MEK Inhibitor and Thoracic Radiotherapy Trial

Inclusion Criteria:

* Histologically or cytologically confirmed NSCLC either inoperable, stage III NSCLC or stage IV NSCLC with dominant chest symptoms.
* Patient age ≥18
* Willingness and able to comply with treatment, tests and attend the required follow-up
* Prior chemotherapy is permitted provided the interval between day 8 of the last cycle of chemotherapy and day 1 of AZD6244 dosing is ≥2 weeks
* No prior radiotherapy or investigational agents
* Life expectancy estimated to be greater than 3 months
* Performance status(ECOG) 0 or 1
* MRC dyspnoea score \<3
* Patient considered able to tolerate radical radiotherapy
* FEV1 \>40% of predicted and DLCO (transfer factor for carbon monoxide) \>40% of predicted
* Disease which can be encompassed within a radical radiotherapy treatment volume(V20 ≤35% and maximum cord dose 48Gy) on the radiotherapy planning scan
* Left ventricular ejection fraction \>50% on baseline echocardiogram
* Adequate renal function - defined by GFR \>50 ml/min (calculated Cockcroft and Gault) or by isotope GFR.
* Adequate bone marrow reserve: white cell count \>3 x 109/l, absolute neutrophil count \>1.5 x 109/l, haemoglobin \>10.0 g/dl and platelet count \>100 x 109/l (Blood transfusion permitted to achieve Hb \>10g/dl)
* AST/ALT \< 2.5 ULN and bilirubin \<1.5 ULN
* Group D (expanded cohort) only: diameter of the primary tumour should be \> 2 cm

Exclusion Criteria:

* Mixed non-small cell and small cell tumours
* Other previous or current malignant disease likely to interfere with protocol treatment or comparisons
* Lack of recovery from prior chemotherapy toxicity to grade ≤2 except alopecia d)Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption of AZD6244
* Presence of clinically significant fluid accumulations in third spaces which cannot be adequately controlled by drainage or other procedures prior to inclusion in the study.
* History / evidence of active bleeding diatheses
* History of unstable diabetes
* History of interstitial pneumonitis
* Arterial hypertension defined as SBP≥ 160 or DBP ≥100 (antihypertensive medication to achieve these parameters are permissible)
* Myocardial infarction, or unstable or uncontrolled angina, congestive heart failure (NYHA \> class II) within 1 year of enrollment
* Active infection on day of enrollment
* Uncontrolled hypercalcemia \>3.0 or symptomatic
* History of hypersensitivity to active or inactive excipients of AZD6244
* Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) which would prevent administration of study treatment
* Known and symptomatic brain metastases. Brain imaging is not mandatory if patient is asymptomatic.
* Clinical judgement by the investigator that the patient should not participate in the study
* Patients of reproductive potential who are unable to comply with effective contraception if sexually active during the study and for a period of at least 90 days (men) or 6 months after treatment (women)
* Women who are breastfeeding