Experts within the lung cancer community are eagerly anticipating the phase III findings of the KEYNOTE-189 trial, and they are hopeful that the combination of pembrolizumab (Keytruda) plus carboplatin and pemetrexed (Alimta) will demonstrate an overall survival (OS) advantage in patients with nonsquamous nonsmall cell lung cancer (NSCLC).

In the phase III study, the PD-1 inhibitor pembrolizumab plus carboplatin/pemetrexed is being compared with carboplatin/pemetrexed alone in the frontline setting for patients with nonsquamous NSCLC (NCT02578680). It will serve as the confirmatory trial for the FDA&rsquo;s accelerated approval of the regimen, which occurred in May 2017.

The decision of the immunotherapy/carboplatin and pemetrexed approval was based on the findings of cohort G in the phase II KEYNOTE-021 study, in which pembrolizumab combined with carboplatin/pemetrexed demonstrated a 57% objective response rate versus 32% with chemotherapy alone (P = .0029).

Following a median 18.7 months of follow-up, the median progression-free survival (PFS) in the pembrolizumab arm was 19.0 months (95% CI, 8.5-not reached) versus 8.9 months with carboplatin/pemetrexed alone (95% CI, 6.2-11.8). Additionally, the median OS was not reached in the pembrolizumab and carboplatin/pemetrexed arm (22.8-not reached) and was 20.9 months (14.9-not reached) in the carboplatin/pemetrexed arm. The 18-month OS rate with pembrolizumab plus carboplatin/pemetrexed was 70% compared with 56% for those treated with carboplatin/pemetrexed.

&ldquo;It is a really exciting time. Although it appears to be confusing right now, it won&rsquo;t be long before [we have the data of] multiple phase III studies with chemotherapy combinations with [immunotherapy] and we'll know exactly which direction we&rsquo;re going to be able to go in squamous patients or nonsquamous patients,&rdquo; said Hossein Borghaei, DO, MS. &ldquo;A little more patience is required, but data are going to come out soon and we&rsquo;ll know how to guide patients [through] all of the choices they have for treatment. What we want to see are better patient outcomes and it looks like we're definitely heading in that direction. It is welcome news for everybody.&rdquo;

, Borghaei, who is chief, Division of Thoracic Medical Oncology and associate professor, Department of Hematology/Oncology, at Fox Chase Cancer Center in Philadelphia, Pennsylvania, expanded on the importance of the pembrolizumab plus carboplatin/pemetrexed approval, the ongoing KEYNOTE-189 trial, and how the phase III findings could dramatically change clinical practice for patients with nonmutated, nonsquamous NSCLC.

: What are your thoughts on the milestone FDA approval of pembrolizumab in combination with carboplatin and pemetrexed?

: To start with, I have to point out that this is only a randomized phase II study with 60 patients per arm, so the current approval is based on limited experience. The phase III version of the protocol has completed accrual, but we are waiting for the results so we don&rsquo;t have anything [yet] about the phase III [study]. It is important to keep in mind that this is only a phase II clinical trial. It is significant because, for the first time, we are showing that a combination of immunotherapy [IO] drugs with a standard platinum doublet can, in fact, improve PFS, response, and OS. It is [being explored] in an all-comer patient population, regardless of the level of PD-L1 expression. Up to now, IO, specifically with pembrolizumab only, has shown clinical efficacy in only patients with high PD-L1 expression at greater than 50% as a single agent compared head-to-head with chemotherapy. This study would [show] that, if you add carboplatin/pemetrexed to pembrolizumab, then you can apply it to an all-comers patient population. In an intent-to-treat patient population, it improves the clinical outcomes. It is significant because of [those reasons].

It is also a well-tolerated regimen based on all the data that have been presented, suggesting that the addition of carboplatin/pemetrexed to an IO agent does not seem to increase toxicity of either regimen. Granted, every time you add a third drug to a combination of 2 different chemotherapies, there are slightly more adverse events [AEs]. But overall, if you look at the treatment discontinuation rate and all the immune-related AEs, it just did not seem to be a significant increase compared with either therapy alone. Altogether, it appears to be a very good, effective regimen.

The difficulties here are that it is important to try to figure outto tease out&mdash;if patients with no PD-L1 expression or those with high expression are [having] that much benefit from the addition of carboplatin/pemetrexed. With the final analysis, when we have phase III data with larger patient sets, we can with confidence say that even in patients with greater than 50% [PD-L1 expression], they reap the benefit that much more from the addition of chemotherapy. Or, is it going to be that the patients with lower expression of PD-L1, who right now are not able to get pembrolizumab alone, when carboplatin/pemetrexed is added, can have a better response and survival? We don&rsquo;t have any of that information, in terms of the subgroup analysis of patients with different levels of PD-L1 expression.

There is also this idea that perhaps tumor mutational burden can be a better predictor of response to IO. A couple of studies looked at that and we don&rsquo;t have those data here either. I will be curious to see if there is going to be anything like that in terms of identifying patients who could really draw benefit from this &raquo; treatment based on tumor mutational load, though that is sort of a hypothesis.

That is why the study is significant, with the caveat that it is only a phase II study and we're awaiting the results of the phase III trial.

: How could the phase III results of KEYNOTE-189 affect this approval and treatment for patients? What questions are we hoping to have answered?

:The phase III study is going to have to show an OS advantage with the combination. That is how the approval will need to be sustained, honestly, but I don&rsquo;t know what the regulatory agencies are going to say if there is only a PFS and response benefit and not an OS advantage. For a lot of clinicians and patients, the biggest question is, &ldquo;How long am I going to get to live?&rdquo; With any particular treatment&hellip;OS data are going to be significant. That is what all of us want to see in the phase III study and, again, what we would also like to see is the subgroup analysis based on the level of PD-L1 expression, tumor mutational burden, or both, to have both to guide for the management of our patients.

: Will there continue to be a role for chemotherapy in these nonmutated patients?

Depending on the results of the study, chemotherapy could be an integral part of the care of patients who don&rsquo;t have driver mutations. If the phase III study is positive in all-comers, then it would suggest that we should keep the chemotherapy for the frontline setting with a platinum doublet and add an IO agent to it. So, we will continue to use doublet chemotherapy.

But if the results are less than ideal, meaning they don&rsquo;t show an OS advantage, then we are going to be in the same place we are nowmeaning we will offer single-agent pembrolizumab to anyone with greater than 50% PD-L1 expression and, for everybody else, we'll revert back to just chemotherapy for now until there are additional studies.

: Can you describe the synergy between PD-1 inhibitors and chemotherapy?

: In my view, the data are a little bit conflicting. Some data suggest that some chemotherapy drugs can be immune suppressive. Some data suggest that most chemotherapy drugs can be immune stimulatory. There is this idea of immunogenic cell death caused by chemotherapy, suggesting that even if you use chemotherapy then you cause cell death, which exposes potential neoantigens in the immune system that can be activated. With PD-1/PD-L1 inhibitors you activate T cells in the microenvironment that are already primed for chemotherapy, so you can have better responses.

I wouldn&rsquo;t necessarily call it synergism or an additive effect. [With] all of that in mind, it is not quite clear yet. We have to look at cohort G of the KEYNOTE-021 study to say that, based on the response and PFS, and now survival data, there is definitely some sort of interaction. But what it is and how exactly this is happening is still a little bit unknown, and it requires more research [to determine] how chemotherapy is making immunotherapy work better. That is, again, as far as I&rsquo;m concerned, immune suppression.

: How can we continue to utilize PD-L1 expression going forward?

: It all depends on what these [studies] show. If we have convincing evidence that PD-L1 expression is required&hellip;[and patients] get fantastic responses and survival [with the combination], then there is a likelihood that [we] won&rsquo;t be testing anybody for PD-L1. However, if the data are really presented the way we want them tobased on the level of PD-L1 expression&mdash;and we look at the data and we say, &ldquo;Those who have greater than 50% PD-L1 expression did not have a significantly better response with the addition of chemotherapy,&rdquo; then we will continue to use PD-L1 to give only single-agent IO and then everybody [else] will get the combination. But this is hypothetical and we have to wait and see what the data show.

: Currently, what patient characteristics are the deciding factors in whether patients will receive pembrolizumab plus chemotherapy or another regimen?

: At this point, I would still use the PD-L1 marker. If [expression is] 50% or higher, I will only offer pembrolizumab alone to my patients. For everybody else, who is less than 50% and if I have someone who has a significant disease burden and needs a better reduction in disease burden, then I&rsquo;m going to consider the combination. Based on the phase II data, we have close to a 55% response rate versus close to 30% with chemotherapy. That would tell me that a patient who has a heavy burden of disease requires a rapid reduction and, since the response rates are better with the combination, then I would use the combination. If there was any question about patient tolerability or potential toxicity, then I&rsquo;ll just stick with a platinum-doublet chemotherapy.

Remember, we don&rsquo;t have any data right now to tell us if the sequence matters. [This means], is it better to start with chemotherapy and then, at progression, bring in the IO agent? Or, is it simply better to start with that whole &ldquo;kitchen sink&rdquo; approach right off the bat? We don&rsquo;t have any information like that. These are the types of questions that subsequent studies will shed some light on and help us guide the treatment for the patients. Basically, what I described is what I do in my practice.

: How do you feel these decision-making factors will be different following confirmatory results from the KEYNOTE-189 trial?

: It would be different if again, in all subgroups, chemotherapy with IO is shown to be better. For a phase III study, we must have phase III data to sort of change our practice. Simply having a response or PFS should not be the criteria for changing this kind of care. I feel strongly that survival should be looked at very carefully and should be the determining factor on whether practice should change or not. What about the utility of maintenance therapy with pemetrexed for these types of patients? That is the standard of care right now. We do 4 cycles of a platinum doublet if they have a nonsquamous histology and, for those who are responding and tolerating, you give maintenance pemetrexed. The way cohort G of the KEYNOTE-021 trial was done is that everybody would continue on pemetrexed, and that was a sign to give pembrolizumab. As it stands now, the data would suggest that we should continue to use pemetrexed in a maintenance setting in this particular patient population, because that&rsquo;s where we have the best data. If the phase III study shows the same thing and follows the phase II design, then we are going to have to stick with that.

Borghaei H, Langer CJ, Papadimitrakopoulou V, et al. Updated results from KEYNOTE-021 cohort G: A randomized, phase 2 study of pemetrexed and carboplatin (PC) with or without pembrolizumab (pembro) as first-line therapy for advanced nonsquamous NSCLC [published online ahead of print September 18, 2017]. Ann Oncol. 2017;28(5): doi: 10.1093/annonc/mdx440.052.

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Clinical Articles

Experts within the lung cancer community are eagerly anticipating the phase III findings of the KEYNOTE-189 trial, and they are hopeful that the combination of pembrolizumab (Keytruda) plus carboplatin and pemetrexed (Alimta) will demonstrate an overall survival advantage in patients with nonsquamous non&ndash;small cell lung cancer.

Expert Shares Significance of Pembrolizumab Plus Carboplatin/Pemetrexed Approval and What It Bodes for NSCLC Landscape

NSCLC originates from lung epithelial cells of the central bronchi to terminal alveoli,

nonsquamous NSCLC will generally originate in peripheral lung tissue, and squamous cell carcinoma (SCC) primarily originates near a central bronchus.

Lung cancer, including both NSCLC and SCLC, contributes to the most cancer-related deaths in the United States, with 155,870 deaths estimated for 2017.

Molecularly targeted therapies have been developed based on the identification of mutations in lung cancer, a move that has led to improved survival in specific subsets of patients with metastatic disease.

Unfortunately, patients who do not harbor these mutations do not benefit from these new treatments and continue to experience poor outcomes. Being aware of current approaches to NSCLC diagnosis and assessment of disease criteria, relevant to current treatment selection strategies, is therefore a prerequisite for tailoring treatment for each patient.

NSCLC includes nonsmall cell carcinoma not otherwise specified (<5%), SCC (25%- 30%), and nonsquamous carcinoma (adenocarcinoma, large cell, and undifferentiated carcinoma; 70%-75%) (FIGURE 1).

A recent systematic review reported that the median age at diagnosis of advanced NSCLC ranged between 59 and 68 years.

An estimated 80% of patients with NSCLC receive an initial diagnosis after their cancer has already spread to regional lymph nodes or has metastasized, leading to 5-year survival rates of patients with stage IV cancer of <5%.

A recent study&rsquo;s results revealed that patients with nonsquamous NSCLC without known actionable mutations had a median overall survival (OS) of 10 months (95% CI, 9.4-10.8).

Also, the results of a prospective cohort study of patients with metastatic NSCLC conducted in Australia revealed that patients with actionable mutations had a significant survival advantage compared with patients without actionable mutations (HR, 0.49; 95% CI, 0.33-0.71; P <.01).

Smoking is the greatest risk factor for developing lung cancer, contributing to an approximate 10-fold increased risk compared with lifetime nonsmokers.

