South Asian Journal of Cancer

REVIEW ARTICLE
Year
: 2019  |  Volume : 8  |  Issue : 1  |  Page : 1--17

Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line – Indian consensus statement update


Kumar Prabhash 
 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India

Abstract

The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming increasingly complex with the identification of driver mutations/rearrangements and development/availability of appropriate targeted therapies. In 2017, an expert group of medical oncologists with expertise in treating lung cancer used data from published literature and experience to arrive at practical consensus recommendations on treatment of advanced NSCLC for use by the community oncologists. This was published subsequently in the Indian Journal of Cancer with a plan to be updated annually. The present document is an update to the 2017 document.



How to cite this article:
Prabhash K. Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line – Indian consensus statement update.South Asian J Cancer 2019;8:1-17


How to cite this URL:
Prabhash K. Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line – Indian consensus statement update. South Asian J Cancer [serial online] 2019 [cited 2019 Apr 24 ];8:1-17
Available from: http://journal.sajc.org/text.asp?2019/8/1/1/250088


Full Text

 Introduction



In the last decade, lung cancer treatment has changed from histology-based to target-based approach. Newer molecular alterations and driver mutations/rearrangements have been identified which can be targeted with appropriate therapeutic interventions. With the availability of newer targeted therapies, the treatment of advanced/metastatic nonsmall cell lung cancer (NSCLC) has become increasingly complex. In 2016, 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 consensus statements to provide practical recommendations for the community oncologists for the treatment of this complex disease which was subsequently published in the Indian Journal of Cancer in 2017. 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. The present document is an update to the previous consensus document and reflects changes in the evidence since the previous consensus.

 Methods



A total of 55 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 the literature was presented to the panel. This was followed by a discussion on the consensus statements which were voted for by all the panellists 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 December 2017.

 First-Line Therapy



Should programmed death ligand 1 testing be considered as a part of initial diagnostic workup for a patient diagnosed with lung cancer?

Understanding tumor-immune interactions and development of immune checkpoint inhibitors has changed the therapeutic landscape of NSCLC. The excitement about using immunotherapy has been primarily driven by the fact that antagonist antibodies to programmed death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have prolonged tumor responses in patients with metastatic NSCLC progressing on the first-line chemotherapy.[1],[2],[3],[4] Treatment with pembrolizumab (an anti-PD-1 antibody) in treatment naïve patients with least 50% tumor cell staining for PD-L1 as determined by the 22C3 pharmDx test, resulted in significant prolongation of progression-free survival (PFS) and overall survival (OS).[5] The median PFS was 10.3 months (95% confidence interval [CI]: 6.7–not reached) versus 6.0 months (95% CI: 4.2–6.2) for pembrolizumab compared with chemotherapy, respectively, (hazard ratio [HR] = 0.50; 95% CI: 0.37–0.68; P < 0.001). The 6-month OS rate was 80.2% in the pembrolizumab arm and 72.4% in the chemotherapy arm (HR = 0.60; 95% CI: 0.41–0.89; P = 0.005).

Consensus

Inappropriate setting, PD L1 testing determined by the 22C3 pharmDx test may be included as a part of initial diagnostic workup for lung cancer patients, especially when planned to be treated with pembrolizumab in the first line.

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.[6],[7],[8],[9],[10],[11],[12] Addition of a third cytotoxic agent improves the response rate (odds ratio [OR]: 0.66; 95% 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).[13] Pooled analysis of six randomized trials has shown that platinum-based doublets improved objective 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.[14] For patients who are the elderly or those with PS 2, single-agent vinorelbine and gemcitabine has shown to improve OS without compromising the quality of life.[15],[16] In a phase III trial comparing docetaxel versus vinorelbine in elderly patients with PS ≥2, docetaxel improved PFS (median 5.5 months 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, 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).[17] Lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity.[18] Cisplatin-containing regimens are associated with more nephrotoxicity, nausea, and vomiting and carboplatin combinations cause more severe thrombocytopenia.

An exploratory phase II study evaluated pembrolizumab in combination with chemotherapy versus chemotherapy alone in chemotherapy-naive, Stage IIIB or IV, non-squamous NSCLC without targetable epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genetic aberrations.[19] The combination of pembrolizumab and chemotherapy resulted in improved response rates (ORR 55% vs. 29%; P = 0.0016) and prolongation of PFS. An updated analysis has shown that the median OS was not reached (22.8–NR) for pembrolizumab + chemotherapy and 20.9 (14.9–NR) chemotherapy arm. The HR for OS was 0.59 (95% CI: 0.34–1.05; P = 0.0344).

