eUpdate – Metastatic Non-Small-Cell Lung Cancer

eUpdate – Metastatic Non-small-cell Lung Cancer (1): Treatment Recommendations and Revised ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) Grading

Published: 28 June 2017. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

This update refers to the Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Novello S, Barlesi F, Califano R et al., Ann Oncol 2016; 27(Suppl 5): v1–v27.

Section

Management of advanced/metastatic disease - Second-line treatment of EGFR- and ALK-negative disease

Text update 1

Ramucirumab combined with docetaxel is, therefore, a treatment option in second-line treatment of advanced NSCLC with PS 0-2, regardless of histology [I, B; ESMO-MCBS v1.0 score: 2].

Text update 2

In the phase III trial, nivolumab was better tolerated than docetaxel, with 85% of nivolumab patients receiving at least 90% of their planned dose intensity, compared with 69% of docetaxel patients, together with a treatment discontinuation rate of 3% versus 10% of the patients treated with nivolumab and docetaxel, respectively.

Text update 3

Afatinib versus erlotinib was tested in a phase III trial on 795 advanced SCC patients. PFS at the primary analysis was significantly longer with afatinib than with erlotinib, with a median of 2.4 months (95% CI: 1.9–2.9) versus 1.9 months (95% CI: 1.9–2.2); HR 0.82, 95% CI: 0.68–1.00, P = 0.0427. OS was a median of 7.9 months (95% CI: 7.2–8.7) versus 6.8 months (95% CI: 5.9–7.8); HR 0.81, 95% CI: 0.69–0.95, P = 0.0077.

Afatinib could be an additional option for the treatment of Eastern Cooperative Oncology Group PS 0-2 patients with locally advanced or metastatic SCC progressing on or after platinum-based chemotherapy [I, C; ESMO-MCBS v1.0 score: 1] [101].

Text update 4

Nivolumab at 3 mg/kg every 2 weeks represents a treatment option in pretreated patients with advanced NSCC [I, B; ESMO MCBS v1.0 score: 5] and should be administered in second-line NSCC patients. Patients with PD-L1-positive tumours extract an OS benefit compared with docetaxel [II, A], while in PD-L1-negative tumours, both the use of nivolumab and docetaxel resulted in similar OS outcomes, with a more favourable profile regarding nivolumab [II, B].

Recommendation update

Ramucirumab combined with docetaxel is, therefore, a treatment option in second-line treatment of advanced NSCLC with PS 0-2, regardless of histology [I, B; ESMO-MCBS v1.0 score: 2].

Section

Management of advanced/metastatic disease - EGFR-mutated NSCLC patients

Text update

The recently presented phase IIb study LUX-LUNG 7 showed that afatinib achieves a modestly higher RR and a longer PFS [11 versus 10.9 months, HR (95% CI): 0.73 (0.57–0.95); P = 0.0165] than gefitinib as first-line treatment of patients with advanced NSCLC with common activating mutations (del19 or L858R) [II, B]. Similar improvements from baseline in EQ-5D utility and EQ-VAS scores were seen in both treatment groups [114].

Section

Management of advanced/metastatic disease - ALK-rearranged NSCLC patients

Text update

Alectinib is another second-generation ALK inhibitor, which has been approved in Japan for all patients with advanced ALK-positive NSCLC. Two phase II studies have also demonstrated RR between 45% and 50% and PFS of 8.9 months [140, 141]. Alectinib was also effective for brain metastases. The J-ALEX trial, a randomised open-label phase III trial was presented recently, demonstrating the superiority of alectinib versus crizotinib as an initial targeted treatment [142]. This trial compared alectinib (300 mg b.i.d.) with crizotinib (250 mg b.i.d.) in ALK-positive NSCLC patients without prior ALK inhibitor treatment. Two hundred and seven patients were enrolled, when an independent data monitoring committee recommended the release of study data, because the superiority in the primary endpoint PFS had been demonstrated at planned interim analysis. The PFS HR of the alectinib arm compared with the crizotinib arm was 0.34 (99.6826% CI: 0.17–0.70, P < 0.0001). Median PFS was not reached (95% CI: 20.3–NE) in the alectinib arm, while it was 10.2 months (95% CI: 8.2–12.0) in the crizotinib arm. A similar global trial in ALK+ treatment-naïve patients has completed accrual, and results will be presented in 2017 (NCT02075840).

A new reference 142 for the J-ALEX study replaces the original reference 142:

142. Hida T, Nokihara H, Kondo M et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017 [Epub ahead of print].

Section

Table 4. Summary of recommendations - Second-line treatment of EGFR- and ALK-negative disease (SCC and NSCC)

Recommendation update 1

Nivolumab at 3 mg/kg every 2 weeks represents a treatment option in pretreated patients with advanced NSCC [I, B; ESMO MCBS v1.0 score: 5] and should be administered in second-line NSCC patients. Patients with PD-L1-positive tumours extract an OS benefit compared with docetaxel [II, A], while in PD-L1-negative tumours, both the use of nivolumab and docetaxel resulted in similar OS outcomes, with a more favourable profile regarding nivolumab [II, B].

Recommendation update 2

Ramucirumab combined with docetaxel is a treatment option in patients with NSCLC progressing after first-line chemotherapy with PS 0-2 [I, B; ESMO-MCBS v1.0 score: 2].

Recommendation update 3

In patients with SCC unfit for chemotherapy, afatinib is a potential option in patients with unknown EGFR status or EGFR WT patients with PS 0-2 [I, C; ESMO-MCBS v1.0 score: 1].

Section

Table 5. Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in Non-Small-Cell Lung Cancer*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) QoL/toxicity MCBS score**
Afatinib, an irreversible ErbB family blocker Advanced 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 [101]
 
Phase III
 
NCT01523587
Erlotinib, as second-line treatment of patients with advanced SCC of the lung. Median OS 6.6 months OS gain:
1.1 months
OS: HR for death 0.81 (0.69-0.95)

Similar toxicity profile

Improved overall health-related QoL

1 (Form 2a)
Bevacizumab, a humanised anti-VEGF monoclonal antibody, in combination with erlotinib Advanced Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC) harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study [116]
 
Phase II
 
Japan Pharmaceutical Information Center, number JapicCTI-111390
Erlotinib alone as a first-line therapy until disease progression or unacceptable toxicity. Median PFS 9.7 months PFS gain:
6.3 months
PFS: HR 0.54 (0.36-0.79) Deteriorated toxicity profile. No improvement in QoL 2 (Form 2b)
Erlotinib, an EGFR TKI Advanced Erlotinib as maintenance treatment in advanced NSCLC: a multicentre, randomised,
placebo-controlled phase 3 study [77]
 
Phase III
 
NCT00556712
Placebo, as maintenance treatment in advanced NSCLC. Control PFS 11.1 weeks PFS gain:
1.2 weeks
PFS: HR 0.71 (0.62-0.82) Deteriorated toxicity profile 1 (Form 2b)
Necitumumab, a second-generation, recombinant, human IgG1 EGFR antibody in combination with gemcitabine and cisplatin Advanced Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous NSCLC (SQUIRE): an open-label, randomised, controlled phase 3 trial [52]
 
Phase III
 
NCT00981058
Gemcitabine and cisplatin as first-line therapy in patients with stage IV SCC. Control OS 9.6 months OS gain:
1.6 months
OS: HR for death 0.84 (0.74-0.96) Deteriorated toxicity profile 1 (Form 2a)
Nivolumab, a fully human IgG4 PD-1 immune-checkpoint–inhibitor antibody Advanced

Nivolumab versus docetaxel in advanced squamous-cell NSCLC [98]

Phase III
 
NCT01642004

Docetaxel in patients with advanced SCC who have disease progression during or after first-line chemotherapy. Control OS 6 months OS gain:
3.2 months. 2-year survival gain 15%
OS: HR for death 0.59 (0.44-0.79) Improved toxicity profile 5 (Form 2a)***
Nivolumab, a fully human IgG4 PD-1 immune-checkpoint–inhibitor antibody Advanced

Nivolumab versus docetaxel in advanced non-squamous NSCLC [104]

Phase III
 
NCT01673867

Docetaxel in patients with NSCC that had progressed during or after platinum-based doublet chemotherapy. Control OS 9.4 months OS gain: 2.8 months. 2-year survival gain 16% OS: HR for death
 0.73 (0.59-0.89)
Improved toxicity profile 5 (Form 2a)
Ramucirumab, a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR2, in combination with docetaxel Advanced

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV NSCLC after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial [94]

Phase III
 
NCT01168973

Placebo plus docetaxel in patients with SCC or NSCC who had progressed during or after a first-line platinum-based chemotherapy regimen. Control OS 9.1 months

OS gain: 1.4 months.

2-year survival gain 3.5%

OS: HR for death 0.86 (0.75-0.98) --- 2 (Form 2a)
Pembrolizumab, an anti-PD-1 monoclonal antibody Advanced Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial [96]
 
Phase III
 
NCT01905657

Docetaxel in patients with previously treated, PD-L1-positive, advanced NSCLC.

Control OS 8.5 months

In PD-L1 >1%:****

OS gain: 1.9 months

In PD-L1 >50%:****

OS gain: 6.7 months

In PD-L1 >1%:****

OS: HR for death 0.71 (0.58–0.88)

In PD-L1 >50%:****

OS: HR for death 0.54 (0.38–0.77)

Improved toxicity profile

In PD-L1 >1%: 3

(Form 2a)

In PD-L1 >50%: 5

(Form 2a)

*EMA approvals in 2016 to end January 2017.

**ESMO-MCBS version 1.0 [181]

***EMA approval, October 2015

****Co-primary endpoints (overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells)

CI, confidence interval; EGFR, endothelial growth factor receptor; HR, hazard ratio; IgG1, immunoglobulin G1; MCBS, Magnitude of Clinical Benefit Scale; NSCC, non-squamous cell carcinoma; OS, overall survival; PD-1, programmed death 1; PFS, progression-free survival; QoL, quality of life; SCC, squamous cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2.

Relevant references from the original publication as listed in the table:

52. Thatcher N, Hirsch FR, Luft AV et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–774.

77. Cappuzzo F, Ciuleanu T, Stelmakh L 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: 521–529

94. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–673.

96. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387: 1540–1550.

98. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123–135.

101. Soria JC, Felip E, Cobo M et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16: 897–907.

104. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373: 1627–1639.

116. Seto T, Kato T, Nishio M et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014; 15: 1236–1244.

181. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anticancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.