Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.

Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.

[Trimodal Therapy for Stage IIIA-B NSCLC Involving High Dose Neoadjuvant Chemoradiotherapy. Is Surgery a Rational Option?] / Trimodale Therapie des NSCLC im Stadium IIIA-B mittels neoadjuvanter Hochdosisradiochemotherapie. Stellt die Operation eine sinnvolle Option dar?

Introduction Stage III non-small cell lung cancer (NSCLC) and its possible multimodal therapy present a challenge to the responsible oncologist, chest surgeon and radiologist. The aim of the present retrospective study was to analyse and evaluate the treatment algorithm in our hospital for patients with stage III NSCLC (intention to treat). We compared an aggressive treatment regime with primary trimodal therapy (high dose radiochemotherapy and resection), independently of "multilevel" N2 or "single level" N3 status. These results were then compared with a historical group of our patients who solely received simultaneous radiochemotherapy (bimodal therapy). Materials and Methods Within the period of the study, 156 patients were diagnosed with stage III NSCLC and treated with trimodal therapy. The median age was 71 years. 103 patients (60%) were male, 53 (34%) female. In the group with bimodal therapy, 102 patients were evaluated. Results After radiological restaging and checking functional resectability, 90 patients (57.7%) in the trimodal therapy group received secondary resection, including 37 (41.1%) lobectomies/bilobectomies, 37 (41.1%) sleeve lobectomies, 13 (14.4%) pneumonectomies and 3 (3.3%) segmentectomies (for severely restricted pulmonary function). The median survival time in the trimodal therapy group was 535 days and in the bimodal group 388 days; this difference was not statistically significant (p = 0.1377). Finally the 5-year survival after actual therapy was performed ("as-treated trimodally" vs. "as-treated bimodally"). The median survival time was then 807 days for trimodal therapy and 427 days for bimodal therapy. Conclusion High dose neoadjuvant radiochemotherapy followed by secondary resection is still a valuable option for selected patients with stage III NSCLC. However, this retrospective analysis failed to find a statistically significant survival advantage for the "intention-to-treat" trimodal patients.

GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin. METHODS: Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS). RESULTS: A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively. DISCUSSION: Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.

Combined point mutation in KRAS or EGFR genes and EML4-ALK translocation in lung cancer patients.

A total of three cases with novel constellations regarding mutation patterns in non-small-cell lung cancer (NSCLC) are reported. The mutation patterns that are observed are novel and unexpected. First, a combined simultaneous KRAS mutation and EML4-ALK translocation, both in the main tumor and a bone metastasis, were observed, these mutations are assumed to mutually exclude each other. A further two cases include a father and a daughter, both of whom are suffering from NSCLC with different EGFR mutation patterns. A common cause was assumed; however, could not be deduced to mutations in the KRAS, BRAF and EGFR genes. The aforementioned cases are important, as it must be taken into account that mutations previously assumed to be exclusive can occur in combination, may influence the clinical outcome and may require different therapy compared with single mutated tumors. It has to be discussed whether diagnostic algorithms need to be adapted. The cases of father and daughter show that further unknown factors can influence development of NSCLC.

Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial.

UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer.

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

Stereotactic, high single-dose irradiation of stage I non-small cell lung cancer (NSCLC) using four-dimensional CT scans for treatment planning.

We reviewed response rates, local control, survival and side effects after non-fractionated stereotactic high single-dose body radiation therapy for lung tumors. Forty patients with stage I non-small cell lung cancer (NSCLC) underwent radiosurgery involving single-dose irradiation. The standard dose prescribed to the isocenter was 30Gy with an axial safety margin of 10mm and a longitudinal safety margin of 15mm. The planning target volume (PTV) was defined using three CT scans with reference to the phases of respiration so that the movement span of the clinical target volume (CTV) was enclosed. The volume of the bronchial carcinomas varied from 4.2 to 130cm(3) (median: 19.5cm(3)), and the PTV derived from four-dimensional CT (4D-CT) scans using image fusion ranged from 15.6 to 390.5cm(3) (median: 101cm(3)). Tumor size ranged from 1.7 to 10cm at largest focuses. Follow-up periods varied from 6.0 to 61.5 months (median: 20 months). We observed three local tumor recurrences, resulting in an actuarial local tumor control of 81% at 3 years. With the exception of two rib fractures, no serious late toxicity was observed. The overall survival probability rates were: 2 years: 66%, 3 years: 53% (median overall survival: 37 months). Cancer-specific survival probability was: 2 years: 71%, 3 years: 57%. Non-fractionated high single-dose SBRT for NSCLC is more convenient for the patient and less time-consuming than hypofractionated SBRT, but data dealing with this method are still scanty. This alternative treatment results in favourable local control and acceptable toxicity.

A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer.

BACKGROUND: BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS: ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS: Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.

Large cell neuroendocrine lung carcinoma induces peripheral T-cell repertoire alterations with predictive and prognostic significance.

OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) ß-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial. RESULTS AND CONCLUSION: Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (p < 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p < 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p < 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.

Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors.

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.

A phase II study of irinotecan (CPT-11) and carboplatin in patients with limited disease small cell lung cancer (SCLC).

PURPOSE: The aim of this phase II trial was to evaluate the efficacy and safety of a combination chemotherapy containing irinotecan (CPT-11) and carboplatin as first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: From December 2002 to May 2004 61 patients with limited disease (IASLC classification) were enrolled who were not suitable for concurrent chemo-radiotherapy. Eighteen of the 61 patients (29.5%) had malignant pleural or pericardial effusion and 4 patients (6.6%) had involved supra- or infraclavicular lymph nodes. Patients received irinotecan 50mg/m(2) on days 1, 8 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. RESULTS: A total of 233 chemotherapy cycles were administered. The median number of cycles per patient was 4. The overall response rate to chemotherapy on an intention-to-treat basis was 64%. The median overall survival was 13.8 months, the median disease-free survival 8.0 months, the 1-year survival rate 53.5%, and the 2-year survival rate 17.9%. Haematological and non-hematogical toxicities were low (CTC-grade 3 neutropenia 14.8%, grade 3 thrombocytopenia 5.2%, grade 3/4 anemia 5.1%, grade 3 nausea/vomiting 5.1%, grade 3 diarrhea 3.6%, grade 3 alopecia 3.6% of pts). CONCLUSION: The results suggest that the combination of irinotecan (CPT-11) and carboplatin is active and well tolerable in patients with limited disease SCLC who were not suitable for concurrent chemotherapy.

65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer.

BACKGROUND: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). RESULTS: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0-1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03-1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195-2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS. CONCLUSION: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0-1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy.

Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics-Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer.

Companion diagnostics (CDx) have become a major tool in molecular pathology and assist in therapy decisions in an increasing number of various cancers. Particularly, the developments in lung cancer have been most impressing in the last decade and consequently lung cancer mutation testing and molecular profiling has become a major business of diagnostic laboratories. However, it has become difficult to decide which biomarkers are currently relevant for therapy decisions, as many of the new biomarkers are not yet approved as therapy targets, remain in the status of clinical studies, or still have not left the experimental phase. The current review is focussed on those markers that do have current therapy implications, practical implications arising from the respective companion diagnostics, and thus is focused on daily practice.

Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study).

INTRODUCTION: Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival. METHODS: Two adjuvant regimens were evaluated for feasibility in 132 patients with NSCLC: the standard regimen of cisplatin and vinorelbine (CVb) (cisplatin 50 mg/m(2) on day 1 and day 8 and vinorelbine 25 mg/m(2) on days 1, 8, 15, and 22 every 4 weeks) and a regimen consisting of cisplatin and pemetrexed (CPx) (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 every 3 weeks). The primary end-point analysis showing that CPx is safe and feasible with dose delivery superior to that of CVb has already been published. Here we report the 3-year follow-up results of the secondary efficacy end points-overall, relapse-free, distant metastasis-free, and local relapse-free survival-also with regard to histologic diagnosis. RESULTS: After a median of 39 months, no significant differences in any of the outcome parameters between CVb and CPx were observed. Also, histologic diagnosis and tumor size in stage IB did not influence survival in the CPx-treated patients. Yet, Cox regression analyses showed that overall survival at 3 years was significantly correlated with feasibility and the occurrence of dose-limiting toxicity. CONCLUSIONS: Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial.

Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients.

INTRODUCTION: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. METHODS: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. RESULTS: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean ± SD, 61 ± 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). CONCLUSIONS: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear.

Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC).

OBJECTIVES: This single-arm multicenter Phase II study investigated the efficacy and safety of pemetrexed (Pem) and cisplatin (Cis) induction chemotherapy (CT) followed by full-dose Pem-Cis plus concurrent radiotherapy (RT) in patients with locally advanced non-squamous NSCLC. MATERIALS AND METHODS: Patients with unresectable Stage III non-squamous NSCLC received two 21-day cycles of Pem 500 mg/m(2) (vitamin/folic acid supplementation and dexamethasone prophylaxis per Pem-label)+Cis 75 mg/m(2) on Day 1. Eligible patients who had not progressed continued with 2 further cycles of full-dose Pem-Cis plus concurrent RT (2 Gy/fraction, 5 days/week, 66 Gy total). Primary endpoint was the 1-year progression-free survival (PFS) rate. RESULTS: Of 90 patients enrolled (all treated; median age 61 years, male/female 57%/43%, ECOG performance status 0/1 66%/34%, adenocarcinoma 90%, Stage III 36%/62%), 75 (83%) completed induction CT and started concurrent CT+RT. 64 (71%) patients received all 4 CT cycles and an RT dose ≥60 Gy. The 1-year PFS rate was 51.3% (95%CI: 42.0, 60.5). Median PFS was 10.6 months (95%CI: 8.6, 17.3), median OS was 26.2 months (95%CI: 16.7, not estimable). One patient died from enteritis (treatment-related) during Cycle 4. Four patients discontinued due to treatment-related adverse events, 1 on induction CT (renal failure), 3 on concurrent CT+RT (1 hypoacusis, 2 acute esophagitis). During induction CT, 18.9% of patients reported Grade 3/4 CTCAEs, only neutropenia (2.2%) and syncope (2.2%) were reported by >1 patient. During concurrent CT+RT, 41.3% of patients reported G3/4 CTCAEs, mainly esophagitis (12.0%), neutropenia (10.7%), and leukopenia (9.3%). CONCLUSION: In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.

A randomized Phase 2 study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB or II Non-Small-Cell Lung Cancer.

OBJECTIVES: We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC). MATERIALS AND METHODS: Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety. RESULTS: We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group. CONCLUSION: Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC.

MET amplification status in therapy-naïve adeno- and squamous cell carcinomas of the lung.

PURPOSE: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. EXPERIMENTAL DESIGN: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. RESULTS: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. CONCLUSION: MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors.