The Keys to Obtaining Best Value in Non-Small Cell Lung Cancer

Lung cancer remains a most difficult cancer to treat, because of its seemingly intractable progression and the fact that it is usually diagnosed at a late stage. The prevalence of lung cancer, which is directly related to the incidence of tobacco smoking and unacceptable levels of air pollution, continues to challenge scientists and health economists worldwide.

A Quarter-Million Americans to Be Diagnosed This Year

Lung cancer accounts for 14% of all new cases of cancer today, and of the many forms of lung cancer, non—small cell lung cancer (NSCLC) is the most prevalent, accounting for 85% to 90% of all lung cancer cases.¹Of patients with NSCLC, adenocarcinomas comprise the greatest proportion (40%), followed by squamous cell tumors (up to 30%) and large-cell tumors (up to 15%), with miscellaneous types comprising the remainder.¹

According to the American Cancer Society’s latest estimates, lung cancer (all forms) will be diagnosed in 226,000 men and women in 2012, and will result in more than 160,000 deaths—this represents 28% of all yearly cancer deaths.¹

If diagnosed at the earliest stage (1A), the 5-year survival associated with NSCLC is 49%. Those patients whose lung cancer is classified as stage 2 at the time they are diagnosed have a 30% 5-year survival, and this figure drops precipitously with more advanced disease. Despite major gains in our understanding of how NSCLC develops and spreads, survival gains have been slow and incremental. The best chance of a cure is still surgery, which is most effective in the earliest stages of NSCLC.¹

Multiple Treatments Available and a Full Pipeline of Targets Await

In an effort to gain a foothold in the war on lung cancer, many approaches to treatment of NSCLC have been tried over the last 2 decades. This has resulted in complex treatment algorithms, as reflected in the National Comprehensive Cancer Network guidelines. Treatment considerations can include surgical resection (with or without preoperative chemoradiation) with lymph-node dissection or sampling and followed by adjuvant treatment (typically radiotherapy and/or chemotherapy [often cisplatin and vinorelbine or etoposide]). For patients with inoperable or recurrent disease, first-line chemotherapy may consist of double treatment (usually cisplatin and another agent); bevacizumab plus chemotherapy; cisplatin/pemetrexed; or a combination of cetuximab, vinorelbine, and cisplatin, all of which is partly based on the specific NSCLC subtype (ie, adenocarcinoma vs squamous cell or large cell). Secondline chemotherapy may add crizotinib, docetaxel, erlotinib, or gemcitabine to the mix of options. In addition to the medications already mentioned, patients with advanced or metastatic NSCLC may also receive carboplatin, ifosfamide, irinotecan, or mitomycin. Treatment recommendations will vary based on a finding of adenocarcinoma or squamous cell carcinoma and on the patient’s performance status rating.²Recent emphasis has been placed on identifying patients who overexpress epidermal growth factor receptor (EGFR). In patients with EGFR overexpression and recurrent or advanced disease, targeted monotherapy with erlotinib, a tyrosine-kinase inhibitor, has been found to offer a 2-month survival advantage over patients receiving placebo.³Cetuximab, the latest EGFR inhibitor used for NSCLC, works by binding to the extracellular domain of EGFR, blocking activation of the EGFR pathway.

Newer treatments are needed to fight this tenacious cancer, as progress in increasing survival in NSCLC has been challenging. Some promise was seen with vascular-disruptive agents (eg, ASA404) and with other tyrosinekinase inhibitors (eg, vandetanib and sorafenib), but the outcomes of these trials have been disappointing.⁴It may well be that medications such as these are effective in patients with a specific biomarker that has not yet been recognized— that is, some medications are awaiting identification of a patient subpopulation.

Studies of the use of immunotherapy and therapeutic vaccines in NSCLC a marketing partner as clinical trials progress. However, the vaccines, like other modalities in NSCLC, are likely to be used with other therapies. For example, it may be optimal to use therapeutic vaccines in combination with antibodies to amplify the immune response.⁶

Optimizing the Value of Care in NSCLC

This incremental improvement in survival in NSCLC (especially overall survival) has placed payers between the proverbial rock and a hard place. Do they see value in the newer treatments (which are commonly more expensive than older platinum-based therapies), while seeing a limited survival benefit for only a portion of patients? And, it is exceedingly difficult, from the health plan or insurer’s perspective, to restrict cancer therapies shown to have even very limited clinical benefit.

