Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update

Two trials reported significant differences for OS or median survival in the second-line setting.

“Two trials reported significant differences for OS or median survival.”

Fifteen trials reported significant differences for PFS or TTP in the second-line setting.

“Fifteen trials reported significant differences for PFS or TTP.”

Six trials reported significant differences for OS or median survival.

“Six trials reported significant differences for OS or median survival.”

A total of 87 publications concerning 73 phase III RCTs met the systematic review eligibility criteria and form the evidentiary basis for the guideline recommendations.

“A total of 87 publications concerning 73 phase III RCTs met the systematic review eligibility criteria and form the evidentiary basis for the guideline recommendations.”

In the study by Maemondo et al, there were no statistically significant differences in OS between carboplatin plus paclitaxel and gefitinib.

“no statistically significant differences in OS with chemotherapy”

• cites [20] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In the study by Maemondo et al, adverse events occurred at a higher frequency with carboplatin plus paclitaxel than with gefitinib.

“adverse events occurred at a higher frequency with carboplatin plus paclitaxel.”

• cites [20] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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There were 22 trials of second- and third-line therapies.

“There were 22 trials of second- and third-line therapies;”

In the study by Maemondo et al, carboplatin plus paclitaxel resulted in poorer outcomes in PFS and TTP compared with gefitinib.

“In the study by Maemondo et al,20 this regimen resulted in poorer outcomes in PFS and TTP and no statistically significant differences in OS with chemotherapy; adverse events occurred at a higher frequency with carboplatin plus paclitaxel.”

• cites [20] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Eighteen trials reported significant differences for PFS or time to progression (TTP).

“Eighteen trials reported significant differences for PFS or time to progression (TTP).”

Patients with severe comorbidity experienced more thrombocytopenia (46% v 36%; P = .03).

“They also experienced more thrombocytopenia (46% v 36%; P = .03).”

• cites [19] Grønberg BH, Sundstrøm S, Kaasa S, et al. Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy. Eur J Cancer. 2010;46:2225–2234. doi: 10.1016/j.ejca.2010.04.009. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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One trial that included cisplatin plus docetaxel in the control arm did not find the intervention arm (intravenous vinorelbine and oral vinorelbine plus cisplatin) to be superior.

“one trial that included cisplatin plus docetaxel in the control arm and did not find the intervention arm to be superior (intravenous vinorelbine and oral vinorelbine plus cisplatin).69”

• cites [69] Tan EH, Rolski J, Grodzki T, et al. Global Lung Oncology Branch Trial 3 (GLOB3): Final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol. 2009;20:1249–1256. doi: 10.1093/annonc/mdn774. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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A major gap in current evidence is a lack of direct comparisons of platinum plus pemetrexed with or without bevacizumab.

“A major gap in current evidence is a lack of direct comparisons of platinum plus pemetrexed with or without bevacizumab.”

None of the carboplatin regimens listed have shown clear superiority over the others.

“As with the cisplatin regimens, none of the carboplatin regimens listed have shown clear superiority over the others.”

QoL was better with combination therapy in the trial of cisplatin plus gemcitabine versus gemcitabine.

“QoL was also better; however, the trial had low accrual and was stopped early58”

• cites [58] Morabito A, Gebbia V, Di Maio M, et al. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study. Lung Cancer. 2013;81:77–83. doi: 10.1016/j.lungcan.2013.04.008. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Twenty-six of 44 new first-line studies in the updated systematic review included patients with PS 2.

“Twenty6,13,18,27,28,34,36,38,39,44,52,53,55,58,70,79–82 of 44 new first-line studies in the updated systematic review included patients with PS 2.”

In a second trial comparing maintenance pemetrexed plus bevacizumab with bevacizumab alone after first-line induction with bevacizumab, cisplatin, and pemetrexed, the study met its primary end point of statistically significantly longer PFS with bevacizumab plus pemetrexed (7.4 v 3.7 months; HR, 0.48; 95% CI, 0.35 to 0.66; P < .001).

“A second trial33 compared maintenance pemetrexed plus bevacizumab with bevacizumab alone (after first-line induction with bevacizumab, cisplatin, and pemetrexed). The study met its primary end point of statistically significantly longer PFS with bevacizumab plus pemetrexed (7.4 v 3.7 months; hazard ratio [HR], 0.48; 95% CI, 0.35 to 0.66; P < .001).”

• cites [33] Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non–small-cell lung cancer: AVAPERL (MO22089) J Clin Oncol. 2013;31:3004–3011. doi: 10.1200/JCO.2012.42.3749. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that afatinib study, survival was not significantly longer (16.6 v 14.8 months).

“Survival was not significantly longer (16.6 v 14.8 months).”

• cites [86] sourceNot checked yet

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At the time of study publication, OS had not yet been reached in the trial comparing maintenance pemetrexed plus bevacizumab with bevacizumab alone.

“At the time of study publication, OS had not yet been reached.”

• cites [33] Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non–small-cell lung cancer: AVAPERL (MO22089) J Clin Oncol. 2013;31:3004–3011. doi: 10.1200/JCO.2012.42.3749. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Patients with PS 2 make up fewer than half of patients enrolled onto clinical trials.

“Patients with PS 2 make up fewer than half of patients enrolled onto clinical trials.84”

• cites [84] Sargent DJ, Köhne CH, Sanoff HK, et al. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol. 2009;27:1948–1955. doi: 10.1200/JCO.2008.20.2879. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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Since the publication of the ASCO 2009 guideline and the ASCO EGFR provisional clinical opinion, results from seven trials of first-line EGFR TKIs for patients with EGFR mutations have been published.

“Since the publication of the ASCO 2009 guideline and the ASCO EGFR provisional clinical opinion,59 results from seven trials of first-line EGFR TKIs for patients with EGFR mutations have been published.11,13,29,31,34,36,40”

• cites [11] Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [13] Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/S1470-2045(11)70184-X. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [29] Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. doi: 10.1016/S1470-2045(11)70393-X. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In the three-arm study by Treat et al, there were fewer adverse effects without the platinum agent.

“there were fewer adverse effects (eg, neuropathy) without the platinum agent.”

• cites [73] Treat JA, Gonin R, Socinski MA, et al. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010;21:540–547. doi: 10.1093/annonc/mdp352. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In an interim analysis of the second-line trial comparing crizotinib with chemotherapy, median OS was 20.3 months (95% CI, 18.1 to not reached) for crizotinib versus 22.8 months (95% CI, 18.6 to not reached) for chemotherapy (HR, 1.02; 95% CI, 0.68 to 1.54; P = .54).

“An interim analysis found a median OS of 20.3 months (95% CI, 18.1 to not reached) for crizotinib versus 22.8 months (95% CI, 18.6 to not reached) for chemotherapy (HR, 1.02; 95% CI, 0.68 to 1.54; P = .54).”

• cites [56] Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–2394. doi: 10.1056/NEJMoa1214886. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In PROFILE 1014, survival was not significantly different (P = .36).

“Survival was not significantly different (P = .36).”

• cites [54] Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–2177. doi: 10.1056/NEJMoa1408440. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In a trial comparing vinorelbine plus gemcitabine followed by docetaxel with carboplatin plus paclitaxel, OS and PFS were not statistically significantly different.

“Another trial, in which vinorelbine plus gemcitabine followed by docetaxel was compared with carboplatin plus paclitaxel, found that OS and PFS were not statistically significantly different for efficacy, although the response rate was higher with carboplatin plus paclitaxel; each regimen had different toxicity rates that were higher than the other.74”

• cites [74] Kubota K, Kawahara M, Ogawara M, et al. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: A randomised, open-label, phase III study. Lancet Oncol. 2008;9:1135–1142. doi: 10.1016/S1470-2045(08)70261-4. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that second-line trial, PFS was 7.7 months (95% CI, 6.0 to 8.8) with crizotinib compared with 3.0 months (95% CI, 2.6 to 4.3) with chemotherapy (HR, 0.49; 95% CI, 0.37 to 0.64; P < .001).

“The PFS results were 7.7 months (95% CI, 6.0 to 8.8) with crizotinib compared with 3.0 months (95% CI, 2.6 to 4.3) with chemotherapy (HR, 0.49; 95% CI, 0.37 to 0.64; P < .001).”

• cites [56] Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–2394. doi: 10.1056/NEJMoa1214886. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In a trial comparing docetaxel plus gemcitabine with docetaxel alone, OS showed a statistically significant difference of 1.1 months in favor of the doublet.

“In a trial comparing docetaxel plus gemcitabine with docetaxel alone, the OS results showed a statistically significant difference of 1.1 months in favor of the doublet; the study was closed prematurely.52”

• cites [52] Georgoulias V, Androulakis N, Kotsakis A, et al. Docetaxel versus docetaxel plus gemcitabine as front-line treatment of patients with advanced non-small cell lung cancer: A randomized, multicenter phase III trial. Lung Cancer. 2008;59:57–63. doi: 10.1016/j.lungcan.2007.07.021. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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The updated systematic review identified two small trials specifically comparing single-agent versus combination chemotherapy in patients with PS 2.

“The updated systematic review identified two small trials specifically comparing single agent versus combination chemotherapy in patients with PS 2.”

In the updated systematic review, in the three-arm study by Treat et al, efficacy did not differ between the two platinum-containing arms and the paclitaxel plus gemcitabine arm.

“In the updated systematic review, in the three-arm study by Treat et al,73 although efficacy did not differ between the two platinum-containing arms and the paclitaxel plus gemcitabine arm, there were fewer adverse effects (eg, neuropathy) without the platinum agent.”

• cites [73] Treat JA, Gonin R, Socinski MA, et al. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann Oncol. 2010;21:540–547. doi: 10.1093/annonc/mdp352. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In one small study comparing first-line erlotinib with chemotherapy, there was a PFS benefit with erlotinib (9.7 v 5.2 months; HR, 0.37; 95% CI, 0.25 to 0.54; P < .001).

“In one small study, there was a PFS benefit with erlotinib (9.7 v 5.2 months; HR, 0.37; 95% CI, 0.25 to 0.54; P < .001); OS had not been reached by the time of publication.29”

• cites [29] Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. doi: 10.1016/S1470-2045(11)70393-X. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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One study with PFS as primary outcome compared first-line afatinib with cisplatin plus pemetrexed and showed improvement with afatinib (11.1 v 6.9 months; HR, 0.58; 95% CI, 0.43 to 0.78; P = .001).

“One study, with PFS as primary outcome, compared first-line afatinib with cisplatin plus pemetrexed. The results showed improvement with afatinib (11.1 v 6.9 months; HR, 0.58; 95% CI, 0.43 to 0.78; P = .001).”

• cites [86] sourceNot checked yet

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A prespecified analysis of patients with common EGFR mutations showed a PFS of 13.6 versus 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001).

“A prespecified analysis of patients with these common mutations showed a PFS of 13.6 versus 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001).11”

• cites [11] Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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There is no evidence of any differential effect of histology on treatment for nonplatinum combinations.

“There is no evidence of any differential effect of histology on treatment for nonplatinum combinations.”

One trial of two different doses of bevacizumab in combination with cisplatin plus gemcitabine versus placebo provided updated OS results that were not statistically significantly different.

“One trial of two different doses of bevacizumab in combination with cisplatin plus gemcitabine versus a placebo provided updated OS results (earlier results were reviewed in 2009 guideline). The results were not statistically significantly different and therefore do not provide support for changing the current recommendation.76”

• cites [76] Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: Results from a randomised phase III trial (AVAiL) Ann Oncol. 2010;21:1804–1809. doi: 10.1093/annonc/mdq020. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The trial by Scagliotti et al comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed demonstrated improved OS for patients with SCC treated with cisplatin plus gemcitabine.

“The trial by Scagliotti et al68 comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed demonstrated improved OS for patients with SCC treated with cisplatin plus gemcitabine.”

• cites [68] Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551. doi: 10.1200/JCO.2007.15.0375. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that trial, response rate was higher with carboplatin plus paclitaxel.

“although the response rate was higher with carboplatin plus paclitaxel”

• cites [74] Kubota K, Kawahara M, Ogawara M, et al. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: A randomised, open-label, phase III study. Lancet Oncol. 2008;9:1135–1142. doi: 10.1016/S1470-2045(08)70261-4. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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PROFILE 1014, with 343 participants, reached its primary end point of higher PFS with crizotinib (10.9 v 7 months; HR, 0.454; 95% CI, 0.346 to 0.596; P < .001).

“This trial of 343 participants reached its primary end point of higher PFS with crizotinib (10.9 v 7 months; HR, 0.454; 95% CI, 0.346 to 0.596; P < .001).”

• cites [54] Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–2177. doi: 10.1056/NEJMoa1408440. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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A retrospective review of trials of antimicrotubule plus platinum chemotherapy conducted by SWOG reported no differential effect of histology on treatment.

“A retrospective review of trials of antimicrotubule plus platinum chemotherapy conducted by SWOG reported no differential effect of histology on treatment.85”

• cites [85] Chansky K, Mack P, Crowley J, et al. Chemotherapy outcomes by histologic subtype of non-small cell lung cancer (NSCLC): Analysis of the SWOG database for antimicrotubule-platinum therapy. J Thorac Oncol. 2009;4(suppl 1) doi: 10.1016/j.cllc.2013.06.010. abstr B2.7. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The Cochrane systematic review on chemotherapy and supportive care, updated in 2012, continued to show that chemotherapy and best supportive care versus supportive care alone benefit patients, including those who have PS 2.

“The Cochrane systematic review on chemotherapy and supportive care, updated in 2012, continued to show that chemotherapy and best supportive care versus supportive care alone benefit patients, including those who have PS 2.83”

• cites [83] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2010;5:CD007309. doi: 10.1002/14651858.CD007309.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]Not checked yet

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In a second small study comparing first-line erlotinib with chemotherapy, there was a longer PFS (erlotinib: 13.7 months; 95% CI, 10.6 to 15.3; control: 4.6 months; 95% CI, 4.2 to 5.4; HR, 0.164; 95% CI, 0.11 to 0.26; P < .001).

“In the second small study, which was a publication of an abstract in the provisional clinical opinion, there was a longer PFS (erlotinib: 13.7 months; 95% CI, 10.6 to 15.3; control: 4.6 months; 95% CI, 4.2 to 5.4; HR, 0.164; 95% CI, 0.11 to 0.26; P < .001); OS had not yet been reached.13,14”

• cites [13] Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/S1470-2045(11)70184-X. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [14] Chen G, Feng J, Zhou C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) Ann Oncol. 2013;24:1615–1622. doi: 10.1093/annonc/mdt012. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Most of the trials evaluating chemotherapy options in the first-line setting did not report any differential efficacy in patients with SCC.

“Most of the trials evaluating chemotherapy options in the first-line setting did not report any differential efficacy in patients with SCC.”

There are no results from direct comparative trials of different EGFR TKIs.

“There are no results from direct comparative trials of different EGFR TKIs.”

In the IPASS trial comparing gefitinib with carboplatin plus paclitaxel, a statistically significant PFS was found for all patients treated with gefitinib, including those whose tumors were EGFR mutation positive.

“A statistically significant PFS was found for all patients in the trial treated with gefitinib, including those whose tumors were EGFR mutation positive.61”

• cites [61] Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957. doi: 10.1056/NEJMoa0810699. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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ALK gene rearrangements are identified in a small proportion of newly diagnosed patients with NSCLC (approximately 5%).

“ALK gene rearrangements are identified in a small proportion of newly diagnosed patients with NSCLC (approximately 5%).77,87–89”

• cites [77] Blackhall F, Peters S, Kerr Kea. Prevalence and cinical outcomes for patients with ALK gene rearrangment in Europe: Preliminary results for the European Thoracic Oncology Platform Lungscape Project. Ann Oncol. 2012;23:ix73–ix94. abstr 1670. [Google Scholar] sourceNot checked yet

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• cites [87] Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566. doi: 10.1038/nature05945. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [88] Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–1203. doi: 10.1016/j.cell.2007.11.025. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [89] Camidge DR, Doebele RC. Treating ALK-positive lung cancer: Early successes and future challenges. Nat Rev Clin Oncol. 2012;9:268–277. doi: 10.1038/nrclinonc.2012.43. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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A study published after the close of the date parameters for the systematic review included 50 patients from a second-line crizotinib trial who had ROS1 rearrangements.

“A study78 was published after the close of the date parameters for the systematic review that included 50 patients from a second-line crizotinib trial who had ROS1 rearrangements.”

• cites [78] Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–1971. doi: 10.1056/NEJMoa1406766. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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Evidence was not found in the systematic review to include gemcitabine as a second-line option.

“This recommendation does not include gemcitabine as an option, because evidence was not found in the systematic review.”

An early clinical trial showed a benefit for ramucirumab when administered with docetaxel compared with docetaxel alone, with a 1.4-month OS advantage.

“An early clinical trial showed a benefit for ramucirumab when administered with docetaxel compared with docetaxel alone, with a 1.4-month OS advantage.”

Most second-line studies in the systematic review included patients with SCC.

“Most second-line studies in this systematic review included patients with SCC.”

Most trials in the systematic review did not find differences between docetaxel, erlotinib, gefitinib, and pemetrexed as second-line options for advanced NSCLC.

“Most of the trials in the systematic review did not find differences between the four agents that this guideline presents as second-line options.”

In IFCT 0501, the OS of patients with PS 2 was inferior to that of patients with PS 0 to 1 in multivariable analysis.

“However, the OS of patients with PS 2 was inferior to that of patients with PS 0 to 1 in multivariable analysis.”

• cites [53] Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011;378:1079–1088. doi: 10.1016/S0140-6736(11)60780-0. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that ROS1 study, median duration of response was 17.6 months (95% CI, 14.5 to not reached).

“Median duration of response was 17.6 months (95% CI, 14.5 to not reached).”

• cites [78] Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–1971. doi: 10.1056/NEJMoa1406766. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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In a trial of patients with wild-type EGFR, docetaxel resulted in longer overall survival than erlotinib (8.2 vs 5.4 months; P = .10).

“The participants who received chemotherapy experienced longer OS compared with those who received erlotinib (8.2 v 5.4 months; P = .10).”

• cites [41] Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): A randomised controlled trial. Lancet Oncol. 2013;14:981–988. doi: 10.1016/S1470-2045(13)70310-3. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Multiple trials did not identify age as a pretreatment risk factor for either tolerance or response to treatment with cytotoxic therapy.

“However, multiple trials did not identify age as a pretreatment risk factor for either tolerance or response to treatment with cytotoxic therapy.1”

• cites [1] Azzoli CG, Baker S, Jr, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. 2009;27:6251–6266. doi: 10.1200/JCO.2009.23.5622. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The studies found in the current systematic review included the IFCT 0501 trial, the largest prospective trial to successfully compare a platinum-based combination regimen with single-agent chemotherapy in an elderly population.

“The studies found in the current systematic review included the French multicenter randomized phase III trial Intergroupe Francophone de Cancérologie Thoracique (IFCT) 0501,53 the largest prospective trial to successfully compare a platinum-based combination regimen with single-agent chemotherapy in an elderly population.”

• cites [53] Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011;378:1079–1088. doi: 10.1016/S0140-6736(11)60780-0. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that trial, adverse events were not uniformly less common in one arm versus the other.

“Adverse events were not uniformly less common in one arm versus the other.67”

• cites [67] Pallis AG, Agelaki S, Agelidou A, et al. A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer. 2010;10:633. doi: 10.1186/1471-2407-10-633. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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No data meeting the inclusion criteria were available to inform Clinical Question B3.a.

“Given that there were no data meeting the inclusion criteria to inform this question, the Update Committee relied on clinical experience, training, and judgment to formulate this recommendation.”

• AssumptionThe authors state this as an assumption: For recommendations B3.a and B3.b, clinical experience, training, and judgment are sufficient to formulate recommendations when no data meet inclusion criteria.

In the PARAMOUNT trial, OS was 2.9 months longer with pemetrexed maintenance (13.9 v 11 months; unadjusted HR P = .019).

“OS was 2.9 months longer (13.9 v 11 months; unadjusted HR P = .019).”

• cites [7] Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. 2013;31:2895–2902. doi: 10.1200/JCO.2012.47.1102. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [8] Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): A double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012;13:247–255. doi: 10.1016/S1470-2045(12)70063-3. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In that ROS1 study, median PFS was 19.2 months (95% CI, 14.4 to not reached).

“Median PFS was 19.2 months (95% CI, 14.4 to not reached).”

• cites [78] Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–1971. doi: 10.1056/NEJMoa1406766. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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No data meeting the inclusion criteria were available to inform Clinical Question B3.b.

“Given that there were no data meeting the inclusion criteria to inform this question, the Update Committee relied on clinical experience, training, and judgment to formulate this recommendation.”

• AssumptionThe authors state this as an assumption: For recommendations B3.a and B3.b, clinical experience, training, and judgment are sufficient to formulate recommendations when no data meet inclusion criteria.

There is some evidence that continued chemotherapy may do harm, including the foregoing of advance care planning, palliative care consultation, and early use of hospice.

“there some evidence that continued chemotherapy may do harm, including the foregoing of advance care planning, palliative care consultation, and early use of hospice.”

There is no high-level evidence to guide treatment for patients with ALK mutations who experience disease progression with crizotinib.

“There is no high-level evidence to guide the physician or patient in this situation.”

Palliative care has been associated with equal or longer survival in randomized and nonrandomized trials of patients with advanced cancer.

“In distinction from chemotherapy after the second-line setting, palliative care has been associated with equal103–106 or longer107–109 survival in randomized and nonrandomized110 trials of patients with advanced cancer.”

• cites [103] Gade G, Venohr I, Conner D, et al. Impact of an inpatient palliative care team: A randomized control trial. J Palliat Med. 2008;11:180–190. doi: 10.1089/jpm.2007.0055. [DOI] [PubMed] [Google Scholar]Not checked yet

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• cites [104] Brumley R, Enguidanos S, Jamison P, et al. Increased satisfaction with care and lower costs: Results of a randomized trial of in-home palliative care. J Am Geriatr Soc. 2007;55:993–1000. doi: 10.1111/j.1532-5415.2007.01234.x. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [105] Finn JW, Pienta, Kenneth J, et al. Hospice of Michigan, Detroit; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. Proc Am Soc Clin Oncol. 2002;21(suppl):154s. abstr 1452. [Google Scholar] sourceNot checked yet

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• cites [106] Zimmermann C, Swami N, Krzyzanowska M, et al. Early palliative care for patients with advanced cancer: A cluster-randomised controlled trial. Lancet. 2014;383:1721–1730. doi: 10.1016/S0140-6736(13)62416-2. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [107] Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: The Project ENABLE II randomized controlled trial. JAMA. 2009;302:741–749. doi: 10.1001/jama.2009.1198. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [108] Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733–742. doi: 10.1056/NEJMoa1000678. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [109] Bakitas M, Tosteson T, Li Z, et al. The ENABLE III randomized controlled trial of concurrent palliative oncology care. J Clin Oncol. 2014;32(suppl 5s):605s. doi: 10.1200/JCO.2014.58.6362. abstr 9512. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [110] Lee YJ, Yang JH, Lee JW, et al. Association between the duration of palliative care service and survival in terminal cancer patients. Support Care Cancer. 2014;23:1057–1062. doi: 10.1007/s00520-014-2444-4. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In the intervening years, the method of assessing EGFR expression by immunohistochemistry has not been shown to be feasible.

“In the intervening years, this method of assessing EGFR expression has not been shown to be feasible.”

There is a lack of conclusive data for treating patients with EGFR mutations who progress after a first-line EGFR TKI, especially with a second TKI.

“There is a lack of conclusive data for treating this population, especially with a second TKI.”

In the Gridelli et al trial, crossover prevented analysis of the association of mutation status with OS.

“There was crossover in this study, so the authors could not analyze the association of mutation status with OS.”

• cites [102] Gridelli C, Maione P, Rossi A. The PARAMOUNT trial: A phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. Rev Recent Clin Trials. 2013;8:23–28. doi: 10.2174/15748871112079990040. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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There are no data that suggest a benefit to additional chemotherapy compared with alternative forms of non-chemotherapy-based care, such as hospice or palliative care.

“There are no data that suggest a benefit to additional chemotherapy compared with alternative forms of non–chemotherapy-based care, such as hospice or palliative care.”

Some second-line studies included patients who had received more than two previous regimens.

“Some of the second-line studies included patients who had received > two previous regimens.15,23,47,48,51,65”

• cites [15] Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528–538. doi: 10.1016/S1470-2045(12)70087-6. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [23] Maruyama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non–small-cell lung cancer. J Clin Oncol. 2008;26:4244–4252. doi: 10.1200/JCO.2007.15.0185. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [47] Lee DH, Park K, Kim JH, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16:1307–1314. doi: 10.1158/1078-0432.CCR-09-1903. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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There are no data to suggest that patients with EGFR mutations for whom EGFR TKIs fail do poorly with chemotherapy.

“Given that there are no data to suggest that patients with EGFR mutations for whom EGFR TKIs fail do poorly with chemotherapy, the Update Committee opted to make a consensus recommendation for chemotherapy as a second-line treatment.”

There are no data to suggest that the benefits of continued chemotherapy outweigh the risks.

“There are no data to suggest that the benefits of continued chemotherapy outweigh the risks”

There are no published phase III trials on ceritinib that met inclusion criteria for this systematic review.

“There are no published phase III trials on ceritinib (or other studies that met inclusion criteria for this systematic review).”

There have been no prospective, randomized studies investigating the efficacy of second-line chemotherapy in patients with EGFR mutations who have responded to a first-line EGFR TKI.

“There have been no prospective, randomized studies investigating the efficacy of second-line chemotherapy in patients with EGFR mutations who have responded to a first-line EGFR TKI.”

Disparities in race, sex, socioeconomic status, level of education, residence, and insurance status, among other factors, continue to be associated with outcomes such as mortality, incidence, stage at diagnosis, and timely receipt of recommended treatment for patients with NSCLC.

“The results show that disparities in race,128–131 sex,132 socioeconomic status,132–135 level of education,136 residence,128,136 and insurance status,137–139 among other factors, continue to be associated with outcomes such as mortality,128,140 incidence,137,140 stage at diagnosis, and timely receipt of recommended treatment129,131 for patients with NSCLC.”

• cites [128] Hayanga AJ, Zeliadt SB, Backhus LM. Residential segregation and lung cancer mortality in the United States. JAMA Surg. 2013;148:37–42. doi: 10.1001/jamasurgery.2013.408. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [129] Bryant AS, Cerfolio RJ. Impact of race on outcomes of patients with non-small cell lung cancer. J Thorac Oncol. 2008;3:711–715. doi: 10.1097/JTO.0b013e31817c60c7. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [130] Bergamo C, Lin JJ, Smith C, et al. Evaluating beliefs associated with late-stage lung cancer presentation in minorities. J Thorac Oncol. 2013;8:12–18. doi: 10.1097/JTO.0b013e3182762ce4. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [131] Shugarman LR, Mack K, Sorbero ME, et al. Race and sex differences in the receipt of timely and appropriate lung cancer treatment. Med Care. 2009;47:774–781. doi: 10.1097/MLR.0b013e3181a393fe. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [132] Hardy D, Liu CC, Xia R, et al. Racial disparities and treatment trends in a large cohort of elderly black and white patients with nonsmall cell lung cancer. Cancer. 2009;115:2199–2211. doi: 10.1002/cncr.24248. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [137] Slatore CG, Au DH, Gould MK. An official American Thoracic Society systematic review: Insurance status and disparities in lung cancer practices and outcomes. Am J Respir Crit Care Med. 2010;182:1195–1205. doi: 10.1164/rccm.2009-038ST. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [138] Rasco DW, Yan J, Xie Y, et al. Looking beyond Surveillance, Epidemiology, and End Results: Patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population. J Thorac Oncol. 2010;5:1529–1535. doi: 10.1097/JTO.0b013e3181e9a00f. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [139] Mack JW, Chen K, Boscoe FP, et al. Underuse of hospice care by Medicaid-insured patients with stage IV lung cancer in New York and California. J Clin Oncol. 2013;31:2569–2579. doi: 10.1200/JCO.2012.45.9271. [DOI] [PMC free article] [PubMed] [Google Scholar]Not checked yet

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Most available data regarding MCCs in advanced NSCLC are collected and reported as comorbidity.

