martes, 7 de mayo de 2019

Non-Small Cell Lung Cancer Treatment (PDQ®) 10/10 —Health Professional Version - National Cancer Institute

Non-Small Cell Lung Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

Progressive Stage IV, Relapsed, and Recurrent NSCLC Treatment

Standard Treatment Options for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

Standard treatment options for patients with progressive stage IV, relapsed, and recurrent non-small cell lung cancer (NSCLC) (second-line therapy and beyond) include the following:
  1. Chemotherapy.
  2. Epidermal growth factor receptor (EGFR)-directed therapy.
    1. EGFR-directed therapy after first-line chemotherapy.
    2. EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy.
  3. Anaplastic lymphoma kinase (ALK)-directed tyrosine kinase inhibitors (TKI).
    1. ALK-directed TKI after first-line chemotherapy.
    2. ALK-directed TKI after prior ALK TKI therapy.
  4. ROS1-directed therapy.
  5. BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations).
  6. Immunotherapy.

Chemotherapy

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[1][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[2,3] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.
Docetaxel
Evidence (docetaxel):
  1. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[4,5] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[6]
  2. A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[7] In that analysis, the following was shown:
    • Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
    • Significantly less severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both); however, no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.
Docetaxel plus ramucirumab
Evidence (docetaxel plus ramucirumab):
  1. In a double-blind, placebo-controlled, phase III study, 1,253 patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 who had progressive disease after first-line chemotherapy were randomly assigned to receive docetaxel and placebo or docetaxel and ramucirumab.[8][Level of evidence: 1iiA] Ramucirumab is a human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2. The primary endpoint of the study was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and objective response rate (ORR). The study enrolled patients with either nonsquamous or squamous NSCLC; however, patients with poorly controlled hypertension, gastrointestinal perforation or fistulae, arterial thromboembolic event within 6 months (before random assignment), gross hemoptysis within 2 months, or grade 3 to 4 gastrointestinal bleeding within 3 months were excluded. In addition, the trial did not include patients with tumors that had major blood vessel involvement or intratumor cavitation.
    • The addition of ramucirumab to docetaxel compared with placebo plus docetaxel led to an increase in median OS (10.5 months vs. 9.1 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), ORR (23% vs. 14%), and PFS (4.5 months vs. 3 months). The improvement in OS from the addition of ramucirumab appeared consistent across subgroups including squamous and nonsquamous histologies.
    • Grade 3 to 4 treatment-related adverse events occurred in 79% of patients who received docetaxel and ramucirumab as compared with 71% of patients who received docetaxel and placebo. Febrile neutropenia, fatigue, and hypertension were among the toxicities that were more common with the addition of ramucirumab to docetaxel. There was no significant difference in the incidence of grades 3 to 4 hemorrhage between the groups.
    • On the basis of this study, the addition of ramucirumab to docetaxel chemotherapy can be considered for patients with good PS with advanced NSCLC who have progressive disease after first-line chemotherapy.
Pemetrexed
Evidence (pemetrexed):
  1. A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, PFS, or OS.[9][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel, and those with nonsquamous histologies appeared to benefit more from pemetrexed.[10]

EGFR-directed therapy

EGFR-directed therapy after first-line chemotherapy
Erlotinib
Evidence (erlotinib):
  1. Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared with placebo [11,12] but does not improve survival compared with standard second-line chemotherapy with docetaxel or pemetrexed.[13]
    1. The trial of erlotinib versus best supportive care included 731 patients; 49% had received two previous chemotherapy regimens, and 93% had received platinum-based chemotherapy.
      • OS was 6.7 months among those who had received two previous chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[11][Level of evidence: 1iiA]
    2. In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy after disease progression on first-line platinum combination therapy, 424 patients were randomly assigned.
      • There was no difference in the primary endpoint of OS (median OS, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[13][Level of evidence: 1iiA]
Gefitinib
Evidence (gefitinib):
  1. A randomized phase III trial evaluated gefitinib versus placebo in 1,692 previously treated NSCLC patients and showed the following:
    • Gefitinib does not improve OS.
    • Median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 months vs. 5.4 months; HR, 0.84; CI, 0.68–1.03; P = .089).
    • Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 months vs. 6.1 months) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 months vs. 5.5 months).[14][Level of evidence: 1iiA]
  2. In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[15] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high EGFR gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day PO; n = 733) or docetaxel (75 mg/m2 IV every 3 weeks; n = 733).
    • Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
    • In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
    • This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.
ORR to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[16-22] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR- [17-19,21,22] and, with the absence of, KRAS mutations.[20-22][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situhybridization studies,[21,22] but the clinical utility of EGFR testing by immunohistochemistry has been questioned.[23]
Afatinib
Evidence (afatinib):
  1. Afatinib, an irreversible inhibitor of the ErbB-family of receptors, has been compared with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. In a randomized, controlled, phase III trial (LUX-Lung 8 [NCT01523587]), patients with stage IIIB/IV squamous cell NSCLC with disease progression after frontline platinum-based chemotherapy were randomly assigned in a 1:1 ratio to receive afatinib (398 patients, 40 mg PO qd) or erlotinib (397 patients, 150 mg PO qd).[24][Level of evidence: 1iiDiii] The primary endpoint was PFS. Secondary endpoints included OS and response rate.
    • After a median follow-up of 6.7 months, the PFS was 2.4 months versus 1.9 months (HR, 0.82; 95% CI, 0.68–1.00).
    • After a median follow-up of 18.4 months, the median OS was significantly longer in the afatinib arm (7.9 months vs. 6.8 months; HR, 0.81; 95% CI, 0.69–0.95; P = .007). Survival at 6 months (63.6% vs. 54.6%; P = .009), 12 months (36.4% vs. 28.2%; P = .015), and 18 months (22% vs. 14.4%; P = .013) were all significantly better in patients who received afatinib.
    • There was no significant difference in response rate between the two arms (6% vs. 3%; P = .551).
    • The frequency of adverse events was similar between the two groups with 57% of the patients experiencing a rate of grade 3 or higher adverse events. Grade 3 treatment-related diarrhea and stomatitis occurred more frequently with afatinib; however, grade 3 rash or acne were more common in patients who received erlotinib.
    • Afatinib, as compared with erlotinib, represents another option for the second-line treatment of patients with stage IV squamous cell NSCLC.
EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy
Osimertinib
Evidence (osimertinib):
  1. An open-label, phase III trial (AURA 3 [NCT02151981]) studied osimertinib in NSCLC patients with EGFR-sensitizing mutations whose disease had progressed after first-line EGFR inhibitors and who had the T790M EGFR resistance mutation as determined by the Cobas® EGFR Mutation Test.[25] The trial randomly assigned 419 patients (with a 2:1 ratio) to receive either osimertinib 80 mg PO qd or pemetrexed plus carboplatin or cisplatin IV every 3 weeks for up to six cycles; maintenance pemetrexed was allowed for the chemotherapy group. The primary endpoint was PFS.
    • Osimertinib was superior to chemotherapy in prolonging median PFS (10.1 months vs. 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P < .001).
    • The ORR was 71% with osimertinib versus 31% with platinum therapy (odds ratio for objective response, 5.39; 95% CI, 3.47–8.48; P < .001).
    • Among 144 patients with central nervous system (CNS) metastases, median PFS duration was 8.5 months with osimertinib versus 4.2 months with platinum therapy (HR, 0.32; 95% CI, 0.21–0.49).
    • Adverse events of grade 3 or greater occurred in 23% of osimertinib-treated patients versus 47% of platinum-treated patients.[25][Level of evidence: 1iiDiii]

ALK-directed tyrosine kinase inhibitors (TKI)

ALK-directed TKI after first-line chemotherapy
Crizotinib
Evidence (crizotinib):
  1. A study (NCT00585195) that screened 1,500 patients with NSCLC for ALKrearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual and ALK inhibitor of 250 mg bid in 28-day cycles.[26] Most of the patients had received previous treatment.
    • At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and one confirmed complete response); 27 patients (33%) had stable disease.[26][Level of evidence: 3iiiD]
    • The estimated probability of 6-month PFS was 72%.
    • 1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
    • Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [95% CI, 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [95% CI, 23–64], and 2-year OS, 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[27][Level of evidence: 3iiiD]
    • Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
    • Patients with ALK rearrangements tended to be younger than those without the rearrangements; most of the patients had little or no exposure to tobacco; and the patients had adenocarcinomas.
  2. In an open-label, randomized, phase III study, 347 patients with stage IIIB/IV NSCLC-harboring translocations in ALK, who had received one previous regimen of platinum-based chemotherapy, received either crizotinib (250 mg PO twice a day) or chemotherapy (pemetrexed 500 mg/m2 if pemetrexed-naïve or docetaxel 75mg/m2 IV every 21 days).[28]
    • The primary endpoint was PFS. Median PFS was significantly longer in favor of crizotinib (7.7 months vs. 3.0 months, P < .001).[28][Level of evidence: 1iiDiii]
    • OS, a secondary endpoint, was not significantly different, but there was significant crossover in the design.
ALK-directed TKI after prior ALK TKI therapy
Ceritinib
Evidence (ceritinib):
  1. A single-arm, open-label trial enrolled 163 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression while receiving crizotinib or were intolerant to the drug.[29]
    • The primary endpoint was ORR according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) with a secondary endpoint of duration of response (DOR). The ORR by blinded independent review was 43.6% (95% CI, 36–52), and the median DOR was 7.1 months (range, 5.6–not estimable).[29][Level of evidence: 3iiiDiv]
    • Of note, 38% of patients required dose modification because of gastrointestinal toxicity; elevation of alanine transaminase to more than five times the upper limit of normal occurred in 27% of patients.
Alectinib
Evidence (alectinib):
  1. A phase II, open-label trial (NCT01871805) enrolled 87 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression after crizotinib treatment.[30]
    • The primary endpoint was objective response according to RECIST (version 1.1). At the time of primary endpoint analysis of this ongoing study, 48% of patients (95% CI, 36–60) had a confirmed partial response, and 32% had stable disease by blinded independent review. The median DOR was 13.5 months (95% CI, 6.7–not estimable). The estimated median PFS was 8.1 months (95% CI, 6.2–12.6).[30][Level of evidence: 3iiiDiv]
    • Sixteen patients had measurable CNS disease at baseline, of whom 11 had received prior radiation therapy. The CNS ORR was 75% (95% CI, 48–93), with 25% of the patients attaining complete response and 50% of the patients attaining partial response.
    • The most common side effects were grade 1 or 2 in severity; the most frequent adverse events, occurring in 23% to 36% of patients, were constipation, fatigue, myalgia, and peripheral edema. Dose interruption was needed in 36% of patients, and dose reduction occurred in 16%.
  2. A second phase II, open-label trial enrolled 138 patients with ALK-positive stage IIIB/IV NSCLC who had disease progression on crizotinib.[31]
    • The primary endpoint was ORR by independent central review. ORR was 50% (95% CI, 41–59). Median DOR was 11.2 months (95% CI, 9.6–not reached). Median PFS was 8.9 months (95% CI, 5.6–11.3).[31][Level of evidence: 3iiiDiv]
    • CNS ORR in 35 patients with measurable CNS lesions was 57% (95% CI, 39–74).
    • Common adverse events that were mainly grade 1 or 2, which occurred in 25% to 33% of patients, were constipation, fatigue, and peripheral edema.
Brigatinib
Evidence (brigatinib):
  1. A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg qd (n = 112; 109 treated) or 180 mg qd with a 7-day lead-in at 90 mg qd (n = 110).[32]
    • The primary endpoint assessed by the investigators was ORR. ORR was 45% (97.5% CI, 34–56) for patients who received the 90 mg dose and 54% (97.5% CI, 43–65) for patients who received the 180 mg dose.
    • Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–not reached) for patients who received the 180 mg dose.
    • At data cutoff, the median DOR was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.[32][Level of evidence: 1iiDiv]
    • The CNS ORR in patients with measurable CNS lesions was 42% in patients receiving 90 mg qd (n = 26) and 67% in patients receiving 180 mg qd (n = 18).
    • Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.
    • The U.S. Food and Drug Administration (FDA)-approved dose of brigatinib is 90 mg qd for 7 days; if tolerated, the dose is increased to 180 mg qd.

ROS1-directed therapy

ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[33]
Crizotinib
Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.
Evidence (crizotinib):
  1. In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[34] ROS1 rearrangements were identified using break-apart fluorescence in situ hybridization or reverse-transcriptase-polymerase-chain-reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one previous treatment. The primary endpoint was response rate.
    • The overall response rate was 72% (95% CI, 58–84). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
    • Median PFS was 19.2 months (95% CI, 14.4–not reached). The estimated DOR was 17.6 months (95% CI, 14.5–not reached).[34][Level of evidence: 3iiiDiv]
  2. In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[35] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary endpoint was objective response rate by independent review.
    • The objective response rate was 71.7% (95% CI, 63.0–79.3). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses and 16.5% of patients had stable disease as their best response.[35][Level of evidence: 3iiiDiv]
    • Median PFS was 15.9 months (95% CI, 12.9–24). The duration of response was 19.7 months (95% CI, 14.1–not reached).
    • OS was 32.5 months (95% CI, 32.5–not reached).

BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)

BRAFV600E mutations occur in 1% to 2% of lung adenocarcinomas.
Dabrafenib and trametinib
Evidence (dabrafenib and trametinib):
  1. In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 57 patients with progression after at least one to three previous platinum-containing regimens for treatment of metastatic NSCLC, who tested positive for BRAFV600Emutations, were treated with dabrafenib (a BRAF inhibitor) 150 mg bid and trametinib (a MEK inhibitor) 2 mg qd.[36] BRAFV600E mutations were ascertained by local testing. The primary endpoint was investigator-assessed overall response.
    • The overall response rate was 63.2% (95% CI, 49.3–75.6), as determined independently by investigator and independent review committee assessments. There were 2 out of 36 complete responses by investigator assessment; all responses were deemed partial by the independent review committee.
    • The median investigator-assessed PFS was 9.7 months (95% CI, 6.9–19.6 months). The estimated median DOR was 9.0 months (95% CI, 6.9–18.3). The OS data are immature.
    • Forty-nine percent of patients had at least one grade 3 or 4 adverse event, the most common of which were neutropenia, hyponatremia, and anemia.[36][Level of evidence: 3iiiDiv]
The combination of dabrafenib and trametinib received approval for patients with NSCLC whose tumors harbor BRAFV600E mutations as detected by an FDA-approved test.

Immunotherapy

Nivolumab is a fully human monoclonal antibody that inhibits the programmed death-1 (PD-1) co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells.[37,38] Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the PD-1 co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.[39] Atezolizumab is a PD-L1–blocking antibody.
Nivolumab
Evidence (nivolumab):
  1. In two phase III clinical trials, one conducted in patients with advanced platinum-pretreated squamous NSCLC and the other trial conducted in patients with nonsquamous NSCLC, nivolumab demonstrated a significant improvement in OS compared with the previous standard treatment of docetaxel chemotherapy.[37,38][Level of evidence:1iiA] In addition, the rates of grade 3 and 4 treatment-related toxicity in both trials were significantly lower with nivolumab than with docetaxel. Of note, all patients enrolled in phase III studies of nivolumab had an ECOG PS of 0 or 1; patients with autoimmune disease, symptomatic interstitial lung disease, or those receiving systemic immunosuppression were excluded from enrollment.
    1. A randomized, open-label, phase III trial randomly assigned 272 advanced squamous cell NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[37] The primary endpoint of this study was OS.
      • Nivolumab demonstrated a significant improvement in median OS compared with docetaxel (9.2 months vs. 6 months; P < .001). In addition, the ORR (20% vs. 9%; P = .008) and median PFS (3.5 months vs. 2.8 months; P < .001) favored nivolumab.
      • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 58% for nivolumab vs. 86% for docetaxel; grades 3–4, 7% for nivolumab vs. 55% for docetaxel).
    2. A randomized, open-label, phase III trial randomly assigned 582 advanced nonsquamous NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[38] Previous maintenance chemotherapy after first-line platinum-doublet was allowed; patients with EGFR mutations or ALK translocations were allowed to have received an additional regimen of therapy with a TKI. The primary endpoint of this study was OS.
      • Nivolumab demonstrated a significant improvement in patients in median OS compared with docetaxel (12.2 months vs. 9.4 months; HR, 0.73; 96% CI, 0.59–0.89; P = .002). In this study, ORR (19% vs. 12%; P = .02) but not median PFS (2.3 months for nivolumab vs. 4.2 months for docetaxel) favored nivolumab. The median DOR in patients was 17.2 months for nivolumab and 5.6 months for docetaxel.
      • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 69% for nivolumab vs. 88% for docetaxel; grades 3–4, 10% for nivolumab vs. 54% for docetaxel).
    3. Both of these trials demonstrated long-term clinical benefit at the 2-year outcomes. The OS rates for nivolumab at 2 years compared with docetaxel in squamous NSCLC were 23% (95% CI, 16–30) versus 8% (95% CI, 4–13), and OS rates in nonsquamous NSCLC were 29% (95% CI, 24–34) versus 16% (95% CI, 12–20).[40] Ongoing responses at 2 years were observed in 10 (37%) confirmed responders with squamous NSCLC and 19 (34%) of 56 responders with nonsquamous NSCLC. No patient treated with docetaxel in either study had an ongoing response.
Nivolumab is now considered a standard second-line therapy for patients with metastatic NSCLC with progression on or after first-line platinum-based chemotherapy and is associated with improved survival and lower rates of toxicity than docetaxel. However, clinical trials of nivolumab to date have not enrolled patients with a history of autoimmune disease, interstitial lung disease, or an ECOG PS higher than 1. Patients with active autoimmune conditions cannot be treated with nivolumab. Closely monitoring all patients for autoimmune toxicities from treatment is required. Specific algorithms for the management of autoimmune toxicity are included in the FDA label for nivolumab.
Pembrolizumab
Evidence (pembrolizumab):
  1. In a phase I study with multiple expansion cohorts, pembrolizumab demonstrated significant activity with respect to response rate and DOR.[39][Level of evidence: 3iiiDiv]
    • In the study, 495 patients received either pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. No significant differences were seen among the different treatment schedules. Key exclusion criteria were autoimmune disease, history of pneumonitis, requirement for systemic immunosuppressive therapy, and a PS higher than 1. The ORR was 19.4% (95% CI, 16.0–23.2), which included a response rate of 18.0% (95% CI, 14.4–22.2) in 394 previously treated patients and 24.8% (95% CI, 16.7–34.3) in 101 previously untreated patients. Median PFS was 3.7 months (95% CI, 2.9–4.1) for all patients, 3.0 months (95% CI, 2.2–4.0) for previously treated patients, and 6.0 months (95% CI, 4.1–8.6) for previously untreated patients. The median DOR was 12.5 months (range, 1.0–23.3 months) in all patients.
    • The study evaluated the efficacy of pembrolizumab in patients with high levels of PD-L1, as assessed by the anti-PD-L1 antibody clone 22C3. Using the cutoff of membranous staining in at least 50% of tumor cells in a validation group of 73 patients, the response rate was 45.2% (95% CI, 33.5–57.3), and the median PFS in this group was 6.3 months (95% CI, 2.9–12.5). Median OS was not reached at the time of publication.
    • The estimated prevalence of PD-L1 tumor staining from 1,143 screened patients, of whom 824 had evaluable samples, is as follows: 23.2% had 50% or more tumor cells with staining; 37.6% had between 1% and 49% tumor cells with staining; and 39.2% had less than 1% of tumor cells with staining.
    • The most common adverse events were fatigue, pruritus, and decreased appetite. Grade 3 or higher adverse events were reported in 9.5% of patients. Inflammatory and immune-mediated adverse events that occurred in more than 2% of patients were infusion-related reactions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).
  2. In a phase II/III randomized clinical trial, patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were randomly assigned (1:1:1) to receive pembrolizumab (2 mg/kg), pembrolizumab (10 mg/kg), or docetaxel (75 mg/m2) every 3 weeks.[41][Level of evidence: 1iiA] The primary endpoints were OS and PFS in the total population and in patients with PD-L1 expression on at least 50% of tumor cells. This study enrolled 1,034 patients; 345 of them were allocated to pembrolizumab (2 mg/kg); 346 were allocated to pembrolizumab (10 mg/kg); and 343 were allocated to docetaxel.
    • In the total population, median OS was 10.4 months with pembrolizumab (2 mg/kg), 12.7 months with pembrolizumab (10 mg/kg), and 8.5 months with docetaxel. OS was significantly longer for pembrolizumab (2 mg/kg) versus docetaxel (HR 0.71; 95% CI, 0.58–0.88; P = .0008) and for pembrolizumab (10 mg/kg) versus docetaxel (HR, 0.61; CI, 0.49–0.75; P < .0001).
    • In the total population, PFS was not prolonged in the pembrolizumab groups compared with the docetaxel group.
    • Among patients with at least 50% of tumor cells expressing PD-L1, OS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 14.9 months vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P = .0002) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 17.3 months vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P < .0001).
    • In the group of patients with at least 50% of tumor cells expressing PD-L1, PFS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 5.0 months vs. 4.1 months; HR, 0.59; 95% CI, 0.44–0.78; P = .0001) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 5.2 months vs. 4.1 months; HR, 0.59; CI, 0.45–0.78; P < .0001).
    • Grade 3 to 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given pembrolizumab (2 mg/kg), 55 [16%] of 343 patients given pembrolizumab (10 mg/kg), and 109 [35%] of 309 patients given docetaxel).
Pembrolizumab received accelerated approval as a second-line therapy for patients with NSCLC whose tumors express PD-L1 (>50% staining as determined by an FDA-approved test) with progression on or after first-line chemotherapy. Patients with EGFR or ALKgenomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (refer to the FDA label for pembrolizumab).
Atezolizumab
Evidence (atezolizumab):
  1. Two international, randomized, open-label clinical trials (OAK [NCT02008227] and POPLAR [NCT01903993]) demonstrated efficacy and safety in a total of 1,137 patients with NSCLC who previously received platinum chemotherapy.[42,43][Level of evidence: 1iiA] Compared with docetaxel, treatment with atezolizumab in the intended patient population resulted in improved OS rates of 4.2 months in the OAK study and 2.9 months in the POPLAR study.
    • In the OAK trial, the median OS was 13.8 months in the atezolizumab arm (95% CI, 11.8–15.7) compared with 9.6 months in the docetaxel arm (95% CI, 8.6–11.2) (HR = 0.74; 95% CI, 0.63–0.87; P = .0004).
    • The median OS in the POPLAR trial was 12.6 months in the atezolizumab arm (95% CI, 9.7–16.0) and 9.7 months in the docetaxel arm (95% CI, 8.6–12.0) (HR, 0.69; 95% CI, 0.52–0.92).
    • Although the magnitude of improvement correlated with PD-L1 immunohistochemistry expression on tumor cells and tumor-infiltrating immune cells, survival benefit with atezolizumab was seen in patients with tumors with and without PD-L1 expression.
    • In the POPLAR trial, the most common (≥20%) adverse reactions were in patients treated with atezolizumab and included fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.
    • The most common (≥2%) grade 3 to 4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia.
    • Clinically significant immune-related adverse events for patients receiving atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

