Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :1389
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (461 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 » Methods
 » Maintenance Therapy
 » Second-Line Therapy
 » Consensus
 » Consensus
 » First-line Therapy
 »  References

 Article Access Statistics
    Viewed3725    
    Printed109    
    Emailed0    
    PDF Downloaded390    
    Comments [Add]    

Recommend this journal

 

  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 89-103
 

Indian consensus statement for treatment of advanced non small cell lung cancer: First line, maintenance, and second line


,

Date of Web Publication1-Dec-2017

Correspondence Address:
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_136_17

Rights and Permissions

 » Abstract 

The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming complex with the identification of driver mutations and targeted therapies. The expert group of academic medical oncologists used data from published literature, practical experience to arrive at practical consensus recommendations to treat advanced NSCLC for use by the community oncologists.


Keywords: Non-small cell lung cancer, driver mutations, targeted therapies


How to cite this article:
Under the aegis of Lung Cancer Consortium Asia (LCCA), Indian Cooperative Oncology Network (ICON), Indian Society of Medical & Pediatric Oncology (ISMPO), Molecular Oncology Society (MOS) and Association of Physicians of India API). Indian consensus statement for treatment of advanced non small cell lung cancer: First line, maintenance, and second line. Indian J Cancer 2017;54:89-103

How to cite this URL:
Under the aegis of Lung Cancer Consortium Asia (LCCA), Indian Cooperative Oncology Network (ICON), Indian Society of Medical & Pediatric Oncology (ISMPO), Molecular Oncology Society (MOS) and Association of Physicians of India API). Indian consensus statement for treatment of advanced non small cell lung cancer: First line, maintenance, and second line. Indian J Cancer [serial online] 2017 [cited 2020 Apr 6];54:89-103. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/89/219538

Correspondence to: Dr. Prabhash K, E.mail: kumarprabhashtmh@gmail.com



 » Introduction Top


In the last decade, lung cancer treatment has changed from histology based to target-based approach. Newer molecular targets and driver mutations have been identified which can be addressed with appropriate therapeutic intervention. With the availability of newer targeted therapies, the treatment of nonsmall cell lung cancer (NSCLC) has become complex as never before. The experts from the Indian Cooperative Oncology Network, Lung Cancer Consortium Asia, Indian Society of Medical and Pediatric Oncology, Molecular Oncology Society and Association of Physicians of India met to discuss and arrive at the consensus statements to provide practical recommendations for the community oncologists for the treatment of this complex tumor. The discussion was based on the review of the published evidence, subject expertise of the participating faculty and practical experience in real-life management of lung cancer patients.


 » Methods Top


A total of 45 lung cancer experts from all over India participated in the development of the consensus statement. As a part of the background work, the evidence supporting the answer to 18 clinically relevant questions (mentioned below) was compiled by lead discussants, and the review of literature was presented to the panel. This was followed by a discussion on the consensus statements which were voted for by all the panelists using voting pads. The options for voting each consensus statement were “Agree,” “Disagree,” and “Not sure.” The percentage of delegates “agreeing,” “disagreeing,” or “not sure” with each statement have been mentioned. For some statements, the consensus was unanimously passed by voice voting since there was 100% agreement among all the experts. The percentages for these statements have not been mentioned.

Members of the panel were also allowed to share their personal experiences, make comments, and record dissent while voting for the consensus statements. This manuscript is the outcome of the expert group discussion and consensus arrived in October 2016.


 » First-line Therapy Top


Which patients of advanced stage nonsmall cell lung cancer should be treated with chemotherapy?

Literature review

Platinum-based doublet chemotherapy has shown to improve survival compared to best supportive care in patients with good performance status (PS) without impairing the quality of life.[1],[2],[3],[4],[5],[6] This has also been substantiated by a systematic review and meta-analysis.[7] Addition of a third cytotoxic agent improves the response rate (odds ratio [OR] = 0.66; 95% confidence interval [CI] = 0.58–0.75; P < 0.001) and toxicity without an increase in 1-year survival (OR = 1.01; 95% CI = 0.85–1.21; P = 0.88).[8] Pooled analysis of six randomized trials has shown that platinum-based doublets improved overall response rate (ORR) (OR = 3.243; 95% CI = 1.883–5.583) and 1-year survival rate (OR = 1.743; 95% CI = 1.203–2.525) with increased hematological toxicities compared to single agent in patients with PS 2.[9] For patients who are elderly or those with PS 2, single-agent vinorelbine and gemcitabine have shown to improve overall survival (OS) without compromising the quality of life.[10],[11] In a Phase III trial comparing docetaxel versus vinorelbine in elderly patients with PS ≥2, docetaxel improved progression-free survival (PFS) (median = 5.5 vs. 3.1 months; P < 0.001) and response rates (22.7% vs. 9.9%; P = 0.019) versus vinorelbine. The difference in the OS was not statistically significant (median = 14.3 vs. 9.9 months, hazard ratio [HR] for death = 0.78; 95% CI = 0.56–1.09). A French Intergroup study (IFCT-0501) compared monthly carboplatin plus weekly paclitaxel versus single-agent vinorelbine or gemcitabine in patients aged 70–89 years with PS 0–2 and reported a survival advantage for combination therapy (median OS = 10.3 months for doublet vs. 6.2 months for monotherapy, HR = 0.64; 95% CI = 0.52–0.78; P < 0.0001).[12]

Cisplatin-containing regimens are associated with more nephrotoxicity, nausea, and vomiting, and carboplatin combinations cause more severe thrombocytopenia. Lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity.[13]

Consensus

  • All patients of advanced NSCLC with PS 0–2 without driver mutations should be treated with upfront chemotherapy (agree – 100%, disagree – 0%)
  • For patients with PS 0–1:
    • 4–6 cycles of platinum-based doublet chemotherapy should be the standard of care (agree – 100%, disagree – 0%)
    • Carboplatin-based regimens should be used in patients in whom cisplatin is likely to be poorly tolerated. Weekly schedule of paclitaxel plus carboplatin may be considered (agree – 100%, disagree – 0%).
  • For patients with PS ≥2 and elderly patients:
    • Single-agent chemotherapy (vinorelbine, gemcitabine, pemetrexed, or docetaxel) may be appropriate (agree – 100%, disagree – 0%)
    • Carboplatin-based combinations may be considered ineligible patients aged >70 years with PS 0–2 and adequate organ function (agree – 100%, disagree – 0%).
  • Patients with PS 3–4 can be offered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or best supportive care in the absence of activating EGFR mutations or anaplastic lymphoma kinase (ALK)/ROS1 translocations (agree – 100%, disagree – 0%).


What should be the choice of chemotherapy in patients of nonsmall cell lung cancer of nonsquamous histology with no driver mutation?

Literature review

In a Phase III trial, cisplatin plus pemetrexed conferred survival advantage compared to cisplatin plus gemcitabine in patients with adenocarcinoma (median OS = 12.6 months in cisplatin plus pemetrexed arm versus. 10.9 months in cisplatin plus gemcitabine arm).[5] A meta-analysis comparing the efficacy and toxicities of pemetrexed plus platinum with other platinum regimens in patients with previously untreated advanced NSCLC concluded that pemetrexed plus platinum chemotherapy in the first-line setting leads to a significant survival advantage with acceptable toxicities for advanced NSCLC patients, especially those with nonsquamous histology (HR = 0.87; 95% CI = 0.77–0.98; P = 0.02).[14] Addition of bevacizumab to carboplatin-paclitaxel regimen in patients of nonsquamous histology offers high response rates, longer PFS (HR = 0.72; 95% CI = 0.66–0.79; P < 0.001), and improved OS compared (HR = 0.90; 95% CI = 0.81–0.99; P = 0.03) with carboplatin-paclitaxel alone in patients with nonsquamous histology and PS 0–1 and significantly increased risk of Grade ≥ 3 proteinuria, hypertension, hemorrhagic events, neutropenia, and febrile neutropenia. These trials excluded patients with brain metastases or a history of hemoptysis.[15]

Consensus

  • Pemetrexed and platinum agent should be considered as first-line option for patients of nonsquamous histology without driver mutations (agree – 100%, disagree – 0%)
  • Bevacizumab in combination with paclitaxel–carboplatin may be offered to patients with nonsquamous histology and PS 0–1 after exclusion of contraindications (agree – 68% and disagree – 32%).


