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

Abstract

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. 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.

Full text

1/31/2020 Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line – Indian consensus statement update
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348782/ 1/37
South Asian J Cancer. 2019 Jan-Mar; 8(1): 1–17.
doi: 10.4103/sajc.sajc_227_18
PMCID: PMC6348782
PMID: 30766843
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 to: Dr. Kumar Prabhash, E-mail: kprabhash1@gmail.com
[Under the aegis of Lung Cancer Consortium Asia (LCCA), Indian Cooperative Oncology Network (ICON), Indian Society of Medical & Pediatric
Oncology (ISMPO), Molecular Oncology Society (MOS) and Association of Physicians of India API)]
Copyright : © 2019 The South Asian Journal of Cancer
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations
are licensed under the identical terms.
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.
Keywords: Consensus statement, driver mutations, nonsmall cell lung cancer, targeted therapies
Introduction

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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

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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).
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?
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).
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%)

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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?
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

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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.
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?
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]

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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)?
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

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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%).
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]
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?

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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]
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?
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.

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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.
Patients with ALK rearrangements should be treated with alectinib, ceritinib, or crizotinib (all listed in alphabetical order) in the
upfront setting
In case the chemotherapy is started before ALK results are available, chemotherapy may be continued for 4–6 cycles in responding
patients. Switching to alectinib, ceritinib, or crizotinib before completion of 4–6 cycles is a valid option
In carefully selected patients (e.g., in patients with an isolated site of progression which can be treated with local therapy, those with
mild and asymptomatic progression), 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?
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.
Patients with ROS 1 rearrangements should be treated with ceritinib or crizotinib (listed in alphabetical order) in the upfront setting
In 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.

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

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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]
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:

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Literature review
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?
A phase III trial randomized previously treated NSCLC patients to docetaxel (100 mg/m or 75 mg/m every 3 weeks) or
best supportive care. Patients assigned to docetaxel 75 mg/m 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.
2 2
2

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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]
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%)

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Literature review
Consensus
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?
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]
EGFR mutated patients who were treated with combination chemotherapy in the first line should be offered EGFR TKIs (afatinib,
erlotinib, and gefitinib) in the second line if not already treated with EGFR TKIs in the maintenance setting
Patients who progress on first line EGFR TKI must be tested for the T790M mutation on either 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 option
Combination chemotherapy should be preferred as second-line treatment option in patients who were treated with EGFR TKIs in the
first line and who are T790M unknown or T790M-ve
Patients who transition to small cell lung cancer should be treated with appropriate chemotherapy.

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Consensus
Literature review
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?
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]
Patients with ALK-positive NSCLC who have progressed on crizotinib may be offered alectinib or ceritinib. Chemotherapy also
remains an acceptable option for these patients
Chemotherapy 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?
Docetaxel 75 mg/m 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]
2

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Literature review
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]
Patients with good PS should be offered second-line therapy
Atezolizumab, 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 kit
Single-agent chemotherapy and TKIs are also acceptable options. Afatinib may be preferred over erlotinib based on superior OS data.
What should be the treatment of choice for nonsmall cell lung cancer patients with brain metastases?
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

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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]
Treatment of patients with brain metastases depends on age and Karnofsky Index
RPA class I and II patients with >3 mets may be treated with WBRT
Stereotactic radiosurgery (SRS) may be a reasonable option in carefully selected patients with limited disease
In RPA class III patients, BSC is recommended (Agree – 35.29%, Disagree – 41.18%, Neutral – 25.53%)
Patients with single brain metastases may be treated with either surgical resection or SRS/stereotactic radiotherapy (SRT)
Single large symptomatic metastases should be treated with surgery
SRS/SRT is a reasonable alternative to surgery for small (<3 cm) and inaccessible tumors.
Patients of RPA class I and II with 1–3 small brain metastases (<3 cm) should be treated with SRS/SRT alone rather than SRS +
WBRT (Agree – 76.47%, Disagree – 23.53%, 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%)

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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]
Stage IV NSCLC patients with synchronous or metachronous oligometastasis may benefit from surgery and/or radiation therapy.
Metachronous oligometastases has a better prognosis than synchronous
Every attempt must be made to biopsy the second primary tumor in the lung and may be treated with radical intent if possible

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Consensus
For patients with oligometastatic recurrence or progression while on targeted therapy, SBRT may be offered to the progressing sites
(Agree – 42.86%, Disagree – 57.14%, 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 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]
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 previously
Biopsy or cell block (if biopsy specimen is not available) should be used for testing for EGFR, ALK, ROS1 and BRAF testing
ctDNA may be acceptable in cases where mutation status cannot be established either by biopsy or cell block
PD L1 testing on biopsy specimen should be done after progression on first-line chemotherapy if the patient is planned to be treated
with pembrolizumab
PD L1 testing is not required for atezolizumab or nivolumab
PD L1 testing should be done on the approved diagnostic kit.

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Consensus
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]
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 considered
An 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 cancer
If feasible following additional analysis should be done on rebiopsy or cell block of FNAC specimen
Her 2 mutation/amplification
MET 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/m 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]
2

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EGFR testing may be done routinely in patients with squamous cell histology in the first line or on rebiopsy sample once patients
progress on chemotherapy doublet
PD L1 testing should be done for second-line SqCC before prescribing pembrolizumab
PD L1 testing is not required for nivolumab
PD L1 testing should be done on the approved diagnostic kit.
All the consensus statements have been summarised in Table 1

1/31/2020 Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line – Indian consensus statement update
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Table 1
Summary of recommendations

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Open in a separate window
NSCLC=Nonsmall cell lung cancer, EGFR=Epidermal growth factor receptor, TKI=Tyrosine kinase inhibitors, ALK=Anaplastic lymphoma kinase,
MRI=Magnetic resonance imaging, CT=Computed tomography, FNAC=Fine needle aspiration cytology, SBRT=Stereotactic body radiation therapy,
WBRT=Whole brain radiotherapy, SRT=Stereotactic radiotherapy, SRS=Stereotactic radiosurgery, SQCC=Squamous cell carcinoma, MET=MET proto-
oncogene receptor tyrosine kinase, ROS1=c-ros oncogene 1, BRAF=v-raf murine sarcoma viral oncogene homolog B1
First line therapy
• Should PD L1 testing be considered as a part of initial diagnostic work up for a patient diagnosed with lung cancer?
∘In appropriate setting, PD L1 testing determined by the 22C3 pharmDx test may be included as a part of initial diagnostic work up for lung cancer
patients especially when planned to be treated with pembrolizumab in the first line
• Which patients of advanced stage NSCLC should be treated with chemotherapy?
∘All patients of advanced NSCLC with PS 0-2 without driver mutations/rearrangements and PD L1 <50% should be treated with upfront
chemotherapy
∘For patients with PS 0-1
4-6 cycles of platinum based doublet chemotherapy should be the standard of care
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
∘For patients with PS ≥2 and for elderly patients
Single agent chemotherapy (vinorelbine, gemcitabine, pemetrexed or docetaxel) may be appropriate
Carboplatin based combinations may be considered in eligible patients aged >70 years with PS 0-2 and adequate organ function
∘Patients with PS 3-4 can be offered EGFR TKIs (if EGFR wild type) or best supportive care (in the absence of activating EGFR mutations or
ALK/ROS1 translocations)
∘Currently evidence is not enough to make any recommendations on the use of combination of pembrolizumab + chemotherapy in the upfront
setting
• What should be the choice of therapy in patients of NSCLC of nonsquamous histology with no driver mutation/rearrangement?
∘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
∘Pemetrexed and platinum agent should be considered as first line option for patients of nonsquamous histology without driver
mutations/rearrangements and PD-L1 <50%

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Financial support and sponsorship
Academia.
Conflicts of interest
There are no conflicts of interest.
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.
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