Targeted therapy in non-small cell lung cancer

Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes, giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human     

Can we define any marker associated with brain failure in patients with locally advanced non-small cell lung cancer?

PurposeTo define the factors which may be related to brain metastasis (BM) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who developed brain metastases after definitive treatment.Patients and methodsA total of 208 patients with LA-NSCLC, without BM who received definitive radiotherapy (RT) or RT + chemotherapy (CT) between January 2005 and January 2016 were evaluated retrospectively. Platelet, neutrophil, lymphocyte counts, LDH, CRP, Hb levels, neutrophil-to-lymphocyte radio (NLR), platelet-to-lymphocyte radio (PLR), advanced lung cancer inflammation index (ALI) and FDG-PET/CT parameters (SUVmax of the primary tumor and mediastinal lymph nodes), and patient characteristics were evaluated for brain metastasis free survival (BMFS).ResultsMedian follow-up duration was 25 months (range: 3–130 months). Cut-off values for platelet, NLR, PLR, LDH, CRP, and Hb were 290 × 103/μL, 2.6, 198, 468 IU/L, 2.5 mg/dL, and 11.5 g/dl. We defined each parameter as low or high according to the cut-off values. 56 patients (26.9%) developed brain metastases during follow-up. In univariate analysis, high NLR (P = 0.001), PLR (P = 0.037), LDH (P = 0.028), CRP (P = 0.002) values, value ≥ 7.5 for lymph nodes (P = 0.005) and low ALI value (P = 0.002) were poor prognostic factors for BMFS. In multivariate analysis, high NLR (P = 0.022), PLR (P = 0.017), CRP (P = 0.006), stage ≥ IIIB disease (P < 0.001), multi-stational N2 disease (P = 0.036), adenocarcinoma histology (P < 0.001) and SUVmax value ≥ 7.5 (P = 0.035) were poor prognostic factors for BMFS.ConclusionsHigh NLR, PLR, LDH, CRP values, SUVmax values for lymph nodes, and low ALI which indicates high tumor burden were additional prognostic factors besides stage, histology, and lymph node status.     

Prognostic factors in patients with stage Ⅳ non-small cell lung cancer

Objective： To investigate the prognostic factors for stage Ⅳ non-small cell lung cancer （NSCLC） with distant metastasis and establish a reliable model of clinical prognostic index. Methods： From January 1990 to April 2005, 313 primary NSCLC patients with metastasis, who had been treated in Shanghai Chest Hospital, were reviewed. Survival time was estimated according to the Kaplan-Meier method. Cox proportional hazard regression model was used for multivariate analysis. Results：Among the 313 cases of non-small cell lung cancer （NSCLC） at stage Ⅳ, there were 218 and 95 patients with metastasis to single and different organs, respectively. The overall median survival time for all 313 cases of NSCLC patients was 10.8 （9.00, 12.30） months and the overall 1-, 2-, 3-, 4- and 5-year survival rate was 45%, 18%, 12%, 4% and 0%. There were 63, 174, 127, 36, 18, 11 and 5 patients with metastasis to brain （20.13%）, bone （55.59%）, lung （40.58%）, liver （11.50%）, adrenal gland （5.75%）, subcutaneous （3.51%） and others, respectively. The survival time was shortest in subcutaneous metastasis （4.6 months）, and liver 7.0 months, brain 8.0 months, adrenal gland 8.6 months, bone 10.6 months, lung 11.8 months. Kaplan-Meier estimation showed that patients anatomic typing, KPS, numbers of organ with metastasis, appetite, liver, adrenal gland and subcutaneous metastasis, body weight loss, smoking, index of smoking, chemotherapy, cycles of chemotherapy were the predictors of survival. Multivariate analysis showed survival statistically significant correlation with anatomic typing, KPS, appetite, liver and subcutaneous metastasis, body weight loss, cycles of chemotherapy. The relative risk （RR） was 1.51, 1.97, 1.55, 1.67, 2.56, and 2.56 respectively. Conclusion： Survival time decreases distinctly in patients who had distant metastasis to more than two different organs （P〈0.01）. Bone is the commonest organ for distant metastasis in lung cancer. The prognosis is poor when lung cancer appears subcutaneous metastasis and liver metastasis. Independent prognostic factors in patient with stage Ⅳ non-small cell lung cancer were liver and subcutaneous metastasis, anatomic typing, KPS, appetite, body weight loss, cycles of chemotherapy.     

Prognostic factors in patients with stage IV non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths among both men and women over the world. In 2002, lung can- cer accounted for more deaths than breast cancer, prostate cancer, and colon cancer combined[1]. Non-small cell lung cancer (NSCLC) represents 75%–85% of all lung cancers. Lung cancer is hard to discovered until it’s at an advanced stage and the outlook for recovery is poor. Approximately two-thirds of NSCLC patients have advanced-stage at di- agnosis. Stage IV NSCLC denotes …     

Does treatment delay affect survival in non-small cell lung cancer? A retrospective analysis from a single UK centre.

We analysed survival in relation both to time to treatment and other clinical parameters in the care pathway of non-small cell lung cancer (NSCLC) patients. Medical notes of 189 patients diagnosed with NSCLC presenting in 1998 were reviewed. Median time to treatment in all patients was 48 days. In multivariate analysis, time to treatment did not affect survival in patients with any stage of disease. Referral from general practitioner to chest department (P=0.032, HR=0.08), and absence of use of surgery (P=0.006, HR=30.30) were independently significant predictors of survival in stages 1 and 2 subgroup. In stage 3 patients, absence of laboratory abnormality (P=0.002, HR=0.39), and use of combined treatment (P=0.015, HR=0.17) were independent prognosticators. Lastly, in patients with stage 4 disease, presence of bone and/or liver metastasis (P=0.005, HR=2.65), and absence of use of chemotherapy (P<0.001, HR=6.25) were significantly associated with shorter survival. As survival is dependent on classical prognosticators, but not on time from referral to treatment (hospital delay), expanding resources in oncology (equipment, drugs and personnel), and, perhaps, reducing patient delay, rather than reducing hospital delay alone, could be better strategies to improve NSCLC survival.     

Are we treating enough elderly patients with early stage non-small cell lung cancer?

Despite the fact that non-small-cell lung cancer (NSCLC) is very common in the older population, these patients are frequently underrepresented in clinical trials evaluating new anti-cancer agents, and thus it is difficult to reach evidence-based recommendations for this special population.The purpose of the present paper is to present the currently available evidence regarding treatment of early-stages of NSCLC in older patients.Although, age is still considered as a negative factor influencing treatment decisions and curative cancer-directed surgery is often omitted in the older population several studies support that surgical resection is feasible in the older patient and that age per se is not a contraindication for various surgical procedures. Pneumonectomy is associated with a higher mortality in the older population and this issue should be taken into account when deciding whether a patient is suitable for pneumonectomy. Older patients should be considered for adjuvant chemotherapy after surgical resection although little information is available regarding the real benefit and tolerability of these regimens for patients over 75 years of age. Given the lack of demonstrated benefit for the use of adjuvant RT it is also not recommended in older population.     

Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer?

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) might be new therapeutic strategies for advanced non-small cell lung cancer (NSCLC). Here a total of 12,520 patients from 23 randomized controlled trials (RCTs) were enrolled to evaluate the efficacy and safety of VEGFR-TKIs quantitatively in advanced NSCLC. Compared with non-VEGFR-TKIs, VEGFR-TKIs regimen significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.805-0.874, P < 0.001], objective response rates (ORR) [relative risk (RR): 1.374, 95% CI: 1.193-1.583, P < 0.001] and disease control rates (DCR) (RR: 1.113, 95% CI: 1.027-1.206, P = 0.009), but not overall survival (OS) (HR: 0.960, 95% CI: 0.921-1.002, P = 0.060) for NSCLC patients. The RR of all-grade neutropenia, thrombocytopenia, hypertension, hemorrhage, fatigue, anorexia, stomatitis, diarrhea, rash, hand-foot skin reaction (HFSR) were increased in patients received VEGFR-TKIs. As for high-grade (≥ 3) adverse events (AEs), VEGFR-TKIs were associated with higher RR of neutropenia, thrombocytopenia, hypertension, fatigue, stomatitis, diarrhea, rash and HFSR. This study demonstrates VEGFR-TKIs improve PFS, ORR and DCR, but not OS in advanced NSCLC patients. VEGFR-TKIs induce more frequent and serious AEs compared with control therapies.     

Gefitinib (ZD1839): therapy in selected patients with non-small cell lung cancer (NSCLC)?

PURPOSE: To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP). PATIENTS AND METHODS: A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed. RESULTS: In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers. CONCLUSIONS: In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.     

Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer?

Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5–20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c–Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and -independent c-Met activity, with a reduced risk of toxicity compared to non-selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered.     

Targeted therapy in advanced non-small cell lung cancer (NSCLC): Where do we stand?

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.     