Treatment Options under Clinical Evaluation for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

Treatment options under clinical evaluation for progressive stage IV, relapsed, and recurrent NSCLC (second-line therapy) include the following:
  • Clinical trials can be considered as second-line therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Souquet PJ, Chauvin F, Boissel JP, et al.: Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342 (8862): 19-21, 1993. [PUBMED Abstract]
  2. Ellis PA, Smith IE, Hardy JR, et al.: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71 (2): 366-70, 1995. [PUBMED Abstract]
  3. Girling DJ, et al.: Randomized trial of etoposide cyclophosphamide methotrexate and vincristine versus etoposide and vincristine in the palliative treatment of patients with small-cell lung cancer and poor prognosis. Br J Cancer 67 (Suppl 20): A-4;2, 14, 1993.
  4. Fossella FV, DeVore R, Kerr RN, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18 (12): 2354-62, 2000. [PUBMED Abstract]
  5. Shepherd FA, Dancey J, Ramlau R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18 (10): 2095-103, 2000. [PUBMED Abstract]
  6. Huisman C, Smit EF, Giaccone G, et al.: Second-line chemotherapy in relapsing or refractory non-small-cell lung cancer: a review. J Clin Oncol 18 (21): 3722-30, 2000. [PUBMED Abstract]
  7. Di Maio M, Perrone F, Chiodini P, et al.: Individual patient data meta-analysis of docetaxel administered once every 3 weeks compared with once every week second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 25 (11): 1377-82, 2007. [PUBMED Abstract]
  8. Garon EB, Ciuleanu TE, Arrieta O, et al.: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384 (9944): 665-73, 2014. [PUBMED Abstract]
  9. Hanna N, Shepherd FA, Fossella FV, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22 (9): 1589-97, 2004. [PUBMED Abstract]
  10. Scagliotti G, Hanna N, Fossella F, et al.: The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 14 (3): 253-63, 2009. [PUBMED Abstract]
  11. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353 (2): 123-32, 2005. [PUBMED Abstract]
  12. Bezjak A, Tu D, Seymour L, et al.: Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24 (24): 3831-7, 2006. [PUBMED Abstract]
  13. Ciuleanu T, Stelmakh L, Cicenas S, et al.: Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 13 (3): 300-8, 2012. [PUBMED Abstract]
  14. Thatcher N, Chang A, Parikh P, et al.: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366 (9496): 1527-37, 2005 Oct 29-Nov 4. [PUBMED Abstract]
  15. Kim ES, Hirsh V, Mok T, et al.: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372 (9652): 1809-18, 2008. [PUBMED Abstract]
  16. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004. [PUBMED Abstract]
  17. Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004. [PUBMED Abstract]
  18. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004. [PUBMED Abstract]
  19. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004. [PUBMED Abstract]
  20. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005. [PUBMED Abstract]
  21. Tsao MS, Sakurada A, Cutz JC, et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 353 (2): 133-44, 2005. [PUBMED Abstract]
  22. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24 (31): 5034-42, 2006. [PUBMED Abstract]
  23. Clark GM, Zborowski DM, Culbertson JL, et al.: Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol 1 (8): 837-46, 2006. [PUBMED Abstract]
  24. Soria JC, Felip E, Cobo M, et al.: Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 16 (8): 897-907, 2015. [PUBMED Abstract]
  25. Mok TS, Wu Y-L, Ahn M-J, et al.: Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 376 (7): 629-640, 2017. [PUBMED Abstract]
  26. Kwak EL, Bang YJ, Camidge DR, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363 (18): 1693-703, 2010. [PUBMED Abstract]
  27. Shaw AT, Yeap BY, Solomon BJ, et al.: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12 (11): 1004-12, 2011. [PUBMED Abstract]
  28. Shaw AT, Kim DW, Nakagawa K, et al.: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368 (25): 2385-94, 2013. [PUBMED Abstract]
  29. Shaw AT, Kim DW, Mehra R, et al.: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370 (13): 1189-97, 2014. [PUBMED Abstract]
  30. Shaw AT, Gandhi L, Gadgeel S, et al.: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17 (2): 234-42, 2016. [PUBMED Abstract]
  31. Ou SH, Ahn JS, De Petris L, et al.: Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 34 (7): 661-8, 2016. [PUBMED Abstract]
  32. Kim DW, Tiseo M, Ahn MJ, et al.: Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 35 (22): 2490-2498, 2017. [PUBMED Abstract]
  33. Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18 (7): 865-75, 2013. [PUBMED Abstract]
  34. Shaw AT, Ou SH, Bang YJ, et al.: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371 (21): 1963-71, 2014. [PUBMED Abstract]
  35. Wu YL, Yang JC, Kim DW, et al.: Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 36 (14): 1405-1411, 2018. [PUBMED Abstract]
  36. Planchard D, Besse B, Groen HJM, et al.: Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17 (7): 984-993, 2016. [PUBMED Abstract]
  37. Brahmer J, Reckamp KL, Baas P, et al.: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373 (2): 123-35, 2015. [PUBMED Abstract]
  38. Borghaei H, Paz-Ares L, Horn L, et al.: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373 (17): 1627-39, 2015. [PUBMED Abstract]
  39. Garon EB, Rizvi NA, Hui R, et al.: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 (21): 2018-28, 2015. [PUBMED Abstract]
  40. Horn L, Spigel DR, Vokes EE, et al.: Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35 (35): 3924-3933, 2017. [PUBMED Abstract]
  41. Herbst RS, Baas P, Kim DW, et al.: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387 (10027): 1540-50, 2016. [PUBMED Abstract]
  42. Rittmeyer A, Barlesi F, Waterkamp D, et al.: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 (10066): 255-265, 2017. [PUBMED Abstract]
  43. Fehrenbacher L, Spira A, Ballinger M, et al.: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387 (10030): 1837-46, 2016. [PUBMED Abstract]

Changes to This Summary (04/05/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Treatment
Added Brigatinib as a new subsection.
Added Lorlatinib as a new subsection.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Non-Small Cell Lung Cancer Treatment are:
  • Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
  • Patrick Forde, MD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins)
  • Raymond Mak, MD (Harvard Medical School)
  • Arun Rajan, MD (National Cancer Institute)
  • Eva Szabo, MD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389304]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: April 5, 2019
Publicado por en

No hay comentarios:

Publicar un comentario

Suscribirse a: Enviar comentarios (Atom)