What should be the choice of therapy in patients of nonsquamous histology with unknown mutation status?

Literature review

In a country like India, it is possible that the adequate tissue may not always be available for molecular testing at the time of diagnosis. Furthermore, in certain circumstances, the general condition of the patient may warrant treatment before mutation results are available. There are limited clinical data which address the optimal approach in this situation. The choice of agent in such situations may be indirectly guided by the results of TORCH trial which showed that OS was significantly longer in unselected patients assigned to initial chemotherapy followed by second-line erlotinib (median = 11.6 vs. 8.7 months; HR = 1.24; 95% CI = 1.04–1.47). EGFR mutation status was analyzed in 64% of cases, 86% of whom were EGFR wild-type (WT). For a small number of patients who were EGFR mutation negative, OS was significantly longer in patients with initial chemotherapy (median = 9.6 vs. 6.5 months).[16]

The incidence of EGFR mutations in India is 25%–35%, which is higher compared to the Western population.[17],[18],[19],[20] In female and nonsmokers, this could be as high as 50%–55%. Recently, cell-free circulating tumor DNA (ctDNA) has been widely investigated as a potential surrogate for tissue biopsy for noninvasive assessment of tumor-related genomic alterations. In a study which assessed EGFR mutation status in 803 plasma samples, the concordance between baseline tumor and plasma samples was 94.3%, with a sensitivity of 65.7% and specificity of 99.8%.[21] A liquid biopsy may also be useful in detecting ALK rearrangements. In a study, echinoderm microtubule–associated protein-like 4 (EML4)-ALK rearrangements were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in platelets and plasma isolated from blood obtained from 77 patients with NSCLC, 38 of whom had EML4-ALK-rearranged tumors. RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets.[22]

Consensus

  • All attempt should be made to establish the driver mutation status of the patients using biopsy or cell block (if biopsy specimen is not available) to guide the choice of therapy (agree – 100%, disagree – 0%)
  • At this moment, there is not enough evidence to support the use of ctDNA for testing EGFR mutations in the upfront setting although it may be acceptable in cases where mutation status cannot be established either by biopsy or cell block (agree – 100%, disagree – 0%)
  • In case driver mutation testing is not feasible, chemotherapy should be first-line treatment of choice for patients with good PS (agree – 100%, disagree – 0%).


What should be the choice of therapy in patients of nonsmall cell lung cancer with activating mutations in the epidermal growth factor receptor (Del 19 and L858R)?

Literature review

Six randomized clinical trials comparing the first-generation EGFR TKIs (erlotinib and gefitinib) with platinum doublet in patients who are EGFR mutation positive have shown that EGFR TKIs significantly prolonged PFS. There was, however, no difference in the OS both in overall patient population and subgroups of Del 19 and L858R mutations.[23],[24],[25],[26],[27],[28],[29],[30],[31]

The second-generation EGFR TKI, afatinib has also shown significant prolongation of PFS as compared to chemotherapy in patients with EGFR mutations in two separate head-to-head clinical trials.[32],[33] In a preplanned analysis of patients with Del 19 mutation, afatinib has shown to prolong OS by additional 12.2 months in LUX-Lung 3 (33.3 vs. 21.1 months; HR [95% CI] = 0.54 [0.36–0.79]; P = 0.0015) and 13 months in LUX-Lung 6 study (31.4 vs. 18.4 months; HR [95% CI] = 0.64 [0.44–0.94]; P = 0.0229).[34]

Three head-to-head studies, such as WJOG 5108L, CTONG 0901, and LUX-Lung 7, have compared the efficacy of EGFR TKIs.[35],[36],[37] In WJOG 5108L and CTONG 0901 studies, gefitinib demonstrated comparable efficacy with erlotinib. Median PFS and OS times for gefitinib and erlotinib were 6.5 and 7.5 months (HR = 1.125; 95% CI = 0.940–1.347; P = 0.257) and 22.8 and 24.5 months (HR = 1.038; 95% CI = 0.833–1.294; P = 0.768), respectively, in WJOG 5108L trial. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR = 1.093; 95% CI = 0.879–1.358; P = 0.424). In the LUX-Lung 7 trial that compared afatinib with gefitinib, afatinib was superior to gefitinib in terms of PFS (median = 11.0 months [95% CI = 10.6–12.9] with afatinib vs. 10.9 months [9.1–11.5] with gefitinib; HR = 0.73; 95% CI = 0.57–0.95; P = 0.017) and time to treatment failure (TTF) (median = 13.7 months [95% CI = 11.9–15.0] with afatinib vs. 11.5 months [10.1–3.1] with gefitinib; HR = 0.73; 95% CI = 0.58–0.92; P = 0.0073).[37] There was a trend toward improved OS with afatinib versus gefitinib, (median = 27.9 vs. 24.5 months; HR = 0.86 [0.66–1.12]; P = 0.258) but this did not reach statistical significance.[38] Although the incidence of Grade 3–4 adverse events was higher in the afatinib arm, the rate of treatment-related adverse events discontinuation was similar in both arms.

Consensus

  • Patients with EGFR mutations should be treated with an EGFR TKI (afatinib, gefitinib, and erlotinib) in the upfront setting (agree – 95%, disagree – 5%)
  • In case the chemotherapy is started before the mutation test results are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to an EGFR TKI before completion of 4–6 cycles can also be a valid option (agree – 81.82%, disagree – 13.64%, and not sure – 4.55%).


What should be the treatment of choice in patients with uncommon epidermal growth factor receptor mutations?

Most of the Phase III studies with EGFR TKIs included patients with a deletion in exon 19 or the Leu858Arg mutation in exon 21 of EGFR. Retrospective data suggest that rare mutations except Gly719Xaa and Leu861Gln point mutations have decreased responsiveness to erlotinib and gefitinib.[39],[40],[41],[42] In an analysis from the NEJ002 trial, gefitinib was found to be ineffective against both Gly719Xaa and Leu861Gln mutations.[43] In a post hoc analysis from LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 trials, high activity of afatinib was recorded in patients with Gly719Xaa, Leu861Gln, and Ser768Ile mutations with a median PFS of 13.8 months (6.8– NE) not estimable, 8.2 months (4.5–16.6), and 14.7 months (2.6–NE), respectively.[44] Objective response to EGFR TKIs in exon 20 insertions is poor.[44],[45],[46],[47] Furthermore, patients with high allelic frequencies of Thr790Met mutations also do not respond to EGFR TKIs. In the post hoc analysis from LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 trials, afatinib was ineffective in Thr790Met mutations.[44]

Consensus

  • In addition to Del 19 and L858R mutations, the EGFR panel should include testing for uncommon mutations such as de novo T790M, point mutations, duplications exons 18–21, and exon 20 insertions (agree – 100%, disagree – 0%, and not sure – 0%)
  • For specific point mutations such as G719X, S768I, and L861Q, afatinib may be preferred. Erlotinib and gefitinib may also be reasonable (agree – 66.67%, disagree – 12.5%, and not sure – 20.83%)
  • For exon 20 insertions and de novo T790M mutations, chemotherapy may be the preferred treatment of choice (agree – 90.91%, disagree – 4.55%, and not sure – 4.55%).


Should epidermal growth factor receptor tyrosine kinase inhibitors be continued beyond disease progression in the first line?

Literature review

Some patients have rapid disease progression when an EGFR TKI is discontinued after a prolonged course of treatment. Therefore, in certain situations, it may be reasonable to continue an EGFR TKI in the presence of RECIST defined progression. ASPIRATION trial evaluated the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and continuing erlotinib beyond progression. Of 208 patients enrolled, 176 had a PFS1 event, of these, 93 continued erlotinib therapy following progression. Median PFS1 and PFS2 in the 93 continuing patients was 11.0 (95% CI = 9.2–11.1) and 14.1 (95% CI = 12.2–15.9) months, respectively.[48]

The IMPRESS trial enrolled 205 patients with activating EGFR mutations and compared chemotherapy plus gefitinib versus chemotherapy alone after radiological disease progression on first-line gefitinib. Continuation of gefitinib did not prolong PFS. There was a trend toward shorter OS when gefitinib was continued in conjunction with chemotherapy.[49] In LUX-Lung 7 trial, afatinib and gefitinib were continued beyond RECIST progression, and median time to failure was significantly prolonged in afatinib versus gefitinib (median TTF = 13.7 months vs. 11.5 months HR [95% CI] = 0.73 [0.58–0.92]; P = 0.0073).[37]

Consensus

  • Single-agent continuation of EGFR TKI beyond progressive disease (PD) may be beneficial in some patients (e.g., in patients with an isolated site of progression which can be treated with local therapy, those with mild and asymptomatic progression) (agree – 95.24%, disagree – 4.76%, and not sure – 0%)
  • The addition of chemotherapy to TKI after progression on first-line TKI is not recommended. TKI should be discontinued, and patients should be offered chemotherapy (agree – 85%, disagree – 10%, and not sure – 5%).


