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121 Background: In the phase III SOLSTICE study, FTD/TPI plus BEV showed similar efficacy to capecitabine plus BEV as first-line treatment for patients with mCRC ineligible for full-dose combination chemotherapy with oxaliplatin [OX] or irinotecan [IRI] (intensive therapy). We evaluated clinical outcomes of FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients, who were defined to be intolerant to intensive therapy. Methods: This was a multicenter retrospective study of vulnerable patients with unresectable mCRC who received FTD/TPI plus BEV as second- or later lines treatment between May 2014 and October 2020. Main eligibility criteria were histologically proven adenocarcinoma, ECOG PS 0-2, prior chemotherapy for unresectable disease, considered intolerant to intensive therapy, and underwent FTD/TPI plus BEV without prior exposure to at least one key cytotoxic agent (fluoropyrimidines [FP], OX, or IRI). Results: Of 96 patients enrolled from 26 Japanese hospitals, 93 patients were evaluable. Patient characteristics were as follows: median age, 79 years (range 21-90); male, 53%; ECOG PS 0-1, 89%; right-sided primary tumor, 30%; primary tumor resection, 86%; RAS mutant, 63%; BRAF mutant, 1%; second-line treatment, 80%; prior exposure to FP 100%, OX 50%, and IRI 15%. Main reasons for intolerance to intensive therapy were older age (65%), poor PS (20%), and renal failure (5%). Initial dose of FTD/TPI was reduced in 30 (32%) patients. The response rate was 5% and disease control rate was 68%. With median follow-up of 21.6 months, the median progression-free survival, time to treatment failure, and overall survival were 6.3, 4.5, and 18.6 months, respectively. Major grade >3 adverse events were neutropenia (54%), anemia (20%), thrombocytopenia (9%), hypertension (7%), and febrile neutropenia (2%). No treatment-related deaths were observed. The treatment was discontinued in 89 patients due to disease progression (n = 72), patient’s refusal (n = 10), and adverse events (n = 6). After FTD/TPI plus BEV, chemotherapies such as regimens including IRI or OX (n = 20), regorafenib (n = 16), and anti-EGFR antibody monotherapy (n = 7) were performed in 42 patients. Conclusions: FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients with mCRC showed promising clinical activity and acceptable safety profile. This study suggested that FTD/TPI plus BEV could be a treatment option for vulnerable patients with pretreated mCRC. Clinical trial information: UMIN000044136 .

e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).

416 Background: The NIVOLVE trial was designed to assess the efficacy and safety of nivolumab as an adjuvant therapy for HCC, and to identify biomarkers predictive of recurrence in patients after SR or RFA (Registration # UMIN 000026648). Methods: The trial involved 11 sites and was conducted in patients with HCC who showed a complete response after SR (n = 33) or RFA (n = 22) (ITT). Overall, 53 of 55 patients with Child-Pugh A received nivolumab (240 mg/body every 2 weeks (8 cycles)), followed by nivolumab (480 mg/body every 4 weeks [8 cycles]) within 6 weeks after SR or RFA. The primary endpoint was the 1-year recurrence-free survival rate (RFSR). The key secondary endpoint was RFS. Exploratory biomarker analysis included mutations, copy number alterations, and positivity of immune cells. Techniques included next generation sequencing, immunohistochemical staining (IHC) of formalin-fixed paraffin-embedded tissues (n = 31 [13 with recurrence and 18 without]) for CD8, PD-1, PD-L1, Foxp3, and β-catenin, and ctDNA analysis using pre-nivolumab whole blood by deep sequencing (CAPP-seq; Avenio). Results: The 1-year RFSR and median RFS were 78.6% and 26.3 months (95% confidence interval (CI), 16.8-NR), respectively, with no difference between SR and RFA. Copy number gains (CNGs) in WNT/β-catenin related genes ( APC, CTNNB1, TCF7L1, TCF7L2) (n = 30) correlated with shorter RFS (positive: 10.6 months vs. negative: not reached [NR]; p < 0.0001). IHC revealed that negative staining for PD-1 (p < 0.0001), a low combined positive score for PD-L1 (p = 0.005), a low number of CD8+ tumor infiltrating lymphocytes (TILs) (p < 0.001), and positivity for Foxp3+ cells (p = 0.015) correlated with recurrence. HCC cases with low numbers of CD8+ TILs or cases positive for Foxp3+ cells (n = 16) showed a significantly shorter RFS (16.8 months [95% CI, 8.7-25.2]) than those with high numbers of CD8+ TILs and those positive for PD-1/PD-L1 expression (n = 15) (NR [95% CI,26.2months–NR]) (p < 0.0001). HCC cases with activation of the WNT/β-catenin pathway assessed by IHC (n = 9) showed shorter RFS (17.0 months [95% CI,1.1–26.2]) than those without activation (n = 22) (NR [95% CI,23.0 months–NR]) (p = 0.014). Patients positive for ctDNA (n = 15) before nivolumab tended to have shorter RFS than those without ctDNA (n = 9) (26.3 vs. NR). There was no correlation between TMB and RFS. Treatment-emergent adverse events (AEs) (n = 53) were as follows: all grades, 93%; grades 3–4 (18.9%); and immune related AEs, 25%. Conclusions: The 1-year RFSR and RFS in the NIVOLVE trial were 78.6% and 26.3 months, respectively. No new safety signal was observed. CNG in WNT/β-catenin-related genes, activation of the WNT/β-catenin pathway, the presence of Foxp3+ cells, and low numbers of CD8+ TILs may predict recurrence after SR or RFA with adjuvant nivolumab. Clinical trial information: UMIN 000026648.

9037 Background: Although the efficacy of antibodies to programmed cell death–1 (PD-1) appears to be less pronounced in patients with NSCLC harboring epidermal growth factor receptor gene ( EGFR) mutations, patients who develop disease progression (PD) to TKIs due to mechanisms other than secondary T790M mutation of EGFR might be more likely to benefit from NIVO. Here, we report the results of first randomized phase II trial to compare NIVO with the CbPEM in those population. Methods: Pts with advanced EGFR mt NSCLC who experienced PD after EGFR-TKIs were randomized 1:1 to NIVO or CbPEM. Eligibility criteria included the treatment history with TKIs as follow; no evidence of T790M after PD on 1st/2nd generation (gen) TKIs (A) after PD on 3rd gen TKIs as a 2nd line for T790M positive tumor (B) or 3rd gen TKIs as a front-line (C). The primary end point is progression-free survival (PFS) and biomarker analysis were included for exploratory analysis. Results: A total of 102 patients was randomized. Median PFS and overall survival (OS) were 1.7 and 20.7 months (mo), respectively, for NIVO arm (n = 52) versus 5.6 and 19.9 months for CbPEM (n = 50) (Hazard ratio [HR] = 1.92 and 0.88, respectively). Overall response rate and duration of response were 9.6% and 5.3 months for NIVO and 36.0% and 5.5 months for CbPEM. PD-L1 expression on tumor cells and tumor mutation burden (TMB) were evaluated in 77 (TPS 0%. 1-49%, > 50%, n = 46, 20, and 11) and 50 (Median TMB 6.2mt/mb). Immune-related gene expression profiling was under evaluation and the results will be demonstrated in the meeting. The efficacy of NIVO in PD-L1 strong positive (>50%, n = 8) and no evidence of T790M after PD on 1st/2nd gen TKIs (n = 29) was tended to be better than their counterparts. There was no significant correlation between TMB and the efficacy of NIVO. Pneumonitis was observed in one patient (1.0%) for NIVO arm and no new safety signals were noted. Conclusions: NIVO was not associated with longer PFS than CbPEM in selected pts with advanced EGFR mt NSCLC. OS was similar between groups. Baseline PD-L1 status and genetic alteration features may be relevant predictive markers to select pts who would benefit from NIVO. Clinical trial information: jRCTs051180133. [Table: see text]

4070 Background: The NIVOLVE trial was designed to assess the efficacy and safety of nivolumab as an adjuvant therapy for HCC, and to identify biomarkers predictive of recurrence in patients after SR or RFA (Registration # UMIN 000026648). Methods: The trial involved 11 sites and was conducted in patients with HCC who showed a complete response after SR (n = 33) or RFA (n = 22) (ITT). Overall, 53 of 55 patients with Child-Pugh A received nivolumab (240 mg/body every 2 weeks (8 cycles)), followed by nivolumab (480 mg/body every 4 weeks (8 cycles)) within 6 weeks after SR or RFA. The primary endpoint was the 1 year recurrence-free survival rate (RFSR). The key secondary endpoint was RFS. Exploratory biomarker analysis included mutations, copy number alterations, and tumor mutation burden in tumor tissues. Techniques included next generation sequencing, immunohistochemical staining (IHC) of formalin-fixed paraffin-embedded tissues (n = 31, 13 with recurrence and 18 without) for CD8, PD-1, PD-L1, Foxp3, and β-catenin, and ctDNA analysis using pre-nivolumab whole blood by deep sequencing (CAPP-seq; Avenio). Results: The 1-year RFSR and median RFS were 76.7% and 26.0 months (95% confidence interval (CI), 23.9–28.1), respectively, with no difference between SR and RFA. Copy number gains (CNGs) in WNT/β-catenin related genes ( APC, CTNNB1, TCF7L1, TCF7L2) (n = 8) correlated with shorter RFS (positive: 11.8 months vs. negative: not reached [NR]; p = 0.0003). IHC revealed that negative staining for PD-1 (p < 0.0001), a low combined positive score for PD-L1 (p = 0.0113), a low number of CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0130), and positivity for Foxp3+ cells (p = 0.0076) correlated with recurrence. Treatment-related adverse events (AEs) (n = 53) were as follows: all grades, 68%; grades 3–4 (18.9%); and immune related AEs, 25%. HCC cases with low numbers of CD8+ TILs or cases positive for Foxp3+ cells (n = 16) showed a significantly shorter RFS (16.8 months [95% CI, 8.7–25.1]) than those with high numbers of CD8+ TILs and those positive for PD-1/PD-L1 expression (n = 15) (NR [95% CI,26.2months–NR]) (p < 0.0001). HCC cases with activation of the WNT/β-catenin pathway assessed by IHC (n = 9) showed shorter RFS (17.0 months [95% CI,1.1–26.2]) than those without activation (n = 22) (NR [95% CI,24.7 months–NR]) (p = 0.0191). Patients positive for ctDNA (n = 10) before nivolumab tended to have shorter RFS than those without ctDNA (n = 30) (26.2 vs. NR). There was no correlation between TMB and RFS. Conclusions: The 1 year RFSR and RFS in the NIVOLVE trial were 76.6% and 26.0 months, respectively. No new safety signal was observed. CNG in WNT/β-catenin-related genes, activation of the WNT/β-catenin pathway, the presence of Foxp3+ cells, and low numbers of CD8+ TILs may predict recurrence after SR or RFA with adjuvant nivolumab. Clinical trial information: 000026648.

106 Background: CUP has a poor prognosis with a median survival of less than 12 months. Given the recent approval of immune checkpoint inhibitors in several cancer types, we performed a multicenter phase II study of nivolumab in CUP patients (pts). Methods: The main population of this study is CUP pts who were previously treated with more than one line of systemic chemotherapy. Previously untreated CUP pts were also enrolled for exploratory analysis. Pathological examination (including IHC), CT, FDG-PET, gastroscopy and colonoscopy and medical examination were mandatory for diagnosis of CUP before enrollment. CUP pts belonging to favorable prognosis groups were excluded from the trial. Nivolumab (240 mg/body) was delivered as an intravenous infusion every 2 weeks for up to 52 cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 by an Independent Endpoint Review Committee in previously treated pts. The secondary objectives include investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety and the association between the efficacy of nivolumab and PD-L1 expression. Results: A total of 56 CUP pts, 45 previously treated and 11 previously untreated pts, were enrolled in this trial. The median age was 65.5 years, 22 pts were male. Median follow-up was 8.05 mo (range, 0.1 to 20.7 mo). Of 45 previously treated pts, 2 and 9 had an investigator-assessed complete response and partial response (ORR 24.4%, 95% CI: 12.9-39.5%), with a median PFS (mPFS) and OS (mOS) of 5.4 mo (95% CI: 2.6-6.9) and 15.1 mo (95% CI: 8.3-NR), respectively. Among 11 previously untreated pts, 1 pt had partial response (ORR 9.1%, 95% CI: 0.2-41.3%). The mPFS was 3.9 mo and the mOS was not reached in untreated pts (95% CI: 1.1-5.6, and 95% CI: 2.6-NR, respectively). Nivolumab demonstrated a mPFS of 5.1mo (95% CI: 2.7-5.6) and a mOS of 15.9 mo (95% CI: 8.4-NR) in an overall population. Immune-related adverse events occurred in 57% of overall pts with 5% of grade 3 or higher, and the most common were rash (27%), hypothyroidism (16%), and diarrhea/colitis (16%). No treatment related death was observed. Conclusions: In pts with previously treated and untreated CUP, nivolumab demonstrated durable antitumor activity with a manageable safety. Clinical trial information: UMIN000030649.

e15577 Background: Although gene profiling is a promising diagnostic technique to determine the tissue of origin for pts with CUP, we reported that site-specific treatment based on gene profiling using microarray did not result in an improvement the survival compared with empirical therapy in the previous randomized phase 2 trial (Hayashi, et. al, JCO 2019). Recently, we have established new integrative diagnostic system combined the gene expression from RNA-sequencing and mutation/copy number variation data from targeted genomic-sequencing using NGS. We have performed a single-arm phase 2 study to assess the efficacy of site-specific therapy determined by this system in previously untreated pts with CUP. Methods: Comprehensive gene profiling was performed by NGS, and an established algorithm was applied to predict tumor origin. Pts with CUP was received site-specific chemotherapy determined by the predicted site. The primary endpoint was one-year survival rate. Results: A total of 111 pts was enrolled and all had sufficient biopsy tissue for gene profiling. Efficacy analysis was performed for 97 pts who received site-specific treatment. Cancer types most commonly predicted were lung (21%), liver (15%), kidney (15%), and colorectal cancer (12%). The one-year survival rate, median overall survival (OS), and progression free survival (PFS) was 53.1% (95%CI, 42.6-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Median OS (15.7 versus 11.0 months, P = .078) and PFS (5.5 versus 2.8 months, P = .019) were better for predicted tumor types categorized as more responsive types than for less responsive ones. Conclusions: Site-specific treatment based on NGS demonstrated promising efficacy. Pts with CUP predicted to have more responsive tumor types had longer survival compared with pts with less responsive tumor types, suggesting that molecular tumor profiling by both DNA and RNA testing contributes to the management of pts with CUP. Clinical trial information: UMIN051180009.

586 Background: EASL guidelines for management of HCC recommends assessing tumor response according to mRECIST at all stages of the disease (EASL guidelines, J Hep 2018). Several studies have reported that objective response by mRECIST predicted overall survival (OS) but definitive data are still lacking. Methods: The PubMed database and ASCO meeting library were searched for full reports of randomized trials in patients with advanced HCC treated by systemic therapy up to August 31, 2018. We search strategy used the following terms: HCC, mRECIST, OS and objective response rate (ORR). We assess the association between ORR and OS in a meta-analysis of pooled data by using random effects model comparing patients achieving objective response (complete or partial response) versus non responders (stable disease, progressive disease) and displayed the results as per hazard ratio (HR, 95% CI). Results: Among 14 articles assessing response by mRECIST to systemic therapies in randomized studies in advanced HCC, 4 studies (5 trials) including 1,463 patients were considered eligible. Systemic therapies tested included lenvatinib, sorafenib, brivanib and nintedanib. Overall, ORR as per mRECIST ranged from 11.5% to 18.8%, being the median OS for responders of 18.5 to 27.2 mo (as opposed 8.9 to 11.4 for non-responders). As per random effects model, the HR for overall survival (responders versus non responders) was 0.47 (95% confidence interval 0.34–0.66, p

534 Background: In SILIUS (NCT01214343) trial, combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve OS in patients with advanced HCC compared with sorafenib alone (Kudo M, et al. Lancet Gastroenterol Hepatol 2018). In this study, we explored the relationship between OR and OS in the sorafenib group in the SILIUS trial. Methods: Association between OR and OS in patients treated with sorafenib ( n = 103) were analyzed. The median OS of responders was compared with that of non-responders by using Mantel-Byar test to exclude guarantee-time bias. Landmark analyses were performed, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with OR as a time-dependent covariate, with other prognostic factors. Results: OS of responders ( n = 18) was significantly better than that of non-responders ( n = 78) ( p < 0.0001), where median OS was 27.2 (95% CI, 16.0–not reached) months for responders and 8.9 (95% CI, 6.5–12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 ( p = 0.0330), 0.37 ( p = 0.0053), and 0.36 ( p = 0.0083), respectively. OR by sorafenib was an independent predictor of OS based on unstratified Cox regression analyses. Conclusions: In the SILIUS trial, OR achieved by sorafenib per mRECIST is an independent predictor for OS in patients with HCC. [Table: see text]

Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non–small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m2 on day 1)/vindesine (3 mg/m2 on days 1, 8)/cisplatin (80 mg/m2 on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m2)/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. Conclusion Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

4033Background: The prognosis of gastric cancer with serosal invasion is extremely poor. Despite various perioperative adjuvant therapies, peritoneal recurrence is still difficult to control. Since...

e14635 Background: This is a following report of the exploratory phase II study of adjuvant peptide vaccine for thoracic esophageal squamous cell carcinoma (TESCC) (abstract #3087 in ASCO2016), focusing on an association of immunological responses with clinical outcomes. Three HLA-A-24-restricted epitope peptides derived from cancer-testis antigens, up-regulated lung cancer 10 (URLC10), cell division cycle associated 1 (CDCA1) and KH domain-containing protein overexpressed in cancer 1 (KOC1), were used in this study. Methods: TESCC patients who underwent neoadjuvant therapy followed by curative resection (Dec./2009 to Sep./2014) and were found LN metastasis were enrolled. One mg each of three peptides mixed with Montanide was injected to patients with HLA-A*2402 20 times in a 6-months period. No other adjuvant therapy was given until recurrence occurred. Primary endpoint is relapse-free survival (RFS). Immunological responses were examined by ELISPOT assay and immunohistochemistry (IHC). Results: 33 patients were enrolled in the vaccine group (VG) and 30 with non-HLA-A*2402 were used as controls (CG). There was no significant difference in clinical backgrounds between the two groups. 5-year RFS in the VG was 44.6% while that in the CG group was 31.6% (p = 0.207); patients who showed CD8+ CTL induction to multiple peptides tend to show better RFS rate [3/2/1 peptides = 69.0(n = 20)/46.8(n = 11)/0%(n = 2), respectively]. Five-year esophageal cancer-specific survival (ECSS) were 58.4% in the VG compared with 35.4% in the CG (p = 0.156); 90.0% (n = 11) vs. 50.0% (n = 15) and 43.8% (n = 22) vs. 24.0%(n = 15) in pN1 and pN2-3 groups, respectively. Regarding the CD8+ positivity, ECSS was improved only in the negative group (56.6% in VG vs. 26.7% in CG). Classification by T cell positivity and PD-L1 expression [type I(+/+), II(-/-), III(-/+) and IV(+/-)] showed 5-year ECSS to be 100%(n = 3), 66.4%(n = 19), 20.0%(n = 5) and 44.4%(n = 6). Conclusions: Our cancer peptide vaccines induced the antigen-specific CD8+ T cell highly and efficiently, and suppressed recurrence with the strong immune responses. Clinical trial information: UMIN000003557.

3087Background: Three HLA-A-24-restricted epitope peptides have been identified, which were derived from three cancer-testis antigens that are expressed only in esophageal squamous cell carcinoma (...

9598 Background: Superiority of palonosetron to granisetron is uncertain, for patients with breast cancer receiving both steroid and NK1 inhibitor against CINV caused by AC regimen. Methods: We con...

e18013 Background: Although adenocarcinoma (Ad) histology and smoking status are now recognized as possible prognostic factors in advanced NSCLC, the distribution of both extensively overlaps. We a...

7530 Background: Concurrent chemoradiotherapy plays an important role in the treatment of unresectable stage III NSCLC. Our group demonstrated a superiority of MVP with concurrent TRT over that with sequential TRT (Furuse, JCO, 1999), while weekly chemotherapy with concurrent TRT has acceptable toxicities and expected efficacy. We conducted a randomized phase III trial to compare the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP by a non-inferiority design. Methods: Patients were assigned to 3 regimens; MVP: cisplatin (80 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36) and mitomycin (8 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). After then, pts received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2) / carboplatin(AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan(50 mg/m2) / carboplatin(AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2) / carboplatin (AUC 5). Primary endpoint was overall survival. Results: From Sep 2001 to Sep 2005, 456 pts were randomized; 429 pts had evaluated responses. Pretreatment characteristics were well-balanced between 3 arms (median age 63 years (30–74), PS0/1 41/55%, Ad/Sq/others 43/45/12%). The achievement rates of full treatment in MVP, IC and PC were 39.9, 29.7, and 49.3 %; those of full-dose TRT/2 courses of consolidation chemotherapy were 81.1/41.3%, 41.4/29.7% and 59.7/50.0%, respectively. Major toxicities were as follows; G4 neutropenia in MVP, IC, PC were 76.9, 13.1, 4.2% (p No significant financial relationships to disclose.