Consensus

All patients of advanced NSCLC with PS 0-2 without driver mutations/rearrangements and PD L1 <50% 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 for 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 EGFR tyrosine kinase inhibitors (TKIs) (if EGFR wild-type) or best supportive care (in the absence of activating EGFR mutations or ALK/receptor tyrosine kinase gene (ROS 1 translocations) (agree – 100%, disagree – 0%)Currently, the evidence is not enough to make any recommendations on the use of a combination of pembrolizumab + chemotherapy in the upfront setting.

What should be the choice of therapy in patients of nonsmall cell lung cancer of non-squamous histology with no driver mutation/rearrangement?

Literature review

In a phase III trial cisplatin + pemetrexed conferred survival advantage compared to cisplatin + gemcitabine in patients with adenocarcinoma (median OS-12.6 months in cisplatin + pemetrexed arm vs. 10.9 months in cisplatin + gemcitabine arm).[10] 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).[20] Addition of bevacizumab to carboplatin-paclitaxel regimen in patients of non-squamous histology offers high response rates, longer PFS (HR = 0.72; 95% CI: 0.66 and 0.79; P < 0.001), and improved OS compared (HR = 0.90; 95% CI: 0.81 and 0.99; P = 0.03) with carboplatin-paclitaxel alone in patients with non-squamous 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.[21]

Recently, a phase III trial compared pembrolizumab to platinum doublet chemotherapy in 305 treatment naïve advanced NSCLC patients with at least 50% tumor cell staining for PD-L1. Patients with EGFR mutations or ALK translocations were not included in this study.[5] At a median follow-up of 11.2 months, pembrolizumab significantly prolonged the PFS compared with platinum-doublet chemotherapy. The median PFS was 10.3 in pembrolizumab versus 6 months with platinum-doublet chemotherapy (HR = 0.50, 95% CI: 0.37–0.68). ORRs and median duration of response for pembrolizumab and platinum-doublet chemotherapy were 45% and 28% and 12.1 and 5.7 months, respectively. OS was also prolonged with pembrolizumab compared with platinum-doublet chemotherapy (HR = 0.60, 95% CI: 0.41–0.89). About 81.2% of the patients treated with pembrolizumab in this trial had nonsquamous histology. The HR of disease progression or death in this subgroup was 0.55, 95% CI: 0.39–0.76. Severe (Grade 3–5) treatment-related adverse effects were seen in 27% of patients receiving pembrolizumab, compared with 53% in those treated with platinum-doublet chemotherapy.

Consensus

NSCLC patients of nonsquamous histology without driver mutations/rearrangements and PD-L1 ≥50% may be treated with pembrolizumab or pemetrexed and platinum agent in the first line.(agree – 100%, disagree – 0%)Pemetrexed and platinum agent should be considered as first-line option for patients of nonsquamous histology without driver mutations/rearrangements and PD-L1 <50% (agree – 100%, disagree – 0%)Bevacizumab in combination with paclitaxel-carboplatin may be offered to patients with nonsquamous histology, PD-L1 <50% and PS 0–1 after exclusion of contraindications (agree - 68% and disagree – 32%).

What should be the choice of therapy in patients of non-squamous 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 The Towards a Revolution in COPD Health 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. 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).[22]

The incidence of EGFR mutations in India is 25%–35%, which is higher compared to the western population.[23],[24],[25],[26] 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%.[27] 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 nonsmall-cell lung cancer, 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.[28]

Consensus

All attempts should be made to test for driver mutations/rearrangements 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/rearrangement 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 the overall patient population and subgroups of Del 19 and L858R mutations.[29],[30],[31],[32],[33],[34],[35],[36],[37]

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.[38],[39] 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 months 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 months vs. 18.4 months, HR [95% CI] 0.64 [0.44–0.94] P = 0.0229).[40]

Osimertinib is a third-generation, irreversible EGFR-TKI that selectively inhibits both EGFR sensitizing and EGFR T790M resistance mutations, with lower activity against wild-type EGFR.[41] Four head-to-head studies-WJOG 5108 L, CTONG 0901, Lux Lung 7, and FLAURA have compared the efficacy of EGFR TKIs.[42],[43],[44],[45] In WJTOG 5108 L 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 0.257) and 22.8 and 24.5 months (HR = 1.038; 95% CI: 0.833–1.294; P = 0.768), respectively, in WJTOG 5108 L 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 (median 13.7 months [95% CI: 11.9–15.0] with afatinib vs. 11.5 months [10.1–13.1] with gefitinib; HR = 0.73 [95% CI: 0.58–0.92], P = 0.0073).[44] There was a trend toward improved OS with afatinib versus gefitinib (median 27.9 vs. 24.5 mos; HR = 0.86 [0.66–1.12], P = 0.258) but this did not reach statistical significance.[46] Although the incidence of Grade 3–4 adverse events were higher in the afatinib arm, the rate of adverse events related to treatment discontinuation was similar in both arms. FLAURA trial compared osimertinib with erlotinib and gefitinib (standard of care [SOC]) in treatment-naïve, EGFR-mutated advanced NSCLC patients. Osimertinib demonstrated improvement in PFS.[45] The median PFS was 18.9 months in osimertinib arm versus 10.2 months in SOC arm (HR = 0.46, 95% CI: 0.37–0.57). The PFS benefit was consistent across subgroups, including patients with or without brain metastases. There was a nonsignificant trend toward improvement in OS (HR = 0.63); however, OS results were immature, with only 25% of events collected. Response rates for osimertinib and SOC were 80% and 76%, respectively. Grade 3 or higher toxicities were lower for osimertinib versus SOC (34 vs. 45%).