What should be the choice of therapy in patients of nonsmall cell lung cancer with anaplastic lymphoma kinase rearrangements?

Literature review

Results of a Phase III trial comparing ALK inhibition using crizotinib with chemotherapy in treatment-naïve patients have demonstrated a prolongation in PFS (median = 10.9 vs. 7.0 months; HR = 0.45; 95% CI = 0.35–0.60; P < 0.001) and improved response rate (ORR = 74% and 45%, respectively, P < 0.001) and quality of life. Since cross-over to crizotinib was permitted for those treated with chemotherapy, the majority of patients assigned to initial chemotherapy subsequently were treated with crizotinib. Because of the confounding effects of the crossover, no significant differences in OS were seen.[50] In a Phase III trial, comparing crizotinib in patients with ALK-positive lung cancer who had received one prior platinum-based regimen, crizotinib was superior to chemotherapy (pemetrexed or docetaxel) in delaying the risk of disease progression or death. The median PFS was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (HR = 0.49; 95% CI = 0.37–0.64; P < 0.001).[51] In a retrospective analysis of two single arm studies, it was shown that continuing ALK inhibition with crizotinib after PD may provide a survival benefit to patients with advanced ALK-positive NSCLC.[52] The median OS from the time of PD was 16.4 versus 3.9 months; HR = 0.27; 95% CI = 0.17–0.42; P < 0.0001, and from the time of initial crizotinib treatment was 29.6 versus 10.8 months; HR = 0.30; 95% CI = 0.19–0.46; P < 0.0001.

Consensus (the results of J-ALEX and ASCEND-4 trials were not available at the time of this consensus meeting)

  • Patients with ALK rearrangements should be treated with crizotinib in the upfront setting
  • In case the chemotherapy is started before ALK results are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to crizotinib before completion of 4–6 cycles is a valid option
  • In carefully selected patients (e.g., in patients with an isolated site of progression which can be treated with local therapy, those with mild and asymptomatic progression), crizotinib may be continued beyond progression.


What should be the choice of therapy in patients of nonsmall cell lung cancer with ROS1 rearrangements in the first line?

Literature review

In an open-label study of crizotinib in 50 patients with ROS1 translocation, the objective response rate was 72% (3 complete and 33 partial responses). The median duration of response was 17.6 months, and the median PFS was 19.2 months.[53] Similar response rates were observed in another retrospective series of 32 patients treated with crizotinib with ROS1 rearrangement.[54]

Consensus

  • Patients with ROS1 rearrangements should be treated with crizotinib in the upfront setting
  • In case the chemotherapy is started before ROS1 results are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to crizotinib before completion of 4–6 cycles is a valid option
  • Currently, there is no data regarding the use of ceritinib in patients with ROS1 mutations with acquired resistance to crizotinib. Chemotherapy remains an acceptable option in these patients.


What should be the choice of chemotherapy in patients of nonsmall cell lung cancer of squamous histology?

Literature review

Most of the studies evaluating chemotherapy regimens in the first-line setting did not report any differential efficacy in patients with squamous cell carcinoma (SCC). A retrospective analysis of four Southwest Oncology Group randomized studies did not show any correlation between histology and survival for the combination of platinum with paclitaxel, docetaxel, and vinorelbine.[55] Median OS in adenocarcinoma, SCC, large cell carcinoma, and NSCLC not otherwise specified was 8.5, 8.4, 8.2, and 9.6 months, respectively. In a trial comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed, an improved OS was demonstrated for patients with SCC treated with cisplatin plus gemcitabine (median OS = 10.8 vs. 9.4 months in cisplatin plus pemetrexed).[5]

Consensus

  • 4–6 cycles of platinum-doublet chemotherapy should be the standard of care for patients with SCC (agree – 100%, disagree – 0%, and not sure – 0%)
  • Platinum plus pemetrexed should not be used in patients with SCC (agree – 85.71%, disagree – 14.29%, and not sure – 0%)
  • Bevacizumab should not be used in patients with SCC because of the risk of severe bleeding (agree – 95.45%, disagree – 4.55%, and not sure – 0%).



 » Maintenance Therapy Top


Which patients should be offered maintenance therapy?

Literature review

In a large Phase III trial, switch maintenance therapy with pemetrexed after four cycles of nonpemetrexed containing platinum-based doublet (cisplatin or carboplatin plus gemcitabine, docetaxel, or paclitaxel) increased both median PFS (4.3 vs. 2.6 months; HR = 0.50; 95% CI = 0.42–0.61; P < 0.0001) and OS (13.4 vs. 10.6 months; HR = 0.79; 0.65–0.95; P = 0.012) compared with placebo. The benefits of pemetrexed were limited to patients with nonsquamous histology.[56] The PARAMOUNT trial evaluated continuous maintenance with pemetrexed in nonsquamous NSCLC patients who had an objective response or stable disease after four cycles of cisplatin plus pemetrexed. PFS and OS were significantly increased in the pemetrexed arm as compared to placebo arm. The median PFS was 4.1 months for pemetrexed and 2.8 months for placebo (HR = 0.62; 95% CI = 0.49–0.79; P < 0.0001), and median OS was 13.9 months for pemetrexed and 11.0 months for placebo (HR = 0.78; 95% CI = 0.64–0.96; P = 0.0195).[57],[58]

The SATURN trial evaluated erlotinib as maintenance treatment in advanced NSCLC treated with four cycles of platinum-based doublet chemotherapy. There was a modest increase in the PFS (HR = 0.78; 95% CI = 0.63–0.96; P = 0.0185) and OS (HR = 0.77; 95% CI = 0.61–0.97; P = 0.0243) in the EGFR WT patient population. Patients who harbored EGFR mutations had significant prolongation of PFS (HR = 0.10; 95% CI = 0.04–0.25; P < 0.0001).[59]

In a recent Phase III study (IUNO) of erlotinib in EGFR wild patients, OS was not superior in patients who received maintenance erlotinib compared with patients randomized to receive erlotinib on progression. In view of this, the US prescribing information of erlotinib is being revised to limit NSCLC indications to patients with EGFR exon 19 deletions or exon 21 (L858R) substitutions.[60],[61]

Consensus

  • NSCLC patients of nonsquamous histology who have any response or stable disease after 4–6 cycles of first-line chemotherapy are appropriate candidates for maintenance chemotherapy (agree – 100%, disagree – 0%)
  • Maintenance should be continued until progression or unacceptable adverse events (agree – 100%, disagree – 0%)
  • For patients whose initial regimen included bevacizumab, it may be continued as maintenance treatment in the absence of unacceptable toxicity or disease progression (agree – 100%, disagree – 0%)
  • In NSCLC patients without driver mutations:
    • Maintenance therapy with pemetrexed is preferred (agree – 100%, disagree – 0%)
    • EGFR TKIs should not be offered as maintenance therapy in patients who are EGFR WT (agree – 100%, disagree – 0%)
    • Pemetrexed or bevacizumab maintenance should not be used in patients with squamous histology (agree – 100%, disagree – 0%).
  • In NSCLC patients with EGFR mutation or ALK/ROS1 translocation:
    • For patients with advanced NSCLC who were initially treated with chemotherapy but in whom EGFR mutation or ALK/ROS1 translocation has subsequently been identified, a continuation of therapy is indicated with an appropriately targeted agent after the initial cycles of chemotherapy are complete (agree – 100%, disagree – 0%).



 » Second-Line Therapy Top


What should be the appropriate choice of therapy in patients of nonsmall cell lung cancer of nonsquamous histology without driver mutation after progression on first-line chemotherapy?

Literature review

A Phase III trial randomized previously treated NSCLC patients with docetaxel (100 or 75 mg/m 2 every 3 weeks) or best supportive care. Patients assigned to docetaxel 75 mg/m 2 had significantly longer OS (7.5 vs. 4.6 months; log-rank test, P = 0.010), improved pain control, and significantly less deterioration in the quality of life compared to best supportive care.[62],[63] In a secondary analysis of head-to-head trials of pemetrexed versus docetaxel, the OS was significantly longer in patients randomized to pemetrexed in patients of nonsquamous histology (median OS = 9.3 vs. 8.0 months, HR = 0.78; 95% CI = 0.61–1.00) with less Grade 3–4 adverse events.[64],[65],[66]

The addition of nintedanib (an oral triple angiokinase inhibitor) and ramucirumab to docetaxel has been shown to improve OS, particularly in patients who progress within 9 months and who have PD as the best response to first-line chemotherapy (refractory patients) from the start of first-line chemotherapy.[67],[68]

Nivolumab compared to docetaxel significantly prolonged OS in NSCLC patients of nonsquamous histology who progressed on first-line chemotherapy in CheckMate 057 trial.[69] The median OS was 12.2 months (95% CI = 9.7–15.0) in the nivolumab arm and 9.4 months (95% CI = 8.1–10.7) in the docetaxel arm (HR for death = 0.73; 96% CI = 0.59–0.89; P = 0.002). At 1 year and 18 months, the OS rate was 51% (95% CI = 45–56) and 39% (95% CI = 34–45) with nivolumab versus 39% (95% CI = 33–45) and 23% (95% CI = 19–28) with docetaxel, respectively. However, patients with aggressive disease and with low programmed death-ligand 1 (PD-L1) expression may be at a risk of early deaths.[70] Treatment-related adverse events of Grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.

Another immune checkpoint inhibitor, pembrolizumab has also shown promising efficacy patients with ≥1% of PD-L1 expression who progressed after first-line chemotherapy in two different clinical trials KEYNOTE-001 and KEYNOTE-010 study.[71],[72] In KEYNOTE-010 study, previously treated NSCLC patients with PD-L1 expression on at least 1% of tumor cells were randomly assigned to pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m 2 every 3 weeks. OS was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (HR = 0.71; 95% CI = 0.58–0.88; P = 0.0008) and pembrolizumab 10 mg/kg versus docetaxel (HR = 0.61; 95% CI = 0.49–0.75; P < 0.0001). Grade 3–5 treatment-related adverse events were 13% with 2 mg/kg and 16% with 10 mg/kg compared to 35% with docetaxel.

In the BR 21 trial, erlotinib improved OS versus placebo (6.7 months in erlotinib vs. 4.7 months in the placebo, HR = 0.70; P < 0.001) in the second line or third line in all NSCLC histological subtype patients not eligible for further chemotherapy, including patients with PS 3.[73] The TITAN trial compared erlotinib to pemetrexed or docetaxel in NSCLC patients who progressed during or immediately after first-line chemotherapy.[74] There was no difference in OS in patients treated with erlotinib and those treated with docetaxel or pemetrexed. In the INTEREST trial, patients were treated with gefitinib or docetaxel, and there was no difference in OS.[75] The DELTA trial compared erlotinib to docetaxel as second- or third-line therapy. There was no difference in the OS. However, for EGFR WT patients, PFS was significantly greater with docetaxel than erlotinib.[76] In the TAILOR trial comparing erlotinib to docetaxel as second-line therapy, PFS and OS durations were significantly better with docetaxel compared with erlotinib.[77]

Consensus

  • Patients with good PS should be offered second-line therapy (agree – 100%, disagree – 0%)
  • PD-L1 testing is not required for nivolumab. For pembrolizumab, PD-L1 testing is required (agree – 100%, disagree – 0%)
  • PD-L1 testing should be done on the approved diagnostic kit (agree – 100%, disagree – 0%)
  • For patients who are PD-L1 negative/unknown, nivolumab may be considered. For those with PD-L1 > 50%, either nivolumab or pembrolizumab may be considered (agree – 100%, disagree – 0%)
  • For those with rapid progression (<9 months from the start of first-line therapy) and those with PD as the best response to first-line therapy, docetaxel + nintedanib/ramucirumab are acceptable options (agree – 100%, disagree – 0%)
  • For those who cannot afford the above treatments, single-agent docetaxel or pemetrexed (if not used in the first line) are preferred options (agree – 100%, disagree – 0%)
  • EGFR TKIs can be used as second-line therapy in EGFR WT patients who are unwilling for chemotherapy/immunotherapy and may be an option in patients who have poor PS or who are unwilling for chemotherapy or immunotherapy (agree – 100%, disagree – 0%).


What should be the appropriate choice of therapy in nonsmall cell lung cancer patients with epidermal growth factor receptor mutations after progression on first-line therapy?

Literature review

Clinical trials evaluating the first-generation EGFR TKIs in patients with EGFR mutation positive NSCLC have shown that whether EGFR TKIs are given in upfront setting or after progression on chemotherapy, the OS remains same.[14],[15],[16],[17],[18],[19],[20],[21] Therefore, in patients who are offered chemotherapy doublet in the first line must be treated with an EGFRTKI once their disease progress on first-line chemotherapy.

Almost all EGFR-mutated patients who are treated with an EGFR TKI subsequently develop disease progression. T790M mutation in EGFR has been associated with acquired resistance to EGFR TKIs in up to 60% of these cases. Amplification of the MET oncogene has been associated with resistance to EGFR TKIs in 5%–10% of cases. In addition, analyses of tumor tissue have observed the histologic transformation of EGFR mutation-positive NSCLC into small cell lung cancer in approximately 5% of cases.[78]

Osimertinib has shown activity in patients with acquired resistance to a prior EGFR inhibitor. In Phase I/II study, osimertinib showed a response rate of 61% in patients with T790M mutation and median PFS of 10 months. For those whose tumors did not contain the T790M mutation, the response rate was 21%, and the median PFS was 3 months.[79]

Consensus

  • EGFR-mutated patients who were treated with combination chemotherapy in the first line should be offered EGFR TKIs (afatinib, erlotinib, and gefitinib) in the second line if not already treated with EGFR TKIs in the maintenance setting
  • Patients who progress on first-line EGFR TKI must be tested for the T790M mutation on either rebiopsy or cell block or ctDNA (agree – 57.89%, disagree – 21.05%, and not sure – 21.05%)
  • In patients with documented T790M mutation after treatment with the first-/second- generation TKIs, a third-generation TKI-like osimertinib should be considered. In the case of nonavailability of osimertinib, chemotherapy is an acceptable option
  • Combination chemotherapy should be preferred as second-line treatment option in patients who were treated with EGFR TKIs in the first line and who are T790M unknown or T790M −ve
  • Patients who transition to small cell lung cancer should be treated with appropriate chemotherapy.


What should be the choice of therapy in nonsmall cell lung cancer patients with anaplastic lymphoma kinase translocations after progression on first-line crizotinib?

Literature review

While crizotinib is highly active in patients with ALK-positive NSCLC, the majority of the patients will develop resistance to the drug. In a Phase I study, ceritinib has been shown to be efficacious in patients who have progressed on crizotinib with a response rate of 56% and median PFS of 6.9 months.[80]

Consensus

  • Patients with ALK-positive NSCLC who have progressed on crizotinib may be offered ceritinib
  • Chemotherapy remains an acceptable option for patients who progress on crizotinib.


What should be the appropriate choice of therapy in patients of nonsmall cell lung cancer of squamous histology after progression on first-line chemotherapy?

Literature review

Docetaxel 75 mg/m 2 significantly prolonged OS as second-line treatment of NSCLC with improved pain control and significantly less deterioration in the quality of life compared to best supportive care.[62],[63] Ramucirumab added to docetaxel has shown to improve PFS (4.5 vs. 3 months, P < 0.0001) and OS (median OS = 10.5 vs. 9.1 months, HR = 0.86; 95% CI = 0.75–0.98; P = 0.023) compared to docetaxel alone regardless of the histology.[68] Erlotinib improved OS in the second line or third line in all NSCLC histological subtype patients not eligible for further chemotherapy, including patients with PS 3. The median OS in patients with squamous cell histology was 5.6 months with erlotinib versus 3.6 months with placebo HR = 0.67 (0.50–0.90).[73] In the TAILOR trial comparing erlotinib to docetaxel as second-line therapy, PFS and OS durations were significantly better with docetaxel compared with erlotinib in the overall population. However, in patients with squamous cell histology, OS was similar between erlotinib and docetaxel arm (HR for OS = 0.90; 95% CI = 0.49–1.65).[77] A meta-analysis of 8 randomized trials has shown that the OS was similar between TKI and chemotherapy in unselected patient population in the second line.[81] In another meta-analysis carried out on six randomized controlled trials with a total of 990 patients with WT EGFR, PFS was significantly inferior in the EGFR TKI group versus the chemotherapy group (HR = 1.37; 95% CI = 1.20–1.56; P < 0.00001). However, this did not translate into an OS difference (HR = 1.02; 95% CI = 0.87–1.20; P = 0.81).[82] For those progressing on a platinum doublet, the second-generation TKI, afatinib was found to be superior to erlotinib in terms of OS (7.9 vs. 6.8 months HR = 0.81; 95% CI = 0.69–0.95; P = 0.0077).[83]

In a Phase III (CheckMate 017) trial, nivolumab (3 mg/kg every 2 weeks) was shown to be superior to docetaxel in reducing the risk of death by 41% in patients previously treated for SCC. The median OS was 9.2 months (95% CI = 7.3–13.3) with nivolumab versus 6.0 months (95% CI = 5.1–7.3) with docetaxel. At 1 year, the OS rate was 42% (95% CI = 34–50) with nivolumab versus 24% (95% CI = 17–31) with docetaxel. The benefit of nivolumab was irrespective of PD-L1 expression.[84] An updated follow-up reported an 18-month OS of 28% and 13% in the nivolumab and docetaxel arms.[85] In Phase II/III KEYNOTE-010 trial, 1034 patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were to randomized to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m 2 every 3 weeks. 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 vs. 8.2 months; HR = 0.54; 95% CI = 0.38–0.77; P = 0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (median = 17.3 vs. 8.2 months; HR - 0.50, 95% CI = 0.36–0.70; P < 0.0001).[72]

Consensus

  • Patients with good PS should be offered second-line therapy
  • Nivolumab or pembrolizumab is preferred agents for the treatment of NSCLC of squamous histology after progression on first-line chemotherapy:
    • For patients who are PD-L1 negative/unknown, nivolumab may be considered. For those with PD-L1 >50%, either nivolumab or pembrolizumab may be considered
  • PD-L1 testing is not required for nivolumab. For pembrolizumab, PD-L1 testing is required. PD-L1 testing should be done on the approved diagnostic kit
  • Single-agent chemotherapy and TKIs are also acceptable options. Afatinib may be preferred over erlotinib based on superior OS data.


What should be the treatment of choice for nonsmall cell lung cancer patients with brain metastases?

Literature review

Conventional treatment of symptomatic brain metastatic has been whole brain radiotherapy (WBRT) along with supportive care including steroids. In routine clinical practice, the prognostic indices such as recursive partitioning analysis (RPA) and graded prognostic assessment help to differentiate the patients' groups in various survival cohorts. Patients with higher RPA class (Class III) has poor survival than in Class I patients. Their indices are based on performance score, age, number of brain metastasis, and presence of other extracranial disease. WBRT traditionally is believed to improve the quality of life, disease-free survival, and OS. Contrary to the popular practice recent trial of WBRT with steroids versus steroids alone did not demonstrate an improved survival benefit.[86] Apart from this, WBRT demonstrated a short-term cognitive decline in comparisons to patients who were treated with focal treatment. However, these trial had a small number of patients and very small volume disease and <4 metastases.[87] These approaches require intensive imaging surveillance and fraught with increased number of progression in brain other than the area treated in the brain.

In patients with solitary brain metastases where surgical resection is feasible, surgery is advisable, and if surgery is not feasible because tumor is in the eloquent area, focal treatment alone or with WBRT has been recommended.[88],[89] However, addition of WBRT to focal treatment did not yield improved OS benefit.[90] To decrease local recurrences at resection cavities depending volume of the cavity and residual disease high-dose focal radiotherapy has shown to decrease local recurrences at resection cavities.[91]

In patients with a druggable oncogene driver (EGFR, ALK), 45%–60% develop brain metastases in the course of their disease.[92] In such patients, treatment with targeted therapy has shown to improve the outcomes.[93],[94],[95],[96],[97],[98] In prespecified subgroup analyses of EGFR mutation-positive patients with brain metastases enrolled in two Phase III studies, the magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases.[95] The median PFS in patients with brain metastases treated with afatinib was 8.2 versus 5.2 months with chemotherapy (HR = 0.50; P = 0.0297). Crizotinib has been shown to control intracranial disease in patients with ALK-rearranged NSCLC. The intracranial disease control rate (DCR) was 56% and 62% in patients with previously untreated asymptomatic brain metastases and previously treated brain metastases, respectively.[96] In a retrospective review of 94 ALK-rearranged NSCLC patients with brain metastases in a Phase I expansion study of ceritinib, intracranial DCR was reported in 65.3% of crizotinib-pretreated patients and 78.9% of ALK inhibitor-naive patients.[97]

Consensus

  • Treatment of patients with brain metastases depends on age and Karnofsky index
  • RPA Class I and II patients with >3 METs may be treated with WBRT
  • Stereotactic radiosurgery (SRS) may be a reasonable option in carefully selected patients with limited disease
  • In RPA Class III patients, BSC is recommended (agree – 35.29%, disagree – 41.18%, and neutral – 25.53%)
  • Patients with single brain metastases may be treated with either surgical resection or SRS/stereotactic radiotherapy (SRT):
    • Single large symptomatic metastases should be treated with surgery
    • SRS/SRT is a reasonable alternative to surgery for small (<3 cm) and inaccessible tumors.
  • Patients of RPA Class I and II with 1–3 small brain metastases (<3 cm) should be treated with SRS/SRT alone rather than SRS + WBRT (agree – 76.47%, disagree – 23.53%, and not sure – 0%)
  • WBRT is a reasonable option in patients who are not candidates of surgery or whose lesions are too large for radiosurgery (agree – 94.44%, disagree – 5.56%, and not sure – 0%)
  • Patients treated with surgical resection or SRS should have follow-up magnetic resonance imaging (MRI) every 3 months (agree – 88.89%, disagree – 11.11%, and not sure – 0%)
  • Dexamethasone is recommended for patients with symptomatic brain metastases (agree – 100%, disagree – 0%, and not sure – 0%)
  • In patients with druggable oncogenic driver mutation and asymptomatic brain metastases, TKIs may control the brain disease and defer WBRT (agree – 58.82%, disagree – 41.18%, and not sure – 0%)
  • For patients with symptomatic metastases, radiotherapy should be preferred (agree – 100%, disagree – 0%, and not sure – 0%)
  • ALK-positive patients with brain metastases who progress on crizotinib may benefit from ceritinib (agree – 94.12%, disagree – 0%, and not sure – 5.88%)
  • Patients should have follow-up MRI/computed tomography/imaging done every 3 months.


What are the recommendations for the treatment of nonsmall cell lung cancer with oligometastatic disease?

Oligometastatic disease in NSCLC refers to 1–5 disease sites separate from the primary.[99] Patients with oligometastatic NSCLC do not always progress to widespread metastases.[100] Appropriately selected patients can be treated with metastasis-directed surgical or ablative procedures. Identification of such patients is of utmost importance. Factors associated with improved OS in oligometastatic disease include metachronous metastases, better PS, limited nodal disease, the presence of EGFR mutation, and metastases limited to one organ.[101],[102],[103] Surgical resection or definitive radiotherapy of intracranial and extracranial oligometastatic disease has been shown to have a positive effect on survival rates.[104],[105],[106],[107],[108],[109],[110]

In patients who have more than one pulmonary site of cancer, sometimes it can be difficult to distinguish between a second primary and metastasis. The International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee conducted a systematic review to develop clinical and pathologic criteria to identify two foci as separate primary lung cancers versus a metastasis. IASLC recommended a careful review by a multidisciplinary tumor board, and the pursuit of radical therapy, such as that for a synchronous secondary primary tumor, when possible.[111] SRS and surgery have been shown to result in long-term survivors in such patients.[110],[112],[113] Use of targeted agents combined with ablative doses of radiation in the oligometastatic setting has resulted in promising outcomes.[109],[114]

Consensus

  • Stage IV NSCLC patients with synchronous or metachronous oligometastasis may benefit from surgery and/or radiation therapy. Metachronous oligometastases have a better prognosis than synchronous
  • Every attempt must be made to biopsy the second primary tumor in the lung and may be treated with radical intent if possible
  • For patients with oligometastatic recurrence or progression while on targeted therapy, SBRT may be offered to the progressing sites (agree – 42.86%, disagree – 57.14%, and not sure – 0%).


What are the investigations recommended at the time of disease progression?

Scenario 1

Patient of nonsquamous histology has not been tested in the first line and treated with chemotherapy doublet

Literature Review

Literature suggests that the incidence of EGFR mutations in the Indian population varies from 25% to 30% and that of ALK rearrangement varies from 2.5% to 7%. Data from the clinical trials of EGFR TKIs suggest that there is OS benefit even if the patients with EGFR mutations are treated with EGFR TKIs after progression on chemotherapy.[23],[24],[25],[26],[27],[28],[29],[34],[115] The same is true for patients with ALK rearrangements also.[51]



Nivolumab compared to docetaxel significantly prolonged OS in NSCLC patients of nonsquamous histology who progressed on first-line chemotherapy in CheckMate 057 trial.[69] Longer OS and PFS and higher objective response rates were seen with nivolumab at higher levels of PD-L1 expression. Pembrolizumab has also shown promising efficacy patients with ≥50% PD-L1 who progressed after first-line chemotherapy in two different clinical trials.[71],[72]


 » Consensus Top


  • All attempt must be made to get the specimen of the tissue using biopsy or cell block (if biopsy is not possible)
  • All NSCLC patients of nonsquamous histology who progress on chemotherapy should be tested for EGFR, ALK, and ROS status if not tested previously
  • Biopsy or cell block (if biopsy specimen is not available) should be used for EGFR or ALK testing
  • ctDNA may be acceptable in cases where mutation status cannot be established either by biopsy or cell block
  • PD-L1 testing on biopsy specimen should be done after progression on first-line chemotherapy if the patient is planned to be treated with pembrolizumab
  • PD-L1 testing is not required for nivolumab
  • PD-L1 testing should be done on the approved diagnostic kit.


Scenario 2

Patient is epidermal growth factor receptor mutation positive and treated with epidermal growth factor receptor tyrosine kinase inhibitors in the first line

Almost all EGFR-mutated patients who are treated with an EGFR TKI subsequently develop disease progression. T790M mutation in EGFR has been associated with acquired resistance to EGFR TKIs in up to 60% of the cases. Amplification of the MET oncogene has been associated with resistance to EGFR TKIs in 5%–10% of cases. In addition, analyses of tumor tissue have observed the histologic transformation of EGFR mutation-positive NSCLC into small cell lung cancer in approximately 5% of cases. Some patients may develop resistance by Her2 mutation/amplification.[78] Osimertinib has shown activity in patients with acquired resistance to a prior EGFR inhibitor. In Phase I/II study, osimertinib showed a response rate of 61% in patients with T790M mutation and median PFS of 10 months.[79] Afatinib and trastuzumab have shown to be effective in patients with mutations in the kinase domain of Her2/neu.[116],[117] In patients with MET amplification, crizotinib has been found to be effective.[118],[119]


 » Consensus Top


  • Patients who progress on first-line EGFR TKI testing for the T790M mutation on either rebiopsy or cell block of FNAC specimen or ctDNA should be considered
  • An effort should be made to reanalyze the histology of the tumor on the rebiopsy specimen for diagnosing transition into small cell lung cancer
  • If feasible following additional analysis should be performed on rebiopsy or cell block of FNAC specimen
    • Her2 mutation/amplification
    • MET amplification.


What investigations should be performed in patients of squamous cell histology progressing on chemotherapy doublet?

In India, the data from the Tata Memorial Hospital suggest that ~6% of patients of squamous histology may harbor EGFR mutations.[120] Data suggest that patients with EGFR mutations benefit from EGFR-directed therapies. In a Phase III (CheckMate 017) trial, nivolumab (3 mg/kg every 2 weeks) was shown to be superior to docetaxel in reducing the risk of death irrespective of PD-L1 expression.[84] In Phase II/III KEYNOTE-010 trial, 1034 patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were to randomized to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m 2 every 3 weeks. 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 vs. 8.2 months; HR = 0.54; 95% CI = 0.38–0.77; P = 0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 vs. 8.2 months; 0.50, 0.36–0.70; P < 0.0001).[72]

Consensus

  • EGFR testing may be done routinely in patients with squamous cell histology in the first line or on rebiopsy sample once patients progress on chemotherapy doublet
  • PD-L1 testing should be done for second-line SCC before prescribing pembrolizumab
  • PD-L1 testing is not required for nivolumab
  • PD-L1 testing should be done on the approved diagnostic kit.


Acknowledgement

The following authors have contributed to the development of the consensus statements.

Dr. Abdul Rashid Lone, Dr. Amit Agarwal, Dr. Amit Joshi, Dr. Anantbhushan Ranade, Dr. Ashok Kumar Vaid, Dr. Ashutosh Gupta, Dr. B.K. Smruti, Dr. B.K. Mishra, Dr. C. Sairam, Dr. Chirag Desai, Dr. Deepak Abrol, Dr. Deepak Dabkara, Dr. Dinesh Chandra Doval, Dr. Govind Babu, Dr. Joydeep Ghosh, Dr. J.P. Agarwal, Dr. Kajal Shah, Dr. Kishore Kumar, Dr. Madhuchanda Kar, Dr. Manish Kumar, Dr. Naresh Somani, Dr. Navneet Singh, Dr. Nikhil Ghadyal Patil, Dr. Palanki Satya Dattatreya, Dr. Pavithran K, Dr. Peush Bajpai, Dr. Prakash Devde, Dr. Prasad Narayanan, Dr. Purvish M Parikh, Dr. Raj Kumar Shrimali, Dr. Rajeshwar Singh, Dr. Raju Titus Chacko, Dr. S. Subramanian, Dr. Senthil Rajappa, Dr. Sewanti Limaye, Dr. Shailesh Bondarde, Dr. Shekar Patil, Dr. Shyam Aggarwal, Dr. Smita Gupte, Dr. T. Raja, Dr. Tarini Prasad Sahoo, Dr. Tejinder Singh, Dr. TVS Tilak, Dr. Ullas Batra, Dr. Vanita Noronha, Dr. Vijay Patil

Financial support and sponsorship

This manuscript has been prepared under the aegis of Lung Cancer Consortium Asia (LCCA), Indian Cooperative Oncology Network (ICON), Indian Society of Medical & Pediatric Oncology (ISMPO), Molecular Oncology Society (MOS) and Association of Physicians of India API).

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 2012;30:2055-62.  Back to cited text no. 1
[PUBMED]    
2.
Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 2003;98:542-53.  Back to cited text no. 2
    
3.
Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317-23.  Back to cited text no. 3
[PUBMED]    
4.
Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: A multicenter, randomized, phase II trial. Clin Cancer Res 2005;11(2 Pt 1):690-6.  Back to cited text no. 4
    
5.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, 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;26:3543-51.  Back to cited text no. 5
[PUBMED]    
6.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8.  Back to cited text no. 6
[PUBMED]    
7.
NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617-25.  Back to cited text no. 7
[PUBMED]    
8.
Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: A meta-analysis. JAMA 2004;292:470-84.  Back to cited text no. 8
[PUBMED]    
9.
Bronte G, Rolfo C, Passiglia F, Rizzo S, Gil-Bazo I, Fiorentino E, et al. What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis. Crit Rev Oncol Hematol 2015;95:306-17.  Back to cited text no. 9
[PUBMED]    
10.
Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999;91:66-72.  Back to cited text no. 10
[PUBMED]    
11.
Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95:362-72.  Back to cited text no. 11
[PUBMED]    
12.
Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, 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;378:1079-88.  Back to cited text no. 12
    
