Afatinib and Erlotinib in the treatment of squamous-cell lung cancer

ABSTRACT

Introduction

Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC.     

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

ABSTRACT

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting.

Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC.

Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.     

The second annual symposium on the future of lung cancer: a translational focus

Lung cancer continues to be a leading cause of death in the US, and in its most advanced stages remains incurable. Cytotoxic chemotherapies have been the standard of care for the treatment of unresectable disease. However, recent advances in the development of epidermal growth factor receptor (EGFR) inhibitors have led the way to a new generation of targeted biological agents. During the second annual symposium entitled ‘the future of lung cancer: a translational focus’, which was sponsored by the Physician´s Education Resource, new strategies for the treatment of lung cancer were discussed. Besides the role of EGFR inhibitors, potential targets include the angiogenesis pathway; other growth factor pathways, such as phosphoinositol-3 kinase/Akt and Raf-MEK; the 26S proteasome, the histone deacetylase mechanism; and the TNF-related apoptosis-inducing factor receptors. Agents that are directed against these targets are all in varying stages of clinical development. As more is learned about their mechanisms of action and clinical spectrum of activity, the author anticipates their incorporation into novel regimens with enhanced activity against lung cancer.     

Identifying nonsmall‐cell lung tumours bearing the T790M EGFR TKI resistance mutation using PET imaging

Specific mutations significantly affect response to epidermal growth factor tyrosine kinase inhibitor (EGFR‐TKI) treatment in lung cancer patients. Identifying patients with these mutations remains a major clinical challenge. EGFR T790M mutation, which conveys resistance to in the present study, [¹⁸F]FEWZ was assessed in vitro to determine efficacy relative to the starting compound and in vivo to measure the biodistribution and specificity of binding to EGFR wild‐type, L858R and T790M bearing tumours. [¹⁸F]FEWZ is the first evidence of a radiolabeled third generation anilinopyrimidine‐derived tyrosine kinase inhibitor targeting T790M mutation bearing tumours in vivo.     

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.     

Cell cycle inhibitors for the treatment of NSCLC

Introduction: Lung cancer remains to be the leading cause of cancer-related death worldwide. Treatment of lung cancer still poses a significant challenge. Cell cycle is a tightly integrated process and is frequently aberrant in lung cancer. Cell cycle inhibitors have emerged as novel therapeutics, in anticipation of overcoming the unrestricted cell division and growth in lung cancer.

Areas covered: In this article, we first address the potential roles of cell cycle proteins and cell cycle deregulation in the development of lung cancer. The review then provides an overview for several major categories of cell cycle inhibitors with particular attention to their tolerability and disease control in early phases of lung cancer trials.

Expert opinion: Targeted agents against different components of cell cycle regulation, such as cyclin-dependent kinase, polo-like kinase, checkpoint kinase and aurora kinase, are currently in clinical development for lung cancer management. Their clinical benefits remain to be defined. When evaluated as single agents in lung cancer, cell cycle inhibitors are often associated with limited clinical activity and tolerable toxicities. The key challenges in the drug development are to understand resistance mechanisms and to identify predictive biomarkers that can potentially guide patient selection and optimize the utility of these targeted inhibitors.     

Dacomitinib: an investigational drug for the treatment of glioblastoma

ABSTRACT

Introduction: Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only 15 months. It seems imperative to explore new possibilities of treatment based on targetable alterations known to be present in GB. Among others, Epidermal Growth Factor Receptor or EGFR (HER1) mutations or amplifications are the most prevalent alterations in GB. In fact, around 40% of GB cases show amplification of EGFR gene, and half of these patients carry the EGFRvIII mutation, a deletion that generates a continuous activation of the tyrosine kinase domain of the receptor.

Areas covered: We review the current knowledge about Dacomitinib, an oral, irreversible, second-generation, pan-HER tyrosine kinase inhibitor, in the treatment of glioblastoma. Dacomitinib has noteworthy antiglioma activity in preclinical models and has been tested in one phase II trial in patients with recurrent GB with EGFR amplification.