The odds ratio estimate of developing lung cancer for patients who currently smoke versus patients who never smoked was 23.9 (95% CI, 19.7-29.0) in men and 8.7 (95% CI, 7.4-10.3) in women.

Patients who have never smoked also develop NSCLC, with studies reporting frequencies up to approximately 30% (Japan).

Although it has been suggested that lung cancer in never-smokers is a separate disease, descriptive studies are lacking, with many not including a comparison group of ever-smokers.

A recent retrospective study reported that 22.4% of patients with newly diagnosed NSCLC were never-smokers and significantly more likely to be female (P <.001), older (P = .019), and have adenocarcinoma (P <.001).

Other risk factors for lung cancer include secondhand smoke exposure; radiation exposure from radiation therapy to the chest or breast, radon exposure, medical imaging tests (ie, CT scans), or atomic bomb radiation; exposure to asbestos, nickel, chromium, arsenic, beryllium, soot, or tar in the workplace; chronic exposure to air pollution; a family history of lung cancer; HIV infection; and heavy smokers who take beta carotene supplements.

Systemic anticancer therapy recommendations for patients with stage IV NSCLC depend on individual tumor histology, patient performance status, and driver oncogene biomarker status, which are most often anaplastic lymphoma kinase (ALK) translocations and epidermal growth factor receptor (EGFR) mutations (TABLE 1).

Approximately 83% to 85% of patients with stage IV NSCLC do not have activating EGFR mutations or ALK translocations, requiring distinct first-line therapy recommendations.

Common sites of metastasis are other areas of the lung, the adrenal gland, and the brain.

Of patients with advanced NSCLC, 25% to 44% experience dissemination in the central nervous system, particularly in patients diagnosed with adenocarcinoma.

Patients with brain metastases have particularly poor prognoses, leading to a median OS of 4 to 11 weeks or 4 to 15 months in untreated and treated patients, respectively.

Evolving Methods of Nonbiomarker NSCLC Diagnosis

Lung cancer may be found incidentally on chest imaging or may present through signs and symptoms resulting from the location of the primary tumor, compression of adjacent structures, or distant metastases.

Worsening cough or chest pain are the most frequently reported symptoms at presentation; other presenting symptoms include malaise, weight loss, dyspnea, hemoptysis, and hoarseness. Dysphagia, hoarseness, and facial edema and distension of the superficial head and neck veins may be caused by local invasion or compression of the esophagus, laryngeal nerves, or the superior vena cava, respectively. Neurological defects or personality changes may also be present, resulting from brain metastases or pain from bone metastases. Upon physical examination, findings may include enlarged supraclavicular lymphadenopathy, unresolved pneumonia, pleural effusion or lobar collapse, or signs of chronic obstructive pulmonary disease or pulmonary brosis, which are associated diseases.

To make a lung cancer diagnosis, several procedures are needed, including patient history, physical examination, laboratory evaluations, chest x-ray, chest CT scan with contrast material infusion, and biopsy.

&bull; Sputum cytology involves obtaining sputum, or mucus coughed up from the lungs, which is viewed under a microscope by a pathologist to check for cancer cells.

&bull; A fine-needle aspiration biopsy removes tissue or fluid from the lung using a thin needle, which is then examined under a microscope.

&bull; The purpose of a bronchoscopy is to examine the trachea and large airways of the lung for abnormalities. The bronchoscope, a thin, tube-like instrument with a light, is inserted through the nose or mouth into the trachea and lungs.

&bull; For a thoracoscopy, an incision is made between ribs to insert a thoracoscope, a thin, tube-like instrument with a light, to examine organs inside the chest for abnormalities. A thoracentesis is a procedure in which fluid is removed from the space between the chest lining and the lung using a needle. The fluid is then examined under a microscope by a pathologist.

&bull; Immunohistochemistry (IHC) and electron microscopy are valuable for diagnosis and subclassification; however, most lung tumors can be classified by light microscopic criteria.

The World Health Organization/International Association for the Study of Lung Cancer have classified malignant nonsmall cell epithelial lung tumors.

The 3 main types of NSCLC are large cell carcinoma (10%), SCC (25%), and adenocarcinoma (40%) (FIGURE 1), with numerous less frequent subtypes. In large cell carcinoma, the cancer may originate from several types of cells that appear large and abnormal under a microscope. SCC originates in squamous cells, which are thin, at cells that look like fish scales under a microscope. These cells are found in the tissue of the skin surface, the lining of the respiratory and digestive tracts, and the lining of hollow body organs. Adenocarcinoma originates in glandular or secretory cells that line the alveoli and produce mucus and other substances.

According to the 2017 guidelines from the National Comprehensive Cancer Network (NCCN), biomarker testing is recommended for all patients presenting with stage IV NSCLC.

Gregory L. Riely, MD, vice chair, Clinical Trials Office, Department of Medicine, Memorial Sloan Kettering Cancer Center, and a member of the NCCN panel for NSCLC explained, &ldquo;Optimally, it should be done at diagnosis; if it can&rsquo;t be done then, testing before giving second-line [or any subsequent line] therapy has value.&rdquo;

Molecular testing should investigate EGFR mutations, ALK gene arrangements, ROS1 expression, and programmed death ligand-1 (PD-L1) expression.

These biomarkers can be DNA- or protein-based, requiring detection through sequencing and fluorescence in situ hybridization (FISH) of IHC, respectively. Sequencing is used to detect EGFR,

, and MET exon 14 mutations. FISH is used to detect ROS, RET, and ALK. IHC is used to detect ALK, ROS1, PD-L1, and occasionally, EGFR mutations. Other driver oncogenes can be altered in NSCLC, including KRAS, HER2, RET fusions,

Furthermore, other genotypes contribute to 50% of NSCLC diagnoses. Yet, EGFR and ALK mutations are most common in nonsmoking patients with adenocarcinomas, whereas KRAS and BRAF mutations are more commonly found in current or former smokers.

EGFR-mutant NSCLC can be treated more effectively upfront with erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) than platinum doublets. No current therapies target KRAS. ALK fusions can currently be treated with ceritinib (Zykadia), alectinib (Alecensa), and crizotinib (Xalkori);

V600E can be treated with the combination of trametinib (Mekinist) and dabrafenib (Tafinlar); ROS1 fusions and MET exon 14 can be treated with crizotinib; and RET fusions can be treated with cabozantinib (Cabometyx).

Although the prognostic role of PD-L1 expression is unclear, PD-L1&minus;positive expression can be used as a biomarker for selecting patients who may benefit from PD-1/PD-L1 checkpoint inhibitor therapy, and is found in 24% to 60% of patients with NSCLC.

Several factors associated with adverse prognoses have been identified, including the presence of pulmonary symptoms, nonsquamous histology, tumor size larger than 3 cm, metastases to multiple lymph nodes, and vascular invasion.

Disease stage plays a critical role in the selection of therapy based on both clinical and pathological factors.

staging, procedures used to diagnose NSCLC may be used, with the addition of uorodeoxyglucose-positron emission tomography (FDG-PET) scanning. Tissue samples may be obtained via bronchoscopy, mediastinoscopy, or anterior mediastinotomy:

&bull; A mediastinoscopy is a procedure in which an incision is made at the top of the breastbone and a mediastinoscope is inserted into the chest to examine the organs, tissues, and lymph nodes between the lungs for abnormalities.

&bull; An anterior mediastinotomy also uses a mediastinoscope, but is inserted next to the breastbone to examine the organs and tissues between the lungs and between the breastbone and heart. Pathological staging of NSCLC involves examination of the tumor, margin resection, and lymph nodes.

At diagnosis, patients with NSCLC can be classified into 3 groups that reflect the disease extent and the treatment approach, including surgically resectable disease, locally and/or regionally advanced disease, and distant metastatic disease.

Patients with surgically resectable disease are generally stages I, II, and selected stage III tumors. These patients have the best prognosis, depending on other tumor and host factors. Curative radiation therapy may be used in patients who have medical contraindications to surgery. Locally (T3-T4) and regionally (N2- N3) advanced diseases have a diverse natural history, as these patients may benefit from combination treatments. Patients with unresectable disease are often treated with combined radiation and chemotherapy, whereas selected patients can be effectively treated with surgical resection and chemoradiation therapy or preoperative/postoperative chemotherapy. Patients with distant metastatic disease may be treated with chemotherapy or radiation therapy for palliation of symptoms from the primary tumor.

If accurate evaluation of the nodal status is necessary for therapy determination, surgical staging of the mediastinum is considered standard.

CT scanning, primarily used to determine tumor size, should extend inferiorly to include the liver and adrenal glands. No advantage has been reported for MRI scans of the thorax and upper abdomen.

FDG-PET scanning may facilitate identification of patients with metastatic disease that is beyond the scope of surgical resection and is missed by standard preoperative staging procedures, leading to improved patient outcomes.

Using CT imaging and FDG-PET scanning synergistically has improved specificity and sensitivity compared with CT imaging alone. CT or MRI scans may be used to stage patients at risk for brain metastases.

For patients unable to tolerate MRI, contrast-enhanced CT scan may be used.

The Revised International Staging System for Staging Lung Cancer was adopted in 2010 by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer (AJCC) (TABLE 2).

To define NSCLC, the AJCC has designated staging by TNM classification.

The occult carcinoma stage is defined as TX, N0, M0 disease. TX represents primary tumors that cannot be assessed or tumors that have been proven based on the presence of malignant cells in sputum or bronchial washings that have not been visualized by bronchoscopy or imaging. TNM stage 0 is defined as Tis, N0, M0, with Tis representing carcinoma in situ (TABLE 3). Overall, appropriate and timely NSCLC diagnosis is crucial for treatment planning and prognosis determination. In an issue of American Family Physician, Kelly M. Latimer, MD, MPH, and Timothy F. Mott, MD, both of the Naval Hospital, Pensacola, Florida, explain, &ldquo;The diagnostic evaluation and treatment of a patient with lung cancer require a team of specialists, including a pulmonologist, medical oncologist, radiation oncologist, pathologist, radiologist, and a thoracic surgeon. Cancer specimens are tested for various mutations, which, if present, can be treated with new targeted molecular therapies.&rdquo;

Unfortunately, patients with nonsquamous NSCLC who do not have actionable mutations will not benefit from these new targeted therapies and often have a poorer prognosis. Further studies are needed to improve outcomes for this patient population.

American Cancer Society. What is non-small cell lung cancer? ACS website. cancer. org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Updated May 16, 2016. Accessed August 2, 2017.

National Cancer Institute. Non-small cell lung cancer treatment (PDQ)-Health Professional Version. NCI website. cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Updated March 31, 2017. Accessed August 2, 2017.

Pao W, Girard N. New driver mutations in non-small-cell lung cancer.

2011;12(2):175-180. doi: 10.1016/S1470-2045(10)70087-5.

Howlader N, Noone AM, Krapcho M, et al (eds). Surveillance Epidemiology and End Results (SEER) Program: SEER cancer statistics review (CSR) 1975-2012. National Cancer Institute website. seer.cancer.gov/csr/1975_2012/. Updated November 18, 2015. Accessed August 3, 2017.

Herbst RS, Heymach JV, Lippman SM. Lung cancer.

2008;359(13):1367- 1380. doi: 10.1056/NEJMra0802714.

Davies J, Patel M, Gridelli C, de Marinis F, Waterkamp D, McCusker ME. Real-world treatment patterns for patients receiving second-line and third-line treatment for ad- vanced non-small cell lung cancer: a systematic review of recently published studies.

2017;12(4):e0175679. doi: 10.1371/journal.pone.0175679.

SEER cancer statistics factsheets: lung and bronchus cancer, 2015. National Cancer Institute website. seer.cancer.gov/statfacts/html/lungb.html. Accessed August 3, 2017.

Abernethy AP, Arunachalam A, Burke T, et al. Real-world rst-line treatment and over- all survival in non-small cell lung cancer without known EGFR mutations or ALK rear- rangements in US community oncology setting.

2017;12(6):e0178420. doi: 10.1371/journal.pone.0178420.

Tan L, Alexander M, Of cer A, et al. Survival difference according to mutation status in a prospective cohort study of Australian patients with metastatic non-small cell lung carcinoma (NSCLC).

Simonato L, Agudo A, Ahrens W, et al. Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogeneity.

Agudo A, Ahrens W, Benhamou E, et al. Lung cancer and cigarette smoking in women: a multicenter case-control study in Europe.

2000;88(5):820-827. doi: 10.1002/1097-0215(20001201)88:5<820::AID-IJC21>3.0.CO;2-J.

Asahina H, Sekine I, Horinouchi H, et al. Retrospective analysis of third-line and fourth-line chemotherapy for advanced non-small-cell lung cancer.

2012;13(1):39-43. doi: 10.1016/j.cllc.2011.06.010.

Zhou W, Christiani DC. East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians.

2011;30(5):287-292. doi: 10.5732/cjc.011.10106.

Couraud S, Souquet PJ, Paris C, et al; French Cooperative Intergroup IFCT. BioCAST/ IFCT-1002: epidemiological and molecular features of lung cancer in neversmokers.

2015;45(5):1403-1414. doi: 10.1183/09031936.00097214.

Toh CK, Lim WT. Lung cancer in never-smokers.

2007;60(4):337-340. doi: 10.1183/09031936.00046915.

Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular pro les and therapeutic implications.

2009;15(18):5646-5661. doi: 10.1158/1078-0432.CCR-09-0377.

Dias M, Linhas R, Campainha S, Conde S, Barroso A. Lung cancer in never- smokers  what are the differences?

2017;56(7):931-935. doi: 10.1080/0284186X.2017.1287944.

Non&ndash;small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80% to 85% of lung cancer cases, whereas small cell lung cancer (SCLC) comprises approximately 10% to 15% of lung cancer cases.

Diagnosis, Staging, and Testing for Nonsquamous NSCLC

While conventional treatment for patients without driver mutations is platinum-based chemotherapy, much of the field has shifted to first-line use of agents such as bevacizumab (Avastin) or pembrolizumab (Keytruda) plus pemetrexed (Alimta) and carboplatin.

As explained by Thu Oanh Dang, PharmD, BCOP, clinical oncology pharmacist at Memorial Sloan Kettering Cancer Center, New York, &ldquo;for about 2 and a half decades after cisplatin became widely used in the late 1970s, the therapeutic armamentarium of the medical oncologist for the treatment of NSCLC was limited largely to cytotoxic chemotherapy.&rdquo;

Despite advances in chemotherapy, however, "the development of therapeutic resistance to both cytotoxic chemotherapy and targeted therapy is universal" for patients with advanced or metastatic disease. Fortunately, the development and approval of checkpoint inhibitors and antiVEGF therapies over the past decade provide attractive options for delaying recurrence and improving overall survival (OS).

Accelerated Approval for Pembrolizumab Combined With Pemetrexed/Carboplatin

In May 2017, pembrolizumab, an immune checkpoint inhibitor, was granted accelerated approval by the FDA as a part of first-line combination therapy with pemetrexed and carboplatin for untreated, metastatic, nonsquamous NSCLC, regardless of programmed death ligand-1 (PD-L1) expression levels.

The accelerated approval expanded on previous indications for pembrolizumab, which was already approved as a first-line monotherapy for patients with NSCLC with high PD-L1 expression or second-line therapy for NSCLC with any PD-L1 expression.

Approval for pembrolizumab as first-line combination therapy was based on cohort G of the phase II KEYNOTE-021 study that evaluated carboplatin and pemetrexed with or without pembrolizumab. In this cohort, 123 patients with chemotherapy-na&iuml;ve, stage IIIb/IV, nonsquamous NSCLC were stratified by PD-L1 expression, and were randomly assigned to receive 4 cycles of carboplatin and pemetrexed with or without 24 months of pembrolizumab. Pemetrexed maintenance therapy was allowed in both groups.

After a median follow-up of 10.6 months, more patients in the pembrolizumab group compared with the chemotherapy group achieved an objective response (55% vs 29%, respectively; P = .0016).

For patients in the pembrolizumab group, no difference in objective response rate (ORR) was noted for patients with a PD-L1 tumor proportion score (TPS) of less than 1% (57%) or patients with a PD-L1 TPS of at least 1% (54%). The researchers, however, noted an increased ORR among patients with PD-L1 expression of 50% or more compared with those with a score of 1% to 49% (80% vs 26%) (TABLE 1). The incidence of severe treatment-related adverse events (AEs) was similar between the groups (39% vs 26%), with anemia (12%) and decreased neutrophil count (5%) occurring most commonly in the pembrolizumab group (TABLE 2).

In a news release from Merck, the developer of pembrolizumab, announcing the accelerated FDA approval for pembrolizumab as a first-line combination therapy agent, Corey Langer, MD, lead investigator of the KEYNOTE-021 study, noted, &ldquo;This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous nonsmall cell lung cancer, irrespective of PD-L1 expression.&rdquo; Importantly, emphasized, Langer, director of the Thoracic Oncology Program at Penn Medicine in Philadelphia, Pennsylvania, "Physicians should continue to use each patient&rsquo;s individual characteristicsincluding biomarker status, histology, and other clinical factors&mdash;to determine the best treatment plan for each person."

Phase III trials confirming these findings are ongoing.

PD-L1 Expression and First-Line Pembrolizumab

Before pembrolizumab was approved for use as first-line combination therapy, it was approved in October 2016 as monotherapy for metastatic, nonsquamous NSCLC with high PD-L1 expression.

According to Lee Pai-Scherf, MD, of the Center for Drug Evaluation and Research at the FDA, and colleagues, this indication could impact &ldquo;about a quarter of patients with [metastatic NSCLC].&rdquo;

This approval was based on the benefit demonstrated in the KEYNOTE-010 and KEYNOTE-024 clinical trials.

In the randomized, open-label phase III KEYNOTE-024 study, pembrolizumab monotherapy and a platinum-based chemotherapy regimen were compared in patients with PD-L1 expression of at least 50% and no other driver mutations. The primary endpoint of median progression-free survival (PFS) was significantly longer in the pembrolizumab group (10.3 months) compared with standard-of-care chemotherapy (6.0 months; HR, 0.50; P <.001). Moreover, OS at 6 months (80.2% vs 72.4%) and ORRs (44.8% vs 27.8%) were higher in the pembrolizumab group compared with the chemotherapy group, respectively.

Treatment-related AEs were less common in the pembrolizumab groups. Of particular interest, pneumonitis and severe skin reactions occurred in fewer than 4% of patients in either trial.

Dang called the results &ldquo;promising,&rdquo; and indicated that reported cases of durable disease control suggest that &ldquo;pembrolizumab may &lsquo;lift the tail of the curve,' which is a phenomenon similarly observed with advanced, cutaneous melanoma in the era of immunotherapy. Whereby immune checkpoint inhibitor therapy can result in a plateau at the end of a survival curve, non-immunomodulatory strategies usually result in the curve&rsquo;s tail-end returning to zero.&rdquo;

Pemetrexed Disodium Injection: Beneficial for Nonsquamous NSCLC

Pemetrexed in combination with cisplatin has been shown to improve survival of patients with nonsquamous NSCLC. Compared with gemcitabine plus cisplatin, pemetrexed plus cisplatin had noninferior median OS (10.3 vs 10.3 months, respectively; HR, 0.94), median PFS (5.1 vs 4.8 months, respectively; HR, 1.04), and ORRs (24.7% vs 27.1%, respectively). Importantly, the pemetrexed group had fewer grade 3/4 AEs, including neutropenia, anemia, and thrombocytopenia (P <.001 each), febrile neutropenia (P = .002), and alopecia (P <.001). Grade 3/4 nausea, however, was more common in the pemetrexed group (P = .004).

Pemetrexed has also been evaluated in combination with carboplatin. In a clinical trial comparing pemetrexed plus cisplatin versus pemetrexed plus carboplatin, both carboplatin and cisplatin groups met their primary endpoints, but cisplatin may have been slightly more efficacious. Median PFS (6.0 vs 4.7 months), 6-month PFS rate (50.5% vs 34.9%), median OS (11.7 vs 8.9 months), and 1-year OS rate (47.5% vs 39.2%) were all modestly better in the cisplatin group compared with the carboplatin group, respectively. AEs were slightly more common for cisplatin compared with carboplatin, and included neutropenia (16.9% vs 26.2%, respectively), anemia (7.7% vs 10.8%), thrombocytopenia (3.1% vs 16.9%), and nausea (4.6% vs 7.7%).

In an expert review of pemetrexed in NSCLC, Pascale Tomasini, MD, of the Multidisciplinary Oncology and Therapeutic Innovations Department at Aix-Marseille University, Marseille, France, commented, "Pemetrexed is one of the most frequently used drugs in the management of stage IV [nonsquamous] NSCLC patients. The good efficacy and the favorable safety profile make this drug one of the most commonly used in the first-line setting."

Addition of Bevacizumab to Platinum Doublet

Bevacizumab, an anti-VEGF monoclonal antibody, was approved for the treatment of NSCLC in combination with carboplatin and paclitaxel in 2006.11 In a randomized, open-label trial, chemotherapy-na&iuml;ve patients with stage IIIb/IV nonsquamous NSCLC were randomly assigned to receive carboplatin plus paclitaxel with or without bevacizumab. The bevacizumab group had significantly longer median OS (12.3 vs 10.3 months; HR, 0.79; P = .003) and longer median PFS (6.2 vs 4.5 months; HR, 0.66; P <.001). Severe AEs that were more common in patients receiving bevacizumab included neutropenia (26% vs 17% without bevacizumab), fatigue (16% vs 13%), hypertension (7% vs 0.7%), infection without neutropenia (7% vs 3%), and thrombosis/embolism (5% vs 3%), among others.

According to the National Comprehensive Cancer Network (NCCN) guidelines,1 bevacizumab plus carboplatin and paclitaxel has a category 1 recommendation, but bevacizumab combined with other chemotherapy regimens is also an option. Compared with paclitaxel combination therapy, pemetrexed with carboplatin and bevacizumab was shown to have a similar efficacy profile in terms of OS (HR, 1.00; P = .949), with a modest improvement in PFS (HR, 0.83; P = .012). While both regimens were tolerable, the toxicity profiles were shown to be distinct between the 2 regimens. Grade 3/4 anemia, thrombocytopenia, and fatigue were more common with the pemetrexed regimen; grade 3/4 neutropenia, febrile neutropenia, sensory neuropathy, and alopecia were more common with the paclitaxel regimen.

Treatment with bevacizumab has been associated with bleeding-related AEs; however, more recent studies with careful patient selection revealed that bevacizumab is &ldquo;a safe drug with an acceptable safety profile,&rdquo; according to Salvatore Lauro, MD, in the Department of Medical Oncology, Sant'Andrea Hospital, Rome, Italy, and colleagues in a review of bevacizumab treatment.

&ldquo;The results of pivotal studies&hellip;argue in favor of the use of this drug,&rdquo;they concluded, and went on to describe the possible benefits of bevacizumab: improved quality of life, delayed initiation of second-line treatment, and saving other effective treatments for successive lines of therapy.

Considerations When Selecting Between First-Line Therapies

For advanced or metastatic nonsquamous NSCLC, the NCCN recommends that the &ldquo;drug regimen with the highest likelihood of benefit with toxicity deemed acceptable to both the physician and the patient should be given as initial therapy.&rdquo;

Determining the therapy with the highest likelihood of benefit, however, can depend upon a variety of disease factors (stage, histology, PD-L1 expression) and patient factors (ECOG performance status [PS], comorbidities, organ function).

For patients with early-stage NSCLC, surgery with or without adjuvant chemotherapy or radiation therapy is usually the preferred treatment option.

For patients with locally advanced or metastatic NSCLC, clinicians now have more options: platinum doublet chemotherapy with or without bevacizumab, platinum doublet therapy with or without pembrolizumab, or pembrolizumab monotherapy.

With the approval and success of the immune checkpoint inhibitor pembrolizumab, the first tool to stratify patients after tumor genotyping will likely be PD-L1 expression level, quantified via immunohistochemistry. For patients with 50% or more PD-L1 expression, pembrolizumab monotherapy may be preferred due to the superior efficacy and tolerability compared with chemotherapy in this patient population.

Jordi Remon, MD, medical oncologist in the Cancer Medicine Department at Consorci Sanitari del Maresme, Matar&oacute;, Spain, suggested that pembrolizumab &ldquo;should be considered a standard first-line treatment in NSCLC patients with a good performance status whose tumors have PD-L1 expression &ge;50%.&rdquo;

For patients with PD-L1 expression levels less than 50%, pembrolizumab combination therapy with pemetrexed and carboplatin is an option, although the treatment benefits are not as substantial as for patients with high PD-L1 expression.

According to Jong-Mu Sun, MD, of the Division of Hematology-Oncology at Sungkyunkwan University School of Medicine, in Seoul, South Korea, patients with weak or no PD-L1 signals may be considered for combination therapy based on the KEYNOTE-021 trial, &ldquo;although data from large randomized trials are needed to confirm this. In addition, when considering the combination therapy, the physicians should keep in mind additional toxicities and should be more alert for these events. For those with low PD-L1 expression, PD-1/PD-L1 inhibitors can be reserved for second (or beyond)-line therapy following platinum-based chemotherapy.&rdquo;

Performance status and fitness are also important considerations when selecting treatments for patients with nonsquamous NSCLC. For patients with a PS of 3 or 4, the NCCN guidelines recommend best supportive care.

For patients with PS 0 to 2, systemic therapy is recommended as first-line treatment, but multiple options for treatment exist.

For better PS of 0 or 1, category 1 recommendations include various doublet chemotherapy regimens and bevacizumab with carboplatin and pemetrexed. Pembrolizumab with carboplatin and pemetrexed is included as an option but is not considered category 1, while bevacizumab with pemetrexed and platinum-based chemotherapy is.

As explained by Tracey Evans, MD, associate professor of clinical medicine, Department of Medical Oncology at Penn Medicine, Philadelphia, Pennsylvania, in a review, &ldquo;Due to the generally poor outcomes of patients with poor [performance status] treated with chemotherapy, the tendency has been to either not give chemotherapy at all or to give less toxic single-agent chemotherapy. It nevertheless stands to reason that if the patient&rsquo;s poor [performance status] is caused by the cancer, treating the cancer more aggressively may lead to improved outcomes.&rdquo;

Regardless of treatment selection, in most clinical trials, patients with PS 2 have worse clinical outcomes than patients with PS 0 or 1.

Nonetheless, treatment does improve outcomes compared with no treatment.

For patients with PS 2, carboplatin is preferred over cisplatin, likely due to the distinct toxicity profile, and it is recommended as a part of doublet chemotherapy.

Additionally, single-agent chemotherapy is an option recommended in the NCCN guidelines for this patient population. In a study of patients with advanced NSCLC and a PS of 2, combination carboplatin with pemetrexed significantly improved survival compared with pemetrexed alone (9.3 vs 5.3 months; HR, 0.62; P = .001).

Evans suggested that treatment with carboplatin-containing chemotherapy would be the optimal choice in this patient population, &ldquo;for patients with PS 2 who are interested in maximizing OS and who are willing to undergo cytotoxic chemotherapy, carboplatin-based doublet therapy is indicated and is superior to single-agent therapy.&rdquo;

Gemcitabine alone or in combination with docetaxel or vinorelbine is another option for patients with a PS of 2, as is single- agent paclitaxel.

Like PS, older age may be considered a negative predictor of treatment response for some regimens, although older age alone does not preclude patients from receiving treatment.

A review of cisplatin- and carboplatin-based chemotherapies in elderly patients (generally age >70 years) by Remei Blanco, MD,PhD, of Consorci Sanitari de Terrassa in Barcelona, Spain, and colleagues illuminated &ldquo;The feasibility of these schedules in the elderly, as no study showed a significant difference in survival according to age, except for a combined analysis of results from 2 SWOG trials.&rdquo; The study authors also explained that "a nonsignificant trend towards an [OS] benefit with platinum-based doublet therapy over gemcitabine monotherapy was reported, albeit with an increased risk of toxicity."

Pemetrexed has also been shown to be equally efficacious among older and younger patients in terms of OS (HR comparing patients aged <65 years with those aged >65 years, 0.92).

Older age alone is not a contraindication for bevacizumab, since no increase in bleeding-related AEs has been observed in elderly patients.

However, a recent secondary analysis of the PointBreak and ECOG 4599 trials of paclitaxel plus carboplatin with or without bevacizumab evaluated the efficacy and safety of bevacizumab combination chemotherapy specifically in patients grouped by age.

In this report, OS was significantly improved by the addition of bevacizumab to carboplatin and paclitaxel for all age groups younger than 75 years (age <65 years: HR, 0.75; age 65-74 years: HR, 0.80), but no improvement was noted for those patients who were 75 years or older (HR, 1.05). AEs were significantly increased in the bevacizumab group compared with the chemotherapy-alone group among patients age 75 years or older (81% vs 56%; P <.05).

Similar results were reported in another trial that focused on patients aged &ge;65 years.

Based on these data, Evans concluded that it is unclear &ldquo;whether bevacizumab offers benefit, but it is reasonable to offer it to elderly patients who do not have contraindications to taking bevacizumab.&rdquo;

Comorbidities and other patient factors, such as organ function, are important considerations when selecting treatment for patients with nonsquamous NSCLC. For bevacizumab, bleeding risks are often of concern, so exclusion of patients with the presence of hemoptysis is an important consideration.

For cisplatin, poor kidney function is an important contraindication due to the potential for nephrotoxicity, so carboplatin in combination with paclitaxel should be considered as an alternative.

Selection of second-line therapies for nonsquamous NSCLC is dependent upon the choice of first-line therapies. According to Antonio Rossi, MD, of the Division of Medical Oncology at S.G. Moscati Hospital, in Avellino, Italy, &ldquo;If the adequate choice of first-line treatment for NSCLC management is very important, the choice of second-line treatment is of vital importance, too.&rdquo;

On progression of NSCLC, preferred second-line therapy is usually an immune checkpoint inhibitor if one has not been previously given.

In CheckMate-057, nivolumab (Opdivo) was compared with docetaxel in patients with progressive NSCLC following first-line platinum-based chemotherapy.

The nivolumab group had significantly longer median OS compared with the docetaxel group (12.2 vs 9.4 months; P = .002). Additionally, the 1-year ORR was 51% for the nivolumab group compared with 39% in the docetaxel group. The ORR was more durable for patients receiving nivolumab, with a median duration of 17.2 months compared with 5.6 months in the docetaxel group. Moreover, AEs were substantially higher in the docetaxel group, with 54% of patients experiencing grade 3/4 AEs compared with 10% in the nivolumab group. The researchers noted that nivolumab was associated with similarly improved outcomes at all levels of PD-L1 expression over 1%, but improvements were lower for patients with PD-L1negative NSCLC.

Pembrolizumab is another immune checkpoint inhibitor that has been evaluated as second-line therapy. In KEYNOTE-010, pembrolizumab was compared with docetaxel among patients with at least 1% PD-L1 expression.

Median OS was higher in the pembrolizumab groups (10.4 months for 2 mg/kg and 12.7 months for 10 mg/kg) compared with docetaxel (8.5 months), resulting in HRs of 0.71 and 0.61, respectively. Among patients with at least 50% PD-L1 expression, OS was significantly longer with pembrolizumab 2 mg/kg (14.9 months) and 10 mg/kg (17.3 months) compared with docetaxel (8.2 months). As with nivolumab, toxicity with pembrolizumab was lower compared with docetaxel, with 13%, 16%, and 35% of patients in the 2 mg/kg, 10 mg/kg, and docetaxel groups, respectively, experiencing grade 3/4 AEs.

Rossi explained, &ldquo;Considering that the outcomes of the 2 doses of pembrolizumab reported in the KEYNOTE-010 trial were very similar, pembrolizumab was registered, at the lower dose of 2 mg/ kg, for the second-line treatment of patients with NSCLC of any histology with PD-L1 expression &ge;1% with a companion diagnostic.&rdquo;

Atezolizumab (Tecentriq) is another checkpoint inhibitor that is available as second-line therapy for patients with progressive, previously treated NSCLC. In the phase III OAK trial,

patients with previously treated NSCLC were randomly assigned to receive atezolizumab or docetaxel. OS was significantly improved in the atezolizumab group (13.8 vs 9.6 months; HR, 0.73; P = .0003). In subgroup analyses, OS was improved in both PD-L1positive patients (15.7 vs 10.3 months; HR, 0.74; P = .0102) and PD-L1&ndash;negative patients (12.6 vs 8.9 months; HR, 0.75; P = .02). For patients with high PD-L1 expression, OS was 20.5 months compared with 8.9 months in the docetaxel group (HR, 0.41; P <.0001) (TABLE 3). Grade 3/4 AEs were less common with atezolizumab (15%) compared with docetaxel (43%).

In an expert review of second-line therapies for NSCLC, Fernando Santini, MD, of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, and Division of Medical Oncology, in Sao Paolo, Brazil, and of the Division of Medical Oncology, in Sao Paolo, Brazil, concluded, &ldquo;the landscape of second-line treatment of patients with NSCLC has 3 checkpoint inhibitor drugs approved, with similar activities and safety profiles.&rdquo; Of the 3 second-line checkpoint inhibitors, atezolizumab and nivolumab are the only 2 with approval regardless of PD-L1 status.

Although systemic immune checkpoint inhibitors are preferred agents for second-line treatment, they are unlikely to be effective in patients who have already used these regimens. Other systemic therapy options include docetaxel, pemetrexed, gemcitabine, or ramucirumab (Cyramza) plus docetaxel. All of these agents have category 2b recommendations in the NCCN guidelines, indicating an NCCN consensus of appropriate therapy based on lower-level evidence.

Docetaxel has been extensively studied as second-line therapy for NSCLC. In the TAX320 trial, patients were randomized to receive various doses of docetaxel compared with either vinorelbine or ifosfamide.

Although median OS was not significantly different between low-dose docetaxel, high-dose docetaxel, or the control treatment (5.7 vs 5.5 vs 5.6 months, respectively), the rate of patients achieving 1-year survival was significantly higher with docetaxel 75 mg/m2 compared with the control groups (32% vs 19%; P = .025).

"Overall, docetaxel, registered at the 3-weekly dose of 75 mg/m2, has become the standard second-line treatment against which any new drug has to be compared for registrative purposes," noted Rossi.

Docetaxel can also be combined with ramucirumab (Cyramza), an anti-VEGF agent, in the second-line setting. In the REVEL trial,

combination ramucirumab with docetaxel was compared with docetaxel alone in patients with NSCLC who had progressed after platinum-based chemotherapy. Median OS was longer in the combination group compared with docetaxel alone (10.5 vs 9.1 months; HR, 0.86; P = .023) as was PFS (4.5 vs 3.0 months; HR, 0.76; P <.0001). However, grade 3/4 AEs were more common in the ramucirumab group, and included neutropenia (49% vs 40%), febrile neutropenia (16% vs 10%), fatigue (14% vs 10%), leucopenia (14% vs 12%), and hypertension (6% vs 2%).

In an expert commentary on ramucirumab in NSCLC, Oscar Arrieta, MD, of the Instituto Nacional de Cancerolog&iacute;a, in Mexico City, Mexico, and colleagues acknowledged that immune checkpoint therapies are preferred for patients with high PD-L1, but noted,&ldquo;Patients with negative PD-L1 expression might respond better to treatment with ramucirumab.&rdquo;

For patients who were not originally treated with pemetrexed, pemetrexed provides a good second-line option, as well. Compared with docetaxel, pemetrexed was noninferior in previously treated patients with NSCLC (median survival time, 7.9 vs 8.3 months; HR, 0.99; P = .226). Docetaxel, however, was associated with a significantly higher rate of grade 3/4 AEs compared with pemetrexed, including neutropenia (40.2% vs 5.3%; P <.001), febrile neutropenia (12.7% vs 1.9%; P <.001), neutropenia with infections (3.3% vs 0.0%; P <.004), and hospitalizations for neutropenic fever (13.4% vs 1.5%; P <.001).

Maintenance Therapy: Improving Outcomes Following First-Line Treatment

Maintenance therapy is a relatively new phenomenon of utilizing a single agent after successful treatment with first-line therapy &ldquo;in an effort to improve outcomes and maximize therapy with a potentially less toxic and tolerable [treatment],&rdquo; according to Stephanie Brul&eacute;, MD, of the Department of Medical Oncology at the Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.

Two forms of maintenance therapy are used in nonsquamous NSCLC: continuation maintenance, usually with bevacizumab or pemetrexed; or switch maintenance, usually to pemetrexed.

Explaining the differences between the theories behind the 2 approaches, Brul&eacute; commented, &ldquo;switch maintenance therapy leads to increased exposure of tumour cells to non-cross-resistant therapies. Therefore, this may lead to a decreased incidence of chemotherapy resistance and to increased antitumor effects. Further, switch maintenance therapy can act as an early form of second-line therapy,&rdquo; whereas continuation maintenance capitalizes on the response that patients have already exhibited to first-line treatment.

The only category 1 recommendations from NCCN for maintenance therapy are continuation maintenance with bevacizumab or pemetrexed.1 In the PARAMOUNT study,

maintenance therapy with pemetrexed was compared with best supportive care (BSC) following first-line treatment with pemetrexed plus cisplatin. Compared with BSC, maintenance therapy with pemetrexed resulted in a significant reduction in disease progression (HR, 0.62; P <.0001), improvement in median PFS (4.1 vs 2.8 months; P <.0001), and increased median OS (13.9 vs 11.0 months; P = .0195) (TABLE 4).37,38 Grade 3/4 AEs were more common in the pemetrexed group (anemia, neutropenia, and fatigue).

Nonetheless, pemetrexed maintenance therapy is considered to be well tolerated, since quality of life was shown to be similar between placebo and pemetrexed, with pemetrexed delaying worsening of pain and hemoptysis.

Bevacizumab maintenance treatment was evaluated in a retrospective analysis of the ECOG 4599 trial,

Nonsquamous non&#8210;small cell lung cancer (NSCLC) is a heterogeneous disease with multiple treatment options dependent upon staging, presence of metastasis, and patient factors&mdash;including presence of comorbidities&mdash;among other considerations. As such, current treatment options include surgical resection, chemotherapy, radiation, immunotherapy, and targeted therapy.

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