On the Horizon for Non-Small Cell Lung Cancer

Introduction

Cancer of the lung comprises both small cell and non-small cell lung cancers (NSCLCs), with NSCLC being the more common of the 2 types, accounting for 85% of all lung cancers.^1-3 NSCLC can be further classified into various types depending on the type of cells and what they look like under the microscope.¹ The most common of these types are squamous cell, large cell, and adenocarcinoma NSCLC.¹ Lung cancer, including small cell and NSCLC, has the highest mortality rate of all the cancers in the United States for both men and women.⁴ In 2012, lung cancer was estimated to be the cause of death in 160,340 people, roughly 28% of all cancer deaths.⁴ Numerous trials are under way investigating whether newer agents and regimens may improve overall survival.

The treatment of NSCLC has changed drastically over the past decade with a trend toward personalized medicine and targeted therapy, especially in those with metastatic disease. For patients with early stage, resectable lung cancer, surgery is the treatment of choice. If the patient cannot tolerate resection or if the tumor is non-operable, radiation is recommended. For those with stage II or IIIA disease who undergo surgery, adjuvant chemotherapy with cisplatin and vinorelbine is recommended with or without radiation. Stage IIIB patients should receive concurrent chemoradiation with a cisplatin doublet. For stage IV, or metastatic disease, treatment depends upon multiple factors, including tumor histology and epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein- like 4/anaplastic lymphoma kinase (EML-ALK) mutation status. Patients who have certain EGFR mutation should receive erlotinib. Crizotinib, an ALK inhibitor, should be used in patients who are ALK positive. Non-squamous NSCLC should receive platinum doublet therapy with or without bevacizumab. Of note, cisplatin with pemetrexed has shown an increased survival compared with cisplatin with gemcitabine in the non-squamous population. Once patients have received 4 to 6 cycles of the platinum doublet, maintenance therapy is recommended, with options including continuation or switching to single-agent bevacizumab, cetuximab, pemetrexed, gemcitabine, or erlotinib. For squamous cell NSCLC, a platinum doublet is recommended with possible maintenance therapy of continuation or switching to cetuximab or gemcitabine. Treatment of relapsed/refractory NSCLC is patient specific depending on previous therapy and may include single or multi-agent chemotherapy as mentioned previously.⁵

Tyrosine Kinase Inhibitors

Small molecule tyrosine kinase inhibitors (TKIs) are a hot area of research and development for drug manufacturers, with multiple targets having been identified.⁶ While some of these agents have very focused receptor targeting, others have a wide range of activity on multiple targets.⁷ Currently, there are 2 small molecule TKIs approved by the US Food and Drug Administration (FDA) for use in the treatment of NSCLC: crizotinib and erlotinib.⁴ Research has shown that the primary benefit with erlotinib is limited to certain subpopulations of patients with sensitive EGFR mutations, which will be discussed in more detail later.⁸ The recent approval of crizotinib was limited to patients positive for ALK.^4,8-10 While promising results have been seen in progression-free survival (PFS), these agents have so far been unable to improve overall survival (OS), as resistance develops via multiple mechanisms.¹⁰ Irreversible inhibition of the target kinase has been one strategy in drug development to overcome such resistance.³ Other strategies have been to develop agents that can impact multiple targets and redundant pathways, or to use multiple TKIs in combination.³ Most toxicities seen have been mild, with fatigue, nausea, rash, and diarrhea being common within the class; however, some drug-specific toxicities have been identified, such as cholecystitis with motasenib.^11,12 Further, TKIs that target the VEGF pathway have shown common yet not always consistent themes regarding adverse effects, including hypertension, gastrointestinal toxicities, and thromboembolism.

Afatinib

Afatinib is an oral dual irreversible EGFR/HER2 TKI which has promise in dealing with resistance seen with reversible EGFR-TKIs.^13,14 Preliminary results of the LUX-lung 3 randomized phase III trial comparing afatinib with pemetrexed and cisplatin as first-line treatment in patients with EGFR mutation— positive lung cancer showed better PFS results with afatinib (11.1 vs 6.9 months; hazard ratio [HR] 0.58 [0.43- 0.78]; P = .0004).¹⁴ Several other studies (including phase III studies) are currently ongoing.¹⁵

KD019/XL647

KD019/XL647 is a small-molecule TKI that targets multiple receptors, including EGFR, vascular endothelial growth factor receptor 2, HER2, and Ephrin type-B receptor 4. A phase II study evaluating 2 dosing regimens demonstrated a confirmed objective response rate (ORR) of 20% and a PFS of 5.3 months (90% confidence interval, 3.7-6.7). In patients with an EGFR mutation the ORR was 57% and PFS was 9.3 months (90% confidence interval, 5.5-11.7).16 A phase III study investigating the effect on prolonging survival with KD019 versus erlotinib in patients with NSCLC who have progressed after first- or second-line chemotherapy is currently open to accrual.¹⁷

BIBF 1120

BIBF 1120 is an oral indoline derivative which potently blocks VEGFR, plateletderived growth factor receptors (PDGFRs), and fibrolast growth factor receptors (FGFRs).¹⁸ Currently, 2 phase III trials are under way evaluating BIBF 1120 in NSCLC. One is a multinational study with advanced or recurrent NSCLC investigating PFS in patients receiving BIBF 1120 with or without docetaxel.¹⁹ The second ongoing multinational study is evaluating pemetrexed/folic acid with or without BIBF 1120 as second- line therapy in patients with nonsquamous NSCLC.20

Anti-EGFR

EGFR, one of the 4 HER family receptors, is expressed in 80% to 85% of patients and mutated in approximately 10% of Caucasians and 50% of Asians with NSCLC.21 This mutation in the tyrosine kinase portion of the receptor causes EGFR to become constantly active. This leads to an increase in downstream cancer cell growth, invasion, differentiation, and proliferation.²² EGFR mutations are more commonly found in patients who are non-smokers, of Asian descent, women, and those who have adenocarcinoma NSCLC. While EGFR mutations do not have an effect on prognosis, these patients may potentially benefit from an EGFR inhibitor, particularly NSCLC with deletions on exon19 or mutations on exon 21.²³ Currently, only 1 EGFR tyrosine kinase inhibitor, erlotinib, is available in the United States.⁵ Drug development targeting the HER family receptors in NSCLC is ongoing in phase I-III clinical trials.

Dacomitinib

Unlike erlotinib, which only targets EGFR, dacomitinib (PF-00299804) is a TKI with activity against EGFR as well the HER2 and HER4 receptors.²⁴ In a published phase II trial, dacomitinib was compared with erlotinib in 188 patients with progressive NSCLC after treatment with 1 or 2 chemotherapy regimens. The primary end point, median PFS, was 2.86 months in the dacomitinib arm compared with 1.91 months in the erlotinib arm (P = .012). Median OS was non-significant at 9.53 months and 7.44 months, respectively (P = .205). The most common adverse effects were acneiform rash, diarrhea, oral mucositis, and infections of the nails.25 Phase II and III trials are currently being conducted; specifically, the phase III trial, ARCHER 1009, is comparing dacomitinib with erlotinib in patients with relapsed or refractory NSCLC or intolerance to prior treatment regardless of EGFR mutation status.²⁶

Necitumumab

Another EGFR inhibitor in clinical trials is necitumumab (IMC-11F8), a fully humanized IgG monoclonal antibody. Compared with cetuximab, a chimeric monoclonal antibody which has a 20% rate of hypersensitivity reactions, necitumumab has a much lower risk. Also, the immunoglobulin (Ig) G1 monoclonal antibody should be more likely to have an antibody-dependent cell-mediated cytotoxicity compared with IgG2 agents, such as panitumumab.27 In February of 2011, a phase III trial (INSPIRE) of cisplatin and pemetrexed with or without necitumumab for newly diagnosed patients with stage IV non-squamous NSCLC was halted due to rates of thromboembolism in the necitumumab arm.²⁸ No thromboembolic events had been reported previously in the phase I and II trials.²⁹ The SQUIRE trial, a phase III trial in newly diagnosed metastatic squamous NSCLC being treated with cisplatin and gemcitabine for up to 6 cycles with or without necitumumab, has completed enrollment but results have not been reported.³⁰ The most common toxicities seen in trials were dermatologic, including dry skin (14%) and acneiform rash (52%).²⁹

Heat Shock Protein

Ganetespib (STA-9090) is a non-geldanamycin heat shock protein 90 (HSP90) inhibitor currently being studied in multiple malignancies. Heat shock proteins are molecular chaperones which are activated with elevated temperatures.³¹ In particular, HSP 90 is essential in the development and stabilization of proteins. In cancer cells, compared with normal cells, HSP 90 is constantly active.³² Geldanamycin inhibitors of HSP 90 have shown to be active against cancer cell lines, but patient tolerability was poor due to gastrointestinal and liver toxicities. This led to the development of non-geldanamycin compounds such as ganetespib.³³ Ganetespib is currently being studied in phase I-III trials alone or combined with docetaxel or crizotinib in patients with relapsed or refractory stage IIIB or IV NSCLC.³⁴ In early reports of phase II outcomes, out of 73 participants 1 had a partial response and 7 had stable disease. The majority of toxicities were either grade 1 or 2 and included nausea, constipation, diarrhea, and dyspnea.³⁵ Halichondrin b analogue

Eribulin

Eribulin, also known as E7389, is a microtubule inhibitor derived from the Japanese sea sponge Halichondria okadai. Unlike traditional taxanes which inhibitmicrotubule depolymerization, eribulin suppresses microtubule polymerization, which prevents mitotic spindles from forming and causes subsequent cell death.³⁶ Currently eribulin (Halaven) is FDA-approved in the third-line treatment of metastatic breast cancer,³⁷ but this agent is involved in multiple trials for previously treated, advanced or metastatic non-small cell lung cancer as a single agent or combined with other active agents such as pemetrexed or erlotinib.³⁸ Two published phase II trials have studied the effects of single-agent eribulin in a total of 139 patients with stage IIIB or IV non-small lung cancer who have relapsed or have refractory disease during or after receiving traditional platinum doublet chemotherapy. The ORR for eribulin was 4.5% to 11.7% with a median OS of approximately 8.9 to 12.6 months. The most common adverse effect was neutropenia, with neuropathy being the main cause of eribulin discontinuation.^39,40

Taxanes

Solvent-based paclitaxel (sb-paclitaxel) plus carboplatin is a commonly utilized regimen in lung cancer.⁴¹ Unfortunately, this combination is associated with a high incidence of adverse effects, including fatal hypersensitivity reactions, neutropenia, and anemia. Because of the hypersensitivity reactions, premedication with a steroid, diphenhydramine, and an H2 antagonist is recommended.⁴² Two agents being investigated are nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and paclitaxel poliglumex (PPX). Nab-paclitaxel is a unique protein formulation of paclitaxel that may reach the tumor microenvironment more efficiently and may be preferentially taken up by cancer cells while also decreasing toxicities associated with paclitaxel and its solvent.^41,43 Of particular note was the decrease seen in neuropathy in the nab-paclitaxel treatment arm, including a decrease in recovery time from grade 4 neuropathy after the treatment was finished. Additionally, grade 4 neutropenia was significantly less in the nabpaclitaxel group; however, there was an increase observed in the amount of anemia and thrombocytopenia in study subjects. Despite increases in cumulative dosages administered and improvements in PFS, OS was not improved with the use of nab-paclitaxel. Although the results were not as promising as expected, subgroup analysis indicates that patients with squamous cell cancer may experience a greater benefit from nab-paclitaxel. Despite the advantageous adverse effect profile with PPX, no improvements in overall survival or time to progression was seen in studies. ^44,45 No recent information can be found regarding FDA approval or marketing by the manufacturer.

Recombinant lactoferrin

Talactoferrin alpha

Lactoferrin, most commonly found in breast milk,⁴⁶ when given orally causes maturation of dendritic cells in the gut-associated lymphoid tissue which counteracts anti-tumor effects produced by malignant cells.⁴⁷ A recombinant lactoferrin, talactoferrin alfa, has been studied in phase I and II trials in patients with locally advanced or metastatic NSCLC who have failed firstline chemotherapy.⁴⁸ In early August, a phase III trial of talactoferrin alfa as third line in the treatment of NSCLC (FORTIS-M) was closed to accrual due to not meeting its primary end point of OS, which was a median of 7.5 months in the talactoferrin groups compared with 7.7 months in the placebo group (P = .06).⁴⁹ A phase III trial, FORTIS-C, for the treatment of newly diagnosed, stage IIIB or IV lung cancer of talactoferrin or placebo in combination with carboplatin and paclitaxel is still ongoing.⁴⁸

Vaccines

The goal of vaccination in NSCLC is to mount a targeted immune response specifically against the NSCLC cells. In the past, outcomes in vaccine and immunologic research for NSCLC were disappointing. The majority of current phase III research is focused on implementing vaccine therapy after successful response to standard therapy, or as a maintenance phase of treatment.

Astuprotimut-R (MAGE-A3, GSK1572932A)

Melanoma-associated antigen A3 (MAGE A3), a tumor-specific antigen that can be identified by cytotoxic T cells, is overexpressed in 35% to 50% of NSCLC.50,51 This antigen, which is expressed in early carcinogenesis, is most commonly found in squamous NSCLC and is associated with more aggressive disease.50,52 A vaccine, astuprotimut-R, consisting of a recombinant MACE A3 fused with protein D of H influenza, has undergone phase I and II trials in early stage NSCLC.53,54 A randomized phase II trial assigned 182 patients with MAGE A3 expressing stage IB or II NSCLC to astuprotimut-R or placebo following curative surgery. The HR for disease-free interval was 0.74 and OS was 0.66, both non-signficant.⁵⁴ A randomized, double-blind phase III trial, MAGRIT, including patients with stage IB, II, and IIIA NSCLC receiving astuprotimut- R or placebo after surgery or chemotherapy, is ongoing.⁵⁵

Emepepimut-S (Liposomal BLP25 or Stimuvax)

Emepepimut-S is a vaccine with a synthetic MUC-1 peptide core and a liposomal delivery system.⁵⁶ MUC-1 is a glycoprotein overexpressed on cancer cells necessary for tumor cell growth, anti-apoptosis, and chemotherapy resistance. ^57-59 In animal models, emepepimut- S has produced a T-cell mediated response against NSCLC cells.⁶⁰ A total of 171 patients with a response or stable disease after first-line treatment for advanced or metastatic disease NSCLC were randomized to maintenance emepepimut-S, given with cyclophosphamide prior to vaccination, or placebo, which was continued until disease progression. There was no difference in median OS (17.2 months vs 13 months), but a non-significant trend of improved survival was seen in patients with stage IIIB NSCLC without malignant pleural effusions (30.6 months vs 13.3 months). Only 21% of patients mounted a specific T-cell response against MUC-1.^61,62 Adverse effects included mild flu-like symptoms, infections, and injection reactions. Currently, 2 phase III trials, START (closed to accrual) and INSPIRE, are being conducted in stage IIIB patients who have had a response or stable disease to concurrent chemoradiotherapy.⁶³

Belagenpumatucel-L (Lucanix)

Unlike emepepimut and astuprotimut, belagenpumatucel-L includes 4 irradiated NSCLC cell lines—2 adenocarcinoma, 1 squamous cell, and 1 large cell. An antisense gene plasmid, or inhibitor, of transforming growth factor β2 (TGF- β2) is incorporated into these cells for additional efficacy.⁶⁴ TGF- β2 inhibits T-cell activation and maturation and increased levels have been linked to a worse prognosis in patients with NSCLC.^65,66 Seventy-five patients with stage II-IV NSCLC and a tumor burden of ≤125 mL were randomized into a phase II trial to receive 3 different doses of belgenpumatucel- L every 4 or 8 weeks for up to 16 doses following standard chemotherapy. OS was higher in the patients in the 2 higher-dosing groups compared with patients in the lower-dosing group, with an estimated 1-year survival of 68% in the higher-dosing groups (≥25 x 106 cells) compared with 39% in the lowerdosing group. There was no difference in toxicity between the 3 dosing schema, with the most common toxicities being pain, fatigue, cough, and breathing problems.⁶⁷ The STOP trial, a randomized, placebo-controlled, phase III study, is currently comparing belagenpumatucel-L (25 x 106 cells) with placebo in stage IIIA-IV disease following standard chemotherapy. ⁶⁸

C-met Inhibitors

Several cancers have been linked to mutations in the mesenchymal—epithelial transition (MET) gene including NSCLC.⁶⁹ Hepatocyte Growth Factor Receptor (HGFR) or MET is a protein encoded within the MET gene that supports oncogenesis through a wide variety of mechanisms including cell proliferation, cell survival, invasion of surrounding tissue, metastasis, and angiogenesis.⁷⁰ Tivantinib is an orally administered HGFR-selective TKI, which is also the most clinically advanced c-MET inhibitor to date. A randomized controlled phase II study investigating dual EGFR and MET inhibition using erlotinib plus tivantinib or placebo in patients with advanced NSCLC not previously treated with an EGFR inhibitor did not significantly improve PFS (16.1 vs 9.7 weeks) using an intention to treat population (HR 0.81 [95% CI 0.57-1.15; P = .23]).⁷¹ After using a Cox regression model to adjust for prognostic factors including histology and genotype, significant PFS improvement was noted (HR 0.68 [95% CI 0.47- 0.98; P <.05]). Heightened PFS improvement was observed in patients with nonsquamous histology, EGFR wild-type status, and k-RAS mutations.⁷¹ A phase III study closed to accrual but which is still ongoing is evaluating the tivantinib plus erlotinib combination in non-squamous NSCLC.⁷² A second phase III study is investigating the combination in wildtype EGFR patients who have received 1 or 2 prior systemic treatments; however, this study was suspended August 29, 2012.⁷³

In addition to the small-molecule TKIs under development, onartuzumab (MetMab), a monoclonal antibody targeted at HGFR, is also being studied in clinical trials.^69,70 Onartuzumab plus erlotinib versus placebo in 2nd/3rd line NSCLC was evaluated in a randomized phase II study. Preliminary results indicate that it may only benefit patients with tumors that overexpress HGFR. Surprisingly, evidence has further indicated that treatment may lead to worse outcomes in patients that do not exhibit this tumor marker (OS, HR 2.52).⁷⁴ Additional phase II studies evaluating onartuzumab in other combinations are ongoing.^75,76 Furthermore, 1 phase III study evaluating onartuzumab plus erlotinib in patients with MET diagnostic- positive NSCLC who have received chemotherapy for advanced or metastatic disease is currently recruiting.⁷⁷

Conclusion

In the world of NSCLC treatments, the current as well as future horizon contains both good news and bad news for patients. While overall treatment options have reached a plateau in OS, there is good news on a variety of fronts. Research continues to expand our knowledge of the mechanisms of NSCLC and how resistance develops to current treatment regimens. Additionally, there is an abundance of activity surrounding drug development for NSCLC with some promising results in targeted areas. From subset analyses of recent studies and with the identification of additional biomarkers, the use of personalized medication therapy continues to grow. Using appropriate testing and treatment, PFS can be significantly enhanced in certain cancer subtypes such as seen with the use of the recently approved crizotinib and erlotinib. Other smallmolecule TKIs directed at a variety of targets have shown some early positive results, but have often failed in phase III trials. However, new agents that target the MET pathway such as tivantinib, or irreversible inhibitors that can overcome resistance such as afatinib, may expand available treatment options. The VEGF pathway also continues to be the target of many of the drugs being studied, but the risk of thromboembolism and other toxicities remains a concern based on experience with bevacizumab and results have been less than exceptional among many of the small-molecule TKIs targeting this pathway. Monoclonal antibodies under development such as onartuzumab and necitumumab have shown mixed results, but a severe adverse effect remains a concern. Of the vaccines being studied, only belagenpumatucel-L has demonstrated a significant impact on OS, albeit in a small phase II trial. Additional phase III trials with all 3 vaccines are currently ongoing and should help clarify the role of any of these agents in NSCLC. In most cases, the drugs discussed in this article primarily benefit non-squamous NSCLC. However, results from an evaluation of nab-paclitaxel indicate that squamous cell NSCLC may derive a greater therapeutic effect. While the analysis came from a subgroup review, it certainly warrants further study and may expand options in a difficult-to-treat group of patients.

Prior to 1995, most chemotherapeutic agents brought to market cost less than $1000 a month, while medications approved after 2005 often exceed $4000 a month.⁷⁸ The National Institutes of Health estimates that cancer care costs will increase 39% by 2020.⁷⁸ As costs of medications rise, advances in scientific knowledge will become increasingly more important. Cost-effective treatment could be improved by ensuring accurate identification of the patient’s tumor subtype and following evidencebased medicine practice guidelines. As demonstrated in clinical trials, the benefit of many of these medications is limited to very specific patient populations. With marginal benefits in PFS, no benefits in OS, and costs continuing to soar, payers will and should adopt practices such as additional restrictions and pre-certifications as well as increasing copayments such that patients share an increased cost of therapy.

Author Affiliations: From University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus (JMC, BLM), Baton Rouge, LA; Our Lady of the Lake Regional Medical Center (MMM), Baton Rouge, LA. Funding Source: None.

Author Disclosures: Dr Comeau reports that she has attended the Hematology/ Oncology Pharmacy Association meeting sponsored by Bristol-Myers Squibb. The other authors (MMM, BLM) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JMC, MMM, BLM); acquisition of data (JMC, MMM, BLM); analysis and interpretation of data (JMC, MMM, BLM); drafting of the manuscript (JMC, MMM, BLM); and critical revision of the manuscript for important intellectual content (JMC, MMM, BLM).

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