This trial investigates pemetrexed and cisplatin followed by pemetrexed and cisplatin in combination with radiotherapy in participants with locally advanced, non-small cell lung cancer (NSCLC). The purpose of the study is to assess the antitumor activity as measured by progression free survival 1 year after start of treatment with study drug.

The participants will receive 2 cycles of pemetrexed and cisplatin. If the participants achieve complete response, partial response or stable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, have ≤35% of the total calculated lung volume receive more than 20 Gy (V20) according to the 3-dimensional (3-D) radiotherapy planning Dose Volume Histograms, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, have no residual neurological toxicity > Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE), they will receive 2 additional cycles of pemetrexed and cisplatin, combined with radiotherapy. The combination of radiotherapy will begin 22 to 36 days after completion of the second infusion of induction therapy with pemetrexed-cisplatin.

Inclusion Criteria:

• Histologic or cytologic diagnosis of unresectable nonsquamous Stage IIIA or Stage IIIB (without malignant pleural/pericardial effusions) NSCLC.
• Have an ECOG performance status of 0 or 1.
• Previous radiation therapy should have been limited and must not have included thoracic radiation, whole pelvis radiation, or radiation to >25% of the participant's bone marrow, participants must have recovered from the toxic effects of radiation treatment prior to study enrollment (except for alopecia). Prior radiotherapy must be completed 30 days before study entry.
• Have at least 1 unidimensionally measurable lesion meeting RECIST guidelines, version 1.0.
• Estimated life expectancy of at least 12 weeks.
• Participant compliance and geographic proximity that allow adequate follow-up.
• Adequate bone marrow reserve, hepatic-, renal- and pulmonary function.
• Participants must sign an Informed Consent Document.
• Participants must have a total lung V20 less than or equal to 35%.
• For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen, during and for 6 months after the treatment period; must have a negative serum pregnancy test within 7 days before study enrollment and must not be breast-feeding. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period.
• Have not received prior systemic anticancer therapy for NSCLC.

Exclusion Criteria:

• Have received treatment within the last 30 days of enrollment with a drug that has not received regulatory approval for any indication at the time of study entry.
• Have previously completed or withdrawn from this study or any other study investigating pemetrexed.
• Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol.
• Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV.
• Have had a prior malignancy other than NSCLC, carcinoma in situ of the cervix, or non-melanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Participants with a history of low-grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously.
• Are receiving concurrent administration of any other antitumor therapy.
• Have had weight loss of more than 10% over the previous 3 months before study entry.
• Are unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose less than or equal to 1.3 grams per day, for at least 2 days before (5 days for long-acting agents), the day of, and for at least 2 days after administration of pemetrexed.
• Are unable or unwilling to take folic acid or vitamin B12 supplementation.
• Are unable or unwilling to take corticosteroids.
• Have received a recent yellow fever vaccination (within 30 days of enrollment) or are receiving concurrent yellow fever vaccination.
• Have known hypersensitivity to pemetrexed, cisplatin, or any of the excipients in these medicinal products.
• Have evidence of clinical hearing loss.
• Have clinically significant third-space fluid collections, that cannot be controlled by drainage or other procedures prior to study entry.