13.
Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, et al. Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 2006;7:338-43.  Back to cited text no. 13
[PUBMED]    
14.
Li M, Zhang Q, Fu P, Li P, Peng A, Zhang G, et al. Pemetrexed plus platinum as the first-line treatment option for advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials. PLoS One 2012;7:e37229.  Back to cited text no. 14
[PUBMED]    
15.
Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013;24:20-30.  Back to cited text no. 15
[PUBMED]    
16.
Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: The TORCH randomized trial. J Clin Oncol 2012;30:3002-11.  Back to cited text no. 16
[PUBMED]    
17.
Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, et al. Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 2013;8:e76164.  Back to cited text no. 17
[PUBMED]    
18.
Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer 2011;73:316-9.  Back to cited text no. 18
[PUBMED]    
19.
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.  Back to cited text no. 19
[PUBMED]    
20.
Doval DC, Azam S, Batra U, Choudhury KD, Talwar V, Gupta SK, et al. Epidermal growth factor receptor mutation in lung adenocarcinoma in India: A single center study. J Carcinog 2013;12:12.  Back to cited text no. 20
[PUBMED]  [Full text]  
21.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014;9:1345-53.  Back to cited text no. 21
[PUBMED]    
22.
Nilsson RJ, Karachaliou N, Berenguer J, Gimenez-Capitan A, Schellen P, Teixido C, et al. Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 2016;7:1066-75.  Back to cited text no. 22
    
23.
Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-9.  Back to cited text no. 23
[PUBMED]    
24.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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;13:239-46.  Back to cited text no. 24
[PUBMED]    
25.
Sebastian M, Schmittel A, Reck M. First-line treatment of EGFR-mutated nonsmall cell lung cancer: Critical review on study methodology. Eur Respir Rev 2014;23:92-105.  Back to cited text no. 25
[PUBMED]    
26.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, 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;12:735-42.  Back to cited text no. 26
[PUBMED]    
27.
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, 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;29:2866-74.  Back to cited text no. 27
[PUBMED]    
28.
Yang J, Wu YL, Saijo N, Thongprasert S, Chu DT, Chen YM, et al. Efficacy outcomes in first-line treatment of advanced NSCLC with gefitinib (G) vs. carboplatin/paclitaxel (C/P) by epidermal growth factor receptor (EGFR) gene-copy number score and by most common EGFR mutation subtypes – exploratory data from IPASS. Eur J Cancer 2011;47:S633.  Back to cited text no. 28
    
29.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, et al., editors. Updated Overall Survival Results of WJTOG 3405, a Randomized Phase III Trial Comparing Gefitinib (G) with Cisplatin Plus Docetaxel (CD) as the First-line Treatment for Patients with Non-small Cell Lung Cancer Harboring Mutations of the Epidermal Growth Factor Receptor (EGFR). ASCO Annual Meeting Proceedings; 2012.  Back to cited text no. 29
    
30.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54-9.  Back to cited text no. 30
[PUBMED]    
31.
Lee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: A meta-analysis. J Clin Oncol 2015;33:1958-65.  Back to cited text no. 31
[PUBMED]    
32.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.  Back to cited text no. 32
    
33.
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-22.  Back to cited text no. 33
[PUBMED]    
34.
Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16:141-51.  Back to cited text no. 34
[PUBMED]    
35.
Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol 2016;34:3248-57.  Back to cited text no. 35
[PUBMED]    
36.
Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al. A randomized controlled trial of erlotinib versus gefitinib in advanced non-small-cell lung cancer harboring EGFR mutations (CTONG0901). J Thorac Oncol 2015;10:S321.  Back to cited text no. 36
    
37.
Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-89.  Back to cited text no. 37
    
38.
Paz-Ares L, Tan E, Zhang L, Hirsh V, O'Byrne K, Boyer M, et al. Afatinib (A) vs. gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC): Overall survival (OS) data from the phase IIb trial LUX-Lung 7 (LL7). Ann Oncol 2016;27:LBA43.  Back to cited text no. 38
    
39.
Arrieta O, Cardona AF, Corrales L, Campos-Parra AD, Sánchez-Reyes R, Amieva-Rivera E, et al. The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer. Lung Cancer 2015;87:169-75.  Back to cited text no. 39
    
40.
Baek JH, Sun JM, Min YJ, Cho EK, Cho BC, Kim JH, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: A retrospective analysis in Korea. Lung Cancer 2015;87:148-54.  Back to cited text no. 40
[PUBMED]    
41.
Keam B, Kim DW, Park JH, Lee JO, Kim TM, Lee SH, et al. Rare and complex mutations of epidermal growth factor receptor, and efficacy of tyrosine kinase inhibitor in patients with non-small cell lung cancer. Int J Clin Oncol 2014;19:594-600.  Back to cited text no. 41
[PUBMED]    
42.
Lohinai Z, Hoda MA, Fabian K, Ostoros G, Raso E, Barbai T, et al. Distinct epidemiology and clinical consequence of classic versus rare EGFR mutations in lung adenocarcinoma. J Thorac Oncol 2015;10:738-46.  Back to cited text no. 42
[PUBMED]    
43.
Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014;9:189-94.  Back to cited text no. 43
[PUBMED]    
44.
Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-8.  Back to cited text no. 44
[PUBMED]    
45.
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-9.  Back to cited text no. 45
    
46.
De Pas T, Toffalorio F, Manzotti M, Fumagalli C, Spitaleri G, Catania C, et al. Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. J Thorac Oncol 2011;6:1895-901.  Back to cited text no. 46
[PUBMED]    
47.
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812-21.  Back to cited text no. 47
[PUBMED]    
48.
Park K, Yu CJ, Kim SW, Lin MC, Sriuranpong V, Tsai CM, et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: The ASPIRATION Study. JAMA Oncol 2016;2:305-12.  Back to cited text no. 48
[PUBMED]    
49.
Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): A phase 3 randomised trial. Lancet Oncol 2015;16:990-8.  Back to cited text no. 49
[PUBMED]    
50.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77.  Back to cited text no. 50
[PUBMED]    
51.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94.  Back to cited text no. 51
    
52.
Ou SH, Jänne PA, Bartlett CH, Tang Y, Kim DW, Otterson GA, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol 2014;25:415-22.  Back to cited text no. 52
    
53.
Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70.  Back to cited text no. 53
[PUBMED]    
54.
Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J Clin Oncol 2015;33:992-9.  Back to cited text no. 54
    
55.
Kelly K, Chansky K, Mack PC, Lara PN Jr., Hirsch FR, Franklin WA, et al. Chemotherapy outcomes by histologic subtypes of non-small-cell lung cancer: Analysis of the Southwest oncology group database for antimicrotubule-platinum therapy. Clin Lung Cancer 2013;14:627-35.  Back to cited text no. 55
    
56.
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 2009;374:1432-40.  Back to cited text no. 56
[PUBMED]    
57.
Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, 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;13:247-55.  Back to cited text no. 57
[PUBMED]    
58.
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, 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;31:2895-902.  Back to cited text no. 58
[PUBMED]    
59.
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9.  Back to cited text no. 59
    
60.
Important Correction to Drug Information – Genentech. Available from: http://www.gene.com/download/pdf/Tarceva_DHCP_Letter_June2016.pdf. [Last Accessed on 2016 Nov 05].  Back to cited text no. 60
    
61.
European Product Assessment Report. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000618/WC500203053.pdf. [Last Accessed on 2016 Nov 05].  Back to cited text no. 61
    
62.
Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, 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 2000;18:2095-103.  Back to cited text no. 62
    
63.
Dancey J, Shepherd FA, Gralla RJ, Kim YS. Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 2004;43:183-94.  Back to cited text no. 63
[PUBMED]    
64.
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, 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 2004;22:1589-97.  Back to cited text no. 64
[PUBMED]    
65.
Pujol JL, Paul S, Chouaki N, Peterson P, Moore P, Berry DA, et al. Survival without common toxicity criteria grade 3/4 toxicity for pemetrexed compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): A risk-benefit analysis. J Thorac Oncol 2007;2:397-401.  Back to cited text no. 65
[PUBMED]    
66.
Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, et al. The differential efficacy of pemetrexed according to NSCLC histology: A review of two Phase III studies. Oncologist 2009;14:253-63.  Back to cited text no. 66
[PUBMED]    
67.
Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-55.  Back to cited text no. 67
[PUBMED]    
68.
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, 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 2014;384:665-73.  Back to cited text no. 68
[PUBMED]    
69.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.  Back to cited text no. 69
[PUBMED]    
70.
Opdivo European Product Assessment Report; 2016. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/003985/WC500205973.pdf. [Last Accessed on 2016 Nov 05].  Back to cited text no. 70
    
