EGFR TKI combination with immunotherapy in non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation.

Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo naïve NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%). The treatment related Grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib.

Expert opinion: Given the relatively high incidence of treatment-related toxicities associated with combination of EGFR TKI and immunotherapy, further development of this approach remains controversial. Until now, the combination of EGFR TKI and immunotherapy should be investigational.     

Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer

Introduction: First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9–13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice.

Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken.

Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.     

Osimertinib for the treatment of non-small cell lung cancer

Introduction: The T790 M mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR TKI, shows robust clinical efficacy in patients with T790 M-mutated lung cancer.

Areas covered: We analyzed and reviewed clinical data for which patients who experienced acquired resistance to first- or second-generation EGFR TKIs. In addition, we briefly reviewed the potential role of osimertinib as a first-line therapy.

Expert opinion: Osimertinib was recently licensed for use in NSCLC patients with acquired resistance to other EGFR TKIs due to a T790 M mutation. However, unresolved issues surrounding the optimal application of osimertinib remain, specifically the development of a plasma-based mutation test to overcome the difficulty of repeat biopsy, the efficacy of osimertinib for brain or leptomeningeal metastases, the development of resistance to osimertinib, and the use of osimertinib therapy as a first-line treatment. Many ongoing studies are currently exploring these issues.     

Targeting the EGFR T790M mutation in non-small-cell lung cancer

Introduction: The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation.

Areas covered: This review is focused on the implications of tumor heterogeneity for targeting the T790M in patients with NSCLC.

Expert opinion: Pre-clinical and clinical data suggest that the T790M is heterogeneously expressed in tumors that become resistant to first- and second-generation EGFR TKIs. These findings have important implications for the molecular diagnostic of the T790M mutation. Indeed, the analysis of both the circulating free tumor DNA (ctDNA) isolated from plasma and the tumor tissue might provide complimentary information to identify patients carrying the T790M mutation. However, further studies are needed to better understand the influence of tumor heterogeneity on the activity of drugs targeting the T790M.     

The safety of second-line treatment options for non-small cell lung cancer

Introduction: Non-small-cell lung cancer (NSCLC) patients after first-line therapy ultimately suffer progression. At this time, many patients still have a good performance status and can be considered for further active treatment. Two chemotherapeutic agents, docetaxel and pemetrexed (only in non-squamous histology), and the biological drug anti-epidermal growth factor receptor (EGFR) erlotinib, were approved for clinical use in the second-line treatment of NSCLC patients. In the last few years further new second-line therapies have become available in the clinical practice.

Areas covered: This review will discuss the adverse events of the pivotal trials ledding to the approval of second-line therapies for the treatment of not oncogene-addicted NSCLC patients.

Expert opinion: In recent years, new second-line options for NSCLC are: the anti-EGFR, afatinib (only in squamous NSCLC); the anti-angiogenics, nintedanib (only in lung adenocarcinoma) and ramucirumab, in combination with docetaxel; the immunotherapeutics, nivolumab, pembrolizumab, and atezolizumab. In the second-line approach, the main endpoint of treatment should always be survival, but with great respect for symptoms palliation and preserving patients’ quality of life. Therefore, differing toxicity profiles of the available therapeutic options are often a deciding factor in second-line setting for NSCLC.     

Emerging drugs for EGFR-mutated non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity.

Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance.

Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.     

Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple-negative breast cancer

Objective: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC.

Research design and methods: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro.

Results: We observed that breast cancer cells engineered to overexpress OPN are more sensitive to growth inhibition by erlotinib than control cells. The level of response was related to the level of OPN expression, possibly due to increased phosphorylation status of EGFR Tyr1068.

Conclusions: These results indicate that OPN expression levels are related to sensitivity of TNBC cells to growth inhibition by erlotinib. OPN thus is a promising predictive biomarker for anti-EGFR therapy in breast cancer.     

Characteristics and outcomes of patients with EGFR-mutation positive non-small-cell lung cancer receiving gefitinib beyond radiological progression

Background: This study aimed to analyze the characteristics and outcomes of patients suffering from non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor mutations (EGFRm+) receiving gefitinib who remained clinically stable following confirmation of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) (R-PD) and identify those who benefited from tyrosine kinase inhibitor therapy beyond PD.

Research design and methods: The clinical courses of patients with EGFRm+ advanced NSCLC who received first-line gefitinib were investigated. Clinical PD (C-PD) was defined as one or more of the following: (1) symptomatic PD, (2) worsening performance status resulting from PD, (3) threat to a major organ(s), or (4) unequivocal multiorgan PD.

Results: Of 529 patients, 258 experienced R-PD without C-PD. Among 258 patients, 91 received gefitinib beyond R-PD. Females were more likely to receive gefitinib beyond R-PD and exhibit a longer time from R-PD to C-PD than males (median days, 175 vs. 79.5). Survival beyond R-PD tended to be longer for elderly patients who received gefitinib beyond PD than for those who did not (median days, 458 vs. 336), but this was not the case for non-elderly patients (median days, 481 vs. 487).

Conclusions: Some patients may benefit from continuation of gefitinib beyond PD.     

First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL).

Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 – 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL.

Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups.

Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.     

Investigational drugs targeting fibroblast growth factor receptor in the treatment of non-small cell lung cancer

Introduction: Fibroblast growth factor receptor (FGFR) due to its central role in regulating cell survival, is a promising target for cancer therapeutics. Dysregulation of the FGFR pathway has been observed in several malignancies, including non-small cell lung cancer (NSCLC) particularly in patients with squamous histology.

Areas covered: The aim of this article is to review the most relevant findings of clinical trials investigating drugs targeting FGFR pathway: such as FGFR tyrosine kinase inhibitors (TKIs), FGFR monoclonal antibodies and FGF ligand traps in NSCLC patients.

Expert opinion: At present, clinical activity of drugs targeting FGFR in NSCLC is disappointing. Further studies are needed in order to better identify patients who might benefit from these drugs and to clarify the mechanisms of resistance to these compounds.     

Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer

Introduction: Central nervous system (CNS) metastases represent an important cause of morbidity and mortality in non-small cell lung cancer (NSCLC) patients. Local approaches of neurosurgery (usually for single brain lesions), whole brain radiotherapy, and stereotactic radiosurgery are often withheld for the treatment of NSCLC-derived brain metastases (BMs). However, systemic treatment is consistently emerging as an option for patients with asymptomatic BMs, which could allow for delaying cranial radiotherapy at symptomatic/radiological progression.

Areas covered: Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases. Among these, EGFR- and ALK-TKIs will be discussed more in detail owing to their superior efficacy in this context.

Expert opinion: Up-front systemic treatment should be considered for patients with asymptomatic, multiple BMs, as recently acknowledged by the European Society of Medical Oncology guidelines. Nevertheless, it must be emphasized that the best treatment strategy for NSCLC-derived BMs has to be defined within a multidisciplinary team.     

An overview of angiogenesis inhibitors in Phase II studies for non-small-cell lung cancer

Introduction: Angiogenesis plays a major role in the development and progression of solid tumors, including lung cancer. Although some anti-angiogenic agents have demonstrated a statistically significant advantage in terms of primary outcome in clinical trials, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. To better clarify this complex scenario and definitively establish the concrete benefits of anti-angiogenic strategies in lung cancer, several clinical trials have been conducted with others currently ongoing.

Areas covered: In this review, the authors highlight the data ascertained from Phase II trials conducted in NSCLC patients who are treated with recently discovered innovative anti-angiogenic molecules. The authors also discuss older widely investigated anti-angiogenic drugs that have been repurposed or used in different contexts and combinations.

Expert opinion: Globally considered, the results of the countless clinical trials evaluating anti-angiogenic agents suggest that angiogenesis (with its molecules and pathways) represents a non-ideal druggable process for several biologically relevant reasons. Consequently, it is important that the conceptual development and clinical validation of anti-angiogenic agents is different from those employed for traditional target agents (i.e., erlotinib, gefitinib and crizotinib). Indeed, the development and validation of these agents still represents a major challenge for modern scientific research.     

Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.     

Impact of a multivariate serum-based proteomic test on physician treatment recommendations for advanced non-small-cell lung cancer

Objective: The VeriStrat¹ (VS) test is intended to help guide treatment decisions for patients with advanced non-small-cell lung cancer (NSCLC) without an EGFR-sensitizing mutation, classifying patients into two categories. Patients classified as VSGood have a favorable prognosis and significant clinical response to EGFR tyrosine kinase inhibitors (TKIs). Patients classified as VSPoor have a less favorable prognosis and exhibit no significant response to EGFR-TKIs. The objective of this paper is to assess the real-world impact of VS test results on physicians’ treatment recommendations including referrals for best supportive care (BSC).

Methods: Between 1 January 2012 and 1 November 2016, physician respondents were asked to complete standardized questionnaires before and after receiving VS results in patients meeting criteria for the intended use of the VS test. This study evaluated three endpoints: whether physicians followed VS test results in making treatment recommendations, the extent to which tests results changed these treatment recommendations, and the patterns of care subsequent to VS testing.

