Is chemotherapy with a biologic or targeted therapy superior to chemotherapy alone in unselected patients for treatment of stage IV inoperable NSCLC?

From Cancer Guidelines Wiki

Introduction

The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.

Numerous trials have been reported over the years exploring the benefit of adding novel drug therapy to standard chemotherapy. This section will review the evidence for benefit or lack thereof, of the addition of modern biologic or targeted therapy to standard first-line chemotherapy as empirical therapy in “selected" or "unselected" patients. Biologic therapy refers to monoclonal antibodies (MAbs) and will be summarised by the specific MAb target. Molecularly targeted therapy refers to therapy given to patients selected exclusively by the presence of a particular gene or its protein product identified as the specific drug target.

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Chemotherapy and AIs - anti-VEGF Mab (bevacizumab) or anti-VEGF TKIs

There have been two phase III and one phase II RCT of chemotherapy +/- bevacizumab as first-line therapy in patients with stage IV NSCLC.[1][2][3] The first study, a randomised phase II study by Johnston et al showed promising activity with bevacizumab but found an unexpectedly high incidence of pulmonary haemorrhage in patients with SCC.[3] The study by Sandler et al examined carboplatin and paclitaxel +/- bevacizumab, whilst the study by Reck et al examined cisplatin and gemcitabine +/- bevacizumab.[1][2] Consequently both subsequent PIII studies excluded patients with the following: SCC histologic type, brain metastases, clinically significant hemoptysis,inadequate organ function, ECOG PS of 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension. The overall safety and efficacy of chemotherapy and bevacizumab has been summarised in a meta-analysis of four trials with 2101 patients by Yang et al.[4] Bevacizumab has been studies at high dose (HD: 15 mg/kg) or low dose (LD: 7.5 mg/kg) every three weeks with chemotherapy.

Yang et al found that neither HD or LD bevacizumab improved one-year survival when added to chemotherapy.[4] However, the addition of HD bevacizumab increased two-year overall survival (OS) (RR 1.24; 95% CI 1.04 – 1.49) and tumour response rate (RR 1.69; 95% CI 1.21-2.35).[4] However in an independent systematic review by Botrel et al, although an OS benefit was observed with HD bevacizumab (HR 0.89, 95% CI 0.8 – 1.0, p =0.04), there was moderate statistical heterogeneity (Chi2 = 5.09, 3df, p = 017; I2 = 41%), making this finding less certain. Progression free survival (PFS) was improved with both LD bevacizumab (HR 0.76; 95%; CI 0.64-0.90) and HD bevacizumab (HR 0.73; 95%CI 0.65-0.81).[4][5] However, HD bevacizumab was associated with an increase in treatment related deaths (RR 2.07, 95%; CI 1.19-3.59). Patients treated with HD bevacizumab experienced more hypertension, headaches, haemoptysis, neutropaenia and rash than patients on chemotherapy alone.[4] In the phase III trials bevacizumab was continued if tolerated until disease progression.

With regard to the small molecule TKIs, numerous phase III studies have been conducted but only one study has been published in full to date. Scagliotti et al, reported the outcomes of their phase III RCT evaluating the efficacy and safety of sorafenib, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients.[6] The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point for OS. A pre-specified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR 1.85; 95%; CI 1.22 to 2.81).

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Chemotherapy and anti-EGFR TKIs

Following the discovery of the first generation EGFR TKIs gefitinib and erlotinib, four first-line placebo controlled RCTS were undertaken, evaluating the efficacy of the addition of these agents to two commonly used chemotherapy regimens (carboplatin/paclitaxel and cisplatin/gemcitabine)[7][8][9][10] In all four trials the addition of the EGFR TKIs, gefitinib or erlotinib to a standard chemotherapy regimen did not improve outcomes (OS, RR or time to progression (TTP) compared with chemotherapy alone.

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Chemotherapy and anti-EGFR with the Mab cetuximab

The first monoclonal antibody to EGFR to enter the clinic was cetuximab. Two meta-analyses have summarised the evidence for the addition of cetuximab to standard chemotherapy, from four RCTs with 2018 patients with advanced NSCLC (selected by the presence of EGFR-positive tumor as measured by immunohistochemistry (IHC), two of which were phase III RCTs.[11][12][13][14] Both meta-analsyses concur in finding that overall survival was improved by the addition of cetuximab to chemotherapy (HR 0.87; 95%CI, 0.79–0.96; p = 0.004)[12] and overall response rate was increased (50% increase (odds ratio (OR) = 1.48; (CI = 1.22–1.80); p < 0.0001). PFS whilst improved with the addition of cetuximab to chemotherapy was not significantly better than chemotherapy alone (HR, 0.91; 95%CI, 0.83–1.00; p = 0.06).[11][12] Of the two Phase III trials, only the Pirker study which added cetuximab to cisplatin/vinoerlbine was positive for survival, whilst the Lynch study, which added cetuximab to carboplatin/paclitaxel showed improved RR but not PFS or OS.[13][14] The addition of cetuximab was associated with increased grade 3/4 rash and infusion reactions.[11][12] In the phase III trials cetuximab was continued if tolerated until disease progression.

Evidence summary and recommendations

Evidence summary Level References
In carefully selected** patients with advanced NSCLC, high dose bevacizumab improves tumour response rate and progression free survival.

**Patients with the following criteria were excluded from the trials: SCC histologic type, brain metastases, clinically significant haemoptysis,inadequate organ function, ECOG PS of 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension.
Last reviewed December 2015

I [4], [5]
In carefully selected** patients with advanced NSCLC, treatment with high dose bevacizumab is associated with an increase in treatment related deaths.

Last reviewed December 2015

I [4]
Evidence-based recommendationQuestion mark transparent.png Grade
High dose bevacizumab (15 mg/kg three-weekly) may be considered in addition to chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) in carefully selected** patients with non-squamous cell carcinoma.

Last reviewed December 2015

B


Evidence summary Level References
The addition of the EGFR TKIs gefitinib or erlotinib to a standard chemotherapy regimen does not improve outcomes (OS, RR or time to progression (TTP)) compared with chemotherapy alone.

Last reviewed December 2015

II [7], [8], [10], [9]
Evidence-based recommendationQuestion mark transparent.png Grade
The first generation EGFR TKIs gefitinib or erlotinib should not be used in unselected patients in combination with standard chemotherapy.

Last reviewed December 2015

A


Evidence summary Level References
In patients with advanced NSCLC (selected by the presence of EGFR-positive tumour as measured by immunohistochemistry), the addition of cetuximab to chemotherapy increases response rate and improves overall survival. This overall benefit was modest and observed only in the phase III trial using cisplatin/vinorelbine .

Last reviewed December 2015

I [11], [12]
Evidence-based recommendationQuestion mark transparent.png Grade
In patients with advanced NSCLC whose tumours have been shown to express EGFR by immunohistochemistry, cetuximab may be considered in addition to cisplatin/vinorelbine chemotherapy to improve response rate and overall survival.

Last reviewed December 2015

B


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References

  1. 1.0 1.1 Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006 Dec 14;355(24):2542-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17167137.
  2. 2.0 2.1 Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009 Mar 10;27(8):1227-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19188680.
  3. 3.0 3.1 Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004 Jun 1;22(11):2184-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15169807.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Yang K, Wang YJ, Chen XR, Chen HN. Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis. Clin Drug Investig 2010;30(4):229-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20225906.
  5. 5.0 5.1 Botrel TE, Clark O, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis. Lung Cancer 2011 Oct;74(1):89-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21377753.
  6. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010 Apr 10;28(11):1835-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20212250.
  7. 7.0 7.1 Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 2004 Mar 1;22(5):777-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14990632.
  8. 8.0 8.1 Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 2004 Mar 1;22(5):785-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14990633.
  9. 9.0 9.1 Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005 Sep 1;23(25):5892-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16043829.
  10. 10.0 10.1 Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007 Apr 20;25(12):1545-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17442998.
  11. 11.0 11.1 11.2 11.3 Lin H, Jiang J, Liang X, Zhou X, Huang R. Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer 2010 Oct;70(1):57-62 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20149474.
  12. 12.0 12.1 12.2 12.3 12.4 Ibrahim EM, Abouelkhair KM, Al-Masri OA, Chaudry NC, Kazkaz GA. Cetuximab-based therapy is effective in chemotherapy-naïve patients with advanced and metastatic non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Lung 2011 Jun;189(3):193-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21424607.
  13. 13.0 13.1 Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009 May 2;373(9674):1525-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19410716.
  14. 14.0 14.1 Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010 Feb 20;28(6):911-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20100966.

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Appendices

Further resources

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