Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non–small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified.

Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations.

Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.     

Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients?

An ideal target-based agent for the treatment of cancer patients should fulfil a number of requirements, including the availability of biomarkers to select the target population, superiority over existing treatments and specific advantages in terms of pharmacokinetics and/or metabolism. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and afatinib, have been investigated in the treatment of non-small cell lung cancer (NSCLC), and to date a large amount of clinical data are available. The activity of EGFR-TKIs was initially investigated in unselected patients leading to unsatisfactory results. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC, has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status or of clinical and pathological features that are highly associated with the presence of EGFR mutations. In this respect, several phase III randomized trials have demonstrated that first-line EGFR-TKIs, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life in patients carrying EGFR mutations. Although no survival advantage was demonstrated, all the trials suffered of a high post-progression treatment cross-over, which predictably undermined the results. This review will summarize the current evidence that strongly support the hypothesis that gefitinib, erlotinib and afatinib are ideal drugs for NSCLC patients carrying EGFR mutations.     

Estrogen receptor β and epidermal growth factor receptor as early-stage prognostic biomarkers of non-small cell lung cancer

As 20% of stage I NSCLC patients develop recurrent and often incurable cancer, the identification of prognostic markers has a meaningful clinical application. The biological significance of steroid hormone and EGF receptors, able to regulate key physiological functions, remains elusive in NSCLC. Our aim was to investigate the prognostic input of estrogen receptors (ERα, ERβ), progesterone receptors (PR) and EGFR in tumors from 58 stage I NSCLC patients. Antigen expression was analyzed by immunohistochemistry. Prognostic evaluation was performed with the multivariate Cox model. We found that about 70 and 40% of samples expressed ERα or ERβ at cytoplasmic or nuclear level, respectively. Besides, only 12.1% of samples weakly expressed nuclear PR and 62.7% showed membrane EGFR staining. Correlation studies indicated an inverse association between EGFR expression and smoking status (p<0.01). Multivariate studies showed that the lack of nuclear ERβ or the loss of EGFR expression were independent prognosis markers associated with shorter overall survival. We also found that patients whose tumors were negative for these two biomarkers presented the worst outcome. In conclusion, our findings could be useful for selecting stage I NSCLC patients with poor prognosis to apply an earlier treatment that impacts on survival.     

Sensitivities to various epidermal growth factor receptor‐tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor‐tyrosine kinase inhibitor?

Most patients with non‐small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR‐TKI), and their sensitivities to various EGFR‐TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR‐TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3‐L858R), L861Q (Ba/F3‐L861Q) or S768I (Ba/F3‐S768I) mutations were created and their drug sensitivities to various EGFR‐TKI were examined. Both the Ba/F3‐L861Q and Ba/F3‐S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3‐L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3‐L858R cell line. The Ba/F3‐L861Q cell line was similarly sensitive and the Ba/F3‐S768I cell line was less sensitive to osimertinib, compared with the Ba/F3‐L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.     

Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors?

After first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC), many patients remain candidates for a second-line treatment. Docetaxel, pemetrexed and erlotinib are currently approved in the USA and Europe as second-line therapy for NSCLC, while gefitinib is approved and licensed in Europe, but not in the USA, for EGF receptor-mutated patients in the same setting. Results of the registration trials for these four agents show similar efficacy in terms of objective response rate and survival, but significantly different toxicity and tolerability. Therefore, at the time of failure of first-line treatment, it is crucial to evaluate different clinical factors that could help choose the second-line treatment of metastatic NSCLC, as performance status and comorbidities; new predictive biomarkers will be validated in future trials. Considering the different predictive and prognostic factors, tyrosine kinase inhibitors could be a valid option for second-line treatment of NSCLC.     

Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors?

After first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC), many patients remain candidates for a second-line treatment. Docetaxel, pemetrexed and erlotinib are currently approved in the USA and Europe as second-line therapy for NSCLC, while gefitinib is approved and licensed in Europe, but not in the USA, for EGF receptor-mutated patients in the same setting. Results of the registration trials for these four agents show similar efficacy in terms of objective response rate and survival, but significantly different toxicity and tolerability. Therefore, at the time of failure of first-line treatment, it is crucial to evaluate different clinical factors that could help choose the second-line treatment of metastatic NSCLC, as performance status and comorbidities; new predictive biomarkers will be validated in future trials. Considering the different predictive and prognostic factors, tyrosine kinase inhibitors could be a valid option for second-line treatment of NSCLC.     

Epidermal growth factor receptor inhibitors for the treatment of colorectal cancer: a promise fulfilled?

The epidermal growth factor receptor (EGFR) is commonly expressed in colorectal cancers but not in most normal tissues, raising the possibility that this receptor could serve as a target for highly selective therapy. Based on preclinical studies demonstrating that antagonists of EGFR resulted in the inhibition of tumor growth, the development of clinical reagents has been aggressively pursued. Early clinical studies demonstrated antitumor activity of EGFR inhibitors in patients with advanced colorectal cancer, with acceptable toxicity. This early success fueled rapid clinical development. In this article, we will review the current status of EGFR inhibitors in the treatment of patients with colorectal cancer, in an effort to describe both how far we have come as well as where we need to go in optimizing this promising therapeutic approach.     

Prognostic implications of hypoxia-inducible factor-1α in epidermal growth factor receptor-negative non-small cell lung cancer

Hypoxia-inducible factor (HIF)-1α is a regulatory subunit of HIF-1 that is stabilized and activated under hypoxic conditions. In non-small cell lung cancer (NSCLC), over-expression of HIF-1α has been associated with poor overall survival. However, there is conflicting data on the role of HIF-1α as a prognostic factor. Some studies have demonstrated close association between the HIF-1α signal pathways and epidermal growth factor receptors (EGFRs). We evaluated the prognostic significance of HIF-1α expression in 178 NSCLC patients using tissue microarray in the context of EGFR gene copy number and protein expression status. EGFR gene copy number was evaluated using fluorescent in situ hybridization (FISH), and EGFR protein expression was determined using immunohistochemistry (IHC). The difference in overall survival (OS) between HIF-1α-positive and HIF-1α-negative groups was statistically significant in patients with low EGFR gene copy number and negative EGFR expression (log-rank test, P = 0.03). In univariate and multivariate analyses, HIF-1α was a significant worse prognostic factor for OS in patients with low EGFR gene copy number and negative EGFR expression (hazard ratio = 2.992; 95% CI, 1.113-8.045; P = 0.03 in univariate analysis and hazard ratio = 8.127; 95% CI, 1.874-35.251; P < 0.01 in multivariate analysis). The results demonstrated that the prognostic significance of HIF-1α should be validated in the context of EGFR status in NSCLC patients, and the gene and protein status of EGFR and HIF-1α will be important to help select patients most likely to derive the greatest clinical benefit from EGFR or HIF-1α targeted therapies.     

Why the epidermal growth factor receptor? The rationale for cancer therapy

There is a need for new, selective anticancer agents that differentiate between malignant and nonmalignant cells. The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies. Although expressed in nonmalignant cells, the epidermal growth factor receptor (EGFR) is highly expressed in a variety of tumors, and its expression correlates with poor response to treatment, disease progression, and poor survival. Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor. Activation of the EGFR signaling pathway in cancer cells has been linked with increased cell proliferation, angiogenesis, and metastasis, and decreased apoptosis. Preclinical data show that anti-EGFR therapies can inhibit these effects in vitro and in vivo. In addition, preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents. Following accelerated drug development programs, phase III trials are now under way for a number of EGFR-targeted therapies, including the monoclonal antibody IMC-C225 and the EGFR-tyrosine kinase inhibitors ZD1839 (Iressa) and OSI-774. Thus, the rationale for EGFR-targeted approaches to cancer treatment is apparent and now well established, and there is increasing evidence that they may represent a significant contribution to cancer therapy.     

Effect of κ-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells

Background:

It is becoming increasingly recognised that opioids are responsible for tumour growth. However, the effects of opioids on tumour growth have been controversial.

Methods:

The effects of κ-opioid receptor (KOR) agonist on the growth of non-small cell lung cancer (NSCLC) cells were assessed by a cell proliferation assay. Western blotting was performed to ascertain the mechanism by which treatment with KOR agonist suppresses tumour growth.

Results:

Addition of the selective KOR agonist U50,488H to gefitinib-sensitive (HCC827) and gefitinib-resistant (H1975) NSCLC cells produced a concentration-dependent decrease in their growth. These effects were abolished by co-treatment with the selective KOR antagonist nor-BNI. Furthermore, the growth-inhibitory effect of gefitinib in HCC827 cells was further enhanced by co-treatment with U50,488H. With regard to the inhibition of tumour growth, the addition of U50, 488H to H1975 cells produced a concentration-dependent decrease in phosphorylated-glycogen synthase kinase 3β (p-GSK3β).

Conclusion:

The present results showed that stimulation of KOR reduces the growth of gefitinib-resistant NSCLC cells through the activation of GSK3β.     

Proteins kinase Cɛ is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes

Protein kinase C (PKC)?, a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKC? is frequently overexpressed in epithelial cancers, particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKC? is required for non-small cell lung carcinoma (NSCLC) growth in vitro as well as tumor growth when inoculated into athymic mice. Moreover, sustained delivery of a PKC?-selective inhibitor peptide, ?V1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKC? caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKC?-depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl-2 family, caspase recruitment domain-containing proteins and tumor necrosis factor ligands/receptor superfamily members. Moreover, a Gene Set Enrichment Analysis revealed that a vast majority of the genes changed in PKC?-depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKC? is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKC? may represent an attractive therapeutic target for NSCLC.     

Radiotherapy for stage I–II non-small cell lung cancer

Background. Surgery has been regarded as the standard treatment for patients with non-small cell lung cancer in the early stage, while radiotherapy has become an effective alternative for medically inoperable patients and those who refuse surgery. Methods. We reviewed the records of 31 patients with stage I–II non-small cell lung cancer treated by radiotherapy between 1980 and 1997. There were 15 patients in stage I and 16 in stage II. The variables analyzed for influence on cause-specific survival and loco-regional control were: age, performance status, clinical stage, tumor size, tumor site, radiation field, radiation dose, and combination with chemotherapy. Results. The overall and cause-specific 1-, 2-, 3-, and 5-years survival rates were 71% and 77%; 63% and 73%; 34% and 48%; and 17% and 32%, respectively. Five-year survival rate for patients with peripheral tumor in the lung was 72%, with 70% loco-regional control, while the 5-year survival rate of patients whose tumor originated in the central region was 20%, with 25% loco-regional control. These differences had marginal significance on univariate analysis (P = 0.07), but only tumor site (central vs peripheral ) showed marginal significant influence on cause-specific survival (P = 0.08) and loco-regional control (P = 0.07) on multivariate analysis. There were no fatal complications, including radiation-induced myelopathy. Conclusion. The present series showed satisfactory results with definitive radiotherapy for patients with medically inoperable stage I–II non-small cell lung cancer, with results similar to those in recent reports of radiotherapy. The only significant variable was that patients with peripheral tumors had a better prognosis than patients with central tumors. Received: March 26, 1999 / Accepted: August 9, 1999