Expert opinion: Despite the poor global results of Dacomitinib in recurrent GB shown in a phase II trial, some patients had a significant benefit. Therefore, it is necessary to improve the knowledge about the mechanisms of failure or resistance to EGFR inhibitors in GB.     

Safety of gefitinib in non-small cell lung cancer treatment

ABSTRACT

Introduction: The development of EGFR TKI and the subsequent identification of activating EGFR mutations have dramatically changed how NSCLC is treated. With its recent approval by the US Food and Drug Administration, gefitinib adds to the list of recommended first-line treatments for lung cancer harboring EGFR mutations, which hitherto includes erlotinib and afatinib.

Areas covered: This review summarizes the pharmacological property, clinical efficacy, and safety of gefitinib in major clinical trials and post-marketing studies.

Expert opinion: Gefitinib is a well-tolerated treatment for advanced NSCLC. The most common adverse events are skin reaction and diarrhea, both of which are generally mild, noncumulative, and manageable. Other side effects such as interstitial lung disease and liver toxicity are less common but can be serious. Which EGFR TKI is the preferred first-line treatment is a matter of debate. Gefitinib and erlotinib have comparable efficacy, whereas afatinib may exert superior clinical activity over gefitinib. In terms of the most common toxicities of skin reaction and diarrhea, gefitinib may be the most tolerable of the three. Hence, despite being the earliest EGFR TKI developed, gefitinib continues to be one of the first-line treatments for advanced EGFR-mutated NSCLC, especially when skin and gastrointestinal toxicity is a concern.     

Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer

Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects.     

A safety assessment of crizotinib in the treatment of ALK-positive NSCLC patients

Introduction: In the past decade, the treatment of NSCLC has been revolutionized by the discovery of key oncogenic driver mutations and the therapies that specifically target these mutations. Crizotinib has been shown to be an inhibitor of MET, anaplastic lymphoma kinase (ALK) and ROS1 receptor tyrosine kinases, and is FDA approved for ALK inhibition. Crizotinib is effective in NSCLC that harbors ALK translocations resulting in overexpression of oncogenic ALK fusion proteins.

Areas covered: This paper will review crizotinib as a treatment for ALK-positive NSCLC. It will discuss the drug’s adverse events, drug–drug interactions and other important clinical and safety information related to crizotinib.

Expert opinion: Compared to standard chemotherapy, crizotinib shows improved progression-free survival in ALK-positive NSCLC, with patient’s reporting improved quality of life. However, certain adverse events are more frequent with crizotinib versus standard chemotherapy and must be monitored for closely. The most common adverse events include ocular and gastrointestinal disturbances, cardiac and endocrine abnormalities, and peripheral edema. Many, though not all, of these side effects are likely due to the multiple tyrosine kinases inhibited by crizotinib, and will likely improve with second- and third-generation inhibitors that inhibit ALK more specifically.     

Is there a role for dacomitinib,a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase,in advanced non-small cell lung cancer?

ABSTRACT

Introduction

Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations.     

Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib.

Areas covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed.

Expert opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.     

Anti-EGFR strategies as an incremental step for the treatment of colorectal cancer patients: moving from scientific evidence to clinical practice

The epidermal growth factor receptor (EGFR) is a 170,000 Da transmembrane glycoprotein involved in signalling pathways affecting cellular growth, differentiation and proliferation. An abnormal overexpression of the EGFR has been described in many human tumours and implicated in the development and prognosis of malignancies, thus representing not only a possible prognostic marker, but primarily a rational molecular target for a new class of anticancer agents. Several clinical trials have been reported with the use of EGFR-targeted monoclonal antibodies and tyrosine kinase inhibitors, mainly in combination with chemotherapy for advanced colorectal cancer patients. Taken together, results available so far suggest that anti-EGFR treatment strategies represent an incremental step for the the treatment of colorectal cencer patients with a manageable and acceptable toxicity profile. Nevertheless, many critical issues are yet unresolved, such as the optimal chemotherapy regimen to combine with anti-EGFR treatment and the most adequate patients setting. Moreover, the biological selection of colorectal tumours most likely to benefit from this treatment approach is still to be defined.     

Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo

Summary  Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with non-small cell lung cancer (NSCLC). However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the antitumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor (Zhao260054). In vitro studies in a panel of four different human lung cancer cell lines revealed that Zhao260054 inhibited cell proliferation with high potency and induced G₀/G₁ arrest of cell cycle and apoptosis. Zhao260054 markedly reduced phosphorylation of EGFR and inhibited activation of ERK1/2 and AKT. Oral administration of Zhao260054 (200 mg/kg/day) to BALB/c nude mice bearing SPC-A1 xenografts significantly retarded tumor growth. In conclusion, Zhao260054 has potent antitumor activity on human lung cancer in vitro and in vivo.     

奥希替尼用于EGFR+晚期非小细胞肺癌患者一线治疗的药物经济学评价

目的评估奥希替尼在2020年国家谈判价格下用于有表皮生长因子受体(epidermal growth factor receptor,EGFR)阳性突变的局部晚期或转移性非小细胞肺癌(non-small cell lung cancer,NSCLC)患者一线治疗的成本效用。方法基于卫生服务支付方角度,构建包含无进展生存期(progression-free survival,PFS)和疾病进展期(progressive disease,PD)的分区生存模型,以质量调整生命年(quality-adjusted life years,QALYs)作为结果指标计算增量成本效用比(incremental cost-utility,ICER)。疗效数据来自多中心、随机、对照、双盲的FLAURA试验,成本数据来自招采挂网数据和专家咨询,不同健康状态的健康效用值源于文献。对关键参数进行敏感度分析。结果与厄洛替尼、吉非替尼、阿法替尼和埃克替尼相比,奥希替尼在国家谈判价格下终身成本更高,获得的QALYs也更高。与已过专利期的厄洛替尼和吉非替尼相比,奥希替尼ICER值分别为122 695元和117 359元,约为我国人均GDP的1.7倍;与同样仍在专利期的阿法替尼和埃克替尼相比,奥希替尼ICER值分别为16 502元和43 337元,远低于我国人均GDP。单因素敏感度分析显示,奥希替尼价格是对ICER值影响最大的因素。概率敏感度分析显示,当支付意愿为我国三倍人均GDP时,奥希替尼具有成本效果的概率为100%。结论与厄洛替尼、吉非替尼、阿法替尼和埃克替尼相比,奥希替尼用于EGFR+的局部晚期或转移性NSCLC患者一线治疗更具成本效用。     

Type III or allosteric kinase inhibitors for the treatment of non-small cell lung cancer

Introduction: In recent times, there has been much interest in the development of pharmacological kinase inhibitors that treat NSCLC. Furthermore, treatment options have been guided by the development of a wide panel of synthetic small molecule kinase inhibitors. Most of the molecules developed belong to the type I class of inhibitors that target the ATP-binding site in its active conformation. The high sequence similarity in the ATP-binding site among members of the kinase families often results in low selectivity and additional toxicities. Also, second mutations in the ATP-binding site, such as threonine to methionine at position 790, have been described as a mechanism of resistance to ATP-competitive kinase inhibitors. For these reasons, alternative drug development approaches targeting sites other than the ATP cleft are being pursued. The class III or allosteric inhibitors, which bind outside the ATP-binding site, have been shown to negatively modulate kinase activity.

Areas covered: In this review, the authors discuss the most well-characterised allosteric inhibitors that have reached clinical development in NSCLC.

Expert opinion: Great progress has made in developing inhibitors with entirely new modes of action. That being said, it is important to highlight that despite their apparent simplicity, biochemical assays will remain at the core of drug discovery activities to better explore these new opportunities.     

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.     

