Details about an experimental treatment option for patients with squamous cell non-small cell lung cancer (NSCLC) were presented at the 2014 European Society for Medical Oncology (ESMO) Congress. Suresh S. Ramalingam, MD, presented preliminary data from a randomized, phase II trial that demonstrated an improvement in outcomes with the combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and chemotherapy in patients with this hard-to-treat histology.

In the study, progression-free survival (PFS) was improved by 35% and overall survival (OS) was extended by 30% with the combination of veliparib and chemotherapy in patients with previously untreated metastatic or advanced NSCLC. In patients with squamous histology, PFS was 6.1 months with veliparib compared with 4.1 months (hazard ratio [HR] = 0.50;

= .06) and the OS was 10.3 months with veliparib compared with 8.4 months (HR = 0.71;

Peter Hammerman, MD, PhD, Discusses the Future of the Treatment of Squamous Cell Lung Cancer

Hammerman is an assistant professor of medicine at Harvard Medical School.

Q: How was it discovered that veliparib had utility in lung cancer?

Ramalingam, a professor of medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia, discussed the results of the trial and the potential of veliparib as a treatment for patients with squamous cell NSCLC in an interview with

PARP is a protein that&rsquo;s involved in DNA repair and veliparib is a very potent inhibitor of PARP1 and PARP2. Basically, when you give a PARP inhibitor, the cell is not able to repair DNA damage effectively. What we&rsquo;ve seen in the past is if the cells have deficiency in homologous recombination repairs, which is what happens in

gene mutations, those cells become far more dependent on the basic repair pathway, which is exactly where the PARP comes into play, even though the role of PARP is well known beyond that.

So by blocking DNA in cells that are critically dependent on that pathway, you are able to induce lethal damage. In lung cancer, if you look at what the common modalities of treatment are, we use platinum compounds, which are the cornerstones of therapy, and then we use radiation, and both of these work by inducing DNA damage. Cells that can repair the DNA damage end up not being sensitive to radiation or chemotherapy with platinum-based regimens.

Q: What were the findings from this phase II trial?

We and other labs have been studying the combination of chemotherapy with PARP inhibition, and veliparib in particular, and they have shown that veliparib is associated with increased efficacy when it is combined with chemotherapy or radiation. That was the basis for our clinical evaluation of veliparib in combination with platinum-based chemotherapy.

This was a randomized, placebo-controlled trial where we enrolled patients with previously untreated NSCLC, [as] first-line therapy for metastatic disease, and patients were randomized 2:1 to get carboplatin and paclitaxel with either veliparib or placebo. The veliparib was given for the first 7 days of each cycle, chemotherapy was given on day 3, veliparib was given from days 1 through 7, and the reason we used this strategy was because we wanted to prime the cells with PARP inhibition and then introduce chemotherapy.

Patients were allowed to continue the treatment for a maximum of 6 cycles, there was no maintenance therapy involved, and the primary endpoint for this was PFS. We also looked at OS, objective response rates, and the safety of the regimen as secondary endpoints.

Of a total 158 patients, 105 [were] randomized to the experimental arm with veliparib and 53 patients were enrolled to the control arm with chemotherapy and placebo. In this trial, the baseline characteristics were evenly matched and the main stratification factors were histologyeither squamous or nonsquamous&mdash;and smoking status&mdash;never versus current versus past. The randomization resulted in equal distribution of histology and smoking status across the 2 arms.

As far as safety, we found that the combination was tolerated really well. There were no toxicities that occurred more frequently with veliparib-chemotherapy compared to chemotherapy alone with placebo. Some of the common toxicities that you would see with chemotherapy, like neutropenia, thrombocytopenia, or anemia, were very similar between the 2 arms of the trial. Grade 1/2 toxicities were also very similar. Notably, there was no evidence of more nausea, vomiting, or fatigue with the addition of veliparib to chemotherapy.

When we look at efficacy, the overall primary endpoint, PFS, was 4.2 months median in the control arm and 5.8 months median with veliparib (HR = 0.74). The OS was 9.1 months in the control arm compared with 11.7 months in the veliparib arm. These differences, while clinically meaningful, did not reach statistical significance.

When we look at specific histologies, we found the most exciting data. In squamous histology, the median PFS improved from 4.1 months to 6.1 months with veliparib. In nonsquamous, we did not see a significant difference.

The OS results also mirrored what we saw with PFS. The squamous group had a median OS of 8.4 months with chemotherapy alone and 10.3 months with the combination. These results suggest that the squamous group had the best benefit with the combination.

Another observation that we noted was the response rate, which was very similar between the control and the experimental arm. However, the duration of response was almost 2-fold higher with the addition of veliparib (3.3 months to 6.9 months). What this tells us is that patients whose tumors were sensitive to platinum-based therapy experience an even better response and a longer duration of response with the addition of veliparib.

Q: Can you speculate why the patients with squamous histology responded better to the therapy?

