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

Transcription

1 Clinical Policy Title: Advanced non-small cell lung cancer with TKI and PD-1 drugs Clinical Policy Number: Effective Date: March 1, 2017 Initial Review Date: February 15, 2017 Most Recent Review Date: January 11, 2018 Next Review Date: January 2019 Policy contains: Non-small cell lung cancer (NSCLC). Programmed death 1 (PD-1) receptor immunotherapies. Tyrosine kinase inhibitor (TKI). Related policies: CP# CP# CP# Immunotherapies for prostate cancer and acute lymphoblastic anemia Molecular analysis for targeted therapy for lung cancer Molecular targeted therapy ABOUT THIS POLICY: AmeriHealth Caritas Pennsylvania Community HealthChoices has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Pennsylvania HealthChoices 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 Pennsylvania HealthChoices 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 Pennsylvania HealthChoices 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 Pennsylvania HealthChoices clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas Pennsylvania HealthChoices will update its clinical policies as necessary. AmeriHealth Caritas Pennsylvania HealthChoices clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas Pennsylvania HealthChoices 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 0

2 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. 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 Pennsylvania HealthChoices 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 Pennsylvania HealthChoices considers the use of programmed death 1 (PD-1) receptor immunotherapies nivolumab (Opdivo ), pembrolizumab (Keytruda ) and programmed deathligand 1 (PD-L1) atezolizumab (Tecentriq ) to be medically necessary when ALL of the following are present: Advanced NSCLC. 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 Pennsylvania HealthChoices considers the use of necitumumab (Portrazza ) to be medically necessary for advanced squamous NSCLC, in combination with chemotherapies gemcitabine and cisplatin. Limitations: 1

3 All other targeted therapies or immunotherapies for advanced NSCLC are considered investigational or experimental and not medically necessary. Alternative covered services: 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 and 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 EGFRpositive 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 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 2

4 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). 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 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 thirdline 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. 3

5 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 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, 4

6 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 Pennsylvania HealthChoices 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). We conducted searches on November 17, 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 percent (afatinib), percent (gefitinib), and percent (erlotinib), vs 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). 5

7 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). 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 percent; a disease control rate (DCR) of percent; an average PFS of 7.34 months, and an average OS of 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 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 months. Many other measures were not significantly different between the groups, leading authors to conclude that efficacy is essentially similar (Liu, 2017). 6

8 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). 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). 7

9 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). 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 T790Mpositive 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 8

10 (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 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 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 months) for persons with the ALK mutation (Hu, 2016). 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 ALKpositive 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 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 percent), as well as greater 9

11 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 metaanalysis 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: Citation Content, Methods, Recommendations TKI targeted therapies First and second generation Yang Z (2017) Meta-analysis of eight randomized trials and 82 cohort studies (n = 17,621). Comparison of first and second generation TKI Gefitinib and erlotinib had similar median PFS (Hazard Ratio 1.00), OS (0.99), response rate (1.05), and disease control rate (0.98). inhibitors 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) Wu (2014) 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 months (chemo). Median PFS 11.1 months (afatinib) vs. 6.9 months (chemo). 10

12 Citation Afatinib vs. cisplatin + gemcitabine (LUX Lung 6) Park (2016) Afatinib vs. gefitinib (LUX- Lung 7) Fukuoka (2011) Gefitinib vs. carboplatin + paclitaxel (IPASS) Inoue (2013) Gefitnib vs. carboplatin + paclitaxel (NEI002) Yoshioka (2014) Gefitinib vs. cisplatin + docetaxel (WJTOG3405) Han (2012) Gefitinib vs. cisplatin + gemcitabine (First-Signal) Costa (2014) Erlotinib vs. cisplatin + gemcitabine/docetaxel (EURTAC) Wu (2015) Erlotinib vs. cisplatin + gemcitabine (ENSURE) Zhou (2015) Erlotinib vs. carboplatin + gemcitabine (OPTIMAL) Content, Methods, Recommendations 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 months (chemo). Median PFS 11.0 months (afatinib) vs. 5.6 months (chemo). 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 months (gefitinib). Median PFS 11.0 months (afatinib) vs months (gefitinib). 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 months (chemo). Median PFS 9.5 months (gefitinib) vs. 6.3 months (chemo). 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 months (chemo). Median PFS 10.8 months (gefitinib) vs. 5.4 months (chemo). 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 months (chemo). Median PFS 9.2 months (gefitinib) vs 6.3 months (chemo). 90% Stage IV, 100% Asian, 100% never-smoker, median age 57. Gefitinib (n = 26) vs. cisplatin + gemcitabine (n = 16). Median OS 27.2 months (gefitinib) vs months (chemo). Median PFS 8.0 months (gefitinib) vs. 6.3 months (chemo). 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 months (chemo). Median PFS 10.4 months (erlotinib) vs. 5.1 months (chemo). 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 months (chemo). Median PFS 11.0 months (erlotinib) vs. 5.5 months (chemo). 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 months (chemo). Median PFS 13.1 months (erlotinib) vs. 4.6 months (chemo). 11

13 Citation Gridelli (2012) Content, Methods, Recommendations Erlotinib vs. cisplatin + gemcitabine (TORCH) 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 months (chemo). Median PFS 9.7 months (erlotinib) vs. 6.9 months (chemo). TKI targeted therapies 3 rd generation Ramalingam (2017) Progression free survival of osimertinib, by dose 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 Goss (2016) Osimertinib for patients who had progressed on a TKI (AURA 2 study) Janne (2015) Osimertinib for patients who had progressed on a TKI (AURA 1 study) PD-1 Immunotherapies Crequit (2017) Comparison of PD-1 and PD-L1 immunotherapy with chemotherapy Stage IIIB/IV lung cancer, 30 given 80 mg/day, and 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. Stage IIIB/IV lung cancer, 199 given 80 mg/day (n = 199). Enrollment from May 20, 2014, to September, , cutoff date November 1, 2015, median follow-up 13.0 months. Response rate 70% (3% complete, 67% partial). Serious AEs in 25% of patients (11% related to osimertinib). 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. 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). 12

14 Citation Reck (2016) Pembrolizumab vs. chemotherapy for patients with high levels of PD-L1 expression on tumor cells Herbst (2016) Pembrolizumab vs. docetaxel (KEYNOTE-010) Fehrenbacher (2016) Atezolizumab vs. docetaxel (POPLAR) Borghaei (2015) Nivolumab vs. docetaxel (Checkmate 017) Brahmer (2015) Content, Methods, Recommendations 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. 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 = After median duration of 11.2 months follow-up, median PFS = 10.3 months (pem) vs. 6.0 months (chemo); HR = Treatment-related AE 3 5 was 26.6% (pem) vs. 53.3% (chemo). NSCLC, 70% non-squamous, 19% never-smokers, previously treated, 202 centers, 24 countries, enrolled August 28, 2013, to February 27, 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). NSCLC, 66% non-squamous, 20% never-smokers, previously treated, 61 medical centers, 13 European/N. American countries, enrolled August 5, 2013, to March 31, N = 142 atezolizumab, 135 docetaxel with one or more doses. Response rate 14.6% (atezolizumab) vs. 14.7% (chemo). Median OS 12.6 months (atezolizumab) vs. 9.7 months (chemo). Discontinued from adverse events 8% (atezolizumab) vs. 22% (chemo). Adverse events grade % (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). 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). 13

15 Citation Nivolumab vs. docetaxel (Checkmate 057) Content, Methods, Recommendations 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). References Professional society guidelines/other: Astra Zeneca. Tagrisso demonstrates superiority over chemotherapy in EGFR T790M mutation-positive non-small cell lung cancer. Press release. December 6, Accessed November 17, Bristol-Myers Squibb Inc. Bristol-Myers Squibb announces top-line results from CheckMate-026, a Phase III study of opdivo (nivolumab) in treatment-naïve patients with advanced non-small cell lung cancer. Press release, August 5, Princeton, NJ: Bristol-Myers Squibb, Inc. Accessed November 17, Columbus G. Another year of lung cancer advancements expected in 2017? Cancer Updates, Research and Education. February 16, Accessed November 17, Davenport, L. Osimertinib Officially Standard of Care in T790M-Mutated NSCLC. December 6, Accessed November 17, Ettinger DS, Wood DE, Akerley, W, et al. NCCN guidelines insights: non-small cell lung cancer, version J Natl Compr Canc Netw. 2016;14: Ettinger DS, Wood DE, Alsner DL, et al. Non-small cell lung cancer, version J Natl Compr Canc Netw. 2017;15(4): Accessed November 17, Genentech. Genentech s TECTENTRIQ (Atezolizumab) shows significant survival advantage compared to chemotherapy regardless of PD-L1 status in a specific type of lung cancer in Phase III study. Press release, October 8, South San Francisco, CA: Genentech. Accessed November 17,