Consensus

Patients with EGFR mutations should be treated with an EGFR TKI (afatinib, erlotinib, gefitinib, and osimertinib – all listed in alphabetical order) in the upfront setting (agree – 100%, disagree – 0%)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%, 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 for Gly719Xaa and Leu861Gln point mutations have decreased responsiveness to erlotinib and gefitinib.[47],[48],[49],[50] In an analysis from the NEJ002 trial, gefitinib was found to be ineffective against both Gly719Xaa and Leu861Gln mutations.[51] 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), 8·2 months (4·5–16·6), and 14·7 months (2·6–NE), respectively.[52] Objective response to EGFR TKIs in exon 20 insertions is poor.[52],[53],[54],[55] 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.[52]

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, exon 20 insertions, etc. (Agree – 100%, Disagree – 0%, 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%, 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%, 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. Out of the 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.[56]

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.[57] In LUX-Lung 7 trial afatinib and gefitinib were continued beyond RECIST progression and median time to failure (TTF) was significantly prolonged in afatinib versus gefitinib (median TTF 13.7 months vs. 11.5 months HR = 0.73 95% CI: 0.58–0.92), P = 0.0073.[44]

Consensus

Single-agent continuation of EGFR TKI beyond 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%, Not sure -%)Addition of chemo 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%, 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 months 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 crossover 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.[58] 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).[59] 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.[60] 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.

Second generation ALK inhibitors have shown promising efficacy in advanced ALK-positive NSCLC. In a global phase III study, 303 patients with ALK rearrangements were randomly assigned to the first-line alectinib versus crizotinib (ALEX trial). The rate of investigator-assessed PFS was significantly higher with alectinib than with crizotinib. 12-month event-free survival rate was 68.4% with alectinib versus 48.7% with crizotinib (HR = 0.46, 95% CI: 0.37–0.57).[61] The median PFS with alectinib was not reached versus 11.1 months in crizotinib arm. OS results are not yet mature. The time to central nervous system (CNS) progression in the overall population was improved with alectinib (HR = 0.16, 95% CI: 0.10–0.28). Grade 3–5 toxicities were less frequent with alectinib (41% vs. 50%). Ceritinib is another second generation which has demonstrated improved efficacy over combination chemotherapy in the front-line setting in ASCEND 4 trial.[62] The median PFS for patients treated with 750 mg ceritinib was 16.6 versus 8.1 months with pemetrexed and platinum (HR = 0.55, 95% CI: 0.42–0.73). The ORR (72.5% vs. 26.7%) and duration of response (23.9 vs. 11.1 months) were also higher with ceritinib.

Consensus

Patients with ALK rearrangements should be treated with alectinib, ceritinib, or crizotinib (all listed in alphabetical order) in the upfront settingIn case the chemotherapy is started before ALK results are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to alectinib, ceritinib, or crizotinib before completion of 4–6 cycles is a valid optionIn 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), alectinib, ceritinib, or crizotinib may be continued beyond progression.

What should be the choice of therapy in patients of nonsmall cell lung cancer with receptor tyrosine kinase gene1 rearrangements in the first line?

Literature review

In an open-label, the study of crizotinib in 50 patients with ROS1 translocation, the ORR 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.[63] Similar response rates were observed in another retrospective series of 32 patients treated with crizotinib with ROS1 rearrangement.[64] Second generation inhibitor ceritinib was evaluated in a phase II trial of 28 with advanced ROS1-rearranged NSCLC.[65] The ORR with ceritinib was 62%, and duration of response was 21 months. The median PFS with ceritinib was 9.3 months in the overall population. For patients who were crizotinib-naïve, the median PFS was 19.3 months. The median OS was 24 months. Five of eight patients with brain metastases experienced disease control.

Consensus

Patients with ROS 1 rearrangements should be treated with ceritinib or crizotinib (listed in alphabetical order) in the upfront settingIn case the chemotherapy is started before ROS 1 results are available, chemotherapy may be continued for 4–6 cycles in responding patients. Switching to ceritinib or crizotinib before completion of 4–6 cycles is a valid option.

