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Clinical Policy Title: Advanced non-small cell lung cancer with TKI and PD-1 drugs

Clinical Policy Number: 05.02.11

Effective Date: March 1, 2017

Initial Review Date: February 15, 2017

Most Recent Review Date: January 11, 2018

Next Review Date: January 2019

Related policies:

CP# 05.02.04 Immunotherapies for prostate cancer and acute lymphoblastic anemia

CP# 05.01.04 Molecular analysis for targeted therapy for lung cancer

CP# 05.01.05 Molecular targeted therapy

ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas’

clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas’ clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas’ clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas’ clinical policies are not guarantees of payment.

Coverage policy

AmeriHealth Caritas considers the use of therapies for anaplastic lymphoma kinase (ALK) mutations,

namely alectinib (Alecensa®), brigatinib (Alunbrig®), ceritinib (Zykadia®), and crizotinib (Xalkori®), to be

medically necessary when all of the following are present:

Advanced non-small cell lung cancer (NSCLC).

A positive test for an ALK gene mutation, or for the ROS1 gene mutation (crizotinib [Xalkori]

only).

Patient at least 18 years of age.

Requested indication supported by National Comprehensive Cancer Network (NCCN) Category

1 or 2A level of evidence. If the request is for a Category 2B recommendation, then medical

documentation has been provided to explain why member cannot utilize a treatment regimen

with a higher level of evidence (e.g., allergic reaction or contraindication).

Documentation of results of genetic testing where required per drug package insert.

Policy contains:

Non-small cell lung cancer (NSCLC).

Programmed death 1 (PD-1) receptor

immunotherapies.

Tyrosine kinase inhibitor (TKI).

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Documentation of results of all required laboratory values and patient-specific information

(e.g., weight, ALT/AST, and creatinine kinase) when recommended or required per drug

package insert.

Medication prescribed at a dose within U.S. Federal Drug Administration (FDA)-approved or

NCCN guidelines.

Oncologist prescriber.

AmeriHealth Caritas considers the use of therapies for epidermal growth factor receptor (EGFR) mutations,

namely erlotinib (Tarceva®), gefitinib (Iressa®), afatinib (Gilotrif®), and osimertinib (Tagrisso®), to be

medically necessary when ALL of the above criteria are present, with the following exceptions:

Presence of a positive test for an EGFR mutation, as opposed to an ALK or ROS1 mutation.

(For osimertinib only) Presence of the T790M genetic mutation.

AmeriHealth Caritas considers the use of programmed death 1 (PD-1) receptor immunotherapies

nivolumab (Opdivo®), pembrolizumab (Keytruda®) and programmed death-ligand 1 (PD-L1) atezolizumab

(Tecentriq®) to be medically necessary when ALL of the following are present:

Advanced NSCLC.

Treatment given as monotherapy.

Patient at least 18 years of age.

Metastatic NSCLC tumors express PD-L1 (TPS > 1 percent), with disease progression on or after

platinum-containing chemotherapy (pembrolizumab only)

Requested indication supported by NCCN Category 1 or 2A level of evidence. If the request is

for a Category 2B recommendation, then medical documentation has been provided as to why

member is unable to utilize a treatment regimen with a higher level of evidence (e.g., allergic

reaction or contraindication).

Documentation results of genetic testing where required per drug package insert.

Documentation results of all required laboratory values and patient-specific information (e.g.,

weight, ALT/AST, and creatinine kinase) when recommended or required per drug package

insert.

Medication prescribed at a dose that is within FDA-approved or NCCN guidelines.

Oncologist prescriber (Masters, 2015; NCCN, 2016; Hanna, 2017).

AmeriHealth Caritas considers the use of necitumumab (Portrazza®) to be medically necessary for advanced

squamous NSCLC, in combination with chemotherapies gemcitabine and cisplatin.

Limitations:

All other targeted therapies or immunotherapies for advanced NSCLC are considered investigational or

experimental and not medically necessary.

Alternative covered services:

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Various forms of platinum-based chemotherapy.

Background

Despite the dramatic decline in tobacco use during the past half-century, lung cancer had the second

largest number of newly-diagnosed cases in the United States during 2017, with an estimated number of

222,500 (breast cancer had an estimated 255,180). Lung cancer caused the most deaths of any form of

cancer, with an estimated 160,420 deaths in 2017 — far more than the total of the next three most

common cancers combined (breast, colorectal, and prostate).

Lung cancer survival has historically been poor. The five-year survival rate has only risen from 12.2 to 19.5

percent between patients diagnosed in 1975 – 1977 and 2007 – 2013. Low survival rates are largely due to

the fact that 57 percent of recent cases are categorized as “distant” or metastatic (Stage IV); the current

five-year survival rate for metastatic lung cancer patients is just 4.5 percent, only slightly higher than the

1.9 percent figure 20 years earlier (Howlader, 2017). Because metastatic cancer has spread to multiple sites

before diagnosis, the only appropriate treatment is chemotherapy, which has experienced little success in

controlling the spread of the disease and is often toxic to patients.

About 85 percent of all lung cancers are classified as NSCLC. In recent years, researchers have identified

novel means of treating advanced NSCLC. One of these is “targeted therapy,” a chemical in pill form

designed to be far less toxic than traditional, systemic chemotherapy. Targeted therapy works only on

patients confirmed with specific mutations. One of these mutations is the EGFR-positive gene’s exon 19, 20,

or 21. These mutations are found in about 15 percent of NSCLC patients in the United States, including

about 10 percent of Caucasians and up to 50 percent of Asians (Hirsch, 2009).

In 2003, gefitinib (Iressa) was approved by the FDA for use after chemotherapy; a second targeted therapy

was approved in 2004 (erlotinib [Tarceva]). These were considered first-generation treatments. By 2005,

the FDA withdrew its approval for gefitinib, due to lack of proof it extended life, but reinstated approval as

a first-line treatment for NSCLC in 2015. In 2013, the FDA approved the targeted therapy afatinib (Gilotrif),

considered a second-generation treatment.

Because lung cancer cells inevitably mutate even when targeted therapy is used, new trials were conducted

for these new mutations. About 50 percent of patients on an EGFR-Tyrosine Kinase Inhibitor developed the

T790M mutation. In November 2015, a fourth targeted therapy (and the first to work effectively against the

T790M mutation) was approved (osimertinib [Tagrisso]), a third-generation treatment which can be used as

first-line or second-line therapy. Osimertinib was fast-tracked by the FDA, which gave approval after only a

Phase II clinical trial (Le, 2017). Other targeted therapies are now in various stages of clinical trials but as of

November 2017 are not yet approved by the FDA.

In addition to targeted therapy, a more recent method of treating advanced NSCLC known as

immunotherapy targeting the PD-1 receptor has emerged. Three drugs were approved by the FDA in March

2015, October 2015, and October 2016: nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab

(Tecentriq) (Columbus, 2017).

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Other targeted therapies for NSCLC patients with the ALK gene, which is present in 5 percent of NSCLC

patients, have been approved by the FDA. These include alectinib (Alecensa), brigatinib (Alunbrig), ceritinib

(Zykadia), and crizotinib (Xalkori), approved by the FDA in December 2015, April 2014, and August 2011.

One of these (crizotinib) was also approved by the FDA in March 2016 for the ROS1 mutation, in

combination with platinum chemotherapy; the ROS1 mutation is only found in 1 percent of NSCLC patients

(NCI, 2017).

The above therapies are for adenocarcinoma cases. The other type of NSCLC, squamous cell carcinoma, has

one targeted therapy (necitumumab, or Portrazza), approved by the FDA in November 2015 (FDA, 2015). As

of this writing, there are no approved targeted therapies for small-cell lung cancer.

Other targeted and immunotherapies are being used outside the United States. One such drug is icotinib,

which is commonly used to treat advanced NSCLC in China.

NCCN 2017 guidelines recommend specific treatments for NSCLC patients, according to whether they test

positive for the EGFR mutation (exon 19, 20, and 21). For those testing positive, the drugs gefitinib,

erlotinib, or afatinib are recommended. If a patient progresses on one of these drugs and then tests

positive for the T790M mutation, the drug osimertinib can be used (Ettinger, 2017). There was no third-line

TKI therapy recommended, if progression has been demonstrated for one or two TKIs, as osimertinib had

not yet been approved by the FDA. For EGFR-negative patients, NCCN recommends nivolumab

immunotherapy as second-line treatment for metastatic squamous and non-squamous NSCLC when disease

has progressed with platinum-based chemotherapy (pembrolizumab for those with a PD-L1 score of 50

percent or greater). For ALK-positive patients, the NCCN guidelines recommend alectinib (Alecensa),

ceritinib (Zykadia), or crizotinib (Xalkori); no mention is made of the ROS1 mutation and crizotinib.

The American Society of Clinical Oncology 2015 practice guideline for Stage IV NSCLC includes:

1. Treatment for patients with no pertinent mutations. For patients with performance status 0 to 1

and appropriate patient cases with PS 2 and without an EGFR-sensitizing mutation or ALK gene

rearrangement, combination cytotoxic chemotherapy is recommended, with early concurrent

palliative care. Chemotherapy includes platinum-doublet therapy for those with PS 0 to 1

(bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); and

combination, single-agent chemotherapy or palliative care alone for those with PS 2.

2. Treatment for patients with certain mutations. Afatinib, erlotinib, or gefitinib is recommended for

those with sensitizing EGFR mutations, and crizotinib can be used for those with ALK or ROS1 gene

rearrangement, and can be used following first-line recommendations or using platinum plus

etoposide for those with large-cell neuroendocrine carcinoma.

3. Pemetrexed as maintenance therapy. Pemetrexed continuation for patients with stable disease or

response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a

chemotherapy break is recommended.

4. Second-line treatments. In the second-line setting, recommendations include docetaxel, erlotinib,

gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or

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gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK

rearrangement who experience progression after crizotinib.

5. Third-line treatments. In the third-line setting, for patients who have not received erlotinib or

gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend

routine third-line cytotoxic therapy (Masters, 2015).

In October 2017, the American Society for Clinical Oncology updated its guideline, adding the following:

1. First-line treatment. For NSCLC patients with no mutations for which FDA-approved targeted

therapy exists, pembrolizumab should be used if the PD-L1 is high, and standard chemotherapy

offered if the ligand is low.

2. Second-line treatments after first-line chemotherapy. For NSCLC patients with a positive PD-L1

expression and no prior immune checkpoint inhibitor, single-agent nivolumab, pembrolizumab, or

atezolizumab is recommended. If the tumor has negative or unknown PD-L1 expression, clinicians

should use nivolumab or atezolizumab.

3. Second-line treatments after first-line immune checkpoint inhibitor. For NSCLC patients who

received a first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy.

4. Second-line treatments after first-line chemotherapy. For patients who cannot receive an immune

checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with

nonsquamous NSCLC, pemetrexed is recommended.

5. Second-line treatment after first-line targeted therapy. For NSCLC patients with a sensitizing EGFR

mutation and disease progression after first-line tyrosine kinase inhibitor therapy, osimertinib is

recommended for those with the T790M mutation, and chemotherapy for those without.

6. Second-line treatments with ROS1 gene rearrangement. NSCLC patients with the ROS1 gene

rearrangement without prior crizotinib may be offered crizotinib, or if they previously received

crizotinib, they may be offered chemotherapy.

7. Fourth-line treatments. Fourth line treatments that can be offered include experimental therapy,

clinical trials, or palliative care (Hanna, 2017).

The American College of Chest Physicians has a 2013 guideline that only recommends two targeted

therapies (and no immunotherapies) for Stage IV lung cancer patients with EGFR mutations, as does a 2015

National Institute for Health and Care Excellence guideline (Socinski, 2013; NICE, 2015). However,

guidelines even a few years old must be cautiously interpreted, as the state of knowledge on new

treatments for NSCLC is changing rapidly.

Searches

AmeriHealth Caritas searched PubMed and the databases of:

UK National Health Services Centre for Reviews and Dissemination.

Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other

evidence-based practice centers.

The Centers for Medicare & Medicaid Services (CMS).

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We conducted searches on November 17, 2017. Search terms were: “afatinib,” “erlotinib,” “gefitinib,”

“osimertinib,” “atezolizumab,” “nivolumab,” “pembrolizumab,” “alectinib,” “ceritinib,” “crizotinib,”

“necitumumab,” “brigatinib,” “TKI,” and “PD-1.”

We included:

Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and

greater precision of effect estimation than in smaller primary studies. Systematic reviews use

predetermined transparent methods to minimize bias, effectively treating the review as a

scientific endeavor, and are thus rated highest in evidence-grading hierarchies.

Guidelines based on systematic reviews.

Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple

cost studies), reporting both costs and outcomes — sometimes referred to as efficiency studies

— which also rank near the top of evidence hierarchies.

Findings

TKI for targeted therapy of EGFR mutations — first and second generation:

On November 1, 2016, the Institute for Clinical and Economic Review (ICER) released a report on the clinical

necessity and value of therapies for NSCLC (ICER, 2016). It identified 11 major trials of TKI (afatinib,

erlotinib, and gefitinib, but not osimertinib) as monotherapy vs. platinum-based chemotherapy for EGFR-

positive patients, most of whom had a median age of late 50s to early 60s, and were Asian never-smokers.

The review found several consistent patterns, which are also found in the Summary of Clinical Evidence

section:

1. The Objective Response Rate (ORR) was higher for TKI drugs, ranging from 56 – 67 percent

(afatinib), 62 – 85 percent (gefitinib), and 42 – 83 percent (erlotinib), vs. 15 – 47 percent for

chemotherapy.

2. Higher progression-free survival (PFS) for TKI groups (median PFS 9.2 to 14.5 months, vs. 4.6 to 6.9

months for chemotherapy).

3. Insignificant overall survival (OS) differences (due to a 45 to 90 percent crossover rate after TKI

stopped working).

The ICER report (finished early June 2016) could not include subsequent findings in the literature. A number

of meta-analyses and systematic reviews consistently found that TKI treatment vs. chemotherapy for

advanced NSCLC had better ORR and PFS, with no difference in OS. These reviews also showed no

significant difference in outcomes for any particular TKI (Haspinger, 2014; DesGuetz, 2016; Haaland, 2014;

Popat, 2014; Greenhalgh, 2016). Some meta-analyses and systematic reviews of TKI vs. chemotherapy

found particular patterns, namely:

1. TKI improved ORR, OS, and PFS more for the exon-19 deletion vs. the exon-21 L858R mutation

(Zhang, 2016).

2. Combination TKI and chemotherapy showed improved outcomes compared to only chemotherapy

(LaSalvia, 2016).

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3. TKI (compared to chemotherapy) is more effective for never-smokers, exon-19 deletions, and

Asians (Hasegawa, 2015).