Results: Of the tests ordered by 989 physicians, 2494 VS tests had completed treatment recommendation questionnaires both prior to and after testing. Prior to VS testing, physicians were considering treatment with EGFR-TKIs for 2250 patients (90%). The VS test classified 1950 patients as VSGood and 544 patients as VSPoor. For patients classified as VSPoor, physicians recommended BSC for 25% of patients and standard systemic treatments such as chemotherapies for 65% of patients. Consistent with previous publications, physicians recommended EGFR-TKI therapy for only 10% of VSPoor patients but for 89% of VSGood patients. Overall, physician’s treatment recommendations were consistent with test results in 98% of cases. Availability of test results decreased ineffective treatment recommendations by 89% for VSPoor patients.

Conclusions: Among physicians ordering VS, the test significantly influenced treatment recommendations for patients with NSCLC, reducing ineffective and expensive treatment at the end of life.     

Emerging paradigms in targeted treatments for Asian patients with NSCLC

Introduction: EGFR-targeted drugs have been successfully approved in many countries and have demonstrated higher efficacy and lower toxicity than chemotherapy in molecularly defined subgroups of patients. Significant advances in clinical trials and studies focusing on targeted therapies have rapidly developed in Asia.

Areas covered: In the present review article, all of the published data or meeting abstracts on completed or ongoing trials of targeted treatment for Asian patients with NSCLC were collected and analyzed.

Expert opinion: Routine molecular testing has been used clinically to identify mutations/fusions and guide patient selection for targeted therapies. Based on the evidence presented, we provided up-to-date treatment recommendations for Asian patients with advanced NSCLC. Future directions, including dividing Del19 and L858R patients into two distinct populations, will optimize therapeutic strategies for L858R patients and may inform rational trial design by considering the proportion of type of sensitive EGFR mutation as a stratification factor. Another important aspect to consider involves how to monitor resistance to TKIs, which will improve the outcome for lung cancer patients with driver gene mutations.     

Necitumumab: a new option for first-line treatment of squamous cell lung cancer

Introduction: First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target.

Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex.

Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient’s quality of life with a manageable toxicity profile.     

Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis

Background: A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.

Methods: The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.

Results: Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (OR_PETO:3.26; 95%CI:1.12 to 9.50), nilotinib (OR_PETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (OR_PETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (OR_PETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.

Conclusions: Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.     

The safety of Bosutinib for the treatment of chronic myeloid leukemia

Introduction: Tyrosine kinase inhibitors (TKIs) are a potentially lifelong treatment for patients with chronic myeloid leukemia (CML). Adverse events (AEs) associated with TKIs are significant impediments in the daily life of patients that can impact compliance, and efficacy.

Areas covered: This is a review on safety of bosutinib in the treatment of chronic phase CML. Data is extracted from the latest updates of bosutinib phase I/II and III trials.

Expert opinion: Bosutinib is an effective agent against all phases of CML presently approved for the treatment in patients with resistance or intolerance to prior TKI therapy. Bosutinib has a unique toxicity profile characterized by early and transient diarrhea. Otherwise, the AE profile of bosutinib is comparable to other TKIs, with the exception of cardiovascular AEs that are infrequent in bosutinib-treated patients. Similar to other TKIs, the minimum effective dose of bosutinib remains unknown. Better definition of the optimal effective dose may spare, for those patients otherwise benefitting from treatment, unnecessary AEs.     

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach.

Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies.

Expert opinion: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.     

New systemic strategies for overcoming resistance to targeted therapies in non-small cell lung cancer

Introduction: Although the achievements in the treatment of advanced non-small cell lung cancer (NSCLC) have been translated in improved disease control, response rate and survival, especially in the case of patients with targetable oncogenic drivers, acquired resistance is common after initial benefit; furthermore, primary resistance can occasionally be observed. Due to its clinical implications, the management of treatment-resistant NSCLC is a top topic of the current research, and many efforts are being put in the study of the mechanisms at the base of resistance and in the development of effective therapeutic countermeasures.

Areas covered: This review aims at identifying the most relevant novel chemical therapies designed to overcome resistance in NSCLC, including recently approved agents, as well as compounds in clinical development.

Expert opinion: An improved knowledge of the mechanisms causing resistance to treatments in NSCLC translates into effective innovative chemical therapies able to overcome such occurrence, and the paradigms of this progress are represented by novel inhibitors of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK); however, the study of novel systemic therapies in this setting is challenging, and further efforts in this setting are highly needed.