“Most available data regarding MCCs in advanced NSCLC are collected and reported as comorbidity.19”

• cites [19] Grønberg BH, Sundstrøm S, Kaasa S, et al. Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy. Eur J Cancer. 2010;46:2225–2234. doi: 10.1016/j.ejca.2010.04.009. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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The data informing chemotherapy decisions for patients with PS 2 are insufficient.

“The data informing chemotherapy decisions for patients with PS 2 are insufficient.”

Few therapeutic trials in advanced NSCLC limited to older adults and those with PS ≥ 2 have reported the specific association of MCCs with toxicity and efficacy of treatment as a distinct end point.

“Although there have been several therapeutic trials in advanced NSCLC that have been limited to these populations, few have reported the specific association of MCCs with toxicity and efficacy of treatment as a distinct end point.”

There are few data regarding the impact of specific chronic conditions on outcomes (chemotherapy-related adverse events and survival) in advanced NSCLC.

“There are few data regarding the impact of specific chronic conditions on outcomes (chemotherapy-related adverse events and survival) in advanced NSCLC.”

The cetuximab trial that used carboplatin plus paclitaxel in both arms lacked the power to determine an OS difference.

“it lacked the power to determine an OS difference.71”

• cites [71] Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non–small-cell lung cancer: Results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28:911–917. doi: 10.1200/JCO.2009.21.9618. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Combination therapy improves outcomes for patients with PS 0 to 1 and appropriate patients with PS 2 who are willing to accept the potential risks.

“Combination therapy improves outcomes for patients with PS 0 to 1 and appropriate patients with PS 2 who are willing to accept the potential risks and is therefore recommended by the Update Committee.”

The guideline recommendations were based on a systematic review of phase III randomized controlled trials.

“An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014.”

• Also stated in: § METHODS · plain

  “The recommendations were developed by an Update Committee with multidisciplinary representation using a systematic review of phase III RCTs and clinical experience.”

Cisplatin was slightly superior in efficacy to carboplatin in meta-analysis.

“Two-drug combinations were superior to single-agent therapy, platinum-based two-drug combinations were slightly superior to nonplatinum combinations in meta-analysis, and cisplatin was slightly superior in efficacy to carboplatin in meta-analysis but perhaps not worth the added toxicity in the palliative care setting.”

Platinum-based two-drug combinations were slightly superior to nonplatinum combinations in meta-analysis.

“Two-drug combinations were superior to single-agent therapy, platinum-based two-drug combinations were slightly superior to nonplatinum combinations in meta-analysis, and cisplatin was slightly superior in efficacy to carboplatin in meta-analysis but perhaps not worth the added toxicity in the palliative care setting.”

The combination of cisplatin and pemetrexed is superior to that of cisplatin and gemcitabine in NSCC.

“the combination of cisplatin and pemetrexed is superior to that of cisplatin and gemcitabine in NSCC.”

• cites Scagliotti et al68Not checked yet

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Addition of bevacizumab to carboplatin and paclitaxel improves OS in select patients with NSCC.

“addition of bevacizumab to carboplatin and paclitaxel improves OS in select patients with NSCC”

Two-drug combinations were superior to single-agent therapy.

“Two-drug combinations were superior to single-agent therapy, platinum-based two-drug combinations were slightly superior to nonplatinum combinations in meta-analysis, and cisplatin was slightly superior in efficacy to carboplatin in meta-analysis but perhaps not worth the added toxicity in the palliative care setting.”

There is overwhelming and consistent evidence now from multiple trials that gefitinib, erlotinib, or afatinib have greater activity than platinum-based chemotherapy in the first-line treatment of patients with advanced NSCLC with activating EGFR mutations.

“There is overwhelming and consistent evidence now from multiple trials that gefitinib, erlotinib, or afatinib have greater activity than platinum-based chemotherapy in the first-line treatment of patients with advanced NSCLC with activating EGFR mutations.”

There were no compelling data regarding any single regimen for first-line treatment of stage IV NSCLC.

“There were no compelling data regarding any single regimen for this population; therefore, clinical judgment should guide the choice of therapy among regimens.”

The availability of these agents and companion diagnostics now makes testing for these mutations a new standard of care.

“The availability of these agents and companion diagnostics now makes testing for these mutations a new standard of care.3”

• cites [3] Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol. 2014;32:3673–3679. doi: 10.1200/JCO.2014.57.3055. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The results of the Scagliotti et al trial suggest that a platinum agent plus pemetrexed should not be administered in patients with SCC.

“The results of this trial suggest that a platinum agent plus pemetrexed should not be administered in patients with SCC, and in fact, licensing in many health care jurisdictions limits the use of pemetrexed for patients with nonsquamous histology.”

• cites [68] Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551. doi: 10.1200/JCO.2007.15.0375. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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The data informing chemotherapy decisions for patients with PS 2 are insufficient to make a strong recommendation favoring combination chemotherapy.

“The data informing chemotherapy decisions for patients with PS 2 are insufficient to make a strong recommendation favoring combination chemotherapy.”

None of the trials found provide support for adding bevacizumab to chemotherapy regimens other than carboplatin plus paclitaxel.

“None of the trials found provide support for adding bevacizumab to chemotherapy regimens other than carboplatin plus paclitaxel.”

The Update Committee believes that carboplatin plus paclitaxel is the only regimen for which the data support the addition of bevacizumab.

“The Update Committee believes that carboplatin plus paclitaxel is the only regimen for which the data support the addition of bevacizumab.”

As of the 2011 guideline update, evidence of improvements in OS and PFS with the addition of bevacizumab to carboplatin plus paclitaxel supported the affirmative recommendation for this combination for patients meeting certain criteria, especially NSCC.

“As of the 2011 guideline update, evidence of improvements in OS and PFS with the addition of bevacizumab to carboplatin plus paclitaxel supported the affirmative recommendation for this combination for patients meeting certain criteria, especially the criterion of having NSCC.”

Since the systematic review was performed, nivolumab has emerged for patients with SCC in the second- and third-line settings who experience progression during or after platinum-based therapy.

“Since the systematic review was performed for this guideline, nivolumab has emerged for patients with SCC in the second- and third-line settings who experience progression during or after platinum-based therapy.100”

• cites [100] sourceNot checked yet

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A phase II trial of single-agent nivolumab in patients with SCC who had received at least two prior regimens had an overall response rate of 14.5% (17 of 117; 95% CI, 8.7 to 22.2).

“The primary end point was overall response rate, which occurred in 17 (14.5%) of 117 patients (95% CI 8.7 to 22.2).”

• cites [98] Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 2015;16:257–265. doi: 10.1016/S1470-2045(15)70054-9. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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In an RCT with 272 participants, median OS was 9.2 months with nivolumab versus 6 months with docetaxel (HR, 0.59; 95% CI, 0.44 to 0.79; P < .001).

“Median OS was 9.2 versus 6 months, favoring nivolumab (HR, 0.59; 95% CI, 0.44 to 0.79; P < .001).”

• cites [101] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135. doi: 10.1056/NEJMoa1504627. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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Clinical trials support the use of single-agent therapy for patients with relapsed nonsquamous NSCLC after first-line chemotherapy.

“Clinical trials support the use of single-agent therapy for patients with relapsed nonsquamous NSCLC after first-line chemotherapy.”

On March 14, 2015, the FDA approved nivolumab for patients with metastatic squamous cell NSCLC with disease progression who had received at least one prior platinum-based regimen.

“On March 14, 2015, the FDA approved nivolumab for the treatment of patients with metastatic squamous cell NSCLC with disease progression who had received ≥ one prior platinum-based regimen”

• cites [101] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135. doi: 10.1056/NEJMoa1504627. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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There is evidence that pemetrexed is less effective for patients whose tumors have SCC histology.

“Because there is evidence that pemetrexed is less effective for patients whose tumors have SCC histology, pemetrexed is included only in the NSCC recommendation (Recommendation B1).”

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On December 12, 2014, the FDA approved ramucirumab in combination with docetaxel for patients with metastatic NSCLC who experience disease progression during or after platinum-based chemotherapy.

“On December 12, 2014, the FDA approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic NSCLC who experience disease progression during or after platinum-based chemotherapy”

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In LUX-Lung 1, 63% of patients in the afatinib group and 76% in the control group received at least one subsequent regimen.

“Sixty-three percent of the patients in the afatinib group and 76% in the control group received ≥ one subsequent regimen (all mutation statuses).15”

• cites [15] Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528–538. doi: 10.1016/S1470-2045(12)70087-6. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In IPASS, among patients with EGFR mutation-positive NSCLC randomly assigned to carboplatin plus paclitaxel, 64.3% subsequently received EGFR TKIs.

“Of patients with EGFR mutation–positive NSCLC who were randomly assigned to carboplatin plus paclitaxel, 64.3% subsequently received EGFR TKIs.”

• cites [30] 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;29:2866–2874. doi: 10.1200/JCO.2010.33.4235. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Current FDA approval allows initial therapy with crizotinib for patients with stage IV NSCLC harboring ALK mutations.

“current FDA approval allows for initial therapy with crizotinib for patients with stage IV NSCLC harboring ALK mutations (see Recommendation A5).”

In the group of 80 patients who had received crizotinib in the Shaw et al report, median PFS was 6.9 months (95% CI, 5.3 to 8.8).

“In the group of 80 patients who had received crizotinib, median PFS was 6.9 months (95% CI, 5.3 to 8.8).”

• cites [42] Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. doi: 10.1056/NEJMoa1311107. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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Other studies have randomly assigned patients with EGFR mutations to a first-line EGFR TKI or cytotoxic chemotherapy and found that PFS was improved in those who received the EGFR TKI.

“Other studies have randomly assigned patients with EGFR mutations to a first-line EGFR TKI or cytotoxic chemotherapy and found that PFS was improved in those who received the EGFR TKI.”

• cites [11] Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [13] Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/S1470-2045(11)70184-X. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [20] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1056/NEJMoa0909530. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In LUX-Lung 1, response rate was 7% versus 0.5%.

“Response rate was 7% versus 0.5%.”

• cites [15] Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528–538. doi: 10.1016/S1470-2045(12)70087-6. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Among 96 patients with EGFR mutation-positive tumors in LUX-Lung 1, PFS was 3.3 months with afatinib and 1.0 month with placebo (HR, 0.55; 95% CI, 0.31 to 0.85; P = .009).

“Among these 96 patients, PFS was 3.3 months for those who received afatinib and 1.0 month for those who received placebo (HR, 0.55; 95% CI, 0.31 to 0.85; P = .009).15”

• cites [15] Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528–538. doi: 10.1016/S1470-2045(12)70087-6. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In the Gridelli et al trial, outcomes were worse with first-line erlotinib followed by an immediate switch to chemotherapy at progression.

“Outcomes were worse with first-line erlotinib, followed by an immediate switch to chemotherapy at progression.”

• cites [102] Gridelli C, Maione P, Rossi A. The PARAMOUNT trial: A phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. Rev Recent Clin Trials. 2013;8:23–28. doi: 10.2174/15748871112079990040. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Cetuximab is not approved by regulatory agencies in the United States, Canada, or Europe for patients with NSCLC.