4. TKI (compared to chemotherapy) improved outcomes more for never-smokers (Sohm, 2015).

5. TKI was more effective for patients with mutant tumors, but not EGFR wild-type tumors (Li, 2016).

A systematic evaluation and meta-analysis of 15 studies (n = 2304) of icotinib, a TKI drug commonly used in

China but in no other nation, found an ORR of 40.99 percent; a disease control rate (DCR) of 77.16 percent;

an average PFS of 7.34 months, and an average OS of 14.98 months. In patients with EGFR mutations given

icotinib, better results were observed in ORR (3.67), DCR (OR 1.39), and PFS (11.0 vs. 1.97 months)

(Biaoxue, 2016).

The most recent meta-analyses and systematic reviews for TKI drugs include a meta-analysis of 10 studies

(n = 2703) comparing gefitinib and the chemotherapy drug docetaxel. Although the disease control rate

was an insignificant nine percent greater in the gefitinib group, this group showed significantly greater

improvements than docetaxel for quality of life and a lower rate of grade 3 – 4 adverse events (Wang B,

2017). A meta-analysis of six studies (n = 1,231) compared gefitinib and erlotinib with chemotherapy for a

median 35.0 months follow-up, and found no difference in overall OS between targeted therapy and

chemotherapy. Subjects given the targeted drugs had a significantly prolonged PFS (p < .001), but, following

disease progression, those in the targeted group had a shorter OS than those given chemotherapy (12.8

versus 19.8 months) (Lee, 2017a).

A meta-analysis of 43 studies (n = 7,168) showed the median PFS rates for gefitinib, erlotinib, and icotinib

were 5.48, 5.15, and 5.81 months, respectively, and median OS was 13.26, 13.52, and 12.58 months. Many

other measures were not significantly different between the groups, leading authors to conclude that

efficacy is essentially similar (Liu, 2017).

A meta-analysis of 24 studies (n = 6,196) compared erlotinib doublet therapy with erlotinib monotherapy.

Those in the combination group had significantly greater response rates, PFS, and disease control rates; the

higher OS was not significant (Gao, 2017).

The second-generation TKI drug afatinib, developed a decade after erlotinib and gefitinib, was also the

topic of systematic reviews. A meta-analysis of 90 studies (n = 17,621) documented no convincing evidence

that afatinib was more effective than gefitinib or erlotinib as a first-line therapy, but was more effective

then erlotinib as a second-line treatment of advanced squamous cell carcinoma (Yang Z, 2017). A meta-

analysis of five studies (n = 545) assessed patients who progressed on erlotinib or gefitinib, then were given

afatinib. Despite a response rate of 12 percent and a disease control rate of 60 percent, authors state that

afatinib can be a useful second-line treatment after failure of TKI (Zhang, 2017).

A meta-analysis of 16 trials (n = 2535) comparing three TKI drugs to chemotherapy or placebo showed toxic

deaths were rare (1.7 percent). The discontinuation rate for afatinib was similar to earlier TKI drugs. Among

afatinib patients, the risk of rash (84.8 percent) and diarrhea (91.7 percent) were significantly higher (p <

.01) than for erlotinib or gefitinib (Ding, 2017).

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PD-1 and PD-L1 drugs for immunotherapy:

The ICER report also reviewed four trials of PD-1 immunotherapy (nivolumab and pembrolizumab) and PD-

L1 immunotherapy (atezolizumab), compared with chemotherapy (docetaxel). Most subjects had non-

squamous NSCLC, were non-Asians, and were current or prior smokers. Two trials each involved previously

treated or untreated patients. Results consistently showed:

No significant PFS differences in any study between PD-1 and chemo groups.

Higher OS for PD-1 (two of four significant); benefits EGFR group (HR = 0.66), not EGFR+ (HR =

1.12).

Significantly fewer adverse events (AE) for PD-1 group for all studies.

Higher doses of pembrolizumab improved results in one study, when PD-L1 is > 50 percent

(over half of cancer cells express the PD-L1 ligand).

No evidence from randomized trials comparing PD-1 (as a first-line therapy) to platinum

chemotherapy, but it would be expected to perform no worse as a second-line therapy.

For EGFR+ advanced NSCLC patients who progressed after TKI therapy, no evidence that PD-1

immunotherapy is equal to or better than platinum-based chemotherapy doublet.

The literature also contains meta-analyses and systematic reviews for PD-1 immunotherapy. Compared to

docetaxel, PD-1 immunotherapy had a superior OS (Zhou, 2016; Lee, 2017b), and this outcome was

especially positive in patients with no EGFR mutations and with high PD-L1 scores (Melosky, 2016; Aguiar,

2016). A meta-analysis of 102 randomized trials (n = 36,058) determined nivolumab was 31 percent more

effective than docetaxel and the three first- and second-generation TKIs in OS, a finding consistent for

pembrolizumab, atezolizumab, and pemetrexed plus erlotinib (Crequit, 2017).

A systematic review of 15 publications of patients with advanced NSCLC reviewing outcomes and safety

found significantly improved OS for second-line nivolumab (p < .001), atezolizumab (p = .0003) or

pembrolizumab (p = .0008 and p < .0001 for 2 and 10 mg/kg, respectively), compared to chemotherapy.

The rate of adverse events was mostly higher in subjects undergoing chemotherapy (Ellis, 2017).

A systematic review of 23 studies compared efficacy and safety of PD-1 patients (n = 3,284) and PD-L1

patients (n = 2,460), each of whom had NSCLC. Response rates were similar (19.0 versus 18.6 percent), as

were adverse event rates (64.0 versus 66.0 percent) (Pillai, 2017).

A meta-analysis compared 12 trials (n = 3,232) with PD-1 inhibitors to seven trials (n = 1,806) with PD-L1

inhibitors. Subjects taking PD-1 inhibitors had significantly higher incidence of any grade pneumonitis

compared with PD-L1 inhibitors (3.6 versus 1.3 percent, p < .001), along with grade 3 – 4 pneumonitis

(Khunger, 2017).

A systematic review of four studies (n = 3425) compared outcomes for patients with advanced NSCLC or

melanoma who received 2 versus 10 mg/kg of pembrolizumab every three weeks. There were no significant

differences in response rate, or side effects including rash, vitiligo, diarrhea, hypothyroidism, hepatitis or

elevated transaminases, nephritis, or pneumonitis (Abdel-Rahman, 2016).

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One meta-analysis compared outcomes for two of the PD-1 treatments for NSCLC. In three randomized

trials (n = 1,887) comparing pembrolizumab and nivolumab, no significant difference was observed in

response rates and PFS, although the rate of adverse effects of grade 3 or higher was elevated in patients

taking pembrolizumab (Peng, 2017).

Other meta-analyses and systematic reviews of PD-1 and PD-L1 therapy combine lung with other cancers,

and thus results may not be applicable to this policy.

Osimertinib (first FDA-approved third-generation TKI drug):

The most recent TKI drug approved by the FDA for advanced NSCLC in EGFR+ patients (osimertinib) is the

topic of a growing number of peer-reviewed journal articles. The first such article of a Phase I trial known as

AURA (n = 222) found a 61 percent response rate for patients with the T790M mutation, compared to 21

percent who tested negative. The difference in median PFS was greater in the T790M-positive group (9.6

months vs. 2.8 months), with increasing toxicity rates at doses above 80 mg per day (Janne, 2015).

Phase II AURA results included a 70 percent ORR to osimertinib, and a median PFS of 13.0 months (Goss,

2016). Another found ORR and median PFS to be 66 percent and 11.0 months (Yang, 2016). The most

recent published trial results of osimertinib of 60 patients found a median PFS of 19.3 months for patients

taking 160 mg, and the PFS was not yet reached (will be greater than 19.3 months) for those taking 80 mg.

Doses needed to be reduced more in the 160 mg group (47 percent) than the 80 mg group (10 percent). PFS

at 18 months was 57 and 53 percent for the 80 mg and 160 mg groups (Ramalingen, 2016).

Recent data on osimertinib addressing Phase III of the AURA trial included an announcement at the

December 2016 meeting showing second-line use of the drug’s improvement in PFS vs. chemotherapy,

namely median PFS of 10.1 vs. 4.4 months for chemotherapy (8.5 vs. 4.2 in patients with brain metastases),

and an HR of 0.30. Adverse events of grade 3 or higher were 3 percent for nausea and decreased appetite

for the chemotherapy group; none in the TKI group exceeded 1 percent (Davenport, 2016).

Perhaps the largest median PFS and response rate for any TKI or PD-1/PD-L1 drug for advanced lung cancer

was recorded in a study of 60 patients who had progressed after first-line TKI treatment, and then given

osimertinib, either with 80 mg/day or 160 mg/day. The medians for these groups were 22.1 and 19.3

months, and response rates were 67 and 87 percent (Ramalingam SS, 2017). No meta-analyses or

systematic reviews have been published on the performance of osimertinib as of November 2017.

Targeted therapy for ALK and ROS1 mutations:

Studies on targeted therapy for ALK and ROS1 mutations also exist. The trial that was the basis for FDA

approval for crizotinib in ALK-positive patients (n = 347) found an increase of median PFS compared to

chemotherapy (7.7 vs. 3.0 months), a 46 percent increase in response rate, but no difference in OS

(Kazandijian, 2014). A meta-analysis found crizotinib had a greater average PFS as a first-line therapy vs. a

second-line therapy (11.28 vs. 8.12 months) for persons with the ALK mutation (Hu, 2016).

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A Phase III multi-national trial on first-line ceritinib (n = 189) vs. chemotherapy ( n =187) for ALK-positive

patients found a higher median PFS for the ceritinib group (16.6 vs. 8.1 months), despite high rates of

diarrhea, nausea, and vomiting (85, 69, and 66 percent) (Soria, 2017). A review of 231 patients showed

mixed results for ceritinib compared to standard chemotherapy. Ceritinib subjects had a higher median PFS

(5.4 versus 1.8 months, p < .0001), and the rates of serious adverse events was 11 percent for both groups;

13 ceritinib patients died of disease progression compared to only five chemotherapy patients (Shaw,

2017).

Although data are still preliminary, alectinib may become the preferred ALK inhibitor. A study of ALK-

positive patients with NSCLC compared those given crizotinib (31), alectinib (28), and both (13). The

response rate was higher in the alectinib-only group compared to crizotinib only (80.8 vs. 66.7 percent).

Alectinib also had longer time to treatment failure and overall survival. Best results occurred in patients

treated first with crizotinib then alectiib (Ito, 2017).

Crizotinib was only approved by the FDA for ROS1-positive NSCLC patients in March 2016, and thus

literature on results is limited. A study from China identified 51 ROS1-positive patients; compared with

chemotherapy, the crizotinib group had a higher response rate (80.0 vs. 40.8 percent), as well as greater

average PFS (294 vs. 179 days). In first-line treatment, the difference in average PFS was even greater (209

vs. 146 days) (Zhang L, 2016).

In 2017, the first systematic reviews and meta-analyses were published for ALK inhibitors. In one meta-

analysis of 11 trials (n = 1924), NSCLC patients given crizotinib showed the percent of serious and fatal

adverse events to be 19.9 and 1.4, both significant at p < .001. No significant differences in rates of either

type of adverse event between first-line crizotinib and chemotherapy were identified (Zhu, 2017). A

systematic review of nine studies and 729 patients calculated the median PFS to 9.17 months. Crizotinib

out-performed chemotherapy in total response rate and disease control rate (p < .00001). No difference

was found between the groups in complete response rate (Wang M, 2017).

Targeted therapy for mutations for squamous cell lung cancer:

Necitumumab (Portrazza) is the only drug FDA-approved for first-line targeted therapy (in combination with

chemotherapy) for metastatic squamous cell lung cancer. It was approved in November 2015 after a trial of

1,093 persons determined that those taking necitumumab plus cisplatin lived longer on average than those

taking gemcitabine and cisplatin — the average OS was 11.5 versus 9.9 (FDA, 2015). Little has been

published on efficacy or adverse events of the drug.

Policy updates:

A total of six guidelines/other and 19 peer-reviewed references were added, and one guideline/other was

removed from this policy.

Summary of clinical evidence:

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Citation Content, Methods, Recommendations

TKI targeted therapies – First and second generation

Yang Z (2017) Comparison of first and second generation TKI inhibitors

Key points:

Meta-analysis of eight randomized trials and 82 cohort studies (n = 17,621).

Gefitinib and erlotinib had similar median PFS (Hazard Ratio 1.00), OS (0.99), response rate (1.05), and disease control rate (0.98).

Gefitinib had higher rates than erlotinib of grade 3 – 4 liver dysfunction.

Gefitinib had fewer cases of dose reduction, treatment discontinuation, and various adverse events such as rash and diarrhea.

Afatinib was not more effective than gefitinib or erlotinib as a first-line treatment.

Afatinib was more effective than erlotinib as second-line treatment of advanced squamous cell carcinoma.

Yang (2015) Afatinib vs. cisplatin + pemetrexed (LUX-Lung 3)

Key points:

89% Stage IV, 72% Asian, 68% never-smoker, median age 61.

Afatinib (n = 230) vs. cisplatin + pemetrexed (n = 115).

Median OS 28.2 months (afatinib) vs. 28.2 months (chemo).

Median PFS 11.1 months (afatinib) vs. 6.9 months (chemo).

Wu (2014) Afatinib vs. cisplatin + gemcitabine (LUX Lung 6)

Key points:

94% Stage IV, 100% Asian, 77% never-smoker, median age 58.

Afatinib (n = 242) vs. cisplatin + gemccitabine (n = 122).

Median OS 23.1 months (afatinib) vs. 23.5 months (chemo).

Median PFS 11.0 months (afatinib) vs. 5.6 months (chemo).

Park (2016) Afatinib vs. gefitinib (LUX-Lung 7)

Key points:

97% Stage IV, 57% Asian, 67% never-smoker, median age 63.

Afatinib (n = 160) vs. gefitinib (n = 159).

Median OS 27.9 months (afatinib) vs. 25.0 months (gefitinib).

Median PFS 11.0 months (afatinib) vs. 10.9 months (gefitinib).

Fukuoka (2011) Gefitinib vs. carboplatin + paclitaxel (IPASS)

Key points:

76% Stage IV, 100% Asian, 94% never-smoker, median age 57.

Gefitinib (n = 132) vs. carboplatin + paclitaxel (n = 129).

Median OS 21.6 months (gefitinib) vs. 21.9 months (chemo).

Median PFS 9.5 months (gefitinib) vs. 6.3 months (chemo).

Inoue (2013) Gefitnib vs. carboplatin + paclitaxel (NEI002)

Key points:

75% Stage IV, 100% Asian, 62% never-smoker, median age 63.

Gefitinib (n = 114) vs. carboplatin + paclitaxel (n = 114).

Median OS 27.7 months (gefitinib) vs. 26.6 months (chemo).

Median PFS 10.8 months (gefitinib) vs. 5.4 months (chemo).

Yoshioka (2014) Gefitinib vs. cisplatin + docetaxel (WJTOG3405)

Key points:

48% Stage IV, 100 Asian, 69% never-smoker, median age 64.

Gefitinib (n = 86) vs. cisplatin + docetaxel (n = 86).

Median OS 34.8 months (gefitinib) vs. 37.3 months (chemo).

