Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF.Methods: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100 mg·m⁻²on days 1, 8 and 15) every 3 weeks with or without nintedanib (150 mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS).Results: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67–1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR 0.68, 95% CI 0.50–0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40–0.93) and in those at GAP (gender–age–physiology) stage I (HR 0.61, 95% CI 0.38–0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment.Conclusions: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.

Small cell lung cancer (SCLC) is characterized by a rapid doubling time, a propensity for early dissemination, significant sensitivity to chemotherapy and radiotherapy, and accounts for approximately 15 to 20% of all cases of lung cancer diagnosed. The majority of these patients have extensive stage disease at the time of diagnosis. The standard treatment for patients with extensive stage SCLC is systemic chemotherapy with a combination of cisplatin and etoposide, a regimen that yields a median survival of approximately 9 months and a 2-year survival of less than 10%.¹ x 1 Noda, K, Nishiwaki, Y, Kawahara, M et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002; 346: 85–91 Crossref | PubMed | Scopus (1051) | Google Scholar See all References ^{, 2} x 2 Lara, PN Jr, Natale, R, Crpwley, J et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWAG S0124. J Clin Oncol. 2009; 27: 2530–2535 Crossref | PubMed | Scopus (304) | Google Scholar See all References ^{, 3} x 3 Hanna, N, Bunn, PA Jr, Langer, C et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006; 24: 2038–2043 Crossref | PubMed | Scopus (439) | Google Scholar See all References Nevertheless, elderly or poor performance status (PS) patients often have poor tolerance for a cisplatin-containing regimen. Therefore, carboplatin is widely used as an alternative.⁴ x 4 Okamoto, H, Watanabe, K, Kunikane, H et al. Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer. 2007; 97: 162–169 Crossref | PubMed | Scopus (116) | Google Scholar See all References ^{, 5} x 5 Skarlos, DV, Samantas, E, Kosmidis, P et al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small cell lung cancer. A Hellenic Co-operative Oncology Group Study. Ann Oncol. 1994; 5: 601–607 Crossref | PubMed | Google Scholar See all References

Background: Phase III trials evaluating the efficacy of gefitinib (IRESSA) in non-small cell lung cancer (NSCLC) lend support to the need for improved patient selection in terms of gefitinib use. Mutation of the epidermal growth factor receptor (EGFR) gene is reported to be associated with clinical responsiveness to gefitinib. However, gefitinib-sensitive and prolonged stable-disease-defined tumors withoutEGFRgene mutation have also been reported.Methods: To identify other key factors involved in gefitinib sensitivity, we analyzed the protein expression of molecules within the EGFR family, PI3K-Akt and Ras/MEK/Erk pathways and examined the sensitivity to gefitinib using the MTT cell proliferation assay in 23 lung cancer cell lines.Results: We identified one highly sensitive cell line (PC9), eight cell lines displaying intermediate-sensitivity, and 14 resistant cell lines. Only PC9 and PC14 (intermediate-sensitivity) displayed anEGFRgene mutation including amplification. Eight out of the nine cell lines showing sensitivity had Akt phosphorylation without ligand stimulation, while only three out of the 14 resistant lines displayed this characteristic (P= 0.0059). Furthermore, the ratio of phosphor-Akt/total Akt in sensitive cells was higher than that observed in resistant cells (P= 0.0016). Akt phosphorylation was partially inhibited by gefitinib in all sensitive cell lines.Conclusion: These results suggest that Akt phosphorylation without ligand stimulation may play a key signaling role in gefitinib sensitivity, especially intermediate-sensitivity. In addition, expression analyses of the EGFR family,EGFRgene mutation, and FISH (fluorescencein situhybridization) analyses showed that the phosphorylated state of EGFR and Akt might be a useful clinical marker of Akt activation without ligand stimulation, in addition toEGFRgene mutation and amplification, particularly in adenocarcinomas.

Background: The EML4–ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non–small–cell lung cancers (NSCLCs). The EML4–ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS. Case presentation: We report that a case of EML4–ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor. Conclusions: We described the first clinical report of a patient with EML4–ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4–ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4–ALK-positive NSCLC.

Background: The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer. Methods: We related the cytotoxic activity of each of commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin (CDDP), and carboplatin (CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program. Results: We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster. Conclusion: These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types.