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction

IntroductionErlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.MethodsEscalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib + 300 mg dovitinib) and cohort -1 (150 mg erlotinib + 200 mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.ResultsTwo of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average C_max 2308 ± 698 ng/ml and AUC _0–24 41,030 ± 15,577 ng × h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib C_max and AUC_0–24 decreased significantly by 93% (p = 0.02) and 97% (p < 0.01), respectively, during dovitinib co-administration.ConclusionsThis small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.     

ACR Appropriateness Criteria® postoperative adjuvant therapy in non-small cell lung cancer

Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.     

Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice

Background: Platinum-based combination chemotherapy is recommended as the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), but its benefit is limited to patients with performance status (PS) of 0 or 1. However, it is not clear whether these benefits apply to patients with poor performance status (PS 2 and above) and there are no predictors of outcome to suggest whom to treat. The patients with poor performance status (PS 2 and above) accounts for a significant portion (up to 30%) of patients of our practice. In this retrospective analysis, we have analyzed our experience of chemotherapy in patients with poor performance status. Method: A retrospective analysis of patients of advanced NSCLC with poor PS (ECOG PS 2 or more), treated with chemotherapy from October, 2016 to June, 2018 was done. Patients with driver mutations who were treated with first line tyrosine kinase inhibitors were excluded. Hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Kaplan-Meier curves were drawn to estimate progression free survival. Log-rank test was used to assess factors affecting survival. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). P value <0.05 was taken as significant. Result: A total of 96 patients were included in the analysis. The median age of the patients was 62 years (range 30-84 years). Majority (67.7%) was males and 65% patients were smokers (current or former). Patients with ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 2 constituted 64.5% of this cohort and 34 patients (33.5%) had an ECOG PS of 3 or 4. The most common chemotherapy regimen used was combination of weekly paclitaxel (60 mg/m²) and carboplatin (AUC2) in 57.8%. Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Grade 3⁄4 toxicities were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia). At least one point improvement in ECOG PS from baseline during chemotherapy was observed in 43 patients (45%) after 4 cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively. After a median follows-up of 11.2 months, median progression free survival was 6.3 months (95% confidence interval 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better progression-free survival PFS. Conclusion: Systemic chemotherapy in modified doses and schedules in advanced NSCLC patients with PS 2 and above is feasible and may be associated with better symptom palliation with clinical benefit and improved survival.     

Efficacy of plasma TGF-β1 level in predicting therapeutic efficacy and prognosis in patients with advanced non-small cell lung cancer

We hypothesized that serial assessment of TGF-β1 during chemotherapy might predict therapeutic response and prognosis in non-small cell lung cancer (NSCLC) patients. Plasma TGF-β1 levels were quantified before first, second, and third cycles of chemotherapy in 42 advanced NSCLC patients and correlated with therapeutic response. Plasma TGF-β1 levels measured before first and second cycles of chemotherapy failed to predict response to therapy. The increased presence of TGF-β1 measured before second and third cycles of chemotherapy was associated with poor survival. Estimation of plasma TGF-β1 during the course of chemotherapy might not be a reliable biomarker for predicting therapeutic efficacy in NSCLC.     

Does marital status impact survival and quality of life in patients with non-small cell lung cancer? Observations from the mayo clinic lung cancer cohort

PURPOSE: Previous studies have found that marriage is associated with longer survival and better quality of life among lung cancer patients. The present study used the Mayo Clinic Lung Cancer Cohort to re-examine this issue. METHODS: In total, 5,898 non-small cell lung cancer (NSCLC) patients, who had available information on marital status and who had been enrolled in the Mayo Clinic Lung Cancer Cohort (MCLCC), were the focus of this study. Patients had extensive baseline and follow-up data on cancer stage, cancer treatment, and prognostic factors. All patients had been followed within the MCLCC with at least annual confirmation of vital status and patient-reported quality of life (the Lung Cancer Symptom Scale and the Linear Analogue Scales of Assessment). RESULTS: The numbers of patients who were married, single, divorced, and widowed at the time of cancer diagnosis were 4,457 (76%), 265 (4%), 440 (7%), and 736 (12%), respectively. No statistically significant difference in survival was observed among these four groups, even after adjusting for a variety of prognostic factors, such as age, gender, and tumor stage. However, exploratory analyses suggested that widowed and divorced patients received less aggressive cancer therapy, and certain patient subgroups, such as stage IA widowed patients, had a shorter survival. Divorced patients reported greater financial concerns, and married and widowed patients reported greater spirituality and better social support. CONCLUSION: This study did not observe differences in survival or quality of life based on marital status at the time of diagnosis of NSCLC, but subgroup analyses appear to suggest findings worthy of further exploration.