The costs associated with NSCLC can be extensive. In patients with advanced NSCLC (stage IV disease), the average total cost of care was calculated to be $162,134 in a privately insured population, or $10,284 per patient per month. The newer agents (including pemetrexed, biologics, and tyrosine kinase inhibitors) cost an average $10,141 per patient per month (for the duration of their treatments).⁷

As newer agents have been introduced, the cost of treatment for NSCLC has risen. This is likely due to higher prices for new therapies in general and the prevalence of combination regimens in NSCLC. In 2005, the mean drug cost of second-line therapy was $5939; in 2009, it increased to $10,057.⁸Therefore, payers need to obtain the best value they can from available treatments in NSCLC. New, more effective agents are expected to become available, but one way to increase the value of existing therapies is to better match patients with treatments. Two studies vividly illustrate the point: In one US study of patients receiving second-line therapy for NSCLC, researchers could find no difference in survival outcomes (overall or progression-free survival) among those taking erlotinib, docetaxel, or pemetrexed.⁹However, in an Italian study, patients with NSCLC who did not express the EGFR mutation had significantly worse progression-free survival (PFS) when they were given the EGFR inhibitor erlotinib compared with docetaxel as second-line therapy.¹⁰Furthermore, in a phase III study of an investigational EGFR inhibitor (afatinib), an international team of researchers found a 6.7-month advantage in progression-free survival for patients with the EGFR mutation compared with pemetrexed and cisplatin as first-line therapy.¹¹High levels of ERCC1 overexpression can predict a poor response to platinum-based therapy, but high RRM1 levels are predictive of resistance to gemcitabine-based therapy.¹²Furthermore, low expression of thymidylate synthase may correlate with higher PFS with pemetrexed in patients with adenocarcinoma- type NSCLC.¹³

Researchers are actively evaluating wide panels of serum biomarkers to better understand which therapies may be more effective in certain patients. For example, bevacizumab has been associated with some benefits in NSCLC, and researchers from Rush University in Chicago tested 72 biomarkers from the sera of 93 patients with advanced NSCLC. Of the patients receiving bevacizumab-containing regimens, those with higher serum levels of PDGF-AB/BB had significantly better PFS and overall survival (OS) than the others.¹⁴

Indeed, clinical investigations are under way to determine whether gene amplifications or mutations, involving such genes as KRAS, ALK, FGFR1, DDR2, and PIK3CA, to name a few, can predict who will benefit optimally from therapy and even determine which patients with NSCLC have a better prognosis.

Another potentially valuable asset of biomarker identification could be the mediation or avoidance of therapy-associated side effects, which can add significant costs. For example, the occurrence of chemotherapy-associated peripheral neuropathy resulted in $17,344 higher costs compared with those who did not experience peripheral neuropathy.¹⁵

An important consideration regarding the value of biomarker identification in NSCLC (as well as in most cancers) is the frequency with which the biomarkers appear in the disease. That is, the cost of biomarker identification depends on the cost of the assay to quantify its presence (and of course, the accuracy and sensitivity of the test) and the frequency with which the biomarker can be expected to appear.16 To illustrate, if one were to screen for a biomarker like ALK at an assay cost of $1400 per person, but the biomarker is bevaciexpected to appear in only 2% of the population, screening in all patients with advanced NSCLC for ALK, excluding treatment cost, would be $106,707 per quality-adjusted life-year (QALY). This can drop as low as $4756 per QALY if the biomarker occurs in 36% of patients with NSCLC.¹⁶Therefore, it makes the most sense to screen for high-frequency gene mutations or amplifications, assuming a treatment benefits a patient with the biomarker (or possibly works better in those without it).

Other NSCLC Cost Drivers

Two definitive drivers of cost of NSCLC (or of lung cancer in general) are the prevalence of cigarette smoking and its diagnosis in relatively late stages. The vast majority of patients are diagnosed not in stage I, when surgery may be curative, but in stages III or IV, when survival is much lower.