Median PFS 9.2 months (gefitinib) vs 6.3 months (chemo).

Han (2012) Gefitinib vs. cisplatin + gemcitabine (First-Signal)

Key points:

90% Stage IV, 100% Asian, 100% never-smoker, median age 57.

Gefitinib (n = 26) vs. cisplatin + gemcitabine (n = 16).

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Median OS 27.2 months (gefitinib) vs. 25.6 months (chemo).

Median PFS 8.0 months (gefitinib) vs. 6.3 months (chemo).

Costa (2014) Erlotinib vs. cisplatin + gemcitabine/docetaxel (EURTAC)

Key points:

92% Stage IV, 0% Asian, 69% never-smoker, median age 65.

Erlotinib (n = 86) vs. cisplatin + gemcitabine/docetaxel (n = 87).

Median OS 22.9 months (erlotinib) vs. 22.1 months (chemo).

Median PFS 10.4 months (erlotinib) vs. 5.1 months (chemo).

Wu (2015) Erlotinib vs. cisplatin + gemcitabine (ENSURE)

Key points:

92% Stage IV, 100% Asian, 71% never-smoker, median age 57.

Erlotinib (n = 110) vs. cisplatin + gemcitabine (n = 107).

Median OS 26.3 months (erlotinib) vs. 25.5 months (chemo).

Median PFS 11.0 months (erlotinib) vs. 5.5 months (chemo).

Zhou (2015) Erlotinib vs. carboplatin + gemcitabine (OPTIMAL)

Key points:

90% Stage IV, 100% Asian, 71% never-smoker, median age 58.

Erlotinib (n = 82) vs. carboplatin + gemcitabine (n = 72).

Median OS 22.8 months (erlotinib) vs. 27.2 months (chemo).

Median PFS 13.1 months (erlotinib) vs. 4.6 months (chemo).

Gridelli (2012) Erlotinib vs. cisplatin + gemcitabine (TORCH)

Key points:

89% Stage IV, 3% Asian, 21% never-smoker, median age 62.

Erlotinib (n = 20) vs. cisplatin + gemcitabine (n = 19).

Median OS 18.1 months (erlotinib) vs. 32.5 months (chemo).

Median PFS 9.7 months (erlotinib) vs. 6.9 months (chemo).

TKI targeted therapies – 3rd generation

Ramalingam (2017) Progression free survival of osimertinib, by dose

Key points:

Clinical trial of 60 persons with NSCLC and T790M mutation given osimertinib (80 or 160 mg daily).

Data cutoff date was November 1, 2016; median follow-up 19.1 months.

Response rates were 67% and 87% for 80 mg/day and 160 mg/day groups.

Median PFS was 22.1 months and 19.3 months for 80 mg/day and 160 mg/day groups — highest to date of any TKI drug for NSCLC.

Of 38 patients with post-progression plasma samples, half had no detectable circulating tumor DNA.

Ramalingam (2016) Expansion cohort of the AURA trial of osimertinib, first-line therapy, by dose

Key points:

Stage IIIB/IV lung cancer, 30 given 80 mg/day, 30 given 160 mg/day.

Cutoff date January 4, 2016; patients followed 16.6 months median.

Overall response rate 67% (80 mg) and 87% (160 mg).

PFS at 18 months 57% (80 mg) and 53% (160 mg).

Median PFS 19.3 months (160 mg); PFS for 80 mg group not yet reached.

Dose was reduced in 10% of 80 mg group, 47% of 160 mg group.

Most common Grade 3+ AEs for 160 mg group were diarrhea (7%), stomatitis (3%), and paronychia (7%); 0% reported for 80 mg group.

Goss (2016) Osimertinib for patients who had progressed on a TKI (AURA 2 study)

Key points:

Stage IIIB/IV lung cancer, 199 given 80 mg/day (n = 199).

Enrollment from May 20, 2014, to September, 12 2014, cutoff date November 1, 2015, median follow-up 13.0 months.

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Response rate 70% (3% complete, 67% partial).

Serious AEs in 25% of patients (11% related to osimertinib).

Janne (2015) Osimertinib for patients who had progressed on a TKI (AURA 1 study)

Key points:

Stage IIIB/IV lung cancer patients, n = 222.

Subjects given doses of 20, 40, 80, 160, and 240 mg/day.

ORR 51% (61% with T790M mutation, 21% without T790 mutation).

Median PFS = 9.6 months (with T790), 2.8 months (without T790).

Higher rate of toxicities at 160, 240 mg/day.

PD-1 Immunotherapies

Crequit (2017) Comparison of PD-1 and PD-L1 immunotherapy with chemotherapy

Key points:

Systematic review and meta-analysis of 102 randomized trials (n = 36,058).

Nivolumab had a better OS than docetaxel (HR 0.69), pemetrexed (HR 0.67), erlotinib (0.68), and gefitinib (0.66).

Pembrolizumab, atezolizumab, and pemetrexed plus erlotinib had significantly higher OS than docetaxel, pemetrexed, erlotinib, and gefitinib.

For PFS, erlotinib plus cabozantinib was more effective than docetaxel (HR 0.39), pemetrexed (0.38), erlotinib (0.37), and gefitinib (0.38).

Cabozantinib and pemetrexed plus erlotinib were also significantly more effective than the four recommended treatments.

Authors conclude nivolumab, pembrolizumab, atezolizumab, and pemetrexed plus erlotinib may be the most effective second-line treatments.

Reck (2016) Pembrolizumab vs. chemotherapy for patients with high levels of PD-L1 expression on tumor cells

Key points:

NSCLC, previously untreated, 82% non-squamous, 8% non-smoker, median age 64, PD-L1 > 50% of cancer cells,142 centers in 16 countries.

N = 154 (pembrolizumab) vs. n = 151 (various types of chemotherapy).

Response rate 44.8% (pem) vs. 27.8% (chemo).

OS at six months = 80.2% (pem) vs. 72.4% (chemo); HR = 0.60.

After median duration of 11.2 months follow-up, median PFS = 10.3 months (pem) vs. 6.0 months (chemo); HR = 0.50.

Treatment-related AE 3 – 5 was 26.6% (pem) vs. 53.3% (chemo).

Herbst (2016) Pembrolizumab vs. docetaxel (KEYNOTE-010)

Key points:

NSCLC, 70% non-squamous, 19% never-smokers, previously treated, 202 centers, 24 countries, enrolled August 28, 2013, to February 27, 2015.

N = 345 pembrolizumab 2mg/kg, 346 pembrolizumab 10 mg/kg, 343 docetaxel.

Response rate 18.0% (pem) vs. 9.3% (chemo).

Median PFS 3.9 months (pem-2), 4.0 months (pem-10), 4.0 months (chemo).

Median OS 10.4 months (pem-2), 12.7 months (pem-10), 8.5 moths (chemo).

Median PFS, patients with > 50% of cancer cells expressing PD-L1, 5.0 months (pem-2), 5.2 months (pem-10), 4.1 months (chemo).

Median OS, patients with > 50% of cancer cells expressing PD-L1, 14.9 months (pem-2), 17.3 months (pem-10), 8.2 months (chemo).

Grade 3 – 5 adverse events 13% (pem-2), 16% (pem-10), 35% (chemo).

Fehrenbacher (2016) Atezolizumab vs. docetaxel (POPLAR)

Key points:

NSCLC, 66% non-squamous, 20% never-smokers, previously treated, 61 medical centers, 13 European/N. American countries, enrolled August 5, 2013, to March 31, 2014.

N = 142 atezolizumab, 135 docetaxel with one or more doses.

Response rate 14.6% (atezolizumab) vs. 14.7% (chemo).

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Median OS 12.6 months (atezolizumab) vs. 9.7 months (chemo).

Discontinued from adverse events 8% (atezolizumab) vs. 22% (chemo).

Adverse events grade 3 – 4 11% (atezolizumab) vs. 39% (chemo).

Hazard ratio reduced with presence of tumor cells with PD-L1 expression (1.04 for 0, 0.59 for 1/2/3, 0.54 for 2/3, 0.49 for 3 only).

Borghaei (2015) Nivolumab vs. docetaxel (Checkmate 017)

Key points:

NSCLC, 100% non-squamous, 6% never-smokers, Stage IIIB/IV, previously treated with radiation/surgery (some), doublet platinum chemotherapy (all, progressed), TKI (some).

N = 292 nivolumab, 290 docetaxel.

Response rate 19.2% (nivolumab) vs. 12.4% (chemo).

One year OS 51% (nivolumab) vs. 39% (chemo); 18 month OS 29% and 23%.

Median OS 12.2 months (nivolumab) vs. 9.4 months (chemo).

One year PFS 19% (nivolumab) vs. 8% (chemo).

Median PFS 2.3 months (nivolumab) vs. 4.2 months (chemo).

Treatment-related adverse events 10% (nivolumab) vs. 54% (chemo).

Brahmer (2015) Nivolumab vs. docetaxel (Checkmate 057)

Key points:

NSCLC, 0% non-squamous, 20% never-smokers, Stage IIIB/IV, previously treated with radiation/surgery (some), doublet platinum chemotherapy (all, progressed), TKI (some).

N = 135 (nivolumab), 137 (chemo).

Response rate 20.0% (nivolumab) vs. 8.8% (chemo).

One year OS 42% (nivolumab) vs. 24% (chemo).

Median OS 9.2 months (nivolumab) vs. 6.0 months (chemo).

Median PFS 3.5 months (nivolumab) vs. 2.8 months (chemo).

Treatment-related adverse events 7% (nivolumab) vs. 55% (chemo).

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80.

CMS National Coverage Determinations (NCDs):

No NCDs identified as of the writing of this policy.

Local Coverage Determinations (LCDs):

No LCDs identified as of the writing of this policy.

Commonly submitted codes

Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not

an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill

accordingly.

CPT Code Description Comments

N/A

ICD-10 Code Description Comments

C34.0-C34.92 Non-small cell lung neoplasm

HCPCS

Level II Code Description Comments

J9299 Injection, nivolumab (Opdivo®)

J9271 Injection, pembrolizumab, 1 mg