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1 News from American News from American Society of Clinical Society of Clinical Oncology Meeting June Oncology Meeting June 2011 2011 (Lung and Skin) (Lung and Skin) Paul Donnellan Paul Donnellan Consultant Medical Consultant Medical Oncologist Oncologist Galway University Galway University Hospitals Hospitals

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  • *News from American Society of Clinical Oncology Meeting June 2011(Lung and Skin)

    Paul DonnellanConsultant Medical OncologistGalway University Hospitals

  • Common causes of cancer death in the United States, 2008Rudin C M et al. Clin Cancer Res 2009;15:5622-56252009 by American Association for Cancer Research

  • *Melanoma: Mortality

  • Tsao, H. et al. N Engl J Med 2004;351:998-1012Clinical Images of Pigmented Lesions

  • *Metastatic MelanomaYoung age at onsetDismal prognosis1yr survival 25%; 2yr survival 10% (Korn et al JCO 2008)Chemotherapy ineffectiveDacarbazine (DTIC) response rates 10%median survival < 8 monthsNever shown to improve survival

  • High Dose Interleukin-216% respond (6% completely and for median duration 10 yrs)

  • Immune ERU

    .Kirkwood J M et al. JCO 2008;26:3445-3455

  • KaplanMeier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat PopulationHodi FS et al. N Engl J Med 2010;363:711-723

  • Intracellular Signaling Pathways in Melanoma Known to Be Important in the Response and Resistance to Targeted Therapy.Smalley KS, Sondak VK. N Engl J Med 2010;363:876-878.

  • Targeting Treatment to a Specific Variant in the Melanoma Gene.McDermott U et al. N Engl J Med 2011;364:340-350.

  • Best Tumor Response for Each Patient.Chapman PB et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1103782

  • Chapman PB et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1103782

  • McMullan, D. M. et al. N Engl J Med 2006;354:397A 72-year-old man presented for evaluation of progressive dyspnea and cough

  • Smoking image

  • Lung Cancer

  • TarcevaTablet once a dayFew side effectsIf have the target mutation, the response to treatment is 5 times higher than with chemotherapy!55% vs 11%

  • CrizotinibTablet once a dayTargets EML4-ALK (5% on NSCLC)Few side effectsDramatic response in patients who have failed chemotherapy90% patients respondRandomised Clinical Trial UCHG

    Common causes of cancer death in the United States, 2008. Data are derived from (1). Total lung cancer deaths, estimated to be 161,840 in 2008, have been split into ever smokers and never smokers. Error bars reflect that the number of lung cancer deaths in never smokers, including cases attributable to second hand smoke exposure and cases not attributable to tobacco, are estimated to total 16,000 to 24,000 per year (3). See accompanying article for additional epidemiologic data (5).These are data from irish cancer registry.Overall survival for cases of invasive melanoma diagnosed in1994-2008 was 88% (95% confidence interval 87%-89%)for women five years after diagnosis, and 79% (77%-81%)for men. There was no significant change in survival over thisperiod. Age, sex, tumour thickness and having surgery wereall independent prognostic factors; the hazard ratio for menwas 61% greater than for women when all other factors wereallowed for (Figure 8). Melanoma survival in Ireland wasclose to the European average for both men and women,although poorer than in Northern Ireland, especially for men(Figure 9)Deaths from malignant melanoma increased from 16 a yearin 1955-1960 to 113 a year in 2004-2007.3 Some of theincrease in earlier years is almost certainly due to improvingquality of diagnosis and certification, but the continuingincrease in male mortality rates since the 1990s, in contrastwith the relatively small increase for women (Figure 10), is acause for concern.Melanoma mortality for women in Ireland in 2001-2005 was11th highest of the 29 European countries shown in Figure11, while male mortality was 20th.3 Male mortality was higherthan female in all countries shown, although themale/female ratio in Ireland was one of the lowest. Themuch lower mortality and better survival for melanoma inNorthern Ireland compared to Ireland is striking.Figure 1. Clinical Images of Pigmented Lesions. Multiple clinically atypical nevi are distributed over the back of a patient (Panel A). In Panel B, a cluster of clinically atypical moles have central papular components ("fried-egg nevi") and peripheral diffusion of pigment. A large (2.5-cm) nevus has a fuzzy border but relatively symmetric features (Panel C). In Panel D, superficial spreading melanoma is characterized by a dark brown plaque with highly irregular, scalloped borders and extensive color variegation. In Panel E, acral-lentiginous melanoma appears as a large ulcerative nodule on the plantar surface. In Panel F, lentigo maligna melanoma is manifested as an irregular, kidney-shaped, thin brown plaque on the face. In Panel G, nodular melanoma appears as a relatively symmetric, sharply circumscribed nodule with a blue-gray dermal invasive component. Photographs courtesy of Dr. Richard Allen Johnson.The incidence of metastatic melanoma has increased over the past three decades,1,2 and the death rate continues to rise faster than the rate with most cancers.3 The World Health Organization (WHO) estimates that worldwide there are 66,000 deaths annually from skin cancer, with approximately 80% due to melanoma.4 In the United States alone, an estimated 8600 persons died from melanoma in 2009.1 The median survival of patients with melanoma who have distant metastases (American Joint Committee on Cancer stage IV) is less than 1 year.5,6 No therapy is approved beyond the first-line therapy for metastatic melanoma, and enrollment in a clinical trial is the standard of care. No therapy has been shown in a phase 3, randomized, controlled trial to improve overall survival in patients with metastatic melanoma.6-9 Although it is clear that vaccines are important in the prevention of infectious diseases, their benefits with respect to metastatic cancer have been less clear. The first studies to show improved survival with vaccines among patients with metastatic cancer was reported recently in a study involving men who received sipuleucel-T vaccine for the treatment of metastatic castration-resistant prostate cancer.CTLA4 is a key element in immune tolerance and the main negative regulator of T cell-mediated antitumor immune responses. Cloning the gene for CTLA4 in 1987 allowed further exploration of its role in T-cell tolerance.74 Early preclinical studies suggested that CTLA4 serves as a natural braking mechanism for T-cell activation, allowing a return to homeostasis after an immune response. This was profoundly demonstrated in murine CTLA4 knockout models. Mice lacking CTLA4 developed a massive lymphoproliferative disorder, leading to lymphocytic infiltration and destruction of major organs.75-77 CTLA4 is a homolog of CD28 that functions as an inhibitory receptor for B7 costimulatory molecules expressed on mature APCs.78,79 After T-cell activation, CTLA4 cell-surface receptors are upregulated and successfully compete with CD28 for binding to B7, resulting in an inhibitory signal that downregulates T-cell activation.62,79 This inhibitory signal affects downstream targets of CTLA4 that include cytokine production by Th1 and Th2 cells80 and key components of the cell cycle machinery (Cdk-4, Cdk-6, and cyclin D3) required for cell cycle progression.81-83 Therefore, it was hypothesized that blocking the interaction of B7 with CTLA4 might enhance T-cell activation, leading to a more robust antitumor immune response.Anti-CTLA4 mAbs with a much greater affinity for CTLA4 than B7 (competitive inhibition) were cloned and shown to inhibit the interaction of B7 and CTLA4 (Fig 4).62 The inhibitory signal produced by CTLA4 is therefore blocked, and T-cell activation is enhanced (ie, releasing the "brake"). Multiple animal models have confirmed that CTLA4 blockade, either alone or when combined with other interventions, enhances antitumor T-cell immune function and T-cell-mediated killing, and inhibits tumor recurrence.84-86 In a murine sarcoma model, the combination of CTLA4 blockade and a poxvirus vaccine provided a significant survival advantage compared with vaccine alone (P < .001).87 Treatment with an anti-CTLA4 mAb also reduced tumor recurrence in a murine prostate cancer model.85 Augmentation of IFN- production, upregulation of MHC class I expression on