“Cetuximab is not approved by the regulatory agencies in the United States, Canada, or Europe for patients with NSCLC.”

In the Gridelli et al trial, 13.8% of participants in the intervention arm and 14.6% in the control arm had EGFR mutation-positive disease.

“In the trial by Gridelli et al,102 which was stopped early and is discussed under Recommendation B1, participants were unselected for EGFR mutation status; 13.8% of the participants in the intervention arm and 14.6% in the control arm had EGFR mutation–positive disease.”

• cites [102] Gridelli C, Maione P, Rossi A. The PARAMOUNT trial: A phase III randomized study of maintenance pemetrexed versus placebo immediately following induction first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. Rev Recent Clin Trials. 2013;8:23–28. doi: 10.2174/15748871112079990040. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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Patients whose cancers initially respond to crizotinib often experience a relapse of the disease.

“Patients whose cancers initially respond to crizotinib often experience a relapse of the disease.56”

• cites [56] Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–2394. doi: 10.1056/NEJMoa1214886. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In a subset analysis of the IPASS study, there was no difference in OS between the gefitinib and carboplatin plus paclitaxel arms in either EGFR mutation-positive or EGFR mutation-negative patients.

“A subset analysis of the IPASS study, in which patients with adenocarcinoma of the lung were randomly assigned to receive gefitinib or carboplatin plus paclitaxel, demonstrated no difference in OS in either the EGFR mutation–positive arm or the EGFR mutation–negative arm.”

• cites [30] 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;29:2866–2874. doi: 10.1200/JCO.2010.33.4235. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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At the subsequently approved dose of 750 mg once daily, the response rate with ceritinib was 59% (95% CI, 47 to 70).

“At the subsequently approved dose of 750 mg once daily, the response rate was 59% (95% CI, 47 to 70).”

• cites [42] Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. doi: 10.1056/NEJMoa1311107. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The noncomparative study reported by Kim et al included 163 participants who had received first-line crizotinib and 83 who had not.

“The noncomparative study reported by Kim et al43 included 163 participants who had received first-line crizotinib and 83 who had not.”

• cites [43] Kim DW, Mehra R, Tan DSW. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial. J Clin Oncol. 2014;32(suppl 5s):506s. abstr 8003. [Google Scholar] sourceNot checked yet

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In the Kim et al study, PFS in the population not pretreated with crizotinib was not estimable at the time of presentation.

“PFS in the population of patients who were not pretreated was not estimable at the time of the presentation.”

• cites [43] Kim DW, Mehra R, Tan DSW. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial. J Clin Oncol. 2014;32(suppl 5s):506s. abstr 8003. [Google Scholar] sourceNot checked yet

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In IPASS, OS for patients with EGFR-positive disease was 21.6 months in the gefitinib arm and 21.9 months in the chemotherapy arm (HR, 1.00; 95% CI, 0.76 to 1.33).

“OS for the patients who had EGFR-positive disease was 21.6 months in the gefitinib arm and 21.9 months in the chemotherapy arm (HR, 1.00; 95% CI, 0.76 to 1.33).30”

• cites [30] 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;29:2866–2874. doi: 10.1200/JCO.2010.33.4235. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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In an interim analysis of the Shaw et al report, 12-month OS was 65% for all participants.

“In an interim analysis, 12-month OS was 65% for all participants.42”

• cites [42] Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. doi: 10.1056/NEJMoa1311107. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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The FDA approved ceritinib on the basis of a phase I single-arm trial.

“The FDA approved ceritinib on the basis of a phase I single-arm trial.102b”

• cites 102bNot checked yet

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• AssumptionRests on an assumption: FDA approval is a sufficient basis for including a therapy in a clinical practice guideline recommendation.

The reliability of outcome data from clinical trials for treating index conditions may be limited because their selection criteria may exclude patients with MCCs, creating constraints against making recommendations for care in this heterogeneous patient population.

“As a result, the reliability of outcome data from these studies may be limited, thereby creating constraints against making recommendations for care in this heterogeneous patient population.”

• AssumptionRests on an assumption: The best available evidence for treating index conditions often comes from clinical trials whose study selection criteria may exclude patients with MCCs to avoid potential interaction effects or confounding of results.

Racial, ethnic, and socioeconomic disparities in health care contribute significantly to health disparities in the United States.

“In summary, racial, ethnic, and socioeconomic disparities in health care contribute significantly to health disparities in the United States.”

Hospice use of any type and duration is strongly associated with better overall survival in patients with advanced cancer, including those specifically with lung cancer.

“Hospice use of any type and duration is strongly associated with better OS in patients with advanced cancer,119 including those specifically with lung cancer.120”

• cites [119] Connor SR, Pyenson B, Fitch K, et al. Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symptom Manage. 2007;33:238–246. doi: 10.1016/j.jpainsymman.2006.10.010. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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• cites [120] Saito AM, Landrum MB, Neville BA, et al. Hospice care and survival among elderly patients with lung cancer. J Palliat Med. 2011;14:929–939. doi: 10.1089/jpm.2010.0522. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceNot checked yet

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A cluster RCT published since the provisional clinical opinion, which included participants with NSCLC, showed important improvements in quality of life, symptoms, and caregiver distress.

“In addition, a cluster RCT published since the provisional clinical opinion, which included participants with NSCLC, showed important improvements in QoL, symptoms, and caregiver distress.106”

• cites [106] Zimmermann C, Swami N, Krzyzanowska M, et al. Early palliative care for patients with advanced cancer: A cluster-randomised controlled trial. Lancet. 2014;383:1721–1730. doi: 10.1016/S0140-6736(13)62416-2. [DOI] [PubMed] [Google Scholar] sourceNot checked yet

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