What should be the choice of therapy 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 SWOG randomized studies did not show any correlation between histology and survival for the combination of platinum with paclitaxel, docetaxel, and vinorelbine.[66] 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).[10]

Recently a phase III trial compared pembrolizumab to platinum doublet chemotherapy in 305 treatment naïve advanced NSCLC patients with at least 50% tumor cell staining for PD-L1.[5] Patients with EGFR mutations or ALK translocations were not included in this study. At a median follow-up of 11.2 months, pembrolizumab significantly prolonged the PFS compared with platinum-doublet chemotherapy. The median PFS was 10.3 months in pembrolizumab versus 6 months with platinum-doublet chemotherapy (HR = 0.50, 95% CI: 0.37–0.68). ORRs and median duration of response for pembrolizumab and platinum-doublet chemotherapy were 45% and 28% and 12.1 and 5.7 months, respectively. OS was also prolonged with pembrolizumab compared with platinum-doublet chemotherapy (HR = 0.60, 95% CI: 0.41–0.89). The benefit of pembrolizumab observed in the subgroup of patients with squamous histology (constituting 18.8% of overall population) was notable. The HR for disease progression or death in this subgroup was 0.35, 95% CI: 0.17–0.71. Severe (Grade 3–5) treatment-related adverse effects were seen in 27% of patients receiving pembrolizumab, compared with 53% in those treated with platinum-doublet chemotherapy.

Consensus

4–6 cycles of platinum doublet chemotherapy should be the SOC for patients with SCC of lung and PD L1 <50%.(Agree – 100%, Disagree – 0%, Not sure – 0%)Patients of squamous histology with PD-L1 -50% may be treated with pembrolizumab or platinum doublet chemotherapy in the first line (Agree – 100%, Disagree – 0%)Platinum plus pemetrexed should not be used in patients with SqCC (Agree – 85.71%, Disagree – 14.29%, Not Sure – 0%)Bevacizumab should not be used in patients with SqCC because of the risk of severe bleeding (Agree – 95.45%, Disagree – 4.55%, Not Sure – 0%).

 Maintenance Therapy



Which patients should be offered maintenance therapy?

Literature review

In a large phase III trial, switch maintenance therapy with pemetrexed after four cycles of non pemetrexed containing platinum-based doublet (cisplatin or carboplatin plus gemcitabine, docetaxel, or paclitaxel) increased both median PFS (4.3 months vs. 2.6 months; HR = 0.50, 95% CI: 0.42–0.61, P < 0.0001) and OS (13.4 months 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.[67] 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 pemetrexed arm as compared to the 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).[68],[69]

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 wild type patient population. Patients who harbored EGFR mutations had significant prolongation of PFS (HR = 0·10, 95% CI: 0·04–0·25; P < 0·0001).[70]

In a recent phase 3 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.[71],[72]

Consensus

NSCLC patients of non-squamous 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/rearrangements:

Maintenance therapy with pemetrexed is preferred (Agree– 100%, Disagree– 0%)EGFR TKIs should not be offered as maintenance therapy in patients who are EGFR wild-type (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 appropriate targeted agent after the initial cycles of chemotherapy are complete (Agree – 100%, Disagree – 0%).

 Second Line Therapy



What should be the appropriate choice of therapy in patients of nonsmall cell lung cancer of non-squamous histology without driver mutations/rearrangements after progression on first-line chemotherapy?

Literature review

A phase III trial randomized previously treated NSCLC patients to docetaxel (100 mg/m2 or 75 mg/m2 every 3 weeks) or best supportive care. Patients assigned to docetaxel 75 mg/m2 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.[73],[74] In a secondary analysis of head-to-head trials of pemetrexed vs docetaxel, the OS was significantly longer in patients randomized to pemetrexed in patients of non-squamous histology (median OS-9.3 months vs. 8.0 months, HR = 0.78, 95% CI: 0.61–1.00) with less Grade 3–4 adverse events.[75],[76],[77]

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.[78],[79]

Nivolumab compared to docetaxel significantly prolonged OS in NSCLC patients of non-squamous histology who progressed on first-line chemotherapy in CheckMate 057 trial.[2] 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 PDL1 expression may be at risk of early deaths.[80] 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 check point inhibitor pembrolizumab has also shown promising efficacy patients with ≥1% PD-L1 expression who progressed after first-line chemotherapy in two different clinical trials KEYNOTE-001 and KEYNOTE-010 study.[3],[4] In KEYNOTE-010 study, previously treated NSCLC patients with PD-L1 expression on at least 1% of tumour 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 for pembrolizumab 10 mg/kg versus docetaxel (0.61, 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.

Atezolizumab, which is an immunoglobulin G1 antagonist antibody to PD-L1 was compared with docetaxel in a phase III trial which enrolled 1225 patients with advanced NSCLC who had already been treated with one or more platinum-based combination therapies. In this trial OS was prolonged in patients taking atezolizumab regardless of the PD-L1 expression.[1] The median OS was 13.8 months in atezolizumab arm versus 9.6 months in docetaxel arm. The 12 and 18 month OS rates were 55% and 40% in atezolizumab arm versus 41% and 27% in docetaxel arm. About 16% of enrolled patients had at least 50% of tumor cells or 10% of tumor area with immune cells staining for PD-L1. The median OS with atezolizumab versus docetaxel in this subgroup of patients was 20.5 versus 8.9 months (HR = 0.41, 95% CI: 0.27–0.64). OS was prolonged in atezolizumab arm regardless of NSCLC histology. Median OS with atezolizumab in patients with non-squamous histology was 15.6 months versus 11.2 months in docetaxel (HR = 0.73, 95% CI: 0.60–0.89).

In 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 in the third line in all NSCLC histological subtype patients not eligible for further chemotherapy, including patients with PS 3.[81] TITAN trial compared erlotinib to pemetrexed or docetaxel in NSCLC patients who progressed during or immediately after first-line chemotherapy.[82] 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.[83] DELTA trial compared erlotinib to docetaxel as second or third line therapy. There was no difference in the OS. However, for EGFR wild-type patients, PFS was significantly greater with docetaxel than erlotinib[84] In the TAILOR trial comparing erlotinib to docetaxel as second-line therapy, progression-free and OS durations were significantly better with docetaxel compared with erlotinib.[85]

Consensus

Patients with good PS should be offered second-line therapy (Agree – 100%, Disagree– 0%)PD L1 testing is not required for atezolizumab and 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, atezolizumab or nivolumab may be considered. For those with PD-L1 >1%, atezolizumab or 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 in combination with either nintedanib or ramucirumab is 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 may be used as second-line therapy in EGFR unknown status patients who are unwilling for chemotherapy/immunotherapy or in those with poor PS who are not suitable for either 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 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 EGFR TKI 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 mesenchymal-epithelial transition factor (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.[86]

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.[87]

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 settingPatients who progress on first line EGFR TKI must be tested for the T790M mutation on either re-biopsy or cell block or ctDNA (Agree– 57.89%, Disagree– 21.05%, Not sure– 21.05%)In patients with documented T790M mutation after treatment with first/second generation TKIs, a third generation TKI like osimertinib should be considered. In case of nonavailability of osimertinib, chemotherapy is an acceptable optionCombination 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-vePatients 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 anaplastic lymphoma kinase inhibitor?

Literature Review

While ALK inhibitors are highly active in patients with ALK-positive NSCLC, the majority of the patients will develop resistance to the drug.[88] Various mechanisms of resistance vehave been reported in the literature. Patients who progress on first-generation ALK inhibitor may be responsive to second-generation ALK inhibitors such as ceritinib and alectinib.[89],[90] ASCEND-5 study enrolled 231 ALK-positive patients who had been priorly treated with crizotinib. Patients were randomly assigned to ceritinib or chemotherapy. The median PFS was longer in the ceritinib arm than chemotherapy arm (5.4 vs. 1.6 months; HR = 0.49).[89] The OS analysis is currently immature. Alectinib was evaluated in two phase II studies performed in patients who had progressed after prior platinum-based chemotherapy or crizotinib.[91],[92] In a combined analysis of these two studies, an ORR as assessed by the independent review committee was 51.3% (all PRs), the disease control rate (DCR) was 78.8%, and the median duration of response was 14.9 months.[90]

Consensus

Patients with ALK-positive NSCLC who have progressed on crizotinib may be offered alectinib or ceritinib. Chemotherapy also remains an acceptable option for these patientsChemotherapy is the treatment of choice in patients who progress on first line alectinib or ceritinib.

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/m2 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.[73],[74] 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.[79] Erlotinib improved OS in the second line or in the 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).[81] 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).[85] 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.[93] 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).[94] For those progressing on a platinum doublet, the II 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).[95]

In phase III (Check Mate 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.[96] An updated follow-up reported an 18-month OS of 28% and 13% in the nivolumab and docetaxel arms.[97] 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 months 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 months vs. 8.2 months; 0.50, 0.36–0.70; P < 0.0001).[4]

In a phase III open-label, phase 3 trial (OAK), patients with advanced NSCLC who had already been treated with one or more platinum-based combination therapies, atezolizumab prolonged the OS compared with docetaxel in patients with squamous histology. The median OS in this population was 8.9 versus 7.1 months (HR = 0.73, 95% CI: 0.54–0.98).[1]

Consensus

Patients with good PS should be offered second-line therapyAtezolizumab, nivolumab, or pembrolizumab are preferred agents for the treatment of NSCLC of squamous histology after progression on first line chemotherapy

For patients who are PD L1 negative/unknown, atezolizumab or nivolumab may be considered. For those with PD-L1 >1%, atezolizumab, nivolumab, or pembrolizumab may be considered

PD L1 testing is not required for atezolizumab and nivolumab. For pembrolizumab PD-L1 testing is required. PD L1 testing should be done on the approved diagnostic kitSingle-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 along with supportive care including steroids. In routine clinical practice, the prognostic indices like RPA and GPA 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. Whole brain radiotherapy traditionally is believed to improve quality of life, disease-free survival and OS. Contrary to popular practice recent trial of the whole-brain radiotherapy with steroids versus steroids alone did not demonstrate an improved survival benefit.[98] Apart from this, whole-brain radiotherapy 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.[99] These approaches require intensive imaging surveillance and fraught with an 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 the tumor is in the eloquent area, focal treatment alone or with WBRT has been recommended.[100],[101] However, the addition of WBRT to focal treatment did not yield improved OS benefit.[102] 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.[103]

In patients with a druggable oncogene driver (EGFR, ALK), 45%–60% develop brain metastases in the course of their disease.[104] In such patients, treatment with targeted therapy has shown to improve the outcomes.[105],[106],[107],[108],[109],[110] In a 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.[107] The median PFS in patients with brain metastases treated with afatinib was 8.2 months 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 DCR was 56% and 62% in patients with previously untreated asymptomatic brain metastases and previously treated brain metastases, respectively.[108] 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 in 78.9% of ALK inhibitor-naive patients.[109]

Consensus

Treatment of patients with brain metastases depends on age and Karnofsky IndexRPA class I and II patients with >3 mets may be treated with WBRTStereotactic radiosurgery (SRS) may be a reasonable option in carefully selected patients with limited diseaseIn RPA class III patients, BSC is recommended (Agree – 35.29%, Disagree – 41.18%, 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 surgerySRS/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%, 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%, Not sure – 0%)Patients treated with surgical resection or SRS should have follow-up magnetic reasoning imaging (MRI) every 3 months (Agree– 88.89%, Disagree – 11.11%, Not sure – 0%)Dexamethasone is recommended for patients with symptomatic brain metastases (Agree – 100%, Disagree – 0%, Not sure – 0%)In patients with druggable oncogenic driver mutation/rearrangement and asymptomatic brain metastases, TKIs may control the brain disease and defer WBRT (Agree– 58.82%, Disagree – 41.18%, Not sure – 0%)For patients with symptomatic metastases, radiotherapy should be preferred (Agree – 100%, Disagree – 0%, Not sure – 0%)ALK-positive patients with brain metastases who progress on crizotinib may benefit from alectinib or ceritinib (Agree – 94.12%, Disagree – 0%, Not sure– 5.88%)Patients should have follow-up MRI/CT/imaging done every 3 months.

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

Oligometastatic disease in NSCLC refers to 1-5 disease sites separate from the primary.[111] Patients with oligometastatic NSCLC do not always progress to widespread metastases.[112] 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, metastases limited to one organ.[113],[114],[115] Surgical resection or definitive radiotherapy of intracranial and extracranial oligometastatic disease has been shown to have a positive effect on survival rates.[116],[117],[118],[119],[120],[121],[122]

In patients who have more than one pulmonary site of cancer, sometimes it can be difficult to distinguish between a second primary and metastasis. International Association for the Study of Lung Cancer 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 tumour board, and the pursuit of radical therapy, such as that for a synchronous secondary primary tumour, when possible.[123] SRS and surgery have been shown to result in long-term survivors in such patients.[122],[124],[125] Use of targeted agents combined with ablative doses of radiation in the oligometastatic setting has resulted in promising outcomes.[121],[126]

Consensus

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

 What are the Investigations Recommended at the Time of Disease Progression?



Patient of non-squamous 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 Indian population varies from 25% to 30% and that of ALK rearrangement varies from 2.5% to 9%.[23],[25],[127],[128],[129] Activating BRAF mutations have been observed in 2%–4% of NSCLC.[130] 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.[29],[30],[31],[32],[33],[34],[35],[40],[131] Same is true for patients with ALK or ROS1 rearrangements treated with TKIs.[59],[64] In a phase II study of 57 patients with previously treated, advanced NSCLC with the BRAF V600E mutation, the combination of dabrafenib plus trametinib was associated with an ORR of 63% and the disease control rate of 79%.[132] The median PFS was 9.7 months in these patients.

PD-1 inhibitor nivolumab and PD-L1 inhibitor atezolizumab significantly prolonged OS in NSCLC patients of non-squamous histology, who progressed on first-line chemotherapy in CheckMate 057 and OAK trials, respectively.[1],[2] Longer PFS and higher objective response rates were seen with both these drugs 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.[3],[4]

Consensus

All attempts must be made to get tissue specimen in the form of biopsy or cell block (if a biopsy is not possible)All NSCLC patients of non-squamous histology who progress on chemotherapy should be tested for EGFR, ALK, ROS1 and BRAF status if not tested previouslyBiopsy or cell block (if biopsy specimen is not available) should be used for testing for EGFR, ALK, ROS1 and BRAF testingctDNA may be acceptable in cases where mutation status cannot be established either by biopsy or cell blockPD L1 testing on biopsy specimen should be done after progression on first-line chemotherapy if the patient is planned to be treated with pembrolizumabPD L1 testing is not required for atezolizumab or nivolumabPD L1 testing should be done on the approved diagnostic kit.

Patient is epidermal growth factor receptor mutation positive and treated with epidermal growth factor receptor tyrosine kinase inhibitor 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 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 human epidermal growth factor receptor 2 (Her 2) mutation/amplification.[86] Osimertinib has shown activity in patients with acquired resistance to a prior EGFR inhibitor. In a phase I/II study, osimertinib showed a response rate of 61% in patients with T790M mutation and median PFS of 10 months.[87] Afatinib, trastuzumab, and TD-M1 have shown to be effective in patients with mutations in the kinase domain of Her2/neu.[133],[134],[135] In patients with MET amplification, crizotinib has been found to be effective.[136],[137]

Consensus

In patients who have progressed on first line EGFR TKI, testing for exon 20 T790M mutation on either re-biopsy or cell block of fine needle aspiration cytology (FNAC) specimen or ctDNA should be consideredAn effort should be made to re-analyze the histology of the tumor on the re-biopsy specimen for ruling out transition into small cell lung cancerIf feasible following additional analysis should be done on rebiopsy or cell block of FNAC specimen

Her 2 mutation/amplificationMET amplification.

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

In India, the data from Tata Memorial Hospital suggests that ~ 6% of patients of squamous histology may harbor EGFR mutations.[127] Data suggest that patients with EGFR mutations benefit from EGFR directed therapies. In phase III (Check Mate 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.[96] 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/m2 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 months 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 months vs. 8.2 months; 0.50, 0.36–0.70; P < 0.0001).[4]

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 doubletPD L1 testing should be done for second-line SqCC before prescribing pembrolizumabPD L1 testing is not required for nivolumabPD L1 testing should be done on the approved diagnostic kit.

All the consensus statements have been summarised in [Table 1]{Table 1}

Acknowledgment

We would like to acknowledge Dr. Abdul Rashid Lone, Dr. Amit Agarwal, Dr. Amit Joshi, Dr. Anantbhushan Ranade, Dr. Ashok Kumar Vaid, Dr. Ashutosh Gupta, Dr. B. K. Mishra, Dr. B. K. Smruti, Dr. C. Sairam, Dr. Chirag Desai, Dr. Deepak Abrol, Dr. Deepak Dabkara, Dr. Dinesh Chandra Doval, Dr. Govind Babu, Dr. Indranil Ghosh, Dr. J. P. Agarwal, Dr. Joydeep Ghosh, Dr. Kajal Shah, Dr. Kishore Kumar, Dr. Koushilk Chatterjee, Dr. Kumar Prabhash, Dr. Madhuchanda Kar, Dr. Maheboob Basade, Dr. Manish Kumar, Dr. Naresh Somani, Dr. Navneet Singh, Dr. Nikhil Ghadyal Patil, Dr. Nilesh Lokeshwar, Dr. Palanki Satya Dattatreya, Dr. Pavithran K, Dr. Peai, Dr. Prakash Devde, Dr. Prasad Narayanan, Dr. Prateek Tiwari, Dr. Pritesh Lohar, 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. Suresh Babu, Dr. SVSS Prasad, Dr. T. Raja, Dr. Tarini Prasad Sahoo, Dr. Tejinder Singh, Dr. T. V. S. Tilak, Dr. Ullas Batra, Dr. Vanita Noronha, Dr. Vijay Patil for their contribution to the development of the consensus statements.

Financial support and sponsorship

Academia.

Conflicts of interest

There are no conflicts of interest.

References

1Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, 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 2017;389:255-65.
2Borghaei 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.
3Garon 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.
4Herbst 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.
5Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.
6Socinski 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.
7Danson 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.
8Ohe 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.
9Scagliotti 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;11:690-6.
10Scagliotti 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.
11Schiller 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.
12NSCLC 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.
13Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP, et al. 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.
14Bronte 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.
15Effects 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.
16Gridelli 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.
17Quoix 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.
18Schuette 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.
19Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-508.
20Li 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.
21Soria 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.
22Gridelli 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.
23Chougule 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.
24Sahoo 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.
25Doval 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.
26Doval 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.
27Douillard 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.
28Nilsson 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.
29Wu 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.
30Rosell 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.
31Sebastian 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.
32Zhou 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.
33Fukuoka 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.
34Yang 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.
35Mitsudomi 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.
36Inoue 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-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54-9.
37Lee 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.
38Sequist 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.
39Wu 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.
40Yang 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.
41Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.
42Urata 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.
43Yang 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-S.
44Park 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.
45Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25.
46Paz-Ares L, Tan EH, O'Byrne K, Zhang L, Hirsh V, Boyer M, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase IIb LUX-lung 7 trial. Ann Oncol 2017;28:270-7.
47Arrieta 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.
48Baek 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.
49Keam 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.
50Lohinai 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.
51Watanabe 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.
52Yang 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.
53Sequist 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.
54De 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.
55Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC, et al. 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.
56Park 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.
57Soria 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.
58Solomon 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.
59Shaw 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.
60Ou 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.
61Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829-38.
62Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017;389:917-29.
63Bergethon 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.
64Mazières 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.
65Lim SM, Kim HR, Lee JS, Lee KH, Lee YG, Min YJ, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 2017;35:2613-8.
66Kelly 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.
67Ciuleanu 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.
68Paz-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.
69Paz-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.
70Cappuzzo 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.
71Important Correction to Drug Information – Genentech. Available from: http://www.gene.com/download/pdf/Tarceva_DHCP_Letter_June2016.pdf. [Last Accessed on 2018 May 01].
72European 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 2018 May 01]
73Shepherd 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.
74Dancey 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.
75Hanna 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.
76Pujol 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.
77Scagliotti 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.
78Reck 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.
79Garon 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.
80Opdivo 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 2018 May 01].
81Shepherd 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.
82Ciuleanu 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.
83Kim 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.
84Kawaguchi 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.
85Garassino 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.
86Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013;31:1070-80.
87Jänne 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.
88Shaw 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.
89Shaw AT, Kim TM, Crinò L, Gridelli C, Kiura K, Liu G, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18:874-86.
90Yang JC, Ou SI, De Petris L, Gadgeel S, Gandhi L, Kim DW, et al. Pooled systemic efficacy and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small cell lung cancer. J Thorac Oncol 2017;12:1552-60.
91Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol 2016;34:661-8.
92Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol 2016;17:234-42.
93Li N, Yang L, Ou W, Zhang L, Zhang SL, Wang SY, et al. 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.
94Zhao 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.
95Soria 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.
96Brahmer 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.
97Reckamp 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.
98Mulvenna 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.
99Brown 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.
100Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: A practice guideline. Curr Oncol 2007;14:131-43.
101Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z, et al. 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.
102Soon 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;3:CD009454.
103Yamamoto 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.
104Rangachari 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.
105Zhang 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.
106Watanabe 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.
107Schuler 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.
108Costa 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.
109Kim 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.
110Park 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.
111Palma 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.
112Mehta 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.
113Ashworth 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.
114Parikh 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.
115Hendriks 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.
116Agolli 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.
117Collaud 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.
118De 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.
119Gray 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.
120Hu 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.
121Iyengar 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.
122Tönnies M, Pfannschmidt J, Bauer TT, Kollmeier J, Tönnies S, Kaiser D, et al. Metastasectomy for synchronous solitary non-small cell lung cancer metastases. Ann Thorac Surg 2014;98:249-56.
123Detterbeck 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.
124Chang 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.
125Griffioen GH, Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S, et al. Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or without surgery. Radiother Oncol 2013;107:403-8.
126Weickhardt 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.
127Choughule 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.
128Muthu V, Bal A, Gupta N, Prasad K, Behera D, Singh N. A five-year audit of EGFR and ALK testing at a tertiary care centre in North India: More sensitive methods do make a difference! J Thorac Oncol 2017;12:S2395.
129Dutt S, Advani SH, Dhabhar BN, Dattatreya PS, Patil S, Chatterjee S, et al. Experience of ALK mutation testing in 3351 Indian patients of NSCLC. Ann Oncol 2014;25:iv66.
130Baik CS, Myall NJ, Wakelee HA. Targeting BRAF-mutant non-small cell lung cancer: From molecular profiling to rationally designed therapy. Oncologist 2017;22:786-96.
131Inoue 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.
132Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, 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 2016;17:984-93.
133Cappuzzo 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.
134De 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.
135Li BT, Shen R, Buonocore D, Olah ZT, Ni A, Ginsberg MS, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol 2017;35S: ASCO#8510.
136Moro-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.
137Camidge 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.