16 Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(30): Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, , National Cancer Institute. Bethesda MD: Accessed November 16, Institute for Clinical and Economic Review (ICER). Treatment Options for Advanced Non-Small Cell Lung Cancer: Effectiveness, Value, and Value-Based Price Benchmarks. Final Evidence Report and Meeting Summary. November 1, Accessed November 16, Masters GA, Temin S, Azzoli CG, et al. Systematic therapy for Stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(30): Merck Inc. Merck s KEYTRUDA (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Press release, June 16, KEYTRUDA%C2%AE%C2%A0-pembrolizumab-Demonstrates-Superior-Progression-Free-Survival. Kenilworth NJ: Merck, Inc. Accessed November 17, National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Version 3, Non-small cell lung cancer. November 16, Accessed November 17, National Institute for Health and Care Excellence (NICE). Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy. NICE: December 15, Accessed November 17, Powers, V. Early results positive for first-line avelumab in NSCLC. OncLive, December 5, Plainsboro NJ: Intellisphere LLC. Accessed November 17, Socinski MA, Evans T, Gettinger S, et al. Treatment of stage IV non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e341S-68S. 15

17 U.S. Food and Drug Administration (FDA). FDA approves Portrazza to treat advanced squamous nonsmall cell lung cancer. Silver Spring MD: FDA, November 24, Accessed November 17, U.S. National Cancer Institute (NCI). FDA expands approval of ceritinib for ALK-positive non-small cell lung cancer. Bethesda MD: NCI, June 27, Accessed November 17, Peer-reviewed references: Abdel-Rahman O. Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Immunotherapy. 2016;8(12): Aguiar PN Jr, Santoro IL, Tadokoro H, et al. The role of PD-L1 expression as a predictive biomarker in advanced non-small cell lung cancer: a network meta-analysis. Immunotherapy. 2016;8(4): Biaoxue R, Hua L, Wenlong G, Shuanying Y. Efficacy and safety of icotinib in treating non-small cell lung cancer: a systematic evaluation and meta-analysis based on 15 studies. Oncotarget. 2016;7(52): Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-smallcell lung cancer. NEJM. 2015;373(17): Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-smallcell lung cancer. NEJM. 2015;373(2): Costa C, Molina MA, Drozdowskyj A, et al. The impact of EGFR T790M mutations and BIM mrna expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014;20(7): Crequit P, Chaimani A, Yavchitz A, et al. Comparative efficacy and safety of second-line treatments for advanced non-small cell lung cancer with wild-type or unknown status for epidermal growth factor receptor: a systematic review and network meta-analysis. BMC Med. 2017;15(1):193. Des Guetz G, Landre T, Uzzan B, et al. Is there a survival benefit of first-line epidermal growth factor receptor tyrosine-kinase inhibitor monotherapy versus chemotherapy in patients with advanced nonsmall-cell lung cancer? A meta-analysis. Targ Oncol. 2016;11:

18 Ding PN, Lord SJ, Gebski V. Risk of treatment-related toxicities from EGFR Tyrosine Kinase Inhibitors: A meta-analysis of clinical Trials of gefitinib, erlotinib, and afatinib in advanced EGFR-mutated non-small cell lung cancer. J Thorac Oncol. 2017;12(4): Ellis PM, Vella ET, Ung YC. Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review. Clin Lung Cancer. 2017;18(5): e1. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicenter, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030): Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21): Gao JW, Zhan P, Qiu XY, Jin JJ, Lv TF, Song Y. Erlotinib-based doublet targeted therapy versus erlotinib alone in previously treated advanced non-small-cell lung cancer: a meta-analysis from 24 randomized controlled trials. Oncotarget. 2017;8(42): Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced nonsmall-cell lung cancer (AURA2): a multicenter, open-label, single-arm, phase 2 study. Lancet Oncol. 2016;17(12): Greenhalgh J, Dwan K, Boland A, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev. 2016;5:CD Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatingemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol. 2012;30(24): Haaland B, Tan PS, de Castro G, Lopes G. Meta-analysis of first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutations. J Thorac Oncol. 2014;9: Han JY, Park K, Kim SW, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10): Hasegawa Y, Ando M, Maemondo M, et al. The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials. Oncologist. 2015;20(3):