71.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28.  Back to cited text no. 71
[PUBMED]    
72.
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50.  Back to cited text no. 72
    
73.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.  Back to cited text no. 73
[PUBMED]    
74.
Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, 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 2012;13:300-8.  Back to cited text no. 74
[PUBMED]    
75.
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809-18.  Back to cited text no. 75
[PUBMED]    
76.
Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014;32:1902-8.  Back to cited text no. 76
[PUBMED]    
77.
Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, 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;14:981-8.  Back to cited text no. 77
[PUBMED]    
78.
Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013;31:1070-80.  Back to cited text no. 78
[PUBMED]    
79.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.  Back to cited text no. 79
    
80.
Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97.  Back to cited text no. 80
[PUBMED]    
81.
Li N, Yang L, Ou W, Zhang L, Zhang SL, Wang SY. Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer. PLoS One 2014;9:e102777.  Back to cited text no. 81
[PUBMED]    
82.
Zhao N, Zhang XC, Yan HH, Yang JJ, Wu YL. Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials. Lung Cancer 2014;85:66-73.  Back to cited text no. 82
[PUBMED]    
83.
Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, 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 2015;16:897-907.  Back to cited text no. 83
[PUBMED]    
84.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.  Back to cited text no. 84
    
85.
Reckamp K, Brahmer JR, Spigel DR, Rizvi NA, Poddubskaya E, West H, et al. Phase 3, randomized trial (CheckMate 017) of nivolumab (NIVO) vs. docetaxel in advanced squamous (SQ) cell non-small cell lung cancer (NSCLC). J Thorac Oncol 2015;10:S174-5.  Back to cited text no. 85
    
86.
Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388:2004-14.  Back to cited text no. 86
[PUBMED]    
87.
Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs. radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A Randomized Clinical Trial. JAMA 2016;316:401-9.  Back to cited text no. 87
[PUBMED]    
88.
Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: A practice guideline. Curr Oncol 2007;14:131-43.  Back to cited text no. 88
[PUBMED]    
89.
Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: A systematic review. Med Sci Monit 2015;21:144-52.  Back to cited text no. 89
[PUBMED]    
90.
Soon YY, Tham IW, Lim KH, Koh WY, Lu JJ. Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane Database Syst Rev. 2014:CD009454.  Back to cited text no. 90
[PUBMED]    
91.
Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study. Lancet Oncol 2014;15:387-95.  Back to cited text no. 91
[PUBMED]    
92.
Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015;88:108-11.  Back to cited text no. 92
[PUBMED]    
93.
Zhang J, Yu J, Sun X, Meng X. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from non-small cell lung cancer. Cancer Lett 2014;351:6-12.  Back to cited text no. 93
[PUBMED]    
94.
Watanabe S, Hayashi H, Nakagawa K. Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer? Ann Transl Med 2016;4:225.  Back to cited text no. 94
[PUBMED]    
95.
Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol 2016;11:380-90.  Back to cited text no. 95
    
96.
Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 2015;33:1881-8.  Back to cited text no. 96
[PUBMED]    
97.
Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): Updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 2016;17:452-63.  Back to cited text no. 97
[PUBMED]    
98.
Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012;77:556-60.  Back to cited text no. 98
[PUBMED]    
99.
Palma DA, Salama JK, Lo SS, Senan S, Treasure T, Govindan R, et al. The oligometastatic state – Separating truth from wishful thinking. Nat Rev Clin Oncol 2014;11:549-57.  Back to cited text no. 99
[PUBMED]    
100.
Mehta N, Mauer AM, Hellman S, Haraf DJ, Cohen EE, Vokes EE, et al. Analysis of further disease progression in metastatic non-small cell lung cancer: Implications for locoregional treatment. Int J Oncol 2004;25:1677-83.  Back to cited text no. 100
[PUBMED]    
101.
Ashworth AB, Senan S, Palma DA, Riquet M, Ahn YC, Ricardi U, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346-55.  Back to cited text no. 101
[PUBMED]    
102.
Parikh RB, Cronin AM, Kozono DE, Oxnard GR, Mak RH, Jackman DM, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;89:880-7.  Back to cited text no. 102
[PUBMED]    
103.
Hendriks LE, Derks JL, Postmus PE, Damhuis RA, Houben RM, Troost EG, et al. Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study. Eur J Cancer 2015;51:2534-44.  Back to cited text no. 103
[PUBMED]    
104.
Agolli L, Valeriani M, Nicosia L, Bracci S, De Sanctis V, Minniti G, et al. Stereotactic ablative body radiotherapy (SABR) in pulmonary oligometastatic/oligorecurrent non-small cell lung cancer patients: A new therapeutic approach. Anticancer Res 2015;35:6239-45.  Back to cited text no. 104
[PUBMED]    
105.
Collaud S, Stahel R, Inci I, Hillinger S, Schneiter D, Kestenholz P, et al. Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. Lung Cancer 2012;78:234-8.  Back to cited text no. 105
[PUBMED]    
106.
De Rose F, Cozzi L, Navarria P, Ascolese AM, Clerici E, Infante M, et al. Clinical outcome of stereotactic ablative body radiotherapy for lung metastatic lesions in non-small cell lung cancer oligometastatic patients. Clin Oncol (R Coll Radiol) 2016;28:13-20.  Back to cited text no. 106
[PUBMED]    
107.
Gray PJ, Mak RH, Yeap BY, Cryer SK, Pinnell NE, Christianson LW, et al. Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival. Lung Cancer 2014;85:239-44.  Back to cited text no. 107
[PUBMED]    
108.
Hu C, Chang EL, Hassenbusch SJ 3rd, Allen PK, Woo SY, Mahajan A, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004.  Back to cited text no. 108
[PUBMED]    
109.
Iyengar P, Kavanagh BD, Wardak Z, Smith I, Ahn C, Gerber DE, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 2014;32:3824-30.  Back to cited text no. 109
[PUBMED]    
110.
Tönnies M, Pfannschmidt J, Bauer TT, Kollmeier J, Tönnies S, Kaiser D. Metastasectomy for synchronous solitary non-small cell lung cancer metastases. Ann Thorac Surg 2014;98:249-56.  Back to cited text no. 110
    
111.
Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC lung cancer staging project: Background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2016;11:651-65.  Back to cited text no. 111
[PUBMED]    
112.
Chang JY, Liu YH, Zhu Z, Welsh JW, Gomez DR, Komaki R, et al. Stereotactic ablative radiotherapy: A potentially curable approach to early stage multiple primary lung cancer. Cancer 2013;119:3402-10.  Back to cited text no. 112
[PUBMED]    
113.
Griffioen GH, Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or without surgery. Radiother Oncol 2013;107:403-8.  Back to cited text no. 113
[PUBMED]    
114.
Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA Jr., et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14.  Back to cited text no. 114
    
115.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al., editors. Final Overall Survival Results of NEJ002, a Phase III Trial Comparing Gefitinib to Carboplatin (CBDCA) Plus Paclitaxel (TXL) as the First-line Treatment for Advanced Non-small Cell Lung Cancer (NSCLC) with EGFR Mutations. ASCO Annual Meeting Proceedings; 2011.  Back to cited text no. 115
    
116.
Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 2006;354:2619-21.  Back to cited text no. 116
[PUBMED]    
117.
De Grève J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer 2012;76:123-7.  Back to cited text no. 117
    
118.
Moro-Sibilot D, Le Deley MC, Zalcman G, Bota S, Sabatier R, Souquet PJ, et al. Activity of crizotinib in MET amplified NSCLC: Preliminary results of the AcSé trial. J Thorac Oncol 2015;10: S178.  Back to cited text no. 118
    
119.
Camidge DR, Ou SH, Shapiro G, Otterson GA, Villaruz LC, Villalona-Calero MA, et al., editors. Efficacy and Safety of Crizotinib in Patients with Advanced c-MET-Amplified Non-small Cell Lung Cancer (NSCLC). ASCO Annual Meeting Proceedings; 2014.  Back to cited text no. 119
    
120.
Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S, et al. Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients. Indian J Cancer 2013;50:107-11.  Back to cited text no. 120
  [Full text]  




 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow