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