Sorafenib for the treatment of thyroid cancer: an updated review

Introduction: Sorafenib (Nexavar) is an oral multi-kinase inhibitor targeting B-type Raf kinase (BRAF) (both wild type and BRAF^V600E), VEGFR1, VEGFR2, VEGFR3, PDGFRβ and RET (also RET/PTC) influencing both differentiated thyroid cancer (DTC) cell proliferation and angiogenesis.

Areas covered: Encouraging results achieved in numerous Phase II trials were confirmed in a Phase III study conducted in radioiodine-refractory DTC. Sorafenib compared to placebo significantly prolongs progression-free survival, 10.8 versus 5.8 months, respectively. However, its administration resulted mainly in disease stabilization. No complete remission was obtained in any study. Beneficial effects were also demonstrated for medullary and anaplastic thyroid cancer; however further studies fulfilling evidence based medicine criteria are necessary. Its toxicity profile is convergent with other VEGFR inhibitors. The most common treatment-related side-effects involve skin toxicity (predominantly hand-foot skin reaction, different rashes and alopecia), gastrointestinal disturbances (diarrhea, abdominal pain), constitutional adverse reactions (anorexia, weight loss, fatigue) and hypertension. Although most adverse reactions are manageable, > 50% of patients required dose reduction.

Expert opinion: Sorafenib constitutes the first line treatment option in advanced, radioiodine-refractory DTC. However, there are still no data on its efficacy in patients progressed after another tyrosine kinase inhibitor. Other applications of the drug, such as use as adjuvant therapy to 131-I treatment, requires further studies.     

PROFILing non-small-cell lung cancer patients for treatment with crizotinib according to anaplastic lymphoma kinase abnormalities: translating science into medicine

Introduction: In the recent years, the growing attention to the molecular background of non-small-cell lung cancer (NSCLC) led to the identification of different molecular subtypes according to genetic abnormalities driving the disease development and progression. Whereas the addicted pathways were successfully inhibited (such as the mutant epidermal growth factor receptor), clinicians have witnessed a dramatic survival improvement. In this regard, the molecular portrait of adenocarcinoma was recently enriched by the identification of a specific patients' subgroup characterized by abnormalities in the anaplastic lymphoma kinase (ALK), with unclear prognostic features but impressive response to specific inhibitors.

Areas covered: In this article, updated data derived from the development and the use of crizotinib (the most advanced in development among tyrosine kinase ALK inhibitors) in comparison with standard second-line chemotherapy for patients affected by ALK-altered NSCLC are reviewed.

Expert opinion: Taking into account the available data, pretreated NSCLC patients carrying the ALK-translocation require a selected targeted therapy which significantly improves activity, efficacy and symptoms control versus chemotherapy. In this context, the identification of this disease entity and the availability of such impressive therapeutic targeting represent a further step toward the understanding of the molecular complexity behind the adenocarcinoma of the lung.     

A phase I study of oral ZD 1839 given daily in patients with solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group

Summary Purpose: To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), the biological active (BA) dose and the pharmacokinetics (PK) of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa) when administered continuously as a once daily dose in patients with advanced, incurable solid tumours. Patients and methods: Twenty-eight patients were enrolled in cohorts of three from three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) centers. ZD1839 was given at doses from 150 to 800 mg daily orally and patients underwent a pretreatment and a 28 day post treatment tumor biopsy, while PK sampling was performed on days 8, 15, 22, 29, and a toxicity assessment every 28 days. Results: All twenty-eight patients were evaluable for non-hematological and hematological toxicity. Twenty-seven were evaluable for response. The MTD was not reached but DLT included reversible rash and diarrhea. One patient with urachal cancer had a transient 55% decrease in tumor size and two other patients (breast and non-small cell lung cancer) had minor responses; three additional patients had pharmacodynamic evidence of target effect. PK demonstrated steady state within the first 2 weeks of dosing and dose dependent exposure. Conclusion: It appears that ZD 1839 at a dose of 800 m/day was tolerable, although some patients required dose modification for diarrhea. Doses above 250 m/day demonatrate biologic activity and could be consider for future study in a variety of EGFR positive tumor types.