Cigarette smoking (including chronic inhalation of secondhand smoke) is estimated to cause 85% to 90% of all lung cancers.²The remainder of cases are attributed to environmental factors, such as radon, radiation, or asbestos exposure, and diesel exhaust.¹⁷Cigarette smoking costs the nation $96 billion annually in direct medical expenditures and $97 billion in lost productivity.¹⁸According to an actuarial analysis, exposure to secondhand smoke results in over $10 billion annually in US health expenditures.¹⁹

The Centers for Disease Control and Prevention found that in 2010, 19.3% of US adults smoked, which represented a decline of 3 million smokers from 2005.²⁰

Prevention of NSCLC (or of lung cancer in general) is the favored approach to cost-effective public health; however, smoking in younger people has not decreased substantially. A total of 27.3% of adolescents, teens, and adults reported using tobacco products (including cigarettes, smokeless tobacco, cigars, and pipe tobacco) in 2010.²¹This percentage has declined slowly (Figure).

Lung cancer is most often diagnosed late in the disease course. Identification of cancers earlier in high-risk populations (eg, current smokers) could result in more patients diagnosed with stage 1 NSCLC, with greater chance for cure or longer survival. A recent investigation in the use of spiral-computed tomography (which delivers relatively low doses of radiation compared with conventional scanning) in high-risk patients was found to lower mortality but not necessarily costs.²²This should not be surprising: As patients’ tumors are diagnosed early in the course of disease, they may undergo more cycles of chemotherapy and additional therapies in an effort to arrest its spread than a patient whose tumor is identified in stage III or IV. However, the probability for curing these patients with early-stage NSCLC is still greater.

The screening rates for lung cancer are low, either by chest x-ray or lowdose computed tomography (CT) scan. A recent study revealed that only 2.5% of adults underwent a chest x-ray in 2010 specifically to screen for lung cancer, and 1.3% received a low-dose CT examination.²³

Sniffing Out NSCLC

Patients with lung cancer have compounds (volatile organic compounds) in their exhaled breath that differ from those found in healthy individuals. These aromatic compounds are byproducts of the tumor’s metabolism. Hence, these compounds could be used as a biomarker for distinguishing benign from malignant pulmonary nodules. Various tests for analyzing this exhaled air are being explored. One unique idea is to use sniffer dogs; they have been used in other settings to take advantage of their keen olfactory system. Trials have been conducted that confirm sniffer dogs can identify lung cancer from a breath sample.²⁴

Along these same lines, researchers at Israel’s Technion Institute are moving forward with the Nano Artificial Nose, which may be able to “smell” lung cancer. It is a breath test that differentiates between benign and malignant pulmonary nodules as well as differentiating between small-cell lung cancer and NSCLC. Some evidence shows that it is also able to identify early cancer from more advanced disease.²⁵Early stage trials demonstrate an accuracy of 80% to 90% in differentiating benign from malignant disease. It also demonstrated 90% accuracy in differentiating the 2 types of cancer as well as the progression of the disease.²⁶

Knocking On (or Breaking Down) the Door of Progress

Hope remains that the relatively small gains we make with the completion of each new research study will lead to large gains in prevention and survival in the near future. Perhaps the next 5 years will be key to unlocking the secrets of effectively treating NSCLC.

As in most cancers, prevention represents the best value by far in NSCLC.Earliest possible diagnosis, which offers the best chance for a long remission or cure, can only occur with better compliance with screening guidelines and the use of new diagnostic methods. In terms of active treatment, better targeting of existing, expensive biopharmaceuticals and the introduction of new and novel pipeline products hold the keys to better clinical results and value.

Payer PerspectiveInterview with Allan J. Chernov, MD

EBO: How does Blue Cross and Blue Shield of Texas determine the value of the targeted lung cancer therapies? Are you using a Pharmacy & Therapeutics or technology assessment committee?

Dr Chernov:

Primarily, we use our medical policy process, which is what we call the formal written documents of benefit coverage based on technology assessment. When technologies are drug related, we bring in pharmacy experts to help us make a coverage determination. Technology assessment tends to be easier with drugs, because we can use FDA approval as a reference point for a specific indication. We also evaluate requests—on a case-by-case basis—for offlabel uses of these drugs.

EBO: Does your plan require that patients must undergo biomarker testing or companion tests before receiving targeted agents, such as Erbitux (cetuximab)? Or, is it sort of really up to the doctors’ discretion?

Dr Chernov:This raises 2 questions: (1) Do we pay for those kinds of tests? and (2) Do the tests provide information that will improve outcomes? We evaluate biomarker tests on a separate basis. If we decide that a test will/can help improve patient management, we leave it up to the doctors to decide if it’s appropriate for a specific patient.

We have very few prior authorization requirements. We find that when expensive procedures, products, and therapies are being contemplated, physicians tend to ask us to do pre-service review for medical necessity. This tends to work out best for doctors, their patients, and—in a way—for us, because if you can settle the medical necessity for coverage of a service before it is performed and hits our claim system, it is easier to manage. We get many voluntary requests even though we have very few prior authorization requirements.

Would we require a test as a condition for prescribing a drug? It is certainly possible that if the evidence is strong enough we would want to couple coverage for an extremely expensive chemotherapeutic agent with results of a biomarker test. I suspect that as the validity and value of biomarkers emerge for a variety of drugs, we may consider requiring a positive test as a condition of coverage for a specific drug.

EBO: As the availability of biomarker or companion tests become increasingly available, would you consider developing a specific technology assessment process just for them? Or, would these decisions be handled through existing processes?

Dr Chernov:

The basic principles of technology evaluation apply here, too. We gather the evidence, we look at the published literature, and we look at the clinical impact. The biggest question we try to answer with any new technology is, “So what?” We want to pay for things that make a difference. Unfortunately, it takes time for that evidence to emerge. How do you know that 1 year down the road, it will make a difference in the patient’s outcome?

EBO: New agents introduced to treat non— small cell lung cancer (NSCLC) have generally been associated with modest gains in survival. Does that make it more difficult to determine the value of these agents?

Dr Chernov:

This is a problem in difficult-to-treat cancers that are relatively common. We struggle to find more effective treatments, but the basic principles of evidence still apply. We look for high-quality, well-designed studies. Randomized clinical trials continue to be the gold standard. We are looking for a preponderance of evidence that use of a particular test or procedure is safe, is effective…and has favorable health outcomes.

So, I can say that if hypothetical Product X was found—in a sound study with good statistical power—to improve progression-free survival by 8 weeks in NSCLC, and that the product makes a significant difference in patient management, we would tend toward covering it.

We often see passionate proponents of a technology who feel it is just obvious that product X is wonderful. Our job is to be healthy skeptics: Show me! The basic premise is straightforward, but the execution is hard, because we’re talking about very complex biological processes. We’re talking about complex clinical scenarios. We’re talking about things that are difficult to study in a blinded fashion. It may be almost impossible to find comparison groups.

Our job, however, is to do the best we can to evaluate the available evidence and then make a decision. But the available evidence may change tomorrow— a landmark study could be published next week, for example. The decisions we make today are not for all time. They are based on the strength of today’s evidence. That evidence may change next week, next month, and next year. We must be flexible enough to reevaluate our decisions at the appropriate time.

EBO: When considering outcomes from clinical oncology studies, what types of outcomes are you most interested in? Is it overall survival? Is it progression-free survival? Is it a combination, or something else?

Dr Chernov:

Those are the major, standard outcomes measures of success. That’s what we look for.

EBO: Does Blue Cross and Blue Shield of Texas focus specifically on tobacco-use prevention?

Dr Chernov:

We’re constantly harping on it. It varies by type of benefit plan; for example, not every self-insured plan covers smoking cessation programs. However, we put our money where our mouth is, because we don’t allow smoking in our building and there is a tobacco health insurance surcharge for our own employees who do smoke.

We have a strong commitment to combating smoking. I don’t have the numbers, but my understanding is that the smoking rate of our employees has declined significantly with that very powerful incentive because it hits the pocketbook.

EBO: In an ideal world, where money is no object, what tools would you employ to both prevent lung cancer and to diagnose it earlier?

Dr Chernov:

In the ideal setting, I think it is all about prevention—eliminating smoking and eliminating pollution containing carcinogens. That would have, by far, the most profound impact. Dealing with lung cancer is less about diagnosis and treatment. Once it is present, it is such a terrible, terrible disease. There may be some favorable data emerging about different imaging strategies, especially for high-risk patients. If those prove to be effective, we can certainly get on board and encourage it.

Dr Chernov is medical director, healthcare quality and policy, Blue Cross and Blue Shield of Texas.Funding Source:None.

Author Disclosures:Mr Mehr reports receiving payment for involvement in the preparation of this article. Ms Zimmerman reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

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

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The Keys to Obtaining Best Value in Non-Small Cell Lung Cancer