-1 BLOCKADE, neoantigen, lung cancer, 030104 developmental biology, Carcinoma, Non-Small-Cell Lung/genetics, Carcinoma, Non-Small-Cell Lung/immunology, Carcinoma, Non-Small-Cell Lung/pathology, Carcinoma, Non-Small-Cell Lung/therapy, HLA Antigens/genetics, HLA Antigens/immunology, Lung Neoplasms/genetics, Lung Neoplasms/immunology, Lung Neoplasms/pathology, Lung Neoplasms/therapy, Mutation, Tumor Escape, heterogeneity, TRACERx Consortium, DISCOVERY, CELLS, Immunology, RESISTANCE, Developmental Biology
Abstract

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.

Published
2017
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11. Immune Checkpoint Blockade: A New Era for Non-Small Cell Lung Cancer

Author

Antonio Rossi, Giuseppe Lo Russo, Floriana Morgillo, Keith M. Kerr, Robert D. Morgan, Raffaele Califano, Marina Chiara Garassino, Califano, R., Kerr, K., Morgan, R. D., Russo, G. L., Garassino, M., Morgillo, F., and Rossi, A.

Subjects
0301 basic medicine, PD-L1, Prognosi, medicine.medical_treatment, Pembrolizumab, Bioinformatics, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Immune system, Atezolizumab, CTLA-4, Durvalumab, immune checkpoint, Nivolumab, non-small cell lung cancer, PD-1, antibodies, monoclonal, antibodies monoclonal, humanized, carcinoma, non-small-cell lung, cell cycle checkpoints, humans, prognosis, immunotherapy, oncology, Non-small cell lung cancer, Cell Cycle Checkpoint, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Lung cancer, business.industry, Antibodies, Monoclonal, Immunotherapy, Cell Cycle Checkpoints, medicine.disease, Prognosis, Immune checkpoint, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, business, Human
Abstract

Despite better understanding of it's molecular biology, non-small cell lung cancer (NSCLC) remains a challenging disease to treat. Unfortunately, treatment options are still very limited and prognosis for advanced disease is poor. Immune surveillance plays a crucial role in a host's defence against tumour cells, and this is particular relevant for lung cancer due to it's high somatic mutational load, which increases the chances for the immune system to recognize cancer cells as 'non-self'. Novel immunotherapies are emerging as an effective treatment for this disease. In this review, we present the data on immune checkpoint inhibitors for NSCLC, describing their mechanism of action, data efficacy from recent clinical trials, and strategies to select patients more likely to benefit from these agents.

Published
2016

12. Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): A European survey conducted by the European Society for Medical Oncology (ESMO) Young Oncologists Committee

Author

Jesus Corral, Margaret Hutka, Karin Jordan, Konstantinos Kamposioras, Susana Banerjee, Matthias Preusser, Michalis V. Karamouzis, E. de Azambuja, Raffaele Califano, S. Postel-Vinay, Erika Martinelli, Valter Torri, Valentina Guarneri, Luca Porcu, Califano, R., Karamouzis, M. V., Banerjee, S., de Azambuja, E., Guarneri, V., Hutka, M., Jordan, K., Kamposioras, K., Martinelli, E., Corral, J., Postel-Vinay, S., Preusser, M., Porcu, L., and Torri, V.

Subjects
Pulmonary and Respiratory Medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Decision Making, Specialty, non-small cell lung cancer (NSCLC), Vinorelbine, Medical Oncology, Surveys and Questionnaires, Internal medicine, Carcinoma, Non-Small-Cell Lung, Physicians, medicine, Humans, Surveys and Questionnaire, Stage (cooking), Practice Patterns, Physicians', Lung cancer, Survey, Univariate analysis, business.industry, medicine.disease, R1, Gemcitabine, Adjuvant chemotherapy, Non-Small Cell Lung Cancer, Radiation therapy, Europe, Lung Neoplasm, Incomplete resection, Chemotherapy, Adjuvant, Practice Guidelines as Topic, Female, Radiotherapy, Adjuvant, Adjuvant radiotherapy, business, medicine.drug, Human
Abstract

Background: Early stage Non-Small Cell Lung Cancer (NSCLC) is potentially curable with surgery. ESMO guidelines recommend cisplatin-based adjuvant chemotherapy (CT) for completely resected stage II-III NSCLC. There is limited evidence for the use of adjuvant CT and/or radiotherapy (RT) in incompletely resected (R1) early stage NSCLC. Materials and methods: A European survey of thoracic oncologists was conducted to evaluate use of adjuvant CT and RT for R1-resected NSCLC and to identify factors influencing treatment decisions. Demographics and information on clinical stage, regimens, cycles planned, radiotherapy sites, multidisciplinary management and discussion about inconclusive evidence with the patient were collected. Univariate and multivariate analyses were performed. Results: 768 surveys were collected from 41 European countries. 82.9% of participants were medical oncologists; 49.3% ESMO members; 37.1% based in University Hospitals; 32.6% practicing oncology for over 15 years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT and mostly cisplatin/vinorelbine (81.2%) or cisplatin/gemcitabine (42.9%). 85% discussed limited clinical evidence with the patient. In the univariate analysis, a statistically significant association with CT prescription was found for medical oncology specialty (p

Published
2014

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