the tumor, enhancement of tumor cell apoptosis, and reduction of angiogenesis have been proposed as mechanisms for the antitumor effects of CTLA4 blockade.88 Based on the strength of these preclinical data, clinical trials have been initiated with two fully human anti-CTLA4 mAbs, which have different pharmacokinetic and pharmacodynamic properties (Appendix [online only] contains further information on anti-CTLA4 dosing schedules).Figure 1 KaplanMeier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population. The median follow-up for overall survival (Panel A) in the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group was 21.0 months, and the median overall survival was 10.0 months (95% CI, 8.5 to 11.5); in the ipilimumab-alone group, the median follow-up was 27.8 months, and the median overall survival, 10.1 months (95% CI, 8.0 to 13.8); and in the gp100-alone group, the median follow-up was 17.2 months, and the median overall survival, 6.4 months (95% CI, 5.5 to 8.7). The median progression-free survival (Panel B) was 2.76 months (95% CI, 2.73 to 2.79) in the ipilimumab-plus-gp100 group, 2.86 months (95% CI, 2.76 to 3.02) in the ipilimumab-alone group, and 2.76 months (95% CI, 2.73 to 2.83) in the gp100-alone group. The rates of progression-free survival at week 12 were 49.1% (95% CI, 44.1 to 53.9) in the ipilimumab-plus-gp100 group, 57.7% (95% CI, 48.9 to 65.5) in the ipilimumab-alone group, and 48.5% (95% CI, 39.6 to 56.7) in the gp100-alone group.*Figure 1. Intracellular Signaling Pathways in Melanoma Known to Be Important in the Response and Resistance to Targeted Therapy.Panel A shows two signaling pathways known to be important for the growth and progression of melanoma. Constitutive mitogen-activated protein (MAP) kinase signaling in the RASRAFMEKERK pathway drives the growth of melanoma cells through the up-regulation of cyclin D1 expression. Treatment with PLX4032 can result in the regression of melanomas harboring the BRAF V600E mutation because the drug blocks the activity of the mutant BRAF. Survival of melanoma cells and resistance to apoptosis are often mediated through the constitutive activity of phosphoinositide-3-kinase (PI3K) and the serinethreonine protein kinase AKT, which arises through multiple mechanisms, including loss of expression of the tumor suppressor phosphatase and tensin homologue (PTEN). Panel B illustrates potential mechanisms by which BRAF V600E mutated melanomas may show intrinsic or acquired resistance to BRAF inhibition. Increased signaling through RAF1, possibly due to increased RAF1 expression or increased receptor tyrosine kinase activity, restores MEK and ERK activity and results in cyclin D1 expression. In addition, some melanomas harboring BRAF V600E mutations may already have cyclin D1 amplification, whereas others may have lost PTEN expression; these melanomas may be particularly likely to manifest intrinsic resistance to BRAF-inhibitor therapy. Since resistance to BRAF inhibitors is associated with a continued reliance on the RASRAFMEKERK pathway, MEK inhibitors will probably be useful in the management of acquired resistance to BRAF inhibitors.*Figure 2. Targeting Treatment to a Specific Variant in the Melanoma Gene.Shown are three-dimensional representations of glucose metabolism in 18F-fluorodeoxyglucose (FDG)PET scans obtained at baseline and 2 weeks after the initiation of treatment in a patient with melanoma carrying the V600E BRAF mutation. The patient was treated with the BRAF inhibitor PLX4032. Hypermetabolism of injected radioactive glucose is indicated by the red, green, and yellow signals and is a feature of dividing cancer cells, as well as being a normal feature of brain and bladder metabolism or excretion. (Images courtesy of Grant McArthur, Jason Callahan, and Rod Hicks of the Peter MacCallum Cancer Centre.)*Figure 3. Best Tumor Response for Each Patient.Data regarding the best tumor response are shown for 209 patients in the vemurafenib group (Panel A) and 158 patients in the dacarbazine group (Panel B) who were registered at least 14 weeks before the clinical cutoff date on December 30, 2009, and who had undergone at least one tumor assessment after treatment. Each bar represents data for an individual patient. Colors indicate the tumor substage for each patient. The percent change from baseline in the sum of the diameters of the target lesions is shown on the y axis. Negative values indicate tumor shrinkage.*Figure 2. Progression-free Survival.Panel A shows KaplanMeier estimates of progression-free survival in patients in the intention-to-treat population. Patients could be evaluated for progression-free survival if they had undergone randomization at least 9 weeks before clinical cutoff date. The median progression-free survival was 5.3 months for vemurafenib and 1.6 months for dacarbazine. The vertical lines indicate that patients' data were censored. Panel B shows hazard ratios and 95% confidence intervals (CI) for progression-free survival in prespecified subgroups of patients, according to baseline characteristics. In both panels, data are shown for patients who received no study treatment (48 patients in the dacarbazine group and 2 patients in the vemurafenib group) and for 1 patient who was assigned to the dacarbazine group and who received vemurafenib. NR denotes not reached.A 72-year-old man presented for evaluation of progressive dyspnea and cough. He reported smoking one to two packs of cigarettes a day since the age of 15 years. Standard chest radiography showed a suspicious lesion in the right thoracic cavity. Computed tomography of his chest revealed bullous emphysema (thick arrow), a tumor involving the middle lobe of the right lung (thin arrow), and a pack of cigarettes in his shirt pocket (asterisk). Biopsy of the lesion confirmed the presence of non-small-cell lung cancer.1960s TV ad.Magnificent Seven theme music1971 Governent ban on TV Ads.Image lived onTwo Marlboro men, Wayne McLaren and David McLean, died of lung cancer, McLaren testified in favour of anti-smoking legislatio. Greek (1990s) and German (1998) ads emphasising the super slim, long line of the cigarette- and smoker.