Q: Could veliparib ever be used as monotherapy or combined with agents other than chemotherapy in the future?

Essentially, the results showed that the combination of veliparib with carboplatin and paclitaxel is particularly more efficacious to squamous histology and that is the histologic subtype we are going to be moving into a phase III trial. In fact, a phase III trial is already under way.

At this point, it&rsquo;s hard to say exactly the reasons behind that. We&rsquo;re still trying to understand the differences. We know that DNA repair capacity may depend on histologic subtype but this is something that we are obviously looking into more carefully.

There is certainly room for additional novel combination regimens. As monotherapy in lung cancer, we don&rsquo;t think veliparib is going to be an effective agent unless, of course, we identify potentially a group of patients who have low

function, not mutation. That&rsquo;s a group that&rsquo;s not particularly a high proportion and we haven&rsquo;t done much work in that group with any drug, for that matter. In terms of novel combinations, there are increasing possibilities. We are beginning to understand more and more the role of PARP in similar functions beyond DNA repair and that paves the way for a variety of combinations that one could think about beyond chemotherapy.

Q: What are some of the challenges in treating lung cancer, and how would veliparib, if approved, help overcome those challenges?

What is really interesting is the combination with radiation, where we are seeing very interesting preliminary preclinical observations and, therefore, trials are looking at veliparib in combination with radiation in stage III lung cancer patients.

: Lung cancer is a very heterogeneous disease. In the setting of targeted therapies, we&rsquo;ve seen that adenocarcinoma patients have a number of driver mutations and, therefore, specifically targeted drugs are being studied for them. In squamous cell, we don&rsquo;t have any targeted drug that has been approved by the US Food and Drug Administration (FDA) for treatment and this is very much a patient population that is looking for new ways to treat them. We feel that if the phase II results can be confirmed in a phase III trial, veliparib can be an important component of treating squamous-cell cancer in the first-line setting. Squamous cell patients are 20% to 25% of all our patients with lung cancer in this country and even a bigger proportion in Europe and other countries.

Articles

Clinical Articles

Suresh S. Ramalingam, MD, discussed the potential of veliparib as a treatment for patients with squamous cell NSCLC in an interview with Targeted Oncology.

Veliparib Shows Potential in Squamous Cell NSCLC

Combination therapies with agents such as indoleamine 2,3-dioxygenase (IDO) inhibitors may have the potential to synergize with immunotherapeutic approaches to improve immune function against tumor cells.

The concept of immunotherapy, or using the body&rsquo;s immune system to selectively target tumor cells, is not new, but it has become a more viable and practical option in cancer treatment over the last decade.

Using antibody-based inhibitors of key immunoregulatory checkpointssuch as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death receptor-1 (PD-1), and its ligand, PD-L1&mdash;durable responses have been observed in advanced, metastatic cancers for which no therapy had previously been available.

The rationale of these now-proven immunotherapies is that by augmenting any existing antitumor immune response, and at the same time curtailing tumor-based immune-evasion mechanisms (eg, overexpression of PD-L1 in the tumor microenvironment), a much more effective and durable immune response (with the possible added benefits of T-cell memory) can be mounted against the tumor.

Non-small cell lung cancer (NSCLC) is among the many tumor types in phase III investigation with immunotherapies such as anti-CTLA-4 (ipilimumab) and anti-PD-1/PD-L1 (nivolumab, pembrolizumab).

In addition to antibody-based immunotherapies, the immunoregulatory properties of IDO, an enzyme that plays an integral role in the metabolism of the amino acid tryptophan, has also been recognized as a potential means of promoting tumor-induced tolerance.

The metabolism of tryptophan by IDO appears to function as a critical negative feedback mechanism to prevent uncontrolled cytotoxic immune reactions; overexpression of IDO therefore constitutes a mechanism whereby tumor cells can create a tolerogenic milieu and evade detection and killing by the immune system.

The immunosuppressive prowess of IDO production was illustrated in an elegant experimental study by Swanson et al, which showed that the production of IDO in the lung by interstitial antigen presenting cells (iAPCs) is an effective suppressor of T-cell responses both in vitro and in vivo.

This suppressive effect of iAPC-produced IDO appears to play an important homeostatic role by preventing unnecessary T-cell activation and inflammation in the lungs, which are constantly exposed to inhaled exogenous antigens.

Conversely, however, this same physiologic process has the potential to result in inappropriate immune suppression if co-opted by tumors. Indeed, in experimental models, the overexpression of IDO before transplantation effectively suppressed acute rejection of haplo-mismatched lung allografts in the absence of exogenous immunosuppression.

In his recent presentation at the 12th Annual International Congress on Targeted Therapies in Cancer&reg;, Alex A. Adjei, MD, PhD, professor and chair of the department of medicine, and Katherine Anne Gioia Chair in Cancer Medicine at the Roswell Park Cancer Institute in Buffalo, New York, pointed to evidence for expression of IDO1the gene that encodes the IDO enzyme&mdash;in the microenvironment of many different cancers, including colon and breast, and its association with decreased survival.10 He also noted that, in preclinical models, inhibition of IDO1 reduced tumor growth, augmented antitumor immune responses, and has the potential to synergize with cytotoxic therapies, tumor vaccines, and other immunotherapies.

Accordingly, several inhibitors of IDO, such as 1-methyl-DL-tryptophan (1-MT), have been developed, and are now under investigation for the treatment of various cancers, including NSCLC.

In a phase I, dose-escalation study of patients (N = 52) with advanced cancers, the safety and efficacy of the IDO1 inhibitor INCB024360 were examined.

The treatment was generally well tolerated at doses of up to 700 mg twice a day, and toxicity was not dose related; abdominal pain, hypokalemia, and fatigue were the most common grade 3 or 4 adverse events (AEs), each occurring in 9.6% of patients. After 56 days, stable disease (SD) was seen in 15 patients, and 7 patients had SD lasting 112 days or longer.

Pharmacodynamic effects of this IDO inhibitor could also be observed in the study, with doses of 300 mg twice a day or greater resulting in more than 90% inhibition of IDO1.

Thus, the development of IDO inhibitors has the potential to introduce yet another targetable pathway for the treatment of advanced NSCLC. Commenting on the differences between IDO inhibitors and other targeted therapies in NSCLC, Grace K. Dy, associate professor of oncology in the department of medicine at Roswell Park Cancer Institute, said, &ldquo;Instead of targeting specific mutated proteins derived from oncogenes, IDO inhibitors are small molecules that can potentially augment the response to immunotherapies, by inhibiting the enzyme IDO.&rdquo;

Dy explained that IDO was initially identified in the placenta as an immunosuppressive mechanism for the fetus to escape rejection by the maternal immune system, and that, subsequently, IDO was found to be highly expressed in various malignancies.

&ldquo;This is thought to be one of the mechanisms tumors use to evade immune surveillance, by depleting tryptophan, and causing accumulation of catabolites, which in turn abrogates T-cell function and viability. IDO inhibitors thus have potential for broad applicability across genetically diverse cancer populations,&rdquo; Dy said.

Combination therapies with IDO inhibitors may have the potential to synergize with immunotherapeutic approaches to improve immune function against tumor cells.

Overexpression of IDO constitutes a mechanism whereby tumor cells can create a tolerogenic milieu and evade detection and killing by the immune system.

Inhibition of IDO1 reduced tumor growth and augmented antitumor immune responses in preclinical models, and has the potential to synergize with cytotoxic therapies, tumor vaccines, and other immunotherapies.

Development of IDO inhibitors has the potential to introduce another targetable pathway for the treatment of advanced NSCLC.

The KEYNOTE 037 trial is investigating pembrolizumab with an IDO inhibitor in a 2-part phase I/II study designed to assess the efficacy and safety of pembrolizumab (MK-3475) in combination with an IDO inhibitor (INCB024360) in patients with advanced solid tumors (phase I part of the study), and subsequently evaluate this combination in patients with advanced NSCLC (phase II portion of the trial).

The use of IDO inhibitors as combination therapy also has the potential to further augment responses to existing immunotherapies already under investigation in NSCLC, such as anti-PD-1 agents. In this regard, the KEYNOTE 037 trial is investigating the combination of pembrolizumab (an anti-PD-1 agent) with an IDO inhibitor in a 2-part phase I/II study.

This trial is designed to initially assess the efficacy and safety of pembrolizumab (MK-3475) in combination with an IDO inhibitor (INCB024360) in patients with advanced solid tumors (phase I part of the study), and subsequently, to evaluate this combination in a randomized, double-blinded, placebo-controlled manner in patients with advanced NSCLC (phase II portion of the trial).

Different doses of the IDO inhibitor (in combination with pembrolizumab) will be evaluated in the phase I portion (in various tumor types) to determine the dose for further evaluation, while the phase II portion will include only patients with NSCLC (defined as histologically or cytologically stage 3b, 4, or recurrent NSCLC) and will assess the antitumor efficacy of this combination. The phase II portion will have the primary outcome measure of progression-free survival (PFS), with secondary endpoints of overall response rate and durability of response, as well as AEs.

Commenting on the rationale for the KEYNOTE 037 trial, Dy said: &ldquo;Not all patients derive benefit from single-drug immunotherapies, as there are multiple ways cancers can circumvent T-cell responses. Combination therapies, such as with IDO inhibitors, have the potential to synergize with immunotherapeutic approaches.&rdquo; Completion of the study is anticipated for November 2017.

Aldrich JF, Lowe DB, Shearer MH, Winn RE, Jumper CA, Kennedy RC. Vaccines and immunotherapeutics for the treatment of malignant disease.

Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor?

Munn DH. Blocking IDO activity to enhance anti-tumor immunity.

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

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

Clinicaltrials.gov: Phase 3 Trial in Squamous Non-Small Cell Lung Cancer Subjects Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin. NCT02279732.

Clinicaltrials.gov: Study of BMS-936558 (Nivolumab) Compared to Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC) (CheckMate 017). NCT01642004.

Clinicaltrials.gov: Study of Pembrolizumab (MK-3475) Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non-small Cell Lung Cancer (MK-3475-024/KEYNOTE-024) NCT02142738.

Swanson KA, Zheng Y, Heidler KM, Mizobuchi T, Wilkes DS. CDllc+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase.

Adjei AA. Emerging Targets in Lung Cancer. Available at: http://e-syllabus.gotoper.com/_media/_pdf/ITT14_1011_0930_Adjei_EmergingTargets_FINAL.pdf. Accessed November 5, 2014.

Beatty GL, O&rsquo;Dwyer PJ, Clark J, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.

Clinicaltrials.gov: A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Solid Tumors and Advanced NSCLC (INCB 24360 202 / MK-3475-037 / KEYNOTE-037). NCT02178722.

IDO Inhibitors May Augment Immunotherapy in NSCLC

Peter Hammerman, MD, PhD, assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses the future treatment of squamous cell lung cancer.

Learn more about the treatment of squamous cell lung cancer > >

Peter Hammerman, MD, PhD, assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses the future treatment of squamous cell lung cancer. 

The Future of Squamous Cell Lung Cancer Treatment

Increasing knowledge of the diverse pathologic and molecular phenotypes in non-small cell lung cancer (NSCLC) has driven a more complex treatment algorithm in recent years. This complexity emphasizes the need for a multidisciplinary approach to better manage comprehensive, personalized patient care.

It is estimated that over 224,000 new cases of lung cancer will be diagnosed in the United States alone in 2014.

Considered the leading cause of all cancer-related mortality, the 5-year relative survival rate for this disease is less than 20%.

Benjamin P. Levy, MD, on the Role of Chemotherapy in the Treatment of Lung Cancer

Levy is the director of Thoracic Medical Oncology at Mount Sinai.

Smoking is the predominant risk factor for lung cancer; however, lifelong nonsmokers can also suffer from this disease, in the majority of cases due to adenocarcinomas.

Together with adenocarcinoma, large cell carcinoma and squamous cell carcinoma are the most common histologic subtypes of NSCLC, a classification that comprises any epithelial lung cancer other than small cell lung cancer (SCLC).

As NSCLCs are relatively insensitive to conventional chemotherapy and/or radiation therapy, surgery is often recommended when patients are diagnosed at an early stage. Radiation and/or chemotherapy may be used as neoadjuvant or adjuvant therapy before or after surgery, respectively.

&ldquo;Unfortunately, at this time, up to 60% of patients diagnosed with NSCLC have more advanced disease (beyond stage 1),&rdquo; said Bernard J. Park, MD, deputy chief of thoracic surgery at Memorial Sloan-Kettering Cancer Center.

In advanced/metastatic cases, particularly nonsquamous disease, many patients may benefit from molecularly targeted therapies shown to improve survival in subsets of patients with specific genetic mutations.

&ldquo;It is an exciting time for patients with nonsquamous NSCLC because of recent advances in molecular characterization of tumors,&rdquo; Park added. &ldquo;Up to 40% of patients will have a mutation in their tumor that can be treated with targeted therapy.&rdquo;

Mutations in the epidermal growth factor receptor (

) gene and translocations in the anaplastic lymphoma kinase (

)-tyrosine kinase receptor are 2 of the most common genetic abnormalities for which targeted treatments are available.

Patrick C. Ma, MD, MS, from the Cleveland Clinic Taussig Cancer Institute, added that &ldquo;a timely, multiplexed genomic profiling determination&hellip;is already becoming a new standard.&rdquo;

Overall, &ldquo;the vast majority of these patients require multimodality care with combinations of systemic therapy (chemotherapy, targeted therapy) and local therapy (radiation, surgery),&rdquo; Park stated. As a result of this growing complexity, &ldquo;thoughtful multidisciplinary evaluation is a must.&rdquo;

&ldquo;Our multidisciplinary cancer team,&rdquo; commented Ticiana Leal, MD, assistant professor at the University of Wisconsin Madison Carbone Cancer Center, &ldquo;involves a dedicated group of medical oncologists, radiation oncologists, thoracic surgeons, nurses, thoracic radiologists, pulmonologists, pathologists, social workers, and a palliative care team.&rdquo;

This collaborative group combines a diverse team of experts &ldquo;who work together to assist in providing clinical care that encompasses the initial diagnosis, management, and treatment of patients with lung cancer and also to support the patient and their families,&rdquo; she added.

Initially, for instance, pulmonologists, interventional radiologists, and thoracic surgeons are often the first to perform biopsies of the tumor. At this stage of care, providing adequate tissue samples to the pathologist is crucial to accommodate the growing number of tests that may be required.

As pathologists undergo histologic subtyping and molecular characterization of the tumor, the efficiency of proper testing is paramount in allowing treatment decisions to be made and implemented more quickly.

&ldquo;In the case of advanced NSCLC, it is important to be able to start treatment as soon as possible,&rdquo; noted Rex Yung, MD, of Johns Hopkins University.

&ldquo;The patients can be debilitated and the window of opportunity before they slip further into a worse-functioning status could be short.&rdquo;

Once obtained, test results are utilized by the medical oncologist to make informed treatment decisions for the next phase of patient care. According to Howard (Jack) West, MD, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle, Washington, histologic and molecular test results are often &ldquo;an integral part of the decision-making process.&rdquo;

West explained that, &ldquo;in the setting of advanced-stage disease, there is an early branch point for whether a patient has squamous or nonsquamous [histology]&hellip;Particularly for nonsquamous disease, especially adenocarcinomas, the presence or absence of an activating mutation&hellip;is going to lead to an immediate diversion of the treatment plan.&rdquo;

&ldquo;In terms of targeted therapies,&rdquo; West added, &ldquo;it is becoming more and more granular all the time. We have gone from finding a [single] common activating mutation to now having to look at specific

mutations.&rdquo; According to West, one might individualize the choice of targeted therapy depending upon the subtype of the patient&rsquo;s mutation.

Even conventional chemotherapy can be &ldquo;profoundly affected by the histology itself,&rdquo; noted West. For instance, while the drug bevacizumab (Genentech/Roche) shows a survival benefit in nonsquamous cases, due to the increased risk of hemoptysis, it may be life-threatening in patients with squamous NSCLC.

Irrespective of therapy choice, however, inclusion of other allied health care professionals in the multidisciplinary team is a critical component of ensuring optimal patient care. Individuals such as nurses, nurse practitioners, and social workers work closely with each patient throughout the process to ensure his or her needs are being met.

Margie Cook, RN, OCN, a care support nurse at The West Clinic, commented that &ldquo;helping patients navigate through the system,&rdquo;

in terms of scheduling appointments, understanding their diagnosis and treatment plan, side-effect management, and meeting any transportation, childcare, nutritional, or psychological needs, is another crucial role for allied health care professionals.

Pathologic and molecular findings have added to the complexity of the treatment algorithm for patients with NSCLC, emphasizing the need for a multidisciplinary approach.

Multidisciplary teams may involve medical oncologists, radiation oncologists, thoracic surgeons, nurses, thoracic radiologists, pulmonologists, pathologists, social workers, a palliative care team, and importantly, the patient.

The team works together, providing clinical care that encompasses the initial diagnosis, management, and treatment of patients with lung cancer and offering support to patient and their families

&ldquo;The need for social worker and palliative medicine team input in NSCLC patients cannot be underestimated,&rdquo; stated Ma. &ldquo;Our patients often have significant unmet needs in social and psychological stress after the diagnosis and during treatment.&rdquo;

&ldquo;When patients come to us,&rdquo; Cook added,3 &ldquo;cancer is not usually the only issue they are dealing with. They still have families to take care of, they still have bills to pay, they still have all of these other things on their plate, so we are there to help them deal with everything we can.&rdquo;

A final member of the multidisciplinary team who should not be overlooked is the patient. &ldquo;In my view and practice, the most critical part of forming a &lsquo;personalized treatment plan&rsquo; for my patients involves incorporating the patient's values, culture, social setting, and personal preference into the treatment planning,&rdquo; commented Ma. &ldquo;I call this the &lsquo;patient factor.&rsquo;&rdquo;

&ldquo;As the field becomes more complex,&rdquo; West added, &ldquo;it becomes more important for patients to learn what they can about their treatment options and become active participants in their care.&rdquo;

Overall, the course of patient care in NSCLC has changed significantly over the last decade, since the time of a single, standard treatment algorithm for all metastatic NSCLC.

With today&rsquo;s awareness of the impact of histologic and molecular profiles on the course and proper treatment of this disease, combining the expertise and efficiency of a multidisciplinary team is becoming the only approach to ensuring optimal patient care.

&ldquo;One of the most important advances in the care of cancer, and especially in the care of non-small cell lung cancer&hellip;is the fact that we have forged much better working relationships,&rdquo; said Yung,2 &ldquo;recognizing that for the patient&rsquo;s well being&hellip;we should be practicing in a multidisciplinary approach.&rdquo;

National Cancer Institute at the National Institutes of Health. General information about non-small cell lung cancer (NSCLC). http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/Patient/page1. Accessed November 7, 2014.

Boehringer Ingelheim Pharmaceuticals, Inc. Let&rsquo;s Test website. Multidisciplinary approach. https://www.letstestnow.com/resources_library/videos/multidisciplinary_approach_in_nclc4.html. Accessed November 7, 2014.

Boehringer Ingelheim Pharmaceuticals, Inc. Let&rsquo;s Test website. The multifaceted role of the care support nurse in the NSCLC multidisciplinary team. http://www.letstestnow.com/resources_library/videos/multidisciplinary_approach_in_nclc17.html. Accessed November 7, 2014.

Increasing knowledge of the diverse pathologic and molecular phenotypes in non-small cell lung cancer (NSCLC) has driven a more complex treatment algorithm in recent years.

Multidisciplinary Teams in NSCLC Important for Optimal Patient Care

Benjamin P. Levy, MD, director, Thoracic Medical Oncology, assistant professor, Icahn School of Medicine, Mount Sinai Health System, comments on the role of chemotherapy in the treatment of lung cancer.

Read about the importance of a multidisciplinary team in the treatment of lung cancer > >

Benjamin P. Levy, MD, comments on the role of chemotherapy in the treatment of lung cancer.

The Role of Chemotherapy in the Treatment of Lung Cancer

Abraham Chachoua, MD, director, Thoracic Oncology Research Program, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, discusses some challenges of treating patients with lung cancer.

Learn about early detection and molecular testing in NSCLC > >

Abraham Chachoua, MD, discusses some challenges of treating patients with lung cancer.


The Challenges of Treating Lung Cancer

Q: How do you form a personalized treatment plan for your patients with non-small cell lung cancer (NSCLC)?

Q: What is the importance of histological subtyping and molecular characterization in deciding to treat with conventional or targeted therapy?

Q: Which first-line conventional and targeted therapies are preferred?

Howard (Jack) West, MD, is the medical director of the Thoracic Oncology Program at Swedish Cancer Institute and president and CEO of Global Resource for Advancing Cancer Education.

You need to start with the stage of the cancer. Look at the histological subtype of the lung cancer, the bulk of it, the molecular features, and whether there is a specific molecular marker that could change your treatment. Then, examine the characteristics of the patient: his or her health, goals, and ability to tolerate aggressive treatment safely. There are a great many variables that affect and lead to individualization of the treatment path from one patient to another.

In the setting of advanced-stage disease, there is an early branch point for whether a patient has squamous or nonsquamous histology, with molecular testing being less clearly valuable and indicated for squamous lung cancer. Particularly for nonsquamous disease, especially adenocarcinomas, the presence or absence of an activating mutation, which is most commonly an endothelial growth factor receptor (

) mutation or an anaplastic lymphoma kinase (

) rearrangement, is going to lead to an immediate diversion of the treatment plan between recommending first-line chemotherapy-based treatment and recommending a pill-based targeted therapy as the treatment most likely to lead to a beneficial effect for the patient. It is certainly an integral part of the decision-making process. It is no coincidence that the factors of histology and the presence or absence of molecular markers are very high on my list of variables that lead to individualized treatment for the patient.

There are many different doublet chemotherapy regimensthat is, a 2-drug combination&mdash;and they have largely shown an efficacy that is more similar than different. There are subtle differences that would often lead us to favor one doublet regimen over another, depending on the histology. You can have a preferred chemotherapy regimen, but they really come out quite comparably.

Q: How do you treat patients who have progressed after first-line therapy?

In terms of targeted therapies, however, you have EGFR inhibitor-based treatment, such as erlotinib or afatinib, which are US Food and Drug Administration (FDA)- approved and extremely appropriate for first-line treatment of patients with an

mutation. These days, you should look specifically at the subtype of an EGFR mutation. This might lead you to use afatinib for someone with the specific

mutation (a deletion in exon 19), but not use it for another common

mutation, called an L858R mutation (an exon 21 substitution), which seems to not do especially well with afatinib. It is becoming more and more granular all the time: we have gone from finding a single common activating mutation to now having to look at specific

mutations, where you might individualize therapy to one EGFR tyrosine kinase inhibitor over another.

That is largely based on whether they have a mutation. If not, I would favor docetaxel, or a clinical trial if you have that available. There are only a few agents that have been proven to have a survival benefit in previously treated patients, and that is really limited to erlotinib, docetaxel, and pemetrexed. We have typically favored using pemetrexed in patients with nonsquamous histology; not that it is absolutely the best, but it is certainly a well tolerated option that seems to be among the most effective, for adenocarcinomas at least.

Q: Are there any recent or ongoing clinical trials with emerging therapies that have the potential to greatly impact future treatment of NSCLC?

In the last few years, there have been a couple of trials that directly, head-to-head compared docetaxel to erlotinib in predominantly

Both indicated that second-line docetaxel was at least modestly superior.

Yes. At an international meeting in Chicago (the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology), there was a presentation of second- or third-line nivolumab, which is an immune-checkpoint inhibitor that specifically blocks a target called PD-1.

That was in patients with squamous histology for whom we don&rsquo;t have nearly enough protective agents. Despite that fact that two-thirds of the patients had received 3 or more lines of therapy and 61% of them had progressed on their last line of therapy, they had a 1-year survival after starting this agent of 42% and a median overall survival of approximately 8 months. The response rate was around 15%, which was not as high as we&rsquo;d like, certainly, but after patients have received many, many prior lines of therapy, even that is encouraging. It really indicates that a subset of patients are benefiting profoundly from these novel agents. I think it is very likely to lead to an approval; not with this trial specifically, but other phase 3 trials of nivolumab compared with docetaxel in the second-line setting that we expect to see the results from in 2015.

At the same meeting, a randomized phase II trial suggested a survival benefit in squamous patients who received first-line chemotherapy in combination with a PARP inhibitor called veliparib.

The study looked at chemotherapy with or without the PARP inhibitor and didn&rsquo;t see a significant benefit in the broader population, but in the squamous subset of patients, there was a pretty provocative survival difference that is going to lead to a phase III trial in squamous patients. That could certainly lead to a new class of agents being approved in lung cancer and adding to the treatment arm available for squamous disease.

There was also a phase III trial that showed modest benefit from adding ramucirumab, which is a VEGF inhibitor therapy, or an antiangiogenic therapy, combined with docetaxel in the second-line setting.

Ramucirumab has already been approved in previously treated gastric cancer.

Q: Do you have any closing advice for community oncologists and their patients?

A larger trial is also being done in adenocarcinoma patients randomizing to docetaxel alone or with an oral antiangiogenic inhibitor called nintedanib (or BIBF 1120), and that trial looks encouraging in the second-line setting.

One of the important issues is that we have a growing array of treatment options for patients, but they are only available if the patients avail themselves of these options and if their doctors know about them. As the field becomes more complex, it becomes more important for patients to learn what they can about their treatment options and to become active participants in their care. There is a growing disparity in the options available and in the physicians who are aware of these options and those who aren&rsquo;t as aware and may still recommend a similar treatment option for all of their patients.

Garassino MC, Martelli O, Broggini M et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.

Kawaguchi T, Ando M, Asami, K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonsmall-cell lung cancer: docetaxel and erlotinib lung cancer trial (DELTA).

Gettinger SN, et al. Long-term survival, clinical activity, and safety of nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in patients (pts) with advanced non-small cell lung cancer (NSCLC) : metastatic non-small cell lung cancer.

Ramalingam S, Blais N, Mazieres J, et al. A randomized, double-blind, phase 2 trial of veliparib (ABT-888) with carboplatin and paclitaxel in previously untreated metastatic or advanced non-small cell lung cancer: metastatic non-small cell lung cancer.

Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

Strategies for Precision Medicine in NSCLC: A Q&A With Dr. Howard (Jack) West

As with many cancers, early detection (before the onset of symptoms) offers the possibility for less expensive treatment and better outcomes in patients with non-small cell lung cancer (NSCLC).

To this end, screening for patients at high risk (particularly heavy smokers) can lead to earlier diagnosis and better survival.

Results from the National Lung Screening Trial (NLST) showed that, compared with chest x-ray, death from lung cancer could be reduced by 20% among current and former heavy smokers through a screening process using spiral computed tomography (CT), and this led to the ACS issuance of screening guidance in 2013.

Abraham Chachoua, MD, on the Challenges of Treating Lung Cancer

Chachoua is the director of the Thoracic Oncology Research Program at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center.

Low-dose helical CT (LDCT) scanning has been recommended by the ACS for patients considered high risk for NSCLC, namely, current or former smokers (who quit within past 15 years) who are aged 55 to 74 years, in otherwise good health, and who have a minimum 30 pack-year history.

The ACS emphasizes, however, that because screening also entails risks, it should be a shared decision-making process between the clinician and the patient, including discussion of the benefits and uncertainties associated with screening.

Hongbin Chen, MD, PhD, assistant professor of oncology in the department of medicine at Roswell Park Cancer Institute in Buffalo, New York, noted that results from the NLST established LDCT as the most updated screening method, and that, while there remain issues of regulatory approval and insurance coverage, his institution has a screening program in place for high-risk patients as outlined by the ACS.

&ldquo;Heavy smokers, defined as 30 pack-years or above, or former smokers who quit 15 years ago&hellip; this is the studied population in the NLST trial, and that is [the population of patients] applicable to the recommendation for screening,&rdquo; Chen said.

For screening to be most effective, however, it is important that benefits outweigh the potential risks.

Principle risks associated with screening include radiation exposure, adverse events, costs associated with unnecessary diagnostic interventions, and overdiagnosis (ie, the diagnosis and subsequent treatment of an indolent cancer that would not result in death).

There is also the potential impact of incidental or inconsequential findings (eg, cardiovascular issues, other unrelated lesions/abnormalities, benign or otherwise) that may require additional clinical and/or radiologic follow-up; this must also be considered with any widely implemented screening program.

Regarding assessment of the screening findings, Chen said, &ldquo;You really need to have an experienced, multidisciplinary team who can manage those cases, in an established center, with a lung cancer screening program.&rdquo;

Chen explained that such a team would generally include a radiologist, an interventional pulmonologist, thoracic surgeons, and medical oncologists.

Commenting on the potential for false-positive results, Chen emphasized that &ldquo;You need to have someone with experience to identify these abnormalities, or suspected abnormalities, then from there you can move forward with what to do, such as a biopsy. There will still be false-positives, but the point is, if we do [screening] as prescribed, then the outcomes should be better in terms of reducing the lung cancer mortality.&rdquo;

Lingering, unresolved issues for lung cancer screening include the optimal frequency and duration of screening, how to best manage nodules that are deemed indeterminate, and the overall cost efficacy of screening.

In the future, relevant biomarkers can be expected to more accurately identify at-risk populations for screening; this, combined with continued developments of more sensitive imaging procedures, may enhance acceptance and use of screening programs.

The findings of NLST have nonetheless shown that screening for NSCLC is feasible and beneficial, and as it gains greater acceptance across more centers nationwide, researchers hope that early diagnosis of NSCLC will become a reality for more patients, because only 25% to 30% of patients now present with disease that is localized and potentially curable.

Screening for patients at high risk can lead to earlier diagnosis and better survival in patients with NSCLC.

Results from the NLST showed that, compared with chest x-ray, death from lung cancer could be reduced by 20% among current and former heavy smokers through a screening process using spiral CT.

This finding led to the ACS issuance of screening guidance in 2013.

Once detected and diagnosed through biopsy, molecular testing may provide rapid assessment of mutations that, if detected, could influence treatment decisions.

This year (2014), the ASCO CPG committee announced its endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists (CAP/IASLC/AMP) guidelines for molecular testing.

&ldquo;Approximately 75% of patients present with advanced disease,&rdquo; said Grace K. Dy, MD, associate professor of oncology in the department of medicine at Roswell Park Cancer Institute. Her institution uses low-dose CT scanning with fluorescent bronchoscopy to evaluate central airways as a screening method for high-risk patients, according to Dy. She acknowledged both benefit and risk in screening high-risk patients.

&ldquo;Low-dose CT chest as screening in the high-risk population can decrease deaths due to lung cancer. The caveat is that many positive findings maybe false-positive, [and] thus there is ongoing research on the clinical utility and validity of ancillary diagnostics (eg, blood-based biomarkers such as circulating tumor cells; measurement of volatile gases in exhaled breath, etc) that can improve sensitivity/specificity of nodules detected with imaging scans,&rdquo; Dy stated.

Once NSCLC has been detected and appropriately diagnosed through biopsy, molecular testing is paving the way for rapid assessment of mutations that, if detected, could influence early treatment decisions. This year (2014), the American Society for Clinical Oncology (ASCO) Clinical Practice Guidelines Committee (CPGC) announced its endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists (CAP/IASLC/AMP) guidelines for molecular testing.

These guidelines consist of 37 recommendations about when and how to perform molecular testing for epidermal growth factor receptor (

), and other gene mutations, and how to best implement such testing in patients with advanced-stage lung adenocarcinoma, or those with an adenocarcinoma component, regardless of clinical characteristics.

The findings of this testing could identify patients for whom treatment with targeted therapies, most notably the tyrosine kinase inhibitors (TKIs), could be of benefit, and the ASCO CPGC endorsement is an important step in standardizing molecular testing practices.

Dy emphasized that the ASCO group endorsement is only pertinent for patients with advanced disease, does not really apply to early detection per se, and that molecular testing is meant to identify patients who will be suitable candidates for targeted therapy. Chen added that molecular testing is the first thing to do after a definitive diagnosis has been made, using tissue from the biopsy, if available.

&ldquo;If [the biopsy] tissue is not sufficient, we recommend, in those patients who have nonsquamous lung cancer, to maybe undergo another biopsy, so we don&rsquo;t miss those mutations if they are positive. The reason is that studies have shown that those patients who have those mutations, and who receive targeted therapies, benefit from the treatment, rather than standard chemotherapy,&rdquo; Chen explained.

American Cancer Society. Cancer Facts and Figures 2014. Available at: http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed November 4, 2014.

Gutierrez A, Suh R, Abtin F, Genshaft S, Brown K. Lung cancer screening.

Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society lung cancer screening guidelines.

Finigan JH, Kern JA. Lung cancer screening: past, present and future.

Marshall HM, Bowman RV, Yang IA, Fong KM, Berg CD. Screening for lung cancer with low-dose computed tomography: a review of current status.

NSCLC (Issue 5) | Special Reports