Vassiliki Papadimitrakopoulou, MD, Professor, Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, discusses the implementation of personalized medicine for lung cancer patients.

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Vassiliki Papadimitrakopoulou, MD, from the University of Texas MD Anderson Cancer Center, discusses the implementation of personalized medicine for lung cancer patients. 

The Implementation of Personalized Medicine for Lung Cancer Patients

Roy S. Herbst, MD, PhD, from Yale-New Haven in Connecticut, discusses the benefit of treating lung cancer with immunotherapy. 

The Benefit of Treating Lung Cancer with Immunotherapy

The Cancer Genome Atlas (TCGA) began in 2006, with a total investment of $100 million from the National Cancer Institute and the National Human Genome Research Institute for a 3-year pilot period.

Its remarkable success ensured substantial subsequent investment from the National Institutes of Health. The aim of TCGA is to generate detailed genomic characterization and analysis of more than 20 tumor types, through the cooperation of a national network of clinicians and scientists. &ldquo;TCGA is a multi-institutional consortium,&rdquo; said James Suh, MD, clinical assistant professor in the department of pathology at the New York University Langone Medical Center. Data from these analyses are freely available to support and facilitate worldwide advances in oncology.

The Cancer Genome Atlas has recently characterized the 2 most common subtypes of non-small cell lung carcinoma (NSCLC), namely squamous cell lung carcinoma (which comprises 25%-30% of NSCLC) and lung adenocarcinoma (which accounts for approximately 40% of NSCLC)

&ldquo;As a pathologist involved in the lung cancer project, I reviewed tumor samples to make sure that they contained enough viable tumor cells for the proposed analyses,&rdquo; explained Suh. Tumors from previously untreated patients with disease ranging from stage 1 to stage 4 were used for analysis.

&ldquo;What we know about lung adenocarcinoma (and [this] may also be true of lung squamous cell carcinoma) is that chemotherapy or other therapies may induce dynamic molecular changes in which the genetic profile that you started with may be different after treatment,&rdquo; said Benjamin Levy, MD, director of thoracic medical oncology at the Mount Sinai Beth Israel Hospital and assistant professor at the Icahn School of Medicine, both in New York. &ldquo;I think that we are fairly sure at this point that the genetic underpinnings of a tumor are not static and may change over time, with or without treatment.&rdquo;

Researchers from TCGA published the results of a genomic and epigenomic study of squamous cell lung carcinoma, along with an assessment of possible opportunities for therapy; in 2012.

The researchers utilized tumors from 178 patients, 96% of whom had a history of tobacco use. Squamous cell lung carcinoma was found to have a high somatic mutation rate of 8.1 mutations per megabase. This study revealed that somatic alterations appeared to drive molecular pathways necessary for the initial development and ongoing growth of cancer. Of importance, mutation or somatic copy number alterations were found in genes participating in the differentiation of squamous cells and oxidative stress response. Indeed, 44% of the samples contained alterations in genes involved in squamous cell differentiation.

were amplified and overexpressed, and there were mutations leading to loss of function in

. The researchers also identified the inactivation of a confirmed tumor suppressor gene,

in 72% of cases of squamous cell lung carcinoma

Overall, the authors reported statistically recurrent mutations in 11 genes, and mutation of

are commonly mutated in lung adenocarcinoma, but they were not found to be common among the squamous cell lung carcinoma tumors studied. Instead, 96% of the tumors had mutations in tyrosine kinases, serine/threonine kinases, nuclear hormone receptors, and others, and the authors predicted that 50% to 77% of these mutations were likely to have functional impact. The presence of an inactivating mutation of the

gene suggests use of genotyping to select patients for immunotherapies in NSCLC.

In July 2014, TCGA published a comprehensive molecular profiling of lung adenocarcinoma.

Researchers took tumor specimens from 230 patients, 81% of whom either had a history of tobacco use or were current smokers. Analysis revealed that the tumors had 8.9 mutations per megabase.

Vassiliki Papadimitrakopoulou, MD, on Implementing Personalized Medicine in Lung Cancer

Papadimitrakopoulou is a Professor at the University of Texas, MD Anderson Cancer Center

Among the samples studied, 76% had somatic evidence of

activation. Although it has been established that this pathway is frequently activated in lung adenocarcinoma by mutations in known driver oncogenes, the present study revealed the existence of hitherto unknown mechanisms also capable of activating the pathway. The authors recommended investigating inhibition of other possible target alterations, including MET and ERB2/HER2, and stressed the importance of their discovery of inactivating mutations of

, highlighting a role for the MYC pathway. &ldquo;This study has broadened our knowledge by revealing additional molecular findings (

, loss of function MGA mutations) yet to be this extensively reported on,&rdquo; said Levy. The analysis encountered abnormalities in the PI3K-mTOR pathway (25% of cases), the P53 pathway (63% of cases), and alteration of cell cycle regulators and oxidative stress pathways (64% and 22% of cases, respectively).

&ldquo;This massive undertaking by TCGA was able to identify additional molecular alterations that have potential therapeutic implications, specifically in oncogene negative tumors,&rdquo; stated Levy. &ldquo;This includes identification of aberrations in genes, such as

, that may be actionable and thus have future clinical relevance. The hope is that these new findings will provide further insight that will translate into the development of additional targeted therapies in attempts to improve outcomes.&rdquo;

The aim of TCGA is to generate detailed genomic characterization and analysis of more than 20 tumor types, through the cooperation of a national network of clinicians and scientists.

TCGA has recently characterized the 2 most common subtypes of NSCLC, namely squamous cell lung carcinoma and lung adenocarcinoma.

In a study on squamous cell carcinoma, authors reported statistically recurrent mutations in 11 genes, and mutation of TP53 was found in the majority of samples.

96% of the tumors had mutations in tyrosine kinases, serine/threonine kinases, nuclear hormone receptors, and others.

In July 2014, TCGA published a comprehensive molecular profiling of lung adenocarcinoma

Authors recommended investigating inhibition of target alterations, such as MET and ERB2/HER2, and stressed importance of their discovery of inactivating mutations of MGA, highlighting a role for the MYC pathway.

The Cancer Genome Atlas. Program overview. http://cancergenome.nih.gov/abouttcga/overview. Accessed September 9, 2014.

American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 11, 2014.

Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers.

The Cancer Genome Research Atlas. Comprehensive molecular profiling of lung adenocarcinoma.

Considering the overall impact of this multi-institutional endeavor by TCGA on future drug development in NSCLC, Suh commented, &ldquo;TCGA identifies smaller subsets of patients with actionable targets, enabling clinical research to develop an agent and subsequently obtain FDA approval in a shorter time frame than in the past.&rdquo;

The Cancer Genome Atlas (TCGA) began in 2006, with a total investment of $100 million from the National Cancer Institute and the National Human Genome Research Institute for a 3-year pilot period. 

The Cancer Genome Atlas Plays Role in Future Therapies for NSCLC

Grace K. Dy, MD, is an associate professor in the department of Medicine at Roswell Park Cancer Institute in Buffalo, New York.  Her areas of research interest include phase I clinical trials and novel targets for lung cancer therapy.

Q:  What is your overall approach when evaluating the need for systemic treatment for patients with metastatic NSCLC?

In terms of an overall approach, we take into consideration not just the tumor characteristics, but also the patient&rsquo;s psychosocial setting.  In addition, the standard medical parameters, such as performance status and comorbidities, are some of the key features that help us to devise a treatment plan.&nbsp; In patients with poor performance status, hospice is most appropriate; however, with the new developments in targeted therapies over the past 5 to 10 years, there has been a change in our approach. Nowadays, even in patients with poor performance status, it is imperative that we determine if there are oncogenic drivers in their tumors that might respond to a targeted therapy that is more effective and better tolerated than traditional cytotoxic chemotherapy. &nbsp;For example, the &ldquo;Lazarus effect&rdquo; is well-recognized with the use of EGFR TKIs. Thus, whenever possible, particularly if there&rsquo;s tissue available, you want to check the mutation profile of the tumor. This is because there are several well-tolerated and efficacious targeted agents approved for frontline treatment. This list will likely expand because the field is changing so rapidly.&nbsp; On the other hand, we recognize the limitations with the use of these targeted agents in lung cancer. Cancer cells evolve very fast and develop resistance to targeted therapies as a rule rather than exception. Thus to this date, we still frequently employ cytotoxic chemotherapies in our treatment regimens. The use of standard cytotoxic agents continues to have a role in our lung cancer patients.

Q:  Do you have a go-to regimen for systemic treatment in patients who initially present with metastatic disease?

As an academician, I have available to me multiple clinical trials in various stages of development. Generally, if a patient is fit and can qualify for a suitable clinical trial, my go-to recommendation would be a clinical trial, unless I know there is a certain treatment that would be more advantageous. If the patient is not eligible for a clinical trial, or if there is no identifiable tumor mutation for which there is an FDA-approved drug, then my go-to regimen would be a platinum combination. That combination would be determined by the histology (ie, squamous cell vs nonsquamous cell NSCLC).

Q:  To what extent do molecular testing and the availability of targeted therapies influence your treatment decisions for the patient with metastatic NSCLC?

It&rsquo;s a major component of the overall management plan. Age, gender, and performance status are generally not factors that contraindicate the use of  targeted treatments. Even in patients with poor performance status, as long as their life expectancy is projected to be longer than a month, it is worth performing molecular testing since the therapeutic index may be very favorable depending on the corresponding targeted agent matched to the genomic alteration. However, due to the lag-time between requesting the test and having the results available, in patients who are highly symptomatic, it is imperative to initiate systemic therapy immediately if there is no contraindication otherwise to the use of cytotoxic chemotherapy. On the other hand, even in patients with good performance status who are candidates for platinum-based combination therapy, if their&nbsp; cancer-related symptoms are relatively controlled,&nbsp; waiting for the test results before instituting therapy is reasonable as the targeted agents may have better efficacy and tolerability compared with cytotoxic chemotherapy.

Hongbin Chen, MD, PhD, is an assistant professor in the Department of Medicine at Roswell Park Cancer Institute in Buffalo, New York

.  His research interests include targeted personalized therapy in lung cancer.

When a patient presents with metastatic disease, our first step is usually a positron emission tomography (PET)/computed tomography (CT) scan to evaluate the extent of disease. After this, we offer the patient systemic treatment consisting of either chemotherapy or targeted therapy. We look at the histology or pathology report to see what type of NSCLC the patient has; typically, patients are classified as having squamous cell NSCLC versus nonsquamous cell NSCLC. Under the nonsquamous cell NSCLC umbrella, the most common type is adenocarcinoma. This is important information; nowadays, we offer specific treatment regimens based on histology. If the patient has adenocarcinoma or any other type of nonsquamous cell NSCLC, we usually order a mutational test.&nbsp;

We use a next-generation sequencing test developed at Roswell Park Cancer Institute (OmniSeq Target&trade;) that can evaluate actionable DNA alterations in tumors.  Patient specimens are evaluated for mutations in about 20 genes, including

and others.  In addition, we do fluorescence in situ hybridization to identify translocations, such as

as well as to evaluate copy number variations in

.  We order this testing (which typically takes 1 week to 10 days to be completed) to determine whether there is an actionable mutation, and to determine if there is a relevant clinical trial in which the patient can be enrolled.&nbsp; If he or she is positive for any actionable mutations, we can also offer one of the tyrosine kinase inhibitors (TKIs), such as erlotinib, afatinib, or crizotinib. If the patient is negative, then we would initiate systemic chemotherapy.&nbsp;

For patients with squamous cell NSCLC, we do not routinely order the mutational test because mutations very rarely occur in this setting.  For these patients, we would offer chemotherapy, which would be different from the type of chemotherapy that is used in nonsquamous cell NSCLC.

When patients present with metastatic disease, we begin by evaluating their tolerance level, ECOG performance status, and comorbidity status. The preferred regimen indicated by the guidelines, as well as the results of clinical trials, is platinum-based doublet chemotherapy. This includes cisplatin or carboplatin plus one additional agent, making it a doublet regimen. Several years ago, a study came out that showed there are survival differences when you give different chemotherapies to patients with squamous cell versus nonsquamous cell NSCLC.

So, for a patient with nonsquamous cell adenocarcinoma NSCLC who has tested negative on all the mutational tests and who is eligible for a platinum-based doublet regimen, I usually offer cisplatin or carboplatin with pemetrexed, given for 4 to 6 cycles as frontline chemotherapy.

Another effective regimen in this setting is adding an anti-angiogenic monoclonal antibody bevacizumab to chemotherapy of carboplatin and paclitaxel. We usually do a scan, such as a CT scan, every 2 cycles for disease evaluation.

On the other hand, for a patient with squamous cell NSCLC, we would offer the preferred regimen of a platinum doublet, cisplatin or carboplatin (depending on kidney function and general tolerance level) and an additional agent, such as gemcitabine or nab-paclitaxel; pemetrexed is contraindicated in squamous cell NSCLC. As in nonsquamous cell NSCLC, we do a total of 4 to 6 cycles of first-line chemotherapy, with a CT scan after every 2 cycles to evaluate disease response.

After the first 4 to 6 cycles of frontline chemotherapy, we may also offer maintenance therapythat is, continuation of a single agent, such as pemetrexed or bevacizumab for nonsquamous cell NSCLC, or gemcitabine for squamous cell NSCLC. This would be offered and continued until the patient could not tolerate the chemotherapy regimen or the disease had progressed. This is also based on studies showing that maintenance therapy improves survival.

Q:  To what extent do molecular testing and availability of targeted therapies influence your treatment decisions for the patient with metastatic NSCLC?

Nowadays, when patients present from the community for a second opinion in our institute, in most cases, the community oncologist has already adopted the practice of ordering these tests upfront. We want to know the patient&rsquo;s mutational status before we start systemic therapy, as this can really be beneficial. Although only a minority of patients are tested positive for a mutation, targeted therapy using a specific TKI has been shown to be more effective than just offering chemotherapy.

Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in  chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.

Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

Drs. Grace Dy and Hongbin Chen Discuss Systemic Treatment for Metastatic, Non-Small Cell Lung Cancer (NSCLC)

In Practice: Systemic Treatment for Metastatic NSCLC

Fred R. Hirsch, MD, PhD Professor of Medicine and Pathology, Associate Director for International Programs, University of Colorado Cancer Center, discusses the importance of biomarkers for lung cancer.

Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology, Associate Director for International Programs, University of Colorado Cancer Center, discusses the importance of biomarkers for lung cancer.

The Importance of Biomarkers for Lung Cancer

Immunotherapies have shown great promise in the treatment of advanced cancers, including metastatic melanoma and non-small cell lung cancers (NSCLC).

These therapies include immune checkpoint inhibitors, such as the anti-cytotoxic lymphocyte antigen-4 (anti-CTLA-4) antibody, ipilimumab, and, more recently, antibody inhibitors of the programmed cell death 1 (PD-1) receptor and its ligand, PD-L1, such as pembrolizumab and nivolumab.

In early-phase trials, use of these agents in NSCLC has been associated with dramatic response rates and largely manageable toxicities. &ldquo;Immunotherapies have gone through very promising development in phase I and a few phase II studies, and now there are phase III studies of immunotherapy drugs to be used in the first-line treatment setting,&rdquo; said Grace Dy, MD, an associate professor in the department of medicine at Roswell Park Cancer Institute in Buffalo, New York.  Dy noted that the 2 major classes of checkpoint inhibitors, anti-CTLA-4 agents and anti-PD-1 agents, are the current front-runners for development in many malignancies, including lung cancer. &ldquo;It seems that the PD-1/PD-L1 pathway inhibitors appear to be better tolerated, and that&rsquo;s why there is a great enthusiasm to support the development of these agents. We&rsquo;ve seen, in early phases of development, that most patients tolerate [them] well without the typical chemotherapy side effects. While&hellip;some of the rare side effects can be very serious [eg, pneumonitis], people have learned how to manage them&hellip; and they are not high-frequency events.&rdquo;

Roy Herbst, MD, The Benefits of Using Immunotherapy to Treat Lung Cancer

Herbst is a professor of medicine at the Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital at Yale-New Haven in Connecticut

Some of the immunotherapy agents currently under investigation for lung cancer include CTLA-4 inhibitors (tremelimumab and ipilimumab), anti-PD-1 agents (nivolumab and pembrolizumab ), and anti-PD-L1 antibodies (MPDL3280A and MEDI4736).

These therapies hold great promise for revolutionizing the treatment of NSCLC, as they have for other cancers, such as melanoma, with durable activity and tolerability observed in multiple early-phase studies.

Previous studies examining the impact of antibody-mediated inhibition of the PD-1 ligand, PD-L1, have demonstrated durable tumor regression and disease stabilization, along with a low rate of grade 3 and 4 toxicities (9%) in patients with advanced solid tumors, including those with melanoma and NSCLC.

MPDL3280A is an engineered human IgG1-kappa monoclonal antibody directed against PD-L1.

Phase I studies with this PD-L1 inhibitor (inclusive of 85 patients with NSCLC) have shown no dose-limiting toxicities and a low rate of grade 3 and 4 adverse events (11%); a best overall response rate (ORR) of 23% was observed, and responses appeared to be durable, with most responders completing a full year of treatment with no progression.

The OAK study, which began recruitment in February 2014, is a global, open-label, randomized phase III study that is comparing MPDL3280A with docetaxel for the treatment of patients with locally advanced or metastatic NSCLC, following failure with platinum-based therapy.

Patients in the study will be randomized 1:1 to docetaxel (75 mg/m

IV infusion) or MPDL3280A (1200 mg IV infusion) given every 3 weeks, and treatment will continue for a total of 16 cycles or 12 months of treatment or until unacceptable toxicity or disease progression occurs.

The primary endpoint of the study is overall survival; secondary endpoints include incidence of adverse events, ORR, progression-free survival, and duration of response, determined using Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1).  Patients will be included in the trial if they are 18 or older and have an Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease by RECIST v. 1.1, and locally advanced, unresectable or metastatic NSCLC (stage 3B, stage 4, or recurrent) that progressed during or following a prior platinum-based regimen, or disease progression (within 6 months) on a platinum-based adjuvant/neoadjuvant regimen.&nbsp; The estimated primary completion date is June 2017.

Phase I studies with this PD-L1 inhibitor (N= 85 patients with NSCLC) have shown no dose-limiting toxicities and a low rate of grade 3 and 4 adverse events.

A best ORR of 23% was observed, and responses appeared durable, with most responders completing a full year of treatment with no progression.

The OAK study, which began recruitment in February 2014, is a global, open-label, randomized phase III study comparing MPDL3280A with docetaxel for the treatment of patients with locally advanced or metastatic NSCLC, following failure with platinum-based therapy.

The primary endpoint of the study is overall survival.

The estimated primary completion date is June 2017.

Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Creelan BC. Update on immune checkpoint inhibitors in lung cancer.

Reichert JM. Antibodies to watch in 2014: mid-year update.

ClinicalTrials.gov. A randomized phase 3 study of MPDL3280A (an engineered anti-PDL1 antibody) compared to docetaxel in patients with locally advanced or metastatic non-Small cell lung cancer who have failed platinum therapy  &ldquo;OAK&rdquo;. http://clinicaltrials.gov/show/NCT02008227. Accessed September 13, 2014.

Immunotherapies have shown great promise in the treatment of advanced cancers, including metastatic melanoma and non-small cell lung cancers (NSCLC)

Clinical Trial Profile:  The OAK Study

Oncogenic driver mutations have been detected in over 60% of the non-small cell lung cancer (NSCLC) tumor samples surveyed by the Lung Cancer Mutation Consortium (LCMC).

The increasing use of targeted drugs in the clinic has raised the potential for effective treatment of metastatic NSCLC with fewer side effects than traditional chemotherapeutic drugs.

&ldquo;When we find these specific genetic changes, the doctor can choose drugs and clinical trials specifically targeting those oncogenic drivers,&rdquo; wrote Mark G. Kris, MD, in a press release. Kris, lead author of the LCMC study and the Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Institute in New York City, explained, &ldquo;When that happens, the chance of shrinkage is much higher than with standard chemotherapies. The side effects are much less because the cancer cells are much more dependent on these oncogenes than normal cells.&rdquo;

However, while there are definite advantages to using targeted therapies, the reality is that these agents are associated with toxicities and adverse reactions that must be anticipated and managed by clinicians in order to maximize the benefit to their patients. A variety of side effects have been associated with these agents, including rash, diarrhea, hypertension, hepatotoxicity, and ocular toxicities, among others.

The majority of these side effects can be grouped into general categories, including mechanism-associated toxicities and off-target toxicities. Determining to which category a given side effect belongs is important for choosing an appropriate management strategy.

Targeted therapies typically work by disrupting, in a selective manner, cell-signaling pathways that drive tumor growth. New agents in NSCLC have often targeted the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is expressed in more than 60% of NSCLCs.

Tyrosine kinase inhibitors (TKIs) targeting EGFR that are approved for use in NSCLC include erlotinib and gefitinib.

Under normal circumstances, EGFR is expressed primarily in epithelial cells of the skin and digestive tract; therefore, rash and diarrhea constitute the most common side effects associated with EGFR inhibitors.

Because these side effects are associated with the mechanism of action of the drug (ie, inhibition of EGFR signaling), they may also serve as surrogate markers for an effective antitumor response.

The severity of rash in patients taking erlotinib has indeed been correlated with polymorphisms in the

Furthermore, in a meta-analysis examining the association between skin rash and disease prognosis in patients with NSCLC who were treated with either erlotinib or gefitinib, the occurrence of rash was a predictive factor for improved response rate, progression-free survival (PFS), and overall survival (OS).

Another target of molecular therapies in NSCLC is angiogenesis, specifically signaling by vascular endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody that binds to VEGF-A and is approved for use in patients with metastatic NSCLC in combination with cytotoxic chemotherapy. Studies have revealed a high incidence (23.6%) of hypertension in patients with cancer who are treated with this drug, including a significant number of grade 3/4 events (7.9%).

Similar to the incidence of rash in EGFR inhibitors, hypertension has been found to be associated with positive outcomes in patients with NSCLC.

When dealing with adverse events caused by on-target effects that are correlated with efficacy, it is better for clinicians to pursue a strategy of toxicity management rather than dose reduction, which would reduce the beneficial effects of the drug as well as the toxicities. This is particularly important in the context of metastatic disease, in which few effective alternatives are available.

Side effects involving the eyes are also common with EGFR inhibitors, such as erlotinib and the anti-EGFR antibody, cetuximab. The most common ocular toxicities include blepharitis, trichomegaly, meibomitis, and dysfunctional tear syndrome.

These side effects are often unfamiliar to oncologists and are underreported due to a lack of existing recommendations on routine ophthalmological monitoring regimens.

Ophthalmologic examination before treatment is recommended to enable the identification of ocular toxicities during treatment. Management strategies that avoid dose modifications or interruptions include the use of topical lubricants, anti-inflammatory agents, and corticosteroids.

There are chronic inflammatory and immunologic changes that occur in the lungs in NSCLC that encourage tumor growth. In some cases, these changes can cause severe pneumonitis, and even death, in reaction to TKIs or agents targeting immune checkpoint molecules, such as the programmed cell death-1 receptor (PD-1).

This toxicity is commonly dealt with by cessation of treatment and administration of steroids in severe cases.

MPDL3280A, an antibody targeting the PD-1 ligand (PD-L1), has been the subject of a phase I trial in patients with metastatic NSCLC. Results presented in 2013 indicated that, although grade 3/4 adverse events occurred in 34% of participants, no cases of grade 3-5 pneumonitis were observed,

suggesting that PD-L1 inhibitors might avoid this serious side effect.

In a press release, study author Jean-Charles Soria, MD, PhD, from the Institut Gustave Roussy in France, expressed optimism about antiPD-L1 immunotherapy in advanced NSLC. &ldquo;A new therapy, with few serious adverse side

, that is easy to use  one intravenous infusion every 3 weeks &ndash; and a robust clinical activity as a single agent should soon be available.&rdquo;

Targeted agents for NSCLC may be associated with toxicities and adverse reactions and these must be anticipated and managed by clinicians to maximize benefit to patients.

Rash and diarrhea constitute the most common side effects associated with EGFR inhibitors.

When dealing with adverse events caused by effects correlated with efficacy, clinicians may pursue a strategy of toxicity management rather than dose reduction, which would reduce the beneficial effects of the drug as well as the toxicities.

Side effects involving the eyes are also common with EGFR inhibitors.

Management strategies that avoid dose modifications or interruptions include the use of topical lubricants, anti-inflammatory agents, and corticosteroids.

Results presented in 2013 indicated that, although grade 3/4 adverse events occurred in 34% of participants taking PD-L1 inhibitors, no cases of grade 3-5 pneumonitis were observed, suggesting that PD-L1 inhibitors might avoid this side effect.

Although targeted therapies offer the potential for effective treatment of metastatic NSCLC with better safety profiles than conventional chemotherapy, side effects still occur with these agents. In the case of toxicities associated with the mechanism of action of the drug, symptom management should be attempted and dose reductions avoided, if possible.

Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.

Liu S, Kurzrock R. Toxicity of targeted therapy: implications for response and impact of genetic polymorphisms.

Pastorino U, Andreola S, Tagliabue E, et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis.

Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer.

Rudin CM, Liu W, Desai A, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity.

Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis.

Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis.

Mir O, Coriat R, Cabanes L, et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity.

Koyama N. Adverse cardiovascular events predict survival benefit in non-small lung cancer patients treated with bevacizumab.

Agustoni F, Platania M, Vitali M, et al. Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer.

. 2013. doi: 10.1200/EdBook_AM.2013.33.e280

Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1).

Managing Side Effects of Targeted Therapies for NSCLC May Improve Outcomes

Therapeutic options available for the treatment of metastatic non-small cell lung cancer (NSCLC) include cytotoxic chemotherapies and targeted therapies.

Targeted therapies offer the possibility of increased efficacy and decreased side effects, but their usefulness is often limited to a subset of patients whose tumors harbor driver mutations that make them vulnerable to a given targeted agent. The targeted therapies approved for use in metastatic NSCLC include both small molecules, such as receptor tyrosine kinase inhibitors (TKIs), as well as monoclonal antibodies.

A large survey of tumor samples has reported that known driver mutations are present in more than 60% of lung adenocarcinomas,

suggesting that targeted therapies may be effective as first-line treatment in a majority of cases. However, the best way to incorporate these agents into multimodal treatment regimens remains unclear.

Clinicians must consider the clinical, histological, and molecular features of the disease in each patient when determining the best course of treatment.

According to the current guidelines published by the National Comprehensive Cancer Network, the standard first-line treatment for advanced NSCLC is platinum-doublet chemotherapy for patients who do not have

An important result from clinical trials that have compared chemotherapeutic drugs with various targeted therapies is the finding that the presence of driver mutations increases the efficacy of conventional chemotherapy.

Fred R. Hirsch, MD, PhD, on the Importance of Biomarkers in Lung Cancer

Hirsch is the Associate Director for International Programs at the University of Colorado Cancer Center.

In a phase III, open-label study comparing the EGFR inhibitor gefitinib to carboplatin plus paclitaxel, patients with cancers that were positive for

mutations had an objective response to chemotherapy that was twice the rate observed for patients with adenocarcinomas having wild-type EGFR (47.3% vs 23.5%, respectively).

Similarly, a phase III, open-label study comparing the ALK inhibitor, crizotinib, with cytotoxic chemotherapy found that the response rate of patients with ALK-positive NSCLC was more than double that found in a previous study with a population not tested for ALK status (29% vs 12.8%, respectively).

Although the mechanism involved is currently unknown, the observation that driver mutations increase the sensitivity of NSCLC to chemotherapy suggests that the combination of conventional chemotherapies and targeted drugs may be a promising strategy in this disease.

Small molecule tyrosine kinase inhibitors currently used in the treatment of metastatic NSCLC include EGFR inhibitors, such as erlotinib and gefitinib, and ALK inhibitors, such as crizotinib. EGFR inhibitors are the standard first-line therapy for patients with tumors that have drug-sensitizing

mutations. All phase III trials that have investigated EGFR TKI monotherapy as first-line treatment in EGFR-mutant NSCLC have reported an improved overall survival (OS) with the targeted therapy compared with chemotherapy.

The issue of how to combine anti-EGFR therapy with conventional chemotherapy in NSCLC has been difficult to resolve. In one study, treatment with chemotherapy has been shown to result in both an overall decrease in the rate of

mutations in the study population and to induce

mutations in the previously wild-type tumors of a small number of patients.

These results appear to suggest that EGFR TKIs should be administered as first-line therapy in NSCLC, followed by chemotherapy. However, results from the TORCH study, which investigated the sequencing of erlotinib and chemotherapy in unselected NSCLC patients, revealed significantly inferior outcomes for patients receiving initial treatment with erlotinib followed by cisplatin-gemcitabine after progression compared with the reverse sequence.

A separate study conducted on a selected population that had

mutations, however, found that first-line treatment with EGFR TKIs did not influence the response to subsequent administration of pemetrexed plus platinum chemotherapy.

&ldquo;Chemotherapy remains an important treatment option in the era of targeted therapy,&rdquo; noted the study&rsquo;s senior author, Gee-Chen Chang, MD, of National Yang-Ming University, Taipei, Taiwan. &ldquo;If patients experience resistance to first-line EGFR-TKI therapy, subsequent chemotherapy should be considered undoubtedly, especially for patients with good performance status.&rdquo;

Combining EGFR TKIs and chemotherapy, in contrast to sequential administration, is also under investigation. A meta-analysis of various trials found that while progression- free survival (PFS) was improved in both

-mutation positive and negative patients, OS was unaffected.

The utility of this approach remains uncertain for now.

Bevacizumab is a monoclonal antibody that binds to VEGF-A and thereby inhibits angiogenesis. It is approved for use as a first-line treatment in metastatic non-squamous NSCLC in combination with chemotherapy. Because erlotinib and bevacizumab target different pathways promoting tumor growth, there has been considerable interest in using them in combination to treat NSCLC.

A post-hoc analysis of the phase III BeTa trial found that second-line treatment of

-mutation positive NSCLC with a combination of bevacizumab and erlotinib improved PFS compared with erlotinib alone (17.1 months vs 9.7 months).

The results of a phase II trial testing this combination as first-line therapy in patients with

-mutation positive, advanced NSCLC replicated these positive results in a larger population. Progression-free survival in the group receiving combined bevacizumab/erlotinib therapy was significantly greater than the group receiving erlotinib alone (16 months vs 9.7 months).

The investigational drug MPDL3280A is a monoclonal antibody that targets a component of the immune checkpoint pathway, programmed cell death receptor-1 ligand (PD-L1). Following promising phase I trial results,

a phase II trial has been initiated to test MPDL3280A in metastatic NSCLC.

Commenting on the possible combination of TKIs and checkpoint inhibitors in EGFR-positive NSCLC, Grace K. Dy, MD, associate professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, wrote that TKIs have &ldquo;great potential as they generally induce responses swiftly, but success is plagued by development of acquired resistance. Checkpoint inhibitors, on the other hand, have potential to induce prolonged, sustained clinical response long after cessation of drug administration. These 2 classes of agents thus nicely complement each other.&rdquo;

The expanding repertoire of therapies that have been developed for use in metastatic NSCLC has dramatically increased the number of sequences and combinations that can be deployed in treating this disease. Considering the complementary nature of different approaches, such as TKIs and immunotherapies, there is reason for optimism. However, determining the optimal treatment plan will require further trials and more data.

Standard first-line treatment for advanced NSCLC is platinum-doublet chemotherapy for patients who do not have EGFR mutations or ALK rearrangements.

Driver mutations increase the sensitivity of NSCLC to chemotherapy and the combination of conventional chemotherapies and targeted drugs may prove a promising strategy in this disease.

If patients experience resistance to first-line EGFR-TKI therapy, subsequent chemotherapy is recommended for patients with good performance status.

Because erlotinib and bevacizumab target different pathways promoting tumor growth, there has been considerable interest in using them in combination to treat NSCLC.

A post-hoc analysis of the phase III BeTa trial found that second-line treatment of EGFR-mutation positive NSCLC with a combination of bevacizumab and erlotinib improved PFS compared with erlotinib alone (17.1 months vs 9.7 months).

Checkpoint inhibitors have the potential to induce prolonged, sustained clinical response long after cessation of drug administration.

Binder D, Hegenbarth K. Emerging options for the management of non-small cell lung cancer.

National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Non-small cell lung cancer. Version 4.2014. http://www.nccn.org/. Accessed September 16, 2014.

Kris MG, Hellmann MD, Chaft JE. Chemotherapy for lung cancers: here to stay.

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

Remon J, Mor&aacute;n T, Reguart N, Majem M, Carcereny E, Lianes P. Beyond EGFR TKI in EGFR-mutant non-small cell lung cancer patients: main challenges still to be overcome.

Bai H, Wang Z, Chen K, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer.

Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial.

Tseng JS, Yang TY, Chen KC, et al. Prior EGFR tyrosine-kinase inhibitor therapy did not influence the efficacy of subsequent pemetrexed plus platinum in advanced chemona&iuml;ve patients with EGFR-mutant lung adenocarcinoma.

OuYang PY, Su Z, Mao YP, Deng W, Xie FY. Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis.

Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo- controlled, phase 3 trial.

Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study [published online ahead of print August 27, 2014].

. 2014. doi:10.1016/S1470-2045(14)70381-X.

ClinicalTrials.gov. A phase 2 study of MPDL3280A (an engineered anti-PDL1 antibody) in patients with PD-L1 positive locally advanced or metastatic non-small cell lung cancer  &ldquo;FIR&rdquo;. http://clinicaltrials.gov/ct2/show/NCT01